Selegiline B-Chemical 1
- O 0
induced O 0
postural B-Disease 1
hypotension I-Disease 1
in O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
: O 0
a O 0
longitudinal O 0
study O 0
on O 0
the O 0
effects O 0
of O 0
drug O 0
withdrawal O 0
. O 0

OBJECTIVES O 0
: O 0
The O 0
United O 0
Kingdom O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
Disease I-Disease 1
Research O 0
Group O 0
( O 0
UKPDRG O 0
) O 0
trial O 0
found O 0
an O 0
increased O 0
mortality O 0
in O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
( O 0
PD B-Disease 1
) O 0
randomized O 0
to O 0
receive O 0
10 O 0
mg O 0
selegiline B-Chemical 1
per O 0
day O 0
and O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
compared O 0
with O 0
those O 0
taking O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
alone O 0
. O 0

Recently O 0
, O 0
we O 0
found O 0
that O 0
therapy O 0
with O 0
selegiline B-Chemical 1
and O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
was O 0
associated O 0
with O 0
selective O 0
systolic B-Disease 1
orthostatic I-Disease 1
hypotension I-Disease 1
which O 0
was O 0
abolished O 0
by O 0
withdrawal O 0
of O 0
selegiline B-Chemical 1
. O 0

This O 0
unwanted O 0
effect O 0
on O 0
postural O 0
blood O 0
pressure O 0
was O 0
not O 0
the O 0
result O 0
of O 0
underlying O 0
autonomic O 0
failure O 0
. O 0

The O 0
aims O 0
of O 0
this O 0
study O 0
were O 0
to O 0
confirm O 0
our O 0
previous O 0
findings O 0
in O 0
a O 0
separate O 0
cohort O 0
of O 0
patients O 0
and O 0
to O 0
determine O 0
the O 0
time O 0
course O 0
of O 0
the O 0
cardiovascular O 0
consequences O 0
of O 0
stopping O 0
selegiline B-Chemical 1
in O 0
the O 0
expectation O 0
that O 0
this O 0
might O 0
shed O 0
light O 0
on O 0
the O 0
mechanisms O 0
by O 0
which O 0
the O 0
drug O 0
causes O 0
orthostatic B-Disease 1
hypotension I-Disease 1
. O 0

METHODS O 0
: O 0
The O 0
cardiovascular O 0
responses O 0
to O 0
standing O 0
and O 0
head O 0
- O 0
up O 0
tilt O 0
were O 0
studied O 0
repeatedly O 0
in O 0
PD B-Disease 1
patients O 0
receiving O 0
selegiline B-Chemical 1
and O 0
as O 0
the O 0
drug O 0
was O 0
withdrawn O 0
. O 0

RESULTS O 0
: O 0
Head O 0
- O 0
up O 0
tilt O 0
caused O 0
systolic B-Disease 1
orthostatic I-Disease 1
hypotension I-Disease 1
which O 0
was O 0
marked O 0
in O 0
six O 0
of O 0
20 O 0
PD B-Disease 1
patients O 0
on O 0
selegiline B-Chemical 1
, O 0
one O 0
of O 0
whom O 0
lost O 0
consciousness O 0
with O 0
unrecordable O 0
blood O 0
pressures O 0
. O 0

A O 0
lesser O 0
degree O 0
of O 0
orthostatic B-Disease 1
hypotension I-Disease 1
occurred O 0
with O 0
standing O 0
. O 0

Orthostatic B-Disease 1
hypotension I-Disease 1
was O 0
ameliorated O 0
4 O 0
days O 0
after O 0
withdrawal O 0
of O 0
selegiline B-Chemical 1
and O 0
totally O 0
abolished O 0
7 O 0
days O 0
after O 0
discontinuation O 0
of O 0
the O 0
drug O 0
. O 0

Stopping O 0
selegiline B-Chemical 1
also O 0
significantly O 0
reduced B-Disease 1
the I-Disease 1
supine I-Disease 1
systolic I-Disease 1
and I-Disease 1
diastolic I-Disease 1
blood I-Disease 1
pressures I-Disease 1
consistent O 0
with O 0
a O 0
previously O 0
undescribed O 0
supine O 0
pressor O 0
action O 0
. O 0

CONCLUSION O 0
: O 0
This O 0
study O 0
confirms O 0
our O 0
previous O 0
finding O 0
that O 0
selegiline B-Chemical 1
in O 0
combination O 0
with O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
is O 0
associated O 0
with O 0
selective O 0
orthostatic B-Disease 1
hypotension I-Disease 1
. O 0

The O 0
possibilities O 0
that O 0
these O 0
cardiovascular O 0
findings O 0
might O 0
be O 0
the O 0
result O 0
of O 0
non O 0
- O 0
selective O 0
inhibition O 0
of O 0
monoamine O 0
oxidase O 0
or O 0
of O 0
amphetamine B-Chemical 1
and O 0
metamphetamine B-Chemical 1
are O 0
discussed O 0
. O 0

Further O 0
studies O 0
on O 0
effects O 0
of O 0
irrigation O 0
solutions O 0
on O 0
rat O 0
bladders O 0
. O 0

Further O 0
studies O 0
on O 0
the O 0
effects O 0
of O 0
certain O 0
irrigating O 0
fluids O 0
on O 0
the O 0
rat O 0
bladder O 0
for O 0
18 O 0
hours O 0
are O 0
reported O 0
. O 0

The O 0
results O 0
have O 0
shown O 0
that O 0
the O 0
degradation O 0
product O 0
p B-Chemical 1
- I-Chemical 1
choloroaniline I-Chemical 1
is O 0
not O 0
a O 0
significant O 0
factor O 0
in O 0
chlorhexidine B-Chemical 1
- I-Chemical 1
digluconate I-Chemical 1
associated O 0
erosive O 0
cystitis B-Disease 1
. O 0

A O 0
high O 0
percentage O 0
of O 0
kanamycin B-Chemical 1
- O 0
colistin B-Chemical 1
and O 0
povidone B-Chemical 1
- I-Chemical 1
iodine I-Chemical 1
irrigations O 0
were O 0
associated O 0
with O 0
erosive O 0
cystitis B-Disease 1
and O 0
suggested O 0
a O 0
possible O 0
complication O 0
with O 0
human O 0
usage O 0
. O 0

Picloxydine B-Chemical 1
irrigations O 0
appeared O 0
to O 0
have O 0
a O 0
lower O 0
incidence O 0
of O 0
erosive O 0
cystitis B-Disease 1
but O 0
further O 0
studies O 0
would O 0
have O 0
to O 0
be O 0
performed O 0
before O 0
it O 0
could O 0
be O 0
recommended O 0
for O 0
use O 0
in O 0
urological O 0
procedures O 0
. O 0

Effects O 0
of O 0
tetrandrine B-Chemical 1
and O 0
fangchinoline B-Chemical 1
on O 0
experimental O 0
thrombosis B-Disease 1
in O 0
mice O 0
and O 0
human O 0
platelet B-Disease 1
aggregation I-Disease 1
. O 0

Tetrandrine B-Chemical 1
( O 0
TET B-Chemical 1
) O 0
and O 0
fangchinoline B-Chemical 1
( O 0
FAN B-Chemical 1
) O 0
are O 0
two O 0
naturally O 0
occurring O 0
analogues O 0
with O 0
a O 0
bisbenzylisoquinoline B-Chemical 1
structure O 0
. O 0

The O 0
present O 0
study O 0
was O 0
undertaken O 0
to O 0
investigate O 0
the O 0
effects O 0
of O 0
TET B-Chemical 1
and O 0
FAN B-Chemical 1
on O 0
the O 0
experimental O 0
thrombosis B-Disease 1
induced O 0
by O 0
collagen O 0
plus O 0
epinephrine B-Chemical 1
( O 0
EP B-Chemical 1
) O 0
in O 0
mice O 0
, O 0
and O 0
platelet B-Disease 1
aggregation I-Disease 1
and O 0
blood B-Disease 1
coagulation I-Disease 1
in O 0
vitro O 0
. O 0

In O 0
the O 0
in O 0
vivo O 0
study O 0
, O 0
the O 0
administration O 0
( O 0
50 O 0
mg O 0
/ O 0
kg O 0
, O 0
i O 0
. O 0
p O 0
. O 0
) O 0
of O 0
TET B-Chemical 1
and O 0
FAN B-Chemical 1
in O 0
mice O 0
showed O 0
the O 0
inhibition O 0
of O 0
thrombosis B-Disease 1
by O 0
55 O 0
% O 0
and O 0
35 O 0
% O 0
, O 0
respectively O 0
, O 0
while O 0
acetylsalicylic B-Chemical 1
acid I-Chemical 1
( O 0
ASA B-Chemical 1
, O 0
50 O 0
mg O 0
/ O 0
kg O 0
, O 0
i O 0
. O 0
p O 0
. O 0
) O 0
, O 0
a O 0
positive O 0
control O 0
, O 0
showed O 0
only O 0
30 O 0
% O 0
inhibition O 0
. O 0

In O 0
the O 0
vitro O 0
human O 0
platelet B-Disease 1
aggregations I-Disease 1
induced O 0
by O 0
the O 0
agonists O 0
used O 0
in O 0
tests O 0
, O 0
TET B-Chemical 1
and O 0
FAN B-Chemical 1
showed O 0
the O 0
inhibitions O 0
dose O 0
dependently O 0
. O 0

In O 0
addition O 0
, O 0
neither O 0
TET B-Chemical 1
nor O 0
FAN B-Chemical 1
showed O 0
any O 0
anticoagulation O 0
activities O 0
in O 0
the O 0
measurement O 0
of O 0
the O 0
activated O 0
partial O 0
thromboplastin O 0
time O 0
( O 0
APTT O 0
) O 0
, O 0
prothrombin O 0
time O 0
( O 0
PT O 0
) O 0
and O 0
thrombin O 0
time O 0
( O 0
TT O 0
) O 0
using O 0
human O 0
- O 0
citrated O 0
plasma O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
antithrombosis O 0
of O 0
TET B-Chemical 1
and O 0
FAN B-Chemical 1
in O 0
mice O 0
may O 0
be O 0
mainly O 0
related O 0
to O 0
the O 0
antiplatelet O 0
aggregation O 0
activities O 0
. O 0

Angioedema B-Disease 1
due O 0
to O 0
ACE B-Chemical 1
inhibitors I-Chemical 1
: O 0
common O 0
and O 0
inadequately O 0
diagnosed O 0
. O 0

The O 0
estimated O 0
incidence O 0
of O 0
angioedema B-Disease 1
during O 0
angiotensin B-Chemical 1
- I-Chemical 1
converting I-Chemical 1
enzyme I-Chemical 1
( I-Chemical 1
ACE I-Chemical 1
) I-Chemical 1
inhibitor I-Chemical 1
treatment O 0
is O 0
between O 0
1 O 0
and O 0
7 O 0
per O 0
thousand O 0
patients O 0
. O 0

This O 0
potentially O 0
serious O 0
adverse O 0
effect O 0
is O 0
often O 0
preceded O 0
by O 0
minor O 0
manifestations O 0
that O 0
may O 0
serve O 0
as O 0
a O 0
warning O 0
. O 0

Cocaine B-Chemical 1
- O 0
induced O 0
mood B-Disease 1
disorder I-Disease 1
: O 0
prevalence O 0
rates O 0
and O 0
psychiatric B-Disease 1
symptoms O 0
in O 0
an O 0
outpatient O 0
cocaine B-Chemical 1
- O 0
dependent O 0
sample O 0
. O 0

This O 0
paper O 0
attempts O 0
to O 0
examine O 0
and O 0
compare O 0
prevalence O 0
rates O 0
and O 0
symptom O 0
patterns O 0
of O 0
DSM O 0
substance O 0
- O 0
induced O 0
and O 0
other O 0
mood B-Disease 1
disorders I-Disease 1
. O 0

243 O 0
cocaine B-Chemical 1
- O 0
dependent O 0
outpatients O 0
with O 0
cocaine B-Chemical 1
- O 0
induced O 0
mood B-Disease 1
disorder I-Disease 1
( O 0
CIMD B-Disease 1
) O 0
, O 0
other O 0
mood B-Disease 1
disorders I-Disease 1
, O 0
or O 0
no O 0
mood B-Disease 1
disorder I-Disease 1
were O 0
compared O 0
on O 0
measures O 0
of O 0
psychiatric B-Disease 1
symptoms O 0
. O 0

The O 0
prevalence O 0
rate O 0
for O 0
CIMD B-Disease 1
was O 0
12 O 0
% O 0
at O 0
baseline O 0
. O 0

Introduction O 0
of O 0
the O 0
DSM O 0
- O 0
IV O 0
diagnosis O 0
of O 0
CIMD B-Disease 1
did O 0
not O 0
substantially O 0
affect O 0
rates O 0
of O 0
the O 0
other O 0
depressive B-Disease 1
disorders I-Disease 1
. O 0

Patients O 0
with O 0
CIMD B-Disease 1
had O 0
symptom O 0
severity O 0
levels O 0
between O 0
those O 0
of O 0
patients O 0
with O 0
and O 0
without O 0
a O 0
mood B-Disease 1
disorder I-Disease 1
. O 0

These O 0
findings O 0
suggest O 0
some O 0
validity O 0
for O 0
the O 0
new O 0
DSM O 0
- O 0
IV O 0
diagnosis O 0
of O 0
CIMD B-Disease 1
, O 0
but O 0
also O 0
suggest O 0
that O 0
it O 0
requires O 0
further O 0
specification O 0
and O 0
replication O 0
. O 0

Effect O 0
of O 0
fucoidan B-Chemical 1
treatment O 0
on O 0
collagenase O 0
- O 0
induced O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
in O 0
rats O 0
. O 0

Inflammatory O 0
cells O 0
are O 0
postulated O 0
to O 0
mediate O 0
some O 0
of O 0
the O 0
brain B-Disease 1
damage I-Disease 1
following O 0
ischemic B-Disease 1
stroke I-Disease 1
. O 0

Intracerebral B-Disease 1
hemorrhage I-Disease 1
is O 0
associated O 0
with O 0
more O 0
inflammation B-Disease 1
than O 0
ischemic B-Disease 1
stroke I-Disease 1
. O 0

We O 0
tested O 0
the O 0
sulfated O 0
polysaccharide O 0
fucoidan B-Chemical 1
, O 0
which O 0
has O 0
been O 0
reported O 0
to O 0
reduce O 0
inflammatory O 0
brain B-Disease 1
damage I-Disease 1
, O 0
in O 0
a O 0
rat O 0
model O 0
of O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
induced O 0
by O 0
injection O 0
of O 0
bacterial O 0
collagenase O 0
into O 0
the O 0
caudate O 0
nucleus O 0
. O 0

Rats O 0
were O 0
treated O 0
with O 0
seven O 0
day O 0
intravenous O 0
infusion O 0
of O 0
fucoidan B-Chemical 1
( O 0
30 O 0
micrograms O 0
h O 0
- O 0
1 O 0
) O 0
or O 0
vehicle O 0
. O 0

The O 0
hematoma B-Disease 1
was O 0
assessed O 0
in O 0
vivo O 0
by O 0
magnetic O 0
resonance O 0
imaging O 0
. O 0

Motor O 0
behavior O 0
, O 0
passive O 0
avoidance O 0
, O 0
and O 0
skilled O 0
forelimb O 0
function O 0
were O 0
tested O 0
repeatedly O 0
for O 0
six O 0
weeks O 0
. O 0

Fucoidan B-Chemical 1
- O 0
treated O 0
rats O 0
exhibited O 0
evidence O 0
of O 0
impaired B-Disease 1
blood I-Disease 1
clotting I-Disease 1
and O 0
hemodilution B-Disease 1
, O 0
had O 0
larger O 0
hematomas B-Disease 1
, O 0
and O 0
tended O 0
to O 0
have O 0
less O 0
inflammation B-Disease 1
in O 0
the O 0
vicinity O 0
of O 0
the O 0
hematoma B-Disease 1
after O 0
three O 0
days O 0
. O 0

They O 0
showed O 0
significantly O 0
more O 0
rapid O 0
improvement O 0
of O 0
motor O 0
function O 0
in O 0
the O 0
first O 0
week O 0
following O 0
hemorrhage B-Disease 1
and O 0
better O 0
memory O 0
retention O 0
in O 0
the O 0
passive O 0
avoidance O 0
test O 0
. O 0

Acute O 0
white B-Disease 1
matter I-Disease 1
edema I-Disease 1
and O 0
eventual O 0
neuronal B-Disease 1
loss I-Disease 1
in O 0
the O 0
striatum O 0
adjacent O 0
to O 0
the O 0
hematoma B-Disease 1
did O 0
not O 0
differ O 0
between O 0
the O 0
two O 0
groups O 0
. O 0

Investigation O 0
of O 0
more O 0
specific O 0
anti O 0
- O 0
inflammatory O 0
agents O 0
and O 0
hemodiluting O 0
agents O 0
are O 0
warranted O 0
in O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
. O 0

Recurarization O 0
in O 0
the O 0
recovery O 0
room O 0
. O 0

A O 0
case O 0
of O 0
recurarization O 0
in O 0
the O 0
recovery O 0
room O 0
is O 0
reported O 0
. O 0

Accumulation O 0
of O 0
atracurium B-Chemical 1
in O 0
the O 0
intravenous O 0
line O 0
led O 0
to O 0
recurarization O 0
after O 0
flushing O 0
the O 0
line O 0
in O 0
the O 0
recovery O 0
room O 0
. O 0

A O 0
respiratory B-Disease 1
arrest I-Disease 1
with O 0
severe O 0
desaturation B-Disease 1
and O 0
bradycardia B-Disease 1
occurred O 0
. O 0

Circumstances O 0
leading O 0
to O 0
this O 0
event O 0
and O 0
the O 0
mechanisms O 0
enabling O 0
a O 0
neuromuscular B-Disease 1
blockade I-Disease 1
to O 0
occur O 0
, O 0
following O 0
the O 0
administration O 0
of O 0
a O 0
small O 0
dose O 0
of O 0
relaxant O 0
, O 0
are O 0
discussed O 0
. O 0

The O 0
haemodynamic O 0
effects O 0
of O 0
propofol B-Chemical 1
in O 0
combination O 0
with O 0
ephedrine B-Chemical 1
in O 0
elderly O 0
patients O 0
( O 0
ASA O 0
groups O 0
3 O 0
and O 0
4 O 0
) O 0
. O 0

The O 0
marked O 0
vasodilator O 0
and O 0
negative O 0
inotropic O 0
effects O 0
of O 0
propofol B-Chemical 1
are O 0
disadvantages O 0
in O 0
frail O 0
elderly O 0
patients O 0
. O 0

We O 0
investigated O 0
the O 0
safety O 0
and O 0
efficacy O 0
of O 0
adding O 0
different O 0
doses O 0
of O 0
ephedrine B-Chemical 1
to O 0
propofol B-Chemical 1
in O 0
order O 0
to O 0
obtund O 0
the O 0
hypotensive B-Disease 1
response O 0
. O 0

The O 0
haemodynamic O 0
effects O 0
of O 0
adding O 0
15 O 0
, O 0
20 O 0
or O 0
25 O 0
mg O 0
of O 0
ephedrine B-Chemical 1
to O 0
200 O 0
mg O 0
of O 0
propofol B-Chemical 1
were O 0
compared O 0
to O 0
control O 0
in O 0
40 O 0
ASA O 0
3 O 0
/ O 0
4 O 0
patients O 0
over O 0
60 O 0
years O 0
presenting O 0
for O 0
genito O 0
- O 0
urinary O 0
surgery O 0
. O 0

The O 0
addition O 0
of O 0
ephedrine B-Chemical 1
to O 0
propofol B-Chemical 1
appears O 0
to O 0
be O 0
an O 0
effective O 0
method O 0
of O 0
obtunding O 0
the O 0
hypotensive B-Disease 1
response O 0
to O 0
propofol B-Chemical 1
at O 0
all O 0
doses O 0
used O 0
in O 0
this O 0
study O 0
. O 0

However O 0
, O 0
marked O 0
tachycardia B-Disease 1
associated O 0
with O 0
the O 0
use O 0
of O 0
ephedrine B-Chemical 1
in O 0
combination O 0
with O 0
propofol B-Chemical 1
occurred O 0
in O 0
the O 0
majority O 0
of O 0
patients O 0
, O 0
occasionally O 0
reaching O 0
high O 0
levels O 0
in O 0
individual O 0
patients O 0
. O 0

Due O 0
to O 0
the O 0
risk O 0
of O 0
this O 0
tachycardia B-Disease 1
inducing O 0
myocardial B-Disease 1
ischemia I-Disease 1
, O 0
we O 0
would O 0
not O 0
recommend O 0
the O 0
use O 0
in O 0
elderly O 0
patients O 0
of O 0
any O 0
of O 0
the O 0
ephedrine B-Chemical 1
/ O 0
propofol B-Chemical 1
/ O 0
mixtures O 0
studied O 0
. O 0

Gemcitabine B-Chemical 1
plus O 0
vinorelbine B-Chemical 1
in O 0
nonsmall B-Disease 1
cell I-Disease 1
lung I-Disease 1
carcinoma I-Disease 1
patients O 0
age O 0
70 O 0
years O 0
or O 0
older O 0
or O 0
patients O 0
who O 0
cannot O 0
receive O 0
cisplatin B-Chemical 1
. O 0

Oncopaz O 0
Cooperative O 0
Group O 0
. O 0

BACKGROUND O 0
: O 0
Although O 0
the O 0
prevalence O 0
of O 0
nonsmall B-Disease 1
cell I-Disease 1
lung I-Disease 1
carcinoma I-Disease 1
( O 0
NSCLC B-Disease 1
) O 0
is O 0
high O 0
among O 0
elderly O 0
patients O 0
, O 0
few O 0
data O 0
are O 0
available O 0
regarding O 0
the O 0
efficacy O 0
and O 0
toxicity B-Disease 1
of O 0
chemotherapy O 0
in O 0
this O 0
group O 0
of O 0
patients O 0
. O 0

Recent O 0
reports O 0
indicate O 0
that O 0
single O 0
agent O 0
therapy O 0
with O 0
vinorelbine B-Chemical 1
( O 0
VNB B-Chemical 1
) O 0
or O 0
gemcitabine B-Chemical 1
( O 0
GEM B-Chemical 1
) O 0
may O 0
obtain O 0
a O 0
response O 0
rate O 0
of O 0
20 O 0
- O 0
30 O 0
% O 0
in O 0
elderly O 0
patients O 0
, O 0
with O 0
acceptable O 0
toxicity B-Disease 1
and O 0
improvement O 0
in O 0
symptoms O 0
and O 0
quality O 0
of O 0
life O 0
. O 0

In O 0
the O 0
current O 0
study O 0
the O 0
efficacy O 0
and O 0
toxicity B-Disease 1
of O 0
the O 0
combination O 0
of O 0
GEM B-Chemical 1
and O 0
VNB B-Chemical 1
in O 0
elderly O 0
patients O 0
with O 0
advanced O 0
NSCLC B-Disease 1
or O 0
those O 0
with O 0
some O 0
contraindication O 0
to O 0
receiving O 0
cisplatin B-Chemical 1
were O 0
assessed O 0
. O 0

METHODS O 0
: O 0
Forty O 0
- O 0
nine O 0
patients O 0
with O 0
advanced O 0
NSCLC B-Disease 1
were O 0
included O 0
, O 0
38 O 0
of O 0
whom O 0
were O 0
age O 0
> O 0
/ O 0
= O 0
70 O 0
years O 0
and O 0
11 O 0
were O 0
age O 0
< O 0
70 O 0
years O 0
but O 0
who O 0
had O 0
some O 0
contraindication O 0
to O 0
receiving O 0
cisplatin B-Chemical 1
. O 0

All O 0
patients O 0
were O 0
evaluable O 0
for O 0
response O 0
and O 0
toxicity B-Disease 1
. O 0

Treatment O 0
was O 0
comprised O 0
of O 0
VNB B-Chemical 1
, O 0
25 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
, O 0
plus O 0
GEM B-Chemical 1
, O 0
1000 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
, O 0
both O 0
on O 0
Days O 0
1 O 0
, O 0
8 O 0
, O 0
and O 0
15 O 0
every O 0
28 O 0
days O 0
. O 0

Patients O 0
received O 0
a O 0
minimum O 0
of O 0
three O 0
courses O 0
unless O 0
progressive O 0
disease O 0
was O 0
detected O 0
. O 0

RESULTS O 0
: O 0
One O 0
hundred O 0
sixty O 0
- O 0
five O 0
courses O 0
were O 0
administered O 0
, O 0
with O 0
a O 0
median O 0
of O 0
3 O 0
. O 0

6 O 0
courses O 0
per O 0
patient O 0
. O 0

The O 0
overall O 0
response O 0
rate O 0
was O 0
26 O 0
% O 0
( O 0
95 O 0
% O 0
confidence O 0
interval O 0
, O 0
15 O 0
- O 0
41 O 0
% O 0
) O 0
. O 0

Two O 0
patients O 0
attained O 0
a O 0
complete O 0
response O 0
( O 0
4 O 0
% O 0
) O 0
and O 0
11 O 0
patients O 0
( O 0
22 O 0
% O 0
) O 0
achieved O 0
a O 0
partial O 0
response O 0
. O 0

Eastern O 0
Cooperative O 0
Oncology O 0
Group O 0
performance O 0
status O 0
improved O 0
in O 0
35 O 0
% O 0
of O 0
those O 0
patients O 0
with O 0
an O 0
initial O 0
value O 0
> O 0
0 O 0
, O 0
whereas O 0
relief O 0
of O 0
at O 0
least O 0
1 O 0
symptom O 0
without O 0
worsening O 0
of O 0
other O 0
symptoms O 0
was O 0
noted O 0
in O 0
27 O 0
patients O 0
( O 0
55 O 0
% O 0
) O 0
. O 0

The O 0
median O 0
time O 0
to O 0
progression O 0
was O 0
16 O 0
weeks O 0
and O 0
the O 0
1 O 0
- O 0
year O 0
survival O 0
rate O 0
was O 0
33 O 0
% O 0
. O 0

Toxicity B-Disease 1
was O 0
mild O 0
. O 0

Six O 0
patients O 0
( O 0
12 O 0
% O 0
) O 0
had O 0
World O 0
Health O 0
Organization O 0
Grade O 0
3 O 0
- O 0
4 O 0
neutropenia B-Disease 1
, O 0
2 O 0
patients O 0
( O 0
4 O 0
% O 0
) O 0
had O 0
Grade O 0
3 O 0
- O 0
4 O 0
thrombocytopenia B-Disease 1
, O 0
and O 0
2 O 0
patients O 0
( O 0
4 O 0
% O 0
) O 0
had O 0
Grade O 0
3 O 0
neurotoxicity B-Disease 1
. O 0

Three O 0
patients O 0
with O 0
severe O 0
neutropenia B-Disease 1
( O 0
6 O 0
% O 0
) O 0
died O 0
of O 0
sepsis B-Disease 1
. O 0

The O 0
median O 0
age O 0
of O 0
those O 0
patients O 0
developing O 0
Grade O 0
3 O 0
- O 0
4 O 0
neutropenia B-Disease 1
was O 0
significantly O 0
higher O 0
than O 0
that O 0
of O 0
the O 0
remaining O 0
patients O 0
( O 0
75 O 0
years O 0
vs O 0
. O 0
72 O 0
years O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
047 O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
combination O 0
of O 0
GEM B-Chemical 1
and O 0
VNB B-Chemical 1
is O 0
moderately O 0
active O 0
and O 0
well O 0
tolerated O 0
except O 0
in O 0
patients O 0
age O 0
> O 0
/ O 0
= O 0
75 O 0
years O 0
. O 0

This O 0
age O 0
group O 0
had O 0
an O 0
increased O 0
risk O 0
of O 0
myelosuppression B-Disease 1
. O 0

Therefore O 0
the O 0
prophylactic O 0
use O 0
of O 0
granulocyte O 0
- O 0
colony O 0
stimulating O 0
factor O 0
should O 0
be O 0
considered O 0
with O 0
this O 0
treatment O 0
. O 0

New O 0
chemotherapy O 0
combinations O 0
with O 0
higher O 0
activity O 0
and O 0
lower O 0
toxicity B-Disease 1
are O 0
needed O 0
for O 0
elderly O 0
patients O 0
with O 0
advanced O 0
NSCLC B-Disease 1
. O 0

A O 0
selective O 0
dopamine B-Chemical 1
D4 O 0
receptor O 0
antagonist O 0
, O 0
NRA0160 B-Chemical 1
: O 0
a O 0
preclinical O 0
neuropharmacological O 0
profile O 0
. O 0

NRA0160 B-Chemical 1
, O 0
5 B-Chemical 1
- I-Chemical 1
[ I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
fluorobenzylidene I-Chemical 1
) I-Chemical 1
piperidin I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
yl I-Chemical 1
) I-Chemical 1
ethyl I-Chemical 1
] I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
fluorophenyl I-Chemical 1
) I-Chemical 1
thiazole I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
carboxamide I-Chemical 1
, O 0
has O 0
a O 0
high O 0
affinity O 0
for O 0
human O 0
cloned O 0
dopamine B-Chemical 1
D4 O 0
. O 0
2 O 0
, O 0
D4 O 0
. O 0
4 O 0
and O 0
D4 O 0
. O 0
7 O 0
receptors O 0
, O 0
with O 0
Ki O 0
values O 0
of O 0
0 O 0
. O 0
5 O 0
, O 0
0 O 0
. O 0
9 O 0
and O 0
2 O 0
. O 0
7 O 0
nM O 0
, O 0
respectively O 0
. O 0

NRA0160 B-Chemical 1
is O 0
over O 0
20 O 0
, O 0
000fold O 0
more O 0
potent O 0
at O 0
the O 0
dopamine B-Chemical 1
D4 O 0
. O 0
2 O 0
receptor O 0
compared O 0
with O 0
the O 0
human O 0
cloned O 0
dopamine B-Chemical 1
D2L O 0
receptor O 0
. O 0

NRA0160 B-Chemical 1
has O 0
negligible O 0
affinity O 0
for O 0
the O 0
human O 0
cloned O 0
dopamine B-Chemical 1
D3 O 0
receptor O 0
( O 0
Ki O 0
= O 0
39 O 0
nM O 0
) O 0
, O 0
rat O 0
serotonin B-Chemical 1
( O 0
5 B-Chemical 1
- I-Chemical 1
HT I-Chemical 1
) O 0
2A O 0
receptors O 0
( O 0
Ki O 0
= O 0
180 O 0
nM O 0
) O 0
and O 0
rat O 0
alpha1 O 0
adrenoceptor O 0
( O 0
Ki O 0
= O 0
237 O 0
nM O 0
) O 0
. O 0

NRA0160 B-Chemical 1
and O 0
clozapine B-Chemical 1
antagonized O 0
locomotor O 0
hyperactivity B-Disease 1
induced O 0
by O 0
methamphetamine B-Chemical 1
( O 0
MAP B-Chemical 1
) O 0
in O 0
mice O 0
. O 0

NRA0160 B-Chemical 1
and O 0
clozapine B-Chemical 1
antagonized O 0
MAP B-Chemical 1
- O 0
induced O 0
stereotyped O 0
behavior O 0
in O 0
mice O 0
, O 0
although O 0
their O 0
effects O 0
did O 0
not O 0
exceed O 0
50 O 0
% O 0
inhibition O 0
, O 0
even O 0
at O 0
the O 0
highest O 0
dose O 0
given O 0
. O 0

NRA0160 B-Chemical 1
and O 0
clozapine B-Chemical 1
significantly O 0
induced O 0
catalepsy B-Disease 1
in O 0
rats O 0
, O 0
although O 0
their O 0
effects O 0
did O 0
not O 0
exceed O 0
50 O 0
% O 0
induction O 0
even O 0
at O 0
the O 0
highest O 0
dose O 0
given O 0
. O 0

NRA0160 B-Chemical 1
and O 0
clozapine B-Chemical 1
significantly O 0
reversed O 0
the O 0
disruption O 0
of O 0
prepulse O 0
inhibition O 0
( O 0
PPI O 0
) O 0
in O 0
rats O 0
produced O 0
by O 0
apomorphine B-Chemical 1
. O 0

NRA0160 B-Chemical 1
and O 0
clozapine B-Chemical 1
significantly O 0
shortened O 0
the O 0
phencyclidine B-Chemical 1
( O 0
PCP B-Chemical 1
) O 0
- O 0
induced O 0
prolonged O 0
swimming O 0
latency O 0
in O 0
rats O 0
in O 0
a O 0
water O 0
maze O 0
task O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
NRA0160 B-Chemical 1
may O 0
have O 0
unique O 0
antipsychotic O 0
activities O 0
without O 0
the O 0
liability O 0
of O 0
motor O 0
side O 0
effects O 0
typical O 0
of O 0
classical O 0
antipsychotics O 0
. O 0

Warfarin B-Chemical 1
- O 0
induced O 0
artery B-Disease 1
calcification I-Disease 1
is O 0
accelerated O 0
by O 0
growth O 0
and O 0
vitamin B-Chemical 1
D I-Chemical 1
. O 0

The O 0
present O 0
studies O 0
demonstrate O 0
that O 0
growth O 0
and O 0
vitamin B-Chemical 1
D I-Chemical 1
treatment O 0
enhance O 0
the O 0
extent O 0
of O 0
artery B-Disease 1
calcification I-Disease 1
in O 0
rats O 0
given O 0
sufficient O 0
doses O 0
of O 0
Warfarin B-Chemical 1
to O 0
inhibit O 0
gamma O 0
- O 0
carboxylation O 0
of O 0
matrix O 0
Gla O 0
protein O 0
, O 0
a O 0
calcification B-Disease 1
inhibitor O 0
known O 0
to O 0
be O 0
expressed O 0
by O 0
smooth O 0
muscle O 0
cells O 0
and O 0
macrophages O 0
in O 0
the O 0
artery O 0
wall O 0
. O 0

The O 0
first O 0
series O 0
of O 0
experiments O 0
examined O 0
the O 0
influence O 0
of O 0
age O 0
and O 0
growth O 0
status O 0
on O 0
artery B-Disease 1
calcification I-Disease 1
in O 0
Warfarin B-Chemical 1
- O 0
treated O 0
rats O 0
. O 0

Treatment O 0
for O 0
2 O 0
weeks O 0
with O 0
Warfarin B-Chemical 1
caused O 0
massive O 0
focal O 0
calcification B-Disease 1
of I-Disease 1
the I-Disease 1
artery I-Disease 1
media O 0
in O 0
20 O 0
- O 0
day O 0
- O 0
old O 0
rats O 0
and O 0
less O 0
extensive O 0
focal O 0
calcification B-Disease 1
in O 0
42 O 0
- O 0
day O 0
- O 0
old O 0
rats O 0
. O 0

In O 0
contrast O 0
, O 0
no O 0
artery B-Disease 1
calcification I-Disease 1
could O 0
be O 0
detected O 0
in O 0
10 O 0
- O 0
month O 0
- O 0
old O 0
adult O 0
rats O 0
even O 0
after O 0
4 O 0
weeks O 0
of O 0
Warfarin B-Chemical 1
treatment O 0
. O 0

To O 0
directly O 0
examine O 0
the O 0
importance O 0
of O 0
growth O 0
to O 0
Warfarin B-Chemical 1
- O 0
induced O 0
artery B-Disease 1
calcification I-Disease 1
in O 0
animals O 0
of O 0
the O 0
same O 0
age O 0
, O 0
20 O 0
- O 0
day O 0
- O 0
old O 0
rats O 0
were O 0
fed O 0
for O 0
2 O 0
weeks O 0
either O 0
an O 0
ad O 0
libitum O 0
diet O 0
or O 0
a O 0
6 O 0
- O 0
g O 0
/ O 0
d O 0
restricted O 0
diet O 0
that O 0
maintains O 0
weight O 0
but O 0
prevents O 0
growth O 0
. O 0

Concurrent O 0
treatment O 0
of O 0
both O 0
dietary O 0
groups O 0
with O 0
Warfarin B-Chemical 1
produced O 0
massive O 0
focal O 0
calcification B-Disease 1
of I-Disease 1
the I-Disease 1
artery I-Disease 1
media O 0
in O 0
the O 0
ad O 0
libitum O 0
- O 0
fed O 0
rats O 0
but O 0
no O 0
detectable O 0
artery B-Disease 1
calcification I-Disease 1
in O 0
the O 0
restricted O 0
- O 0
diet O 0
, O 0
growth O 0
- O 0
inhibited O 0
group O 0
. O 0

Although O 0
the O 0
explanation O 0
for O 0
the O 0
association O 0
between O 0
artery B-Disease 1
calcification I-Disease 1
and O 0
growth O 0
status O 0
cannot O 0
be O 0
determined O 0
from O 0
the O 0
present O 0
study O 0
, O 0
there O 0
was O 0
a O 0
relationship O 0
between O 0
higher O 0
serum O 0
phosphate B-Chemical 1
and O 0
susceptibility O 0
to O 0
artery B-Disease 1
calcification I-Disease 1
, O 0
with O 0
30 O 0
% O 0
higher O 0
levels O 0
of O 0
serum O 0
phosphate B-Chemical 1
in O 0
young O 0
, O 0
ad O 0
libitum O 0
- O 0
fed O 0
rats O 0
compared O 0
with O 0
either O 0
of O 0
the O 0
groups O 0
that O 0
was O 0
resistant O 0
to O 0
Warfarin B-Chemical 1
- O 0
induced O 0
artery B-Disease 1
calcification I-Disease 1
, O 0
ie O 0
, O 0
the O 0
10 O 0
- O 0
month O 0
- O 0
old O 0
rats O 0
and O 0
the O 0
restricted O 0
- O 0
diet O 0
, O 0
growth O 0
- O 0
inhibited O 0
young O 0
rats O 0
. O 0

This O 0
observation O 0
suggests O 0
that O 0
increased O 0
susceptibility O 0
to O 0
Warfarin B-Chemical 1
- O 0
induced O 0
artery B-Disease 1
calcification I-Disease 1
could O 0
be O 0
related O 0
to O 0
higher O 0
serum O 0
phosphate B-Chemical 1
levels O 0
. O 0

The O 0
second O 0
set O 0
of O 0
experiments O 0
examined O 0
the O 0
possible O 0
synergy O 0
between O 0
vitamin B-Chemical 1
D I-Chemical 1
and O 0
Warfarin B-Chemical 1
in O 0
artery B-Disease 1
calcification I-Disease 1
. O 0

High O 0
doses O 0
of O 0
vitamin B-Chemical 1
D I-Chemical 1
are O 0
known O 0
to O 0
cause O 0
calcification B-Disease 1
of I-Disease 1
the I-Disease 1
artery I-Disease 1
media O 0
in O 0
as O 0
little O 0
as O 0
3 O 0
to O 0
4 O 0
days O 0
. O 0

High O 0
doses O 0
of O 0
the O 0
vitamin B-Chemical 1
K I-Chemical 1
antagonist O 0
Warfarin B-Chemical 1
are O 0
also O 0
known O 0
to O 0
cause O 0
calcification B-Disease 1
of I-Disease 1
the I-Disease 1
artery I-Disease 1
media O 0
, O 0
but O 0
at O 0
treatment O 0
times O 0
of O 0
2 O 0
weeks O 0
or O 0
longer O 0
yet O 0
not O 0
at O 0
1 O 0
week O 0
. O 0

In O 0
the O 0
current O 0
study O 0
, O 0
we O 0
investigated O 0
the O 0
synergy O 0
between O 0
these O 0
2 O 0
treatments O 0
and O 0
found O 0
that O 0
concurrent O 0
Warfarin B-Chemical 1
administration O 0
dramatically O 0
increased O 0
the O 0
extent O 0
of O 0
calcification B-Disease 1
in O 0
the O 0
media O 0
of O 0
vitamin B-Chemical 1
D I-Chemical 1
- O 0
treated O 0
rats O 0
at O 0
3 O 0
and O 0
4 O 0
days O 0
. O 0

There O 0
was O 0
a O 0
close O 0
parallel O 0
between O 0
the O 0
effect O 0
of O 0
vitamin B-Chemical 1
D I-Chemical 1
dose O 0
on O 0
artery B-Disease 1
calcification I-Disease 1
and O 0
the O 0
effect O 0
of O 0
vitamin B-Chemical 1
D I-Chemical 1
dose O 0
on O 0
the O 0
elevation O 0
of O 0
serum O 0
calcium B-Chemical 1
, O 0
which O 0
suggests O 0
that O 0
vitamin B-Chemical 1
D I-Chemical 1
may O 0
induce O 0
artery B-Disease 1
calcification I-Disease 1
through O 0
its O 0
effect O 0
on O 0
serum O 0
calcium B-Chemical 1
. O 0

Because O 0
Warfarin B-Chemical 1
treatment O 0
had O 0
no O 0
effect O 0
on O 0
the O 0
elevation O 0
in O 0
serum O 0
calcium B-Chemical 1
produced O 0
by O 0
vitamin B-Chemical 1
D I-Chemical 1
, O 0
the O 0
synergy O 0
between O 0
Warfarin B-Chemical 1
and O 0
vitamin B-Chemical 1
D I-Chemical 1
is O 0
probably O 0
best O 0
explained O 0
by O 0
the O 0
hypothesis O 0
that O 0
Warfarin B-Chemical 1
inhibits O 0
the O 0
activity O 0
of O 0
matrix O 0
Gla O 0
protein O 0
as O 0
a O 0
calcification B-Disease 1
inhibitor O 0
. O 0

High O 0
levels O 0
of O 0
matrix O 0
Gla O 0
protein O 0
are O 0
found O 0
at O 0
sites O 0
of O 0
artery B-Disease 1
calcification I-Disease 1
in O 0
rats O 0
treated O 0
with O 0
vitamin B-Chemical 1
D I-Chemical 1
plus O 0
Warfarin B-Chemical 1
, O 0
and O 0
chemical O 0
analysis O 0
showed O 0
that O 0
the O 0
protein O 0
that O 0
accumulated O 0
was O 0
indeed O 0
not O 0
gamma B-Chemical 1
- I-Chemical 1
carboxylated I-Chemical 1
. O 0

These O 0
observations O 0
indicate O 0
that O 0
although O 0
the O 0
gamma B-Chemical 1
- I-Chemical 1
carboxyglutamate I-Chemical 1
residues O 0
of O 0
matrix O 0
Gla O 0
protein O 0
are O 0
apparently O 0
required O 0
for O 0
its O 0
function O 0
as O 0
a O 0
calcification B-Disease 1
inhibitor O 0
, O 0
they O 0
are O 0
not O 0
required O 0
for O 0
its O 0
accumulation O 0
at O 0
calcification B-Disease 1
sites O 0
. O 0

Test O 0
conditions O 0
influence O 0
the O 0
response O 0
to O 0
a O 0
drug O 0
challenge O 0
in O 0
rodents O 0
. O 0

These O 0
studies O 0
were O 0
conducted O 0
to O 0
examine O 0
the O 0
differential O 0
response O 0
to O 0
a O 0
drug O 0
challenge O 0
under O 0
varied O 0
experimental O 0
test O 0
conditions O 0
routinely O 0
employed O 0
to O 0
study O 0
drug O 0
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Moreover O 0
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By O 0
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However O 0
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The O 0
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Hemolysis B-Disease 1
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Tamoxifen B-Chemical 1
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TAM B-Chemical 1
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This O 0
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Furthermore O 0
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L I-Chemical 1
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Two O 0
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Inhibition O 0
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Effects O 0
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is O 0
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dopamine B-Chemical 1
D2 O 0
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and O 0
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) O 0
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by O 0
5 O 0
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this O 0
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. O 0

This O 0
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conducted O 0
to O 0
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whether O 0
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could O 0
abolish O 0
bromocriptine B-Chemical 1
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in O 0
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. O 0

Isoproterenol B-Chemical 1
pretreatment O 0
for O 0
15 O 0
days O 0
caused O 0
cardiac B-Disease 1
hypertrophy I-Disease 1
without O 0
affecting O 0
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blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
. O 0

In O 0
control O 0
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, O 0
intravenous O 0
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) O 0
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significant O 0
hypotension B-Disease 1
and O 0
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. O 0

Bromocriptine B-Chemical 1
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was O 0
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isoproterenol B-Chemical 1
pretreatment O 0
, O 0
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was O 0
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an O 0
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that O 0
was O 0
partly O 0
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by O 0
i O 0
. O 0
v O 0
. O 0
domperidone B-Chemical 1
( O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
) O 0
. O 0

Neither O 0
cardiac O 0
vagal O 0
nor O 0
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tone O 0
was O 0
altered O 0
by O 0
isoproterenol B-Chemical 1
pretreatment O 0
. O 0

In O 0
isolated O 0
perfused O 0
heart O 0
preparations O 0
from O 0
isoproterenol B-Chemical 1
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, O 0
the O 0
isoproterenol B-Chemical 1
- O 0
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maximal O 0
increase O 0
in O 0
left O 0
ventricular O 0
systolic O 0
pressure O 0
was O 0
significantly O 0
reduced O 0
, O 0
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with O 0
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( O 0
the O 0
EC50 O 0
of O 0
the O 0
isoproterenol B-Chemical 1
- O 0
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increase O 0
in O 0
left O 0
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pressure O 0
was O 0
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approximately O 0
22 O 0
- O 0
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) O 0
. O 0

These O 0
results O 0
show O 0
that O 0
15 O 0
- O 0
day O 0
isoproterenol B-Chemical 1
pretreatment O 0
not O 0
only O 0
abolished O 0
but O 0
reversed O 0
bromocriptine B-Chemical 1
- O 0
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tachycardia B-Disease 1
to O 0
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, O 0
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that O 0
is O 0
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to O 0
further O 0
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beta O 0
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of O 0
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of O 0
the O 0
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. O 0

They O 0
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that O 0
, O 0
in O 0
normal O 0
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, O 0
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of O 0
bromocriptine B-Chemical 1
appears O 0
to O 0
predominate O 0
and O 0
to O 0
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bradycardia B-Disease 1
of O 0
this O 0
agonist O 0
at O 0
peripheral O 0
dopamine B-Chemical 1
D2 O 0
receptors O 0
. O 0

A O 0
developmental O 0
analysis O 0
of O 0
clonidine B-Chemical 1
' O 0
s O 0
effects O 0
on O 0
cardiac O 0
rate O 0
and O 0
ultrasound O 0
production O 0
in O 0
infant O 0
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. O 0

Under O 0
controlled O 0
conditions O 0
, O 0
infant O 0
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emit O 0
ultrasonic O 0
vocalizations O 0
during O 0
extreme O 0
cold O 0
exposure O 0
and O 0
after O 0
administration O 0
of O 0
the O 0
alpha O 0
( O 0
2 O 0
) O 0
adrenoceptor O 0
agonist O 0
, O 0
clonidine B-Chemical 1
. O 0

Previous O 0
investigations O 0
have O 0
determined O 0
that O 0
, O 0
in O 0
response O 0
to O 0
clonidine B-Chemical 1
, O 0
ultrasound O 0
production O 0
increases O 0
through O 0
the O 0
2nd O 0
- O 0
week O 0
postpartum O 0
and O 0
decreases O 0
thereafter O 0
. O 0

Given O 0
that O 0
sympathetic O 0
neural O 0
dominance O 0
exhibits O 0
a O 0
similar O 0
developmental O 0
pattern O 0
, O 0
and O 0
given O 0
that O 0
clonidine B-Chemical 1
induces O 0
sympathetic O 0
withdrawal O 0
and O 0
bradycardia B-Disease 1
, O 0
we O 0
hypothesized O 0
that O 0
clonidine B-Chemical 1
' O 0
s O 0
developmental O 0
effects O 0
on O 0
cardiac O 0
rate O 0
and O 0
ultrasound O 0
production O 0
would O 0
mirror O 0
each O 0
other O 0
. O 0

Therefore O 0
, O 0
in O 0
the O 0
present O 0
experiment O 0
, O 0
the O 0
effects O 0
of O 0
clonidine B-Chemical 1
administration O 0
( O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
) O 0
on O 0
cardiac O 0
rate O 0
and O 0
ultrasound O 0
production O 0
were O 0
examined O 0
in O 0
2 O 0
- O 0
, O 0
8 O 0
- O 0
, O 0
15 O 0
- O 0
, O 0
and O 0
20 O 0
- O 0
day O 0
- O 0
old O 0
rats O 0
. O 0

Age O 0
- O 0
related O 0
changes O 0
in O 0
ultrasound O 0
production O 0
corresponded O 0
with O 0
changes O 0
in O 0
cardiovascular O 0
variables O 0
, O 0
including O 0
baseline O 0
cardiac O 0
rate O 0
and O 0
clonidine B-Chemical 1
- O 0
induced O 0
bradycardia B-Disease 1
. O 0

This O 0
experiment O 0
is O 0
discussed O 0
with O 0
regard O 0
to O 0
the O 0
hypothesis O 0
that O 0
ultrasound O 0
production O 0
is O 0
the O 0
acoustic O 0
by O 0
- O 0
product O 0
of O 0
a O 0
physiological O 0
maneuver O 0
that O 0
compensates O 0
for O 0
clonidine B-Chemical 1
' O 0
s O 0
detrimental O 0
effects O 0
on O 0
cardiovascular O 0
function O 0
. O 0

Recurrent O 0
use O 0
of O 0
newer O 0
oral B-Chemical 1
contraceptives I-Chemical 1
and O 0
the O 0
risk O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
. O 0

The O 0
epidemiological O 0
studies O 0
that O 0
assessed O 0
the O 0
risk O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
( O 0
VTE B-Disease 1
) O 0
associated O 0
with O 0
newer O 0
oral B-Chemical 1
contraceptives I-Chemical 1
( O 0
OC B-Chemical 1
) O 0
did O 0
not O 0
distinguish O 0
between O 0
patterns O 0
of O 0
OC B-Chemical 1
use O 0
, O 0
namely O 0
first O 0
- O 0
time O 0
users O 0
, O 0
repeaters O 0
and O 0
switchers O 0
. O 0

Data O 0
from O 0
a O 0
Transnational O 0
case O 0
- O 0
control O 0
study O 0
were O 0
used O 0
to O 0
assess O 0
the O 0
risk O 0
of O 0
VTE B-Disease 1
for O 0
the O 0
latter O 0
patterns O 0
of O 0
use O 0
, O 0
while O 0
accounting O 0
for O 0
duration O 0
of O 0
use O 0
. O 0

Over O 0
the O 0
period O 0
1993 O 0
- O 0
1996 O 0
, O 0
551 O 0
cases O 0
of O 0
VTE B-Disease 1
were O 0
identified O 0
in O 0
Germany O 0
and O 0
the O 0
UK O 0
along O 0
with O 0
2066 O 0
controls O 0
. O 0

Totals O 0
of O 0
128 O 0
cases O 0
and O 0
650 O 0
controls O 0
were O 0
analysed O 0
for O 0
repeat O 0
use O 0
and O 0
135 O 0
cases O 0
and O 0
622 O 0
controls O 0
for O 0
switching O 0
patterns O 0
. O 0

The O 0
adjusted O 0
rate O 0
ratio O 0
of O 0
VTE B-Disease 1
for O 0
repeat O 0
users O 0
of O 0
third O 0
generation O 0
OC B-Chemical 1
was O 0
0 O 0
. O 0
6 O 0
( O 0
95 O 0
% O 0
CI O 0
: O 0
0 O 0
. O 0
3 O 0
- O 0
1 O 0
. O 0
2 O 0
) O 0
relative O 0
to O 0
repeat O 0
users O 0
of O 0
second O 0
generation O 0
pills O 0
, O 0
whereas O 0
it O 0
was O 0
1 O 0
. O 0
3 O 0
( O 0
95 O 0
% O 0
CI O 0
: O 0
0 O 0
. O 0
7 O 0
- O 0
2 O 0
. O 0
4 O 0
) O 0
for O 0
switchers O 0
from O 0
second O 0
to O 0
third O 0
generation O 0
pills O 0
relative O 0
to O 0
switchers O 0
from O 0
third O 0
to O 0
second O 0
generation O 0
pills O 0
. O 0

We O 0
conclude O 0
that O 0
second O 0
and O 0
third O 0
generation O 0
agents O 0
are O 0
associated O 0
with O 0
equivalent O 0
risks O 0
of O 0
VTE B-Disease 1
when O 0
the O 0
same O 0
agent O 0
is O 0
used O 0
repeatedly O 0
after O 0
interruption O 0
periods O 0
or O 0
when O 0
users O 0
are O 0
switched O 0
between O 0
the O 0
two O 0
generations O 0
of O 0
pills O 0
. O 0

These O 0
analyses O 0
suggest O 0
that O 0
the O 0
higher O 0
risk O 0
observed O 0
for O 0
the O 0
newer O 0
OC B-Chemical 1
in O 0
other O 0
studies O 0
may O 0
be O 0
the O 0
result O 0
of O 0
inadequate O 0
comparisons O 0
of O 0
pill O 0
users O 0
with O 0
different O 0
patterns O 0
of O 0
pill O 0
use O 0
. O 0

Differential O 0
effects O 0
of O 0
systemically O 0
administered O 0
ketamine B-Chemical 1
and O 0
lidocaine B-Chemical 1
on O 0
dynamic O 0
and O 0
static O 0
hyperalgesia B-Disease 1
induced O 0
by O 0
intradermal O 0
capsaicin B-Chemical 1
in O 0
humans O 0
. O 0

We O 0
have O 0
examined O 0
the O 0
effect O 0
of O 0
systemic O 0
administration O 0
of O 0
ketamine B-Chemical 1
and O 0
lidocaine B-Chemical 1
on O 0
brush O 0
- O 0
evoked O 0
( O 0
dynamic O 0
) O 0
pain B-Disease 1
and O 0
punctate O 0
- O 0
evoked O 0
( O 0
static O 0
) O 0
hyperalgesia B-Disease 1
induced O 0
by O 0
capsaicin B-Chemical 1
. O 0

In O 0
a O 0
randomized O 0
, O 0
double O 0
- O 0
blind O 0
, O 0
placebo O 0
- O 0
controlled O 0
, O 0
crossover O 0
study O 0
, O 0
we O 0
studied O 0
12 O 0
volunteers O 0
in O 0
three O 0
experiments O 0
. O 0

Capsaicin B-Chemical 1
100 O 0
micrograms O 0
was O 0
injected O 0
intradermally O 0
on O 0
the O 0
volar O 0
forearm O 0
followed O 0
by O 0
an O 0
i O 0
. O 0
v O 0
. O 0
infusion O 0
of O 0
ketamine B-Chemical 1
( O 0
bolus O 0
0 O 0
. O 0
1 O 0
mg O 0
kg O 0
- O 0
1 O 0
over O 0
10 O 0
min O 0
followed O 0
by O 0
infusion O 0
of O 0
7 O 0
micrograms O 0
kg O 0
- O 0
1 O 0
min O 0
- O 0
1 O 0
) O 0
, O 0
lidocaine B-Chemical 1
5 O 0
mg O 0
kg O 0
- O 0
1 O 0
or O 0
saline O 0
for O 0
50 O 0
min O 0
. O 0

Infusion O 0
started O 0
15 O 0
min O 0
after O 0
injection O 0
of O 0
capsaicin B-Chemical 1
. O 0

The O 0
following O 0
were O 0
measured O 0
: O 0
spontaneous O 0
pain B-Disease 1
, O 0
pain B-Disease 1
evoked O 0
by O 0
punctate O 0
and O 0
brush O 0
stimuli O 0
( O 0
VAS O 0
) O 0
, O 0
and O 0
areas O 0
of O 0
brush O 0
- O 0
evoked O 0
and O 0
punctate O 0
- O 0
evoked O 0
hyperalgesia B-Disease 1
. O 0

Ketamine B-Chemical 1
reduced O 0
both O 0
the O 0
area O 0
of O 0
brush O 0
- O 0
evoked O 0
and O 0
punctate O 0
- O 0
evoked O 0
hyperalgesia B-Disease 1
significantly O 0
and O 0
it O 0
tended O 0
to O 0
reduce O 0
brush O 0
- O 0
evoked O 0
pain B-Disease 1
. O 0

Lidocaine B-Chemical 1
reduced O 0
the O 0
area O 0
of O 0
punctate O 0
- O 0
evoked O 0
hyperalgesia B-Disease 1
significantly O 0
. O 0

It O 0
tended O 0
to O 0
reduce O 0
VAS O 0
scores O 0
of O 0
spontaneous O 0
pain B-Disease 1
but O 0
had O 0
no O 0
effect O 0
on O 0
evoked O 0
pain B-Disease 1
. O 0

The O 0
differential O 0
effects O 0
of O 0
ketamine B-Chemical 1
and O 0
lidocaine B-Chemical 1
on O 0
static O 0
and O 0
dynamic O 0
hyperalgesia B-Disease 1
suggest O 0
that O 0
the O 0
two O 0
types O 0
of O 0
hyperalgesia B-Disease 1
are O 0
mediated O 0
by O 0
separate O 0
mechanisms O 0
and O 0
have O 0
a O 0
distinct O 0
pharmacology O 0
. O 0

Development O 0
of O 0
apomorphine B-Chemical 1
- O 0
induced O 0
aggressive B-Disease 1
behavior I-Disease 1
: O 0
comparison O 0
of O 0
adult O 0
male O 0
and O 0
female O 0
Wistar O 0
rats O 0
. O 0

The O 0
development O 0
of O 0
apomorphine B-Chemical 1
- O 0
induced O 0
( O 0
1 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
once O 0
daily O 0
) O 0
aggressive B-Disease 1
behavior I-Disease 1
of O 0
adult O 0
male O 0
and O 0
female O 0
Wistar O 0
rats O 0
obtained O 0
from O 0
the O 0
same O 0
breeder O 0
was O 0
studied O 0
in O 0
two O 0
consecutive O 0
sets O 0
. O 0

In O 0
male O 0
animals O 0
, O 0
repeated O 0
apomorphine B-Chemical 1
treatment O 0
induced O 0
a O 0
gradual O 0
development O 0
of O 0
aggressive B-Disease 1
behavior I-Disease 1
as O 0
evidenced O 0
by O 0
the O 0
increased O 0
intensity O 0
of O 0
aggressiveness B-Disease 1
and O 0
shortened O 0
latency O 0
before O 0
the O 0
first O 0
attack O 0
toward O 0
the O 0
opponent O 0
. O 0

In O 0
female O 0
rats O 0
, O 0
only O 0
a O 0
weak O 0
tendency O 0
toward O 0
aggressiveness B-Disease 1
was O 0
found O 0
. O 0

In O 0
conclusion O 0
, O 0
the O 0
present O 0
study O 0
demonstrates O 0
gender O 0
differences O 0
in O 0
the O 0
development O 0
of O 0
the O 0
apomorphine B-Chemical 1
- O 0
induced O 0
aggressive B-Disease 1
behavior I-Disease 1
and O 0
indicates O 0
that O 0
the O 0
female O 0
rats O 0
do O 0
not O 0
fill O 0
the O 0
validation O 0
criteria O 0
for O 0
use O 0
in O 0
this O 0
method O 0
. O 0

Intracranial B-Disease 1
aneurysms I-Disease 1
and O 0
cocaine B-Disease 1
abuse I-Disease 1
: O 0
analysis O 0
of O 0
prognostic O 0
indicators O 0
. O 0

OBJECTIVE O 0
: O 0
The O 0
outcome O 0
of O 0
subarachnoid B-Disease 1
hemorrhage I-Disease 1
associated O 0
with O 0
cocaine B-Disease 1
abuse I-Disease 1
is O 0
reportedly O 0
poor O 0
. O 0

However O 0
, O 0
no O 0
study O 0
in O 0
the O 0
literature O 0
has O 0
reported O 0
the O 0
use O 0
of O 0
a O 0
statistical O 0
model O 0
to O 0
analyze O 0
the O 0
variables O 0
that O 0
influence O 0
outcome O 0
. O 0

METHODS O 0
: O 0
A O 0
review O 0
of O 0
admissions O 0
during O 0
a O 0
6 O 0
- O 0
year O 0
period O 0
revealed O 0
14 O 0
patients O 0
with O 0
cocaine B-Chemical 1
- O 0
related O 0
aneurysms B-Disease 1
. O 0

This O 0
group O 0
was O 0
compared O 0
with O 0
a O 0
control O 0
group O 0
of O 0
135 O 0
patients O 0
with O 0
ruptured B-Disease 1
aneurysms I-Disease 1
and O 0
no O 0
history O 0
of O 0
cocaine B-Disease 1
abuse I-Disease 1
. O 0

Age O 0
at O 0
presentation O 0
, O 0
time O 0
of O 0
ictus O 0
after O 0
intoxication O 0
, O 0
Hunt O 0
and O 0
Hess O 0
grade O 0
of O 0
subarachnoid B-Disease 1
hemorrhage I-Disease 1
, O 0
size O 0
of O 0
the O 0
aneurysm B-Disease 1
, O 0
location O 0
of O 0
the O 0
aneurysm B-Disease 1
, O 0
and O 0
the O 0
Glasgow O 0
Outcome O 0
Scale O 0
score O 0
were O 0
assessed O 0
and O 0
compared O 0
. O 0

RESULTS O 0
: O 0
The O 0
patients O 0
in O 0
the O 0
study O 0
group O 0
were O 0
significantly O 0
younger O 0
than O 0
the O 0
patients O 0
in O 0
the O 0
control O 0
group O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
002 O 0
) O 0
. O 0

In O 0
patients O 0
in O 0
the O 0
study O 0
group O 0
, O 0
all O 0
aneurysms B-Disease 1
were O 0
located O 0
in O 0
the O 0
anterior O 0
circulation O 0
. O 0

The O 0
majority O 0
of O 0
these O 0
aneurysms B-Disease 1
were O 0
smaller O 0
than O 0
those O 0
of O 0
the O 0
control O 0
group O 0
( O 0
8 O 0
+ O 0
/ O 0
- O 0
6 O 0
. O 0
08 O 0
mm O 0
versus O 0
11 O 0
+ O 0
/ O 0
- O 0
5 O 0
. O 0
4 O 0
mm O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

The O 0
differences O 0
in O 0
mortality O 0
and O 0
morbidity O 0
between O 0
the O 0
two O 0
groups O 0
were O 0
not O 0
significant O 0
. O 0

Hunt O 0
and O 0
Hess O 0
grade O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
005 O 0
) O 0
and O 0
age O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
007 O 0
) O 0
were O 0
significant O 0
predictors O 0
of O 0
outcome O 0
for O 0
the O 0
patients O 0
with O 0
cocaine B-Chemical 1
- O 0
related O 0
aneurysms B-Disease 1
. O 0

CONCLUSION O 0
: O 0
Cocaine B-Chemical 1
use O 0
predisposed O 0
aneurysmal B-Disease 1
rupture I-Disease 1
at O 0
a O 0
significantly O 0
earlier O 0
age O 0
and O 0
in O 0
much O 0
smaller O 0
aneurysms B-Disease 1
. O 0

Contrary O 0
to O 0
the O 0
published O 0
literature O 0
, O 0
this O 0
group O 0
did O 0
reasonably O 0
well O 0
with O 0
aggressive O 0
management O 0
. O 0

Effect O 0
of O 0
intravenous O 0
nimodipine B-Chemical 1
on O 0
blood O 0
pressure O 0
and O 0
outcome O 0
after O 0
acute B-Disease 1
stroke I-Disease 1
. O 0

BACKGROUND O 0
AND O 0
PURPOSE O 0
: O 0
The O 0
Intravenous O 0
Nimodipine B-Chemical 1
West O 0
European O 0
Stroke B-Disease 1
Trial O 0
( O 0
INWEST O 0
) O 0
found O 0
a O 0
correlation O 0
between O 0
nimodipine B-Chemical 1
- O 0
induced O 0
reduction B-Disease 1
in I-Disease 1
blood I-Disease 1
pressure I-Disease 1
( O 0
BP O 0
) O 0
and O 0
an O 0
unfavorable O 0
outcome O 0
in O 0
acute B-Disease 1
stroke I-Disease 1
. O 0

We O 0
sought O 0
to O 0
confirm O 0
this O 0
correlation O 0
with O 0
and O 0
without O 0
adjustment O 0
for O 0
prognostic O 0
variables O 0
and O 0
to O 0
investigate O 0
outcome O 0
in O 0
subgroups O 0
with O 0
increasing O 0
levels O 0
of O 0
BP B-Disease 1
reduction I-Disease 1
. O 0

METHODS O 0
: O 0
Patients O 0
with O 0
a O 0
clinical O 0
diagnosis O 0
of O 0
ischemic B-Disease 1
stroke I-Disease 1
( O 0
within O 0
24 O 0
hours O 0
) O 0
were O 0
consecutively O 0
allocated O 0
to O 0
receive O 0
placebo O 0
( O 0
n O 0
= O 0
100 O 0
) O 0
, O 0
1 O 0
mg O 0
/ O 0
h O 0
( O 0
low O 0
- O 0
dose O 0
) O 0
nimodipine B-Chemical 1
( O 0
n O 0
= O 0
101 O 0
) O 0
, O 0
or O 0
2 O 0
mg O 0
/ O 0
h O 0
( O 0
high O 0
- O 0
dose O 0
) O 0
nimodipine B-Chemical 1
( O 0
n O 0
= O 0
94 O 0
) O 0
. O 0

The O 0
correlation O 0
between O 0
average O 0
BP O 0
change O 0
during O 0
the O 0
first O 0
2 O 0
days O 0
and O 0
the O 0
outcome O 0
at O 0
day O 0
21 O 0
was O 0
analyzed O 0
. O 0

RESULTS O 0
: O 0
Two O 0
hundred O 0
sixty O 0
- O 0
five O 0
patients O 0
were O 0
included O 0
in O 0
this O 0
analysis O 0
( O 0
n O 0
= O 0
92 O 0
, O 0
93 O 0
, O 0
and O 0
80 O 0
for O 0
placebo O 0
, O 0
low O 0
dose O 0
, O 0
and O 0
high O 0
dose O 0
, O 0
respectively O 0
) O 0
. O 0

Nimodipine B-Chemical 1
treatment O 0
resulted O 0
in O 0
a O 0
statistically O 0
significant O 0
reduction B-Disease 1
in I-Disease 1
systolic I-Disease 1
BP I-Disease 1
( O 0
SBP O 0
) O 0
and O 0
diastolic O 0
BP O 0
( O 0
DBP O 0
) O 0
from O 0
baseline O 0
compared O 0
with O 0
placebo O 0
during O 0
the O 0
first O 0
few O 0
days O 0
. O 0

In O 0
multivariate O 0
analysis O 0
, O 0
a O 0
significant O 0
correlation O 0
between O 0
DBP B-Disease 1
reduction I-Disease 1
and O 0
worsening O 0
of O 0
the O 0
neurological O 0
score O 0
was O 0
found O 0
for O 0
the O 0
high O 0
- O 0
dose O 0
group O 0
( O 0
beta O 0
= O 0
0 O 0
. O 0
49 O 0
, O 0
P O 0
= O 0
0 O 0
. O 0
048 O 0
) O 0
. O 0

Patients O 0
with O 0
a O 0
DBP B-Disease 1
reduction I-Disease 1
of O 0
> O 0
or O 0
= O 0
20 O 0
% O 0
in O 0
the O 0
high O 0
- O 0
dose O 0
group O 0
had O 0
a O 0
significantly O 0
increased O 0
adjusted O 0
OR O 0
for O 0
the O 0
compound O 0
outcome O 0
variable O 0
death B-Disease 1
or O 0
dependency O 0
( O 0
Barthel O 0
Index O 0
< O 0
60 O 0
) O 0
( O 0
n O 0
/ O 0
N O 0
= O 0
25 O 0
/ O 0
26 O 0
, O 0
OR O 0
10 O 0
. O 0
16 O 0
, O 0
95 O 0
% O 0
CI O 0
1 O 0
. O 0
02 O 0
to O 0
101 O 0
. O 0
74 O 0
) O 0
and O 0
death B-Disease 1
alone O 0
( O 0
n O 0
/ O 0
N O 0
= O 0
9 O 0
/ O 0
26 O 0
, O 0
OR O 0
4 O 0
. O 0
336 O 0
, O 0
95 O 0
% O 0
CI O 0
1 O 0
. O 0
131 O 0
16 O 0
. O 0
619 O 0
) O 0
compared O 0
with O 0
all O 0
placebo O 0
patients O 0
( O 0
n O 0
/ O 0
N O 0
= O 0
62 O 0
/ O 0
92 O 0
and O 0
14 O 0
/ O 0
92 O 0
, O 0
respectively O 0
) O 0
. O 0

There O 0
was O 0
no O 0
correlation O 0
between O 0
SBP O 0
change O 0
and O 0
outcome O 0
. O 0

CONCLUSIONS O 0
: O 0
DBP O 0
, O 0
but O 0
not O 0
SBP O 0
, O 0
reduction O 0
was O 0
associated O 0
with O 0
neurological O 0
worsening O 0
after O 0
the O 0
intravenous O 0
administration O 0
of O 0
high O 0
- O 0
dose O 0
nimodipine B-Chemical 1
after O 0
acute B-Disease 1
stroke I-Disease 1
. O 0

For O 0
low O 0
- O 0
dose O 0
nimodipine B-Chemical 1
, O 0
the O 0
results O 0
were O 0
not O 0
conclusive O 0
. O 0

These O 0
results O 0
do O 0
not O 0
confirm O 0
or O 0
exclude O 0
a O 0
neuroprotective O 0
property O 0
of O 0
nimodipine B-Chemical 1
. O 0

Neonatal O 0
pyridoxine B-Chemical 1
responsive O 0
convulsions B-Disease 1
due O 0
to O 0
isoniazid B-Chemical 1
therapy O 0
. O 0

A O 0
17 O 0
- O 0
day O 0
- O 0
old O 0
infant O 0
on O 0
isoniazid B-Chemical 1
therapy O 0
13 O 0
mg O 0
/ O 0
kg O 0
daily O 0
from O 0
birth O 0
because O 0
of O 0
maternal O 0
tuberculosis B-Disease 1
was O 0
admitted O 0
after O 0
4 O 0
days O 0
of O 0
clonic B-Disease 1
fits I-Disease 1
. O 0

No O 0
underlying O 0
infective O 0
or O 0
biochemical O 0
cause O 0
could O 0
be O 0
found O 0
. O 0

The O 0
fits B-Disease 1
ceased O 0
within O 0
4 O 0
hours O 0
of O 0
administering O 0
intramuscular O 0
pyridoxine B-Chemical 1
, O 0
suggesting O 0
an O 0
aetiology O 0
of O 0
pyridoxine B-Chemical 1
deficiency O 0
secondary O 0
to O 0
isoniazid B-Chemical 1
medication O 0
. O 0

Ketamine B-Chemical 1
sedation O 0
for O 0
the O 0
reduction O 0
of O 0
children O 0
' O 0
s O 0
fractures B-Disease 1
in O 0
the O 0
emergency O 0
department O 0
. O 0

BACKGROUND O 0
: O 0
There O 0
recently O 0
has O 0
been O 0
a O 0
resurgence O 0
in O 0
the O 0
utilization O 0
of O 0
ketamine B-Chemical 1
, O 0
a O 0
unique O 0
anesthetic O 0
, O 0
for O 0
emergency O 0
- O 0
department O 0
procedures O 0
requiring O 0
sedation O 0
. O 0

The O 0
purpose O 0
of O 0
the O 0
present O 0
study O 0
was O 0
to O 0
examine O 0
the O 0
safety O 0
and O 0
efficacy O 0
of O 0
ketamine B-Chemical 1
for O 0
sedation O 0
in O 0
the O 0
treatment O 0
of O 0
children O 0
' O 0
s O 0
fractures B-Disease 1
in O 0
the O 0
emergency O 0
department O 0
. O 0

METHODS O 0
: O 0
One O 0
hundred O 0
and O 0
fourteen O 0
children O 0
( O 0
average O 0
age O 0
, O 0
5 O 0
. O 0
3 O 0
years O 0
; O 0
range O 0
, O 0
twelve O 0
months O 0
to O 0
ten O 0
years O 0
and O 0
ten O 0
months O 0
) O 0
who O 0
underwent O 0
closed O 0
reduction O 0
of O 0
an O 0
isolated O 0
fracture B-Disease 1
or O 0
dislocation B-Disease 1
in O 0
the O 0
emergency O 0
department O 0
at O 0
a O 0
level O 0
- O 0
I O 0
trauma B-Disease 1
center O 0
were O 0
prospectively O 0
evaluated O 0
. O 0

Ketamine B-Chemical 1
hydrochloride I-Chemical 1
was O 0
administered O 0
intravenously O 0
( O 0
at O 0
a O 0
dose O 0
of O 0
two O 0
milligrams O 0
per O 0
kilogram O 0
of O 0
body O 0
weight O 0
) O 0
in O 0
ninety O 0
- O 0
nine O 0
of O 0
the O 0
patients O 0
and O 0
intramuscularly O 0
( O 0
at O 0
a O 0
dose O 0
of O 0
four O 0
milligrams O 0
per O 0
kilogram O 0
of O 0
body O 0
weight O 0
) O 0
in O 0
the O 0
other O 0
fifteen O 0
. O 0

A O 0
board O 0
- O 0
certified O 0
emergency O 0
physician O 0
skilled O 0
in O 0
airway O 0
management O 0
supervised O 0
administration O 0
of O 0
the O 0
anesthetic O 0
, O 0
and O 0
the O 0
patients O 0
were O 0
monitored O 0
by O 0
a O 0
registered O 0
nurse O 0
. O 0

Any O 0
pain B-Disease 1
during O 0
the O 0
reduction O 0
was O 0
rated O 0
by O 0
the O 0
orthopaedic O 0
surgeon O 0
treating O 0
the O 0
patient O 0
according O 0
to O 0
the O 0
Children O 0
' O 0
s O 0
Hospital O 0
of O 0
Eastern O 0
Ontario O 0
Pain B-Disease 1
Scale O 0
( O 0
CHEOPS O 0
) O 0
. O 0

RESULTS O 0
: O 0
The O 0
average O 0
time O 0
from O 0
intravenous O 0
administration O 0
of O 0
ketamine B-Chemical 1
to O 0
manipulation O 0
of O 0
the O 0
fracture B-Disease 1
or O 0
dislocation B-Disease 1
was O 0
one O 0
minute O 0
and O 0
thirty O 0
- O 0
six O 0
seconds O 0
( O 0
range O 0
, O 0
twenty O 0
seconds O 0
to O 0
five O 0
minutes O 0
) O 0
, O 0
and O 0
the O 0
average O 0
time O 0
from O 0
intramuscular O 0
administration O 0
to O 0
manipulation O 0
was O 0
four O 0
minutes O 0
and O 0
forty O 0
- O 0
two O 0
seconds O 0
( O 0
range O 0
, O 0
sixty O 0
seconds O 0
to O 0
fifteen O 0
minutes O 0
) O 0
. O 0

The O 0
average O 0
score O 0
according O 0
to O 0
the O 0
Children O 0
' O 0
s O 0
Hospital O 0
of O 0
Eastern O 0
Ontario O 0
Pain B-Disease 1
Scale O 0
was O 0
6 O 0
. O 0
4 O 0
points O 0
( O 0
range O 0
, O 0
5 O 0
to O 0
10 O 0
points O 0
) O 0
, O 0
reflecting O 0
minimal O 0
or O 0
no O 0
pain B-Disease 1
during O 0
fracture B-Disease 1
reduction O 0
. O 0

Adequate O 0
fracture B-Disease 1
reduction O 0
was O 0
obtained O 0
in O 0
111 O 0
of O 0
the O 0
children O 0
. O 0

Ninety O 0
- O 0
nine O 0
percent O 0
( O 0
sixty O 0
- O 0
eight O 0
) O 0
of O 0
the O 0
sixty O 0
- O 0
nine O 0
parents O 0
present O 0
during O 0
the O 0
reduction O 0
were O 0
pleased O 0
with O 0
the O 0
sedation O 0
and O 0
would O 0
allow O 0
it O 0
to O 0
be O 0
used O 0
again O 0
in O 0
a O 0
similar O 0
situation O 0
. O 0

Patency O 0
of O 0
the O 0
airway O 0
and O 0
independent O 0
respiration O 0
were O 0
maintained O 0
in O 0
all O 0
of O 0
the O 0
patients O 0
. O 0

Blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
remained O 0
stable O 0
. O 0

Minor O 0
side O 0
effects O 0
included O 0
nausea B-Disease 1
( O 0
thirteen O 0
patients O 0
) O 0
, O 0
emesis B-Disease 1
( O 0
eight O 0
of O 0
the O 0
thirteen O 0
patients O 0
with O 0
nausea B-Disease 1
) O 0
, O 0
clumsiness B-Disease 1
( O 0
evident O 0
as O 0
ataxic B-Disease 1
movements I-Disease 1
in O 0
ten O 0
patients O 0
) O 0
, O 0
and O 0
dysphoric B-Disease 1
reaction I-Disease 1
( O 0
one O 0
patient O 0
) O 0
. O 0

No O 0
long O 0
- O 0
term O 0
sequelae O 0
were O 0
noted O 0
, O 0
and O 0
no O 0
patients O 0
had O 0
hallucinations B-Disease 1
or O 0
nightmares O 0
. O 0

CONCLUSIONS O 0
: O 0
Ketamine B-Chemical 1
reliably O 0
, O 0
safely O 0
, O 0
and O 0
quickly O 0
provided O 0
adequate O 0
sedation O 0
to O 0
effectively O 0
facilitate O 0
the O 0
reduction O 0
of O 0
children O 0
' O 0
s O 0
fractures B-Disease 1
in O 0
the O 0
emergency O 0
department O 0
at O 0
our O 0
institution O 0
. O 0

Ketamine B-Chemical 1
should O 0
only O 0
be O 0
used O 0
in O 0
an O 0
environment O 0
such O 0
as O 0
the O 0
emergency O 0
department O 0
, O 0
where O 0
proper O 0
one O 0
- O 0
on O 0
- O 0
one O 0
monitoring O 0
is O 0
used O 0
and O 0
board O 0
- O 0
certified O 0
physicians O 0
skilled O 0
in O 0
airway O 0
management O 0
are O 0
directly O 0
involved O 0
in O 0
the O 0
care O 0
of O 0
the O 0
patient O 0
. O 0

Cyclosporine B-Chemical 1
and O 0
tacrolimus B-Chemical 1
- O 0
associated O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
. O 0

The O 0
development O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
( O 0
TMA B-Disease 1
) O 0
associated O 0
with O 0
the O 0
use O 0
of O 0
cyclosporine B-Chemical 1
has O 0
been O 0
well O 0
documented O 0
. O 0

Treatments O 0
have O 0
included O 0
discontinuation O 0
or O 0
reduction O 0
of O 0
cyclosporine B-Chemical 1
dose O 0
with O 0
or O 0
without O 0
concurrent O 0
plasma O 0
exchange O 0
, O 0
plasma O 0
infusion O 0
, O 0
anticoagulation O 0
, O 0
and O 0
intravenous O 0
immunoglobulin O 0
G O 0
infusion O 0
. O 0

However O 0
, O 0
for O 0
recipients O 0
of O 0
organ O 0
transplantation O 0
, O 0
removing O 0
the O 0
inciting O 0
agent O 0
is O 0
not O 0
without O 0
the O 0
attendant O 0
risk O 0
of O 0
precipitating O 0
acute O 0
rejection O 0
and O 0
graft O 0
loss O 0
. O 0

The O 0
last O 0
decade O 0
has O 0
seen O 0
the O 0
emergence O 0
of O 0
tacrolimus B-Chemical 1
as O 0
a O 0
potent O 0
immunosuppressive O 0
agent O 0
with O 0
mechanisms O 0
of O 0
action O 0
virtually O 0
identical O 0
to O 0
those O 0
of O 0
cyclosporine B-Chemical 1
. O 0

As O 0
a O 0
result O 0
, O 0
switching O 0
to O 0
tacrolimus B-Chemical 1
has O 0
been O 0
reported O 0
to O 0
be O 0
a O 0
viable O 0
therapeutic O 0
option O 0
in O 0
the O 0
setting O 0
of O 0
cyclosporine B-Chemical 1
- O 0
induced O 0
TMA B-Disease 1
. O 0

With O 0
the O 0
more O 0
widespread O 0
application O 0
of O 0
tacrolimus B-Chemical 1
in O 0
organ O 0
transplantation O 0
, O 0
tacrolimus B-Chemical 1
- O 0
associated O 0
TMA B-Disease 1
has O 0
also O 0
been O 0
recognized O 0
. O 0

However O 0
, O 0
literature O 0
regarding O 0
the O 0
incidence O 0
of O 0
the O 0
recurrence O 0
of O 0
TMA B-Disease 1
in O 0
patients O 0
exposed O 0
sequentially O 0
to O 0
cyclosporine B-Chemical 1
and O 0
tacrolimus B-Chemical 1
is O 0
limited O 0
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
a O 0
living O 0
donor O 0
renal O 0
transplant O 0
recipient O 0
who O 0
developed O 0
cyclosporine B-Chemical 1
- O 0
induced O 0
TMA B-Disease 1
that O 0
responded O 0
to O 0
the O 0
withdrawal O 0
of O 0
cyclosporine B-Chemical 1
in O 0
conjunction O 0
with O 0
plasmapheresis O 0
and O 0
fresh O 0
frozen O 0
plasma O 0
replacement O 0
therapy O 0
. O 0

Introduction O 0
of O 0
tacrolimus B-Chemical 1
as O 0
an O 0
alternative O 0
immunosuppressive O 0
agent O 0
resulted O 0
in O 0
the O 0
recurrence O 0
of O 0
TMA B-Disease 1
and O 0
the O 0
subsequent O 0
loss O 0
of O 0
the O 0
renal O 0
allograft O 0
. O 0

Patients O 0
who O 0
are O 0
switched O 0
from O 0
cyclosporine B-Chemical 1
to O 0
tacrolimus B-Chemical 1
or O 0
vice O 0
versa O 0
should O 0
be O 0
closely O 0
monitored O 0
for O 0
the O 0
signs O 0
and O 0
symptoms O 0
of O 0
recurrent O 0
TMA B-Disease 1
. O 0

Analgesic O 0
effect O 0
of O 0
intravenous O 0
ketamine B-Chemical 1
in O 0
cancer B-Disease 1
patients O 0
on O 0
morphine B-Chemical 1
therapy O 0
: O 0
a O 0
randomized O 0
, O 0
controlled O 0
, O 0
double O 0
- O 0
blind O 0
, O 0
crossover O 0
, O 0
double O 0
- O 0
dose O 0
study O 0
. O 0

Pain B-Disease 1
not O 0
responsive O 0
to O 0
morphine B-Chemical 1
is O 0
often O 0
problematic O 0
. O 0

Animal O 0
and O 0
clinical O 0
studies O 0
have O 0
suggested O 0
that O 0
N B-Chemical 1
- I-Chemical 1
methyl I-Chemical 1
- I-Chemical 1
D I-Chemical 1
- I-Chemical 1
aspartate I-Chemical 1
( O 0
NMDA B-Chemical 1
) O 0
antagonists O 0
, O 0
such O 0
as O 0
ketamine B-Chemical 1
, O 0
may O 0
be O 0
effective O 0
in O 0
improving O 0
opioid O 0
analgesia O 0
in O 0
difficult O 0
pain B-Disease 1
syndromes O 0
, O 0
such O 0
as O 0
neuropathic B-Disease 1
pain I-Disease 1
. O 0

A O 0
slow O 0
bolus O 0
of O 0
subhypnotic O 0
doses O 0
of O 0
ketamine B-Chemical 1
( O 0
0 O 0
. O 0
25 O 0
mg O 0
/ O 0
kg O 0
or O 0
0 O 0
. O 0
50 O 0
mg O 0
/ O 0
kg O 0
) O 0
was O 0
given O 0
to O 0
10 O 0
cancer B-Disease 1
patients O 0
whose O 0
pain B-Disease 1
was O 0
unrelieved O 0
by O 0
morphine B-Chemical 1
in O 0
a O 0
randomized O 0
, O 0
double O 0
- O 0
blind O 0
, O 0
crossover O 0
, O 0
double O 0
- O 0
dose O 0
study O 0
. O 0

Pain B-Disease 1
intensity O 0
on O 0
a O 0
0 O 0
to O 0
10 O 0
numerical O 0
scale O 0
; O 0
nausea B-Disease 1
and O 0
vomiting B-Disease 1
, O 0
drowsiness O 0
, O 0
confusion B-Disease 1
, O 0
and O 0
dry B-Disease 1
mouth I-Disease 1
, O 0
using O 0
a O 0
scale O 0
from O 0
0 O 0
to O 0
3 O 0
( O 0
not O 0
at O 0
all O 0
, O 0
slight O 0
, O 0
a O 0
lot O 0
, O 0
awful O 0
) O 0
; O 0
Mini O 0
- O 0
Mental O 0
State O 0
Examination O 0
( O 0
MMSE O 0
) O 0
( O 0
0 O 0
- O 0
30 O 0
) O 0
; O 0
and O 0
arterial O 0
pressure O 0
were O 0
recorded O 0
before O 0
administration O 0
of O 0
drugs O 0
( O 0
T0 O 0
) O 0
and O 0
after O 0
30 O 0
minutes O 0
( O 0
T30 O 0
) O 0
, O 0
60 O 0
minutes O 0
( O 0
T60 O 0
) O 0
, O 0
120 O 0
minutes O 0
( O 0
T120 O 0
) O 0
, O 0
and O 0
180 O 0
minutes O 0
( O 0
T180 O 0
) O 0
. O 0

Ketamine B-Chemical 1
, O 0
but O 0
not O 0
saline O 0
solution O 0
, O 0
significantly O 0
reduced O 0
the O 0
pain B-Disease 1
intensity O 0
in O 0
almost O 0
all O 0
the O 0
patients O 0
at O 0
both O 0
doses O 0
. O 0

This O 0
effect O 0
was O 0
more O 0
relevant O 0
in O 0
patients O 0
treated O 0
with O 0
higher O 0
doses O 0
. O 0

Hallucinations B-Disease 1
occurred O 0
in O 0
4 O 0
patients O 0
, O 0
and O 0
an O 0
unpleasant O 0
sensation O 0
( O 0
" O 0
empty O 0
head O 0
" O 0
) O 0
was O 0
also O 0
reported O 0
by O 0
2 O 0
patients O 0
. O 0

These O 0
episodes O 0
reversed O 0
after O 0
the O 0
administration O 0
of O 0
diazepam B-Chemical 1
1 O 0
mg O 0
intravenously O 0
. O 0

Significant O 0
increases O 0
in O 0
drowsiness O 0
were O 0
reported O 0
in O 0
patients O 0
treated O 0
with O 0
ketamine B-Chemical 1
in O 0
both O 0
groups O 0
and O 0
were O 0
more O 0
marked O 0
with O 0
ketamine B-Chemical 1
0 O 0
. O 0
50 O 0
mg O 0
/ O 0
kg O 0
. O 0

A O 0
significant O 0
difference O 0
in O 0
MMSE O 0
was O 0
observed O 0
at O 0
T30 O 0
in O 0
patients O 0
who O 0
received O 0
0 O 0
. O 0
50 O 0
mg O 0
/ O 0
kg O 0
of O 0
ketamine B-Chemical 1
. O 0

Ketamine B-Chemical 1
can O 0
improve O 0
morphine B-Chemical 1
analgesia O 0
in O 0
difficult O 0
pain B-Disease 1
syndromes O 0
, O 0
such O 0
as O 0
neuropathic B-Disease 1
pain I-Disease 1
. O 0

However O 0
, O 0
the O 0
occurrence O 0
of O 0
central O 0
adverse O 0
effects O 0
should O 0
be O 0
taken O 0
into O 0
account O 0
, O 0
especially O 0
when O 0
using O 0
higher O 0
doses O 0
. O 0

This O 0
observation O 0
should O 0
be O 0
tested O 0
in O 0
studies O 0
of O 0
prolonged O 0
ketamine B-Chemical 1
administration O 0
. O 0

Paclitaxel B-Chemical 1
, O 0
cisplatin B-Chemical 1
, O 0
and O 0
gemcitabine B-Chemical 1
combination O 0
chemotherapy O 0
within O 0
a O 0
multidisciplinary O 0
therapeutic O 0
approach O 0
in O 0
metastatic O 0
nonsmall B-Disease 1
cell I-Disease 1
lung I-Disease 1
carcinoma I-Disease 1
. O 0

BACKGROUND O 0
: O 0
Cisplatin B-Chemical 1
- O 0
based O 0
chemotherapy O 0
combinations O 0
improve O 0
quality O 0
of O 0
life O 0
and O 0
survival O 0
in O 0
advanced O 0
nonsmall B-Disease 1
cell I-Disease 1
lung I-Disease 1
carcinoma I-Disease 1
( O 0
NSCLC B-Disease 1
) O 0
. O 0

The O 0
emergence O 0
of O 0
new O 0
active O 0
drugs O 0
might O 0
translate O 0
into O 0
more O 0
effective O 0
regimens O 0
for O 0
the O 0
treatment O 0
of O 0
this O 0
disease O 0
. O 0

METHODS O 0
: O 0
The O 0
objective O 0
of O 0
this O 0
study O 0
was O 0
to O 0
determine O 0
the O 0
feasibility O 0
, O 0
response O 0
rate O 0
, O 0
and O 0
toxicity B-Disease 1
of O 0
a O 0
paclitaxel B-Chemical 1
, O 0
cisplatin B-Chemical 1
, O 0
and O 0
gemcitabine B-Chemical 1
combination O 0
to O 0
treat O 0
metastatic O 0
NSCLC B-Disease 1
. O 0

Thirty O 0
- O 0
five O 0
consecutive O 0
chemotherapy O 0
- O 0
naive O 0
patients O 0
with O 0
Stage O 0
IV O 0
NSCLC B-Disease 1
and O 0
an O 0
Eastern O 0
Cooperative O 0
Oncology O 0
Group O 0
performance O 0
status O 0
of O 0
0 O 0
- O 0
2 O 0
were O 0
treated O 0
with O 0
a O 0
combination O 0
of O 0
paclitaxel B-Chemical 1
( O 0
135 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
given O 0
intravenously O 0
in O 0
3 O 0
hours O 0
) O 0
on O 0
Day O 0
1 O 0
, O 0
cisplatin B-Chemical 1
( O 0
120 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
given O 0
intravenously O 0
in O 0
6 O 0
hours O 0
) O 0
on O 0
Day O 0
1 O 0
, O 0
and O 0
gemcitabine B-Chemical 1
( O 0
800 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
given O 0
intravenously O 0
in O 0
30 O 0
minutes O 0
) O 0
on O 0
Days O 0
1 O 0
and O 0
8 O 0
, O 0
every O 0
4 O 0
weeks O 0
. O 0

Although O 0
responding O 0
patients O 0
were O 0
scheduled O 0
to O 0
receive O 0
consolidation O 0
radiotherapy O 0
and O 0
24 O 0
patients O 0
received O 0
preplanned O 0
second O 0
- O 0
line O 0
chemotherapy O 0
after O 0
disease O 0
progression O 0
, O 0
the O 0
response O 0
and O 0
toxicity B-Disease 1
rates O 0
reported O 0
refer O 0
only O 0
to O 0
the O 0
chemotherapy O 0
regimen O 0
given O 0
. O 0

RESULTS O 0
: O 0
All O 0
the O 0
patients O 0
were O 0
examined O 0
for O 0
toxicity B-Disease 1
; O 0
34 O 0
were O 0
examinable O 0
for O 0
response O 0
. O 0

An O 0
objective O 0
response O 0
was O 0
observed O 0
in O 0
73 O 0
. O 0
5 O 0
% O 0
of O 0
the O 0
patients O 0
( O 0
95 O 0
% O 0
confidence O 0
interval O 0
[ O 0
CI O 0
] O 0
, O 0
55 O 0
. O 0
6 O 0
- O 0
87 O 0
. O 0
1 O 0
% O 0
) O 0
, O 0
including O 0
4 O 0
complete O 0
responses O 0
( O 0
11 O 0
. O 0
7 O 0
% O 0
) O 0
. O 0

According O 0
to O 0
intention O 0
- O 0
to O 0
- O 0
treat O 0
, O 0
the O 0
overall O 0
response O 0
rate O 0
was O 0
71 O 0
. O 0
4 O 0
% O 0
( O 0
95 O 0
% O 0
CI O 0
, O 0
53 O 0
. O 0
7 O 0
- O 0
85 O 0
. O 0
4 O 0
% O 0
) O 0
. O 0

After O 0
154 O 0
courses O 0
of O 0
therapy O 0
, O 0
the O 0
median O 0
dose O 0
intensity O 0
was O 0
131 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
for O 0
paclitaxel B-Chemical 1
( O 0
97 O 0
. O 0
3 O 0
% O 0
) O 0
, O 0
117 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
for O 0
cisplatin B-Chemical 1
( O 0
97 O 0
. O 0
3 O 0
% O 0
) O 0
, O 0
and O 0
1378 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
for O 0
gemcitabine B-Chemical 1
( O 0
86 O 0
. O 0
2 O 0
% O 0
) O 0
. O 0

World O 0
Health O 0
Organization O 0
Grade O 0
3 O 0
- O 0
4 O 0
neutropenia B-Disease 1
and O 0
thrombocytopenia B-Disease 1
occurred O 0
in O 0
39 O 0
. O 0
9 O 0
% O 0
and O 0
11 O 0
. O 0
4 O 0
% O 0
of O 0
patients O 0
, O 0
respectively O 0
. O 0

There O 0
was O 0
one O 0
treatment O 0
- O 0
related O 0
death B-Disease 1
. O 0

Nonhematologic O 0
toxicities B-Disease 1
were O 0
mild O 0
. O 0

After O 0
a O 0
median O 0
follow O 0
- O 0
up O 0
of O 0
22 O 0
months O 0
, O 0
the O 0
median O 0
progression O 0
free O 0
survival O 0
rate O 0
was O 0
7 O 0
months O 0
, O 0
and O 0
the O 0
median O 0
survival O 0
time O 0
was O 0
16 O 0
months O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
combination O 0
of O 0
paclitaxel B-Chemical 1
, O 0
cisplatin B-Chemical 1
, O 0
and O 0
gemcitabine B-Chemical 1
is O 0
well O 0
tolerated O 0
and O 0
shows O 0
high O 0
activity O 0
in O 0
metastatic O 0
NSCLC B-Disease 1
. O 0

This O 0
treatment O 0
merits O 0
further O 0
comparison O 0
with O 0
other O 0
cisplatin B-Chemical 1
- O 0
based O 0
regimens O 0
. O 0

Serotonergic B-Chemical 1
antidepressants I-Chemical 1
and O 0
urinary B-Disease 1
incontinence I-Disease 1
. O 0

Many O 0
new O 0
serotonergic B-Chemical 1
antidepressants I-Chemical 1
have O 0
been O 0
introduced O 0
over O 0
the O 0
past O 0
decade O 0
. O 0

Although O 0
urinary B-Disease 1
incontinence I-Disease 1
is O 0
listed O 0
as O 0
one O 0
side O 0
effect O 0
of O 0
these O 0
drugs O 0
in O 0
their O 0
package O 0
inserts O 0
there O 0
is O 0
only O 0
one O 0
report O 0
in O 0
the O 0
literature O 0
. O 0

This O 0
concerns O 0
2 O 0
male O 0
patients O 0
who O 0
experienced O 0
incontinence B-Disease 1
while O 0
taking O 0
venlafaxine B-Chemical 1
. O 0

In O 0
the O 0
present O 0
paper O 0
the O 0
authors O 0
describe O 0
2 O 0
female O 0
patients O 0
who O 0
developed O 0
incontinence B-Disease 1
secondary O 0
to O 0
the O 0
selective O 0
serotonin B-Chemical 1
reuptake O 0
inhibitors O 0
paroxetine B-Chemical 1
and O 0
sertraline B-Chemical 1
, O 0
as O 0
well O 0
as O 0
a O 0
third O 0
who O 0
developed O 0
this O 0
side O 0
effect O 0
on O 0
venlafaxine B-Chemical 1
. O 0

In O 0
2 O 0
of O 0
the O 0
3 O 0
cases O 0
the O 0
patients O 0
were O 0
also O 0
taking O 0
lithium B-Chemical 1
carbonate I-Chemical 1
and O 0
beta O 0
- O 0
blockers O 0
, O 0
both O 0
of O 0
which O 0
could O 0
have O 0
contributed O 0
to O 0
the O 0
incontinence B-Disease 1
. O 0

Animal O 0
studies O 0
suggest O 0
that O 0
incontinence B-Disease 1
secondary O 0
to O 0
serotonergic B-Chemical 1
antidepressants I-Chemical 1
could O 0
be O 0
mediated O 0
by O 0
the O 0
5HT4 O 0
receptors O 0
found O 0
on O 0
the O 0
bladder O 0
. O 0

Further O 0
research O 0
is O 0
needed O 0
to O 0
delineate O 0
the O 0
frequency O 0
of O 0
this O 0
troubling O 0
side O 0
effect O 0
and O 0
how O 0
best O 0
to O 0
treat O 0
it O 0
. O 0

Acute O 0
cocaine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
: O 0
differential O 0
sensitivity O 0
of O 0
six O 0
inbred O 0
mouse O 0
strains O 0
. O 0

Mature O 0
male O 0
and O 0
female O 0
mice O 0
from O 0
six O 0
inbred O 0
stains O 0
were O 0
tested O 0
for O 0
susceptibility O 0
to O 0
behavioral O 0
seizures B-Disease 1
induced O 0
by O 0
a O 0
single O 0
injection O 0
of O 0
cocaine B-Chemical 1
. O 0

Cocaine B-Chemical 1
was O 0
injected O 0
ip O 0
over O 0
a O 0
range O 0
of O 0
doses O 0
( O 0
50 O 0
- O 0
100 O 0
mg O 0
/ O 0
kg O 0
) O 0
and O 0
behavior O 0
was O 0
monitored O 0
for O 0
20 O 0
minutes O 0
. O 0

Seizure B-Disease 1
end O 0
points O 0
included O 0
latency O 0
to O 0
forelimb O 0
or O 0
hindlimb O 0
clonus O 0
, O 0
latency O 0
to O 0
clonic O 0
running O 0
seizure B-Disease 1
and O 0
latency O 0
to O 0
jumping O 0
bouncing O 0
seizure B-Disease 1
. O 0

A O 0
range O 0
of O 0
strain O 0
specific O 0
sensitivities O 0
was O 0
documented O 0
with O 0
A O 0
/ O 0
J O 0
and O 0
SJL O 0
mice O 0
being O 0
most O 0
sensitive O 0
and O 0
C57BL O 0
/ O 0
6J O 0
most O 0
resistant O 0
. O 0

DBA O 0
/ O 0
2J O 0
, O 0
BALB O 0
/ O 0
cByJ O 0
and O 0
NZW O 0
/ O 0
LacJ O 0
strains O 0
exhibited O 0
intermediate O 0
sensitivity O 0
. O 0

EEG O 0
recordings O 0
were O 0
made O 0
in O 0
SJL O 0
, O 0
A O 0
/ O 0
J O 0
and O 0
C57BL O 0
/ O 0
6J O 0
mice O 0
revealing O 0
a O 0
close O 0
correspondence O 0
between O 0
electrical O 0
activity O 0
and O 0
behavior O 0
. O 0

Additionally O 0
, O 0
levels O 0
of O 0
cocaine B-Chemical 1
determined O 0
in O 0
hippocampus O 0
and O 0
cortex O 0
were O 0
not O 0
different O 0
between O 0
sensitive O 0
and O 0
resistant O 0
strains O 0
. O 0

Additional O 0
studies O 0
of O 0
these O 0
murine O 0
strains O 0
may O 0
be O 0
useful O 0
for O 0
investigating O 0
genetic O 0
influences O 0
on O 0
cocaine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
. O 0

Hypotension B-Disease 1
following O 0
the O 0
initiation O 0
of O 0
tizanidine B-Chemical 1
in O 0
a O 0
patient O 0
treated O 0
with O 0
an O 0
angiotensin B-Chemical 1
converting O 0
enzyme O 0
inhibitor O 0
for O 0
chronic O 0
hypertension B-Disease 1
. O 0

Centrally O 0
acting O 0
alpha O 0
- O 0
2 O 0
adrenergic O 0
agonists O 0
are O 0
one O 0
of O 0
several O 0
pharmacologic O 0
agents O 0
used O 0
in O 0
the O 0
treatment O 0
of O 0
spasticity B-Disease 1
related O 0
to O 0
disorders B-Disease 1
of I-Disease 1
the I-Disease 1
central I-Disease 1
nervous I-Disease 1
system I-Disease 1
. O 0

In O 0
addition O 0
to O 0
their O 0
effects O 0
on O 0
spasticity B-Disease 1
, O 0
certain O 0
adverse O 0
cardiorespiratory O 0
effects O 0
have O 0
been O 0
reported O 0
. O 0

Adults O 0
chronically O 0
treated O 0
with O 0
angiotensin B-Chemical 1
converting O 0
enzyme O 0
inhibitors O 0
may O 0
have O 0
a O 0
limited O 0
ability O 0
to O 0
respond O 0
to O 0
hypotension B-Disease 1
when O 0
the O 0
sympathetic O 0
response O 0
is O 0
simultaneously O 0
blocked O 0
. O 0

The O 0
authors O 0
present O 0
a O 0
10 O 0
- O 0
year O 0
- O 0
old O 0
boy O 0
chronically O 0
treated O 0
with O 0
lisinopril B-Chemical 1
, O 0
an O 0
angiotensin B-Chemical 1
converting O 0
enzyme O 0
inhibitor O 0
, O 0
to O 0
control O 0
hypertension B-Disease 1
who O 0
developed O 0
hypotension B-Disease 1
following O 0
the O 0
addition O 0
of O 0
tizanidine B-Chemical 1
, O 0
an O 0
alpha O 0
- O 0
2 O 0
agonist O 0
, O 0
for O 0
the O 0
treatment O 0
of O 0
spasticity B-Disease 1
. O 0

The O 0
possible O 0
interaction O 0
of O 0
tizanidine B-Chemical 1
and O 0
other O 0
antihypertensive O 0
agents O 0
should O 0
be O 0
kept O 0
in O 0
mind O 0
when O 0
prescribing O 0
therapy O 0
to O 0
treat O 0
either O 0
hypertension B-Disease 1
or O 0
spasticity B-Disease 1
in O 0
such O 0
patients O 0
. O 0

Two O 0
mouse O 0
lines O 0
selected O 0
for O 0
differential O 0
sensitivities O 0
to O 0
beta B-Chemical 1
- I-Chemical 1
carboline I-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
are O 0
also O 0
differentially O 0
sensitive O 0
to O 0
various O 0
pharmacological O 0
effects O 0
of O 0
other O 0
GABA B-Chemical 1
( O 0
A O 0
) O 0
receptor O 0
ligands O 0
. O 0

Two O 0
mouse O 0
lines O 0
were O 0
selectively O 0
bred O 0
according O 0
to O 0
their O 0
sensitivity O 0
( O 0
BS O 0
line O 0
) O 0
or O 0
resistance O 0
( O 0
BR O 0
line O 0
) O 0
to O 0
seizures B-Disease 1
induced O 0
by O 0
a O 0
single O 0
i O 0
. O 0
p O 0
. O 0
injection O 0
of O 0
methyl B-Chemical 1
beta I-Chemical 1
- I-Chemical 1
carboline I-Chemical 1
- I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
carboxylate I-Chemical 1
( O 0
beta B-Chemical 1
- I-Chemical 1
CCM I-Chemical 1
) O 0
, O 0
an O 0
inverse O 0
agonist O 0
of O 0
the O 0
GABA B-Chemical 1
( O 0
A O 0
) O 0
receptor O 0
benzodiazepine B-Chemical 1
site O 0
. O 0

Our O 0
aim O 0
was O 0
to O 0
characterize O 0
both O 0
lines O 0
' O 0
sensitivities O 0
to O 0
various O 0
physiological O 0
effects O 0
of O 0
other O 0
ligands O 0
of O 0
the O 0
GABA B-Chemical 1
( O 0
A O 0
) O 0
receptor O 0
. O 0

We O 0
measured O 0
diazepam B-Chemical 1
- O 0
induced O 0
anxiolysis O 0
with O 0
the O 0
elevated O 0
plus O 0
- O 0
maze O 0
test O 0
, O 0
diazepam B-Chemical 1
- O 0
induced O 0
sedation O 0
by O 0
recording O 0
the O 0
vigilance O 0
states O 0
, O 0
and O 0
picrotoxin B-Chemical 1
- O 0
and O 0
pentylenetetrazol B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
after O 0
i O 0
. O 0
p O 0
. O 0
injections O 0
. O 0

Results O 0
presented O 0
here O 0
show O 0
that O 0
the O 0
differential O 0
sensitivities O 0
of O 0
BS O 0
and O 0
BR O 0
lines O 0
to O 0
beta B-Chemical 1
- I-Chemical 1
CCM I-Chemical 1
can O 0
be O 0
extended O 0
to O 0
diazepam B-Chemical 1
, O 0
picrotoxin B-Chemical 1
, O 0
and O 0
pentylenetetrazol B-Chemical 1
, O 0
suggesting O 0
a O 0
genetic O 0
selection O 0
of O 0
a O 0
general O 0
sensitivity O 0
and O 0
resistance O 0
to O 0
several O 0
ligands O 0
of O 0
the O 0
GABA B-Chemical 1
( O 0
A O 0
) O 0
receptor O 0
. O 0

Propylthiouracil B-Chemical 1
- O 0
induced O 0
perinuclear O 0
- O 0
staining O 0
antineutrophil O 0
cytoplasmic O 0
autoantibody O 0
- O 0
positive O 0
vasculitis B-Disease 1
in O 0
conjunction O 0
with O 0
pericarditis B-Disease 1
. O 0

OBJECTIVE O 0
: O 0
To O 0
describe O 0
a O 0
case O 0
of O 0
propylthiouracil B-Chemical 1
- O 0
induced O 0
vasculitis B-Disease 1
manifesting O 0
with O 0
pericarditis B-Disease 1
. O 0

METHODS O 0
: O 0
We O 0
present O 0
the O 0
first O 0
case O 0
report O 0
of O 0
a O 0
woman O 0
with O 0
hyperthyroidism B-Disease 1
treated O 0
with O 0
propylthiouracil B-Chemical 1
in O 0
whom O 0
a O 0
syndrome O 0
of O 0
pericarditis B-Disease 1
, O 0
fever B-Disease 1
, O 0
and O 0
glomerulonephritis B-Disease 1
developed O 0
. O 0

Serologic O 0
testing O 0
and O 0
immunologic O 0
studies O 0
were O 0
done O 0
, O 0
and O 0
a O 0
pericardial O 0
biopsy O 0
was O 0
performed O 0
. O 0

RESULTS O 0
: O 0
A O 0
25 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
with O 0
Graves B-Disease 1
' I-Disease 1
disease I-Disease 1
had O 0
a O 0
febrile B-Disease 1
illness I-Disease 1
and O 0
evidence O 0
of O 0
pericarditis B-Disease 1
, O 0
which O 0
was O 0
confirmed O 0
by O 0
biopsy O 0
. O 0

Serologic O 0
evaluation O 0
revealed O 0
the O 0
presence O 0
of O 0
perinuclear O 0
- O 0
staining O 0
antineutrophil O 0
cytoplasmic O 0
autoantibodies O 0
( O 0
pANCA O 0
) O 0
against O 0
myeloperoxidase O 0
( O 0
MPO O 0
) O 0
. O 0

Propylthiouracil B-Chemical 1
therapy O 0
was O 0
withdrawn O 0
, O 0
and O 0
she O 0
was O 0
treated O 0
with O 0
a O 0
1 O 0
- O 0
month O 0
course O 0
of O 0
prednisone B-Chemical 1
, O 0
which O 0
alleviated O 0
her O 0
symptoms O 0
. O 0

A O 0
literature O 0
review O 0
revealed O 0
no O 0
prior O 0
reports O 0
of O 0
pericarditis B-Disease 1
in O 0
anti O 0
- O 0
MPO O 0
pANCA O 0
- O 0
positive O 0
vasculitis B-Disease 1
associated O 0
with O 0
propylthio B-Chemical 1
- I-Chemical 1
uracil I-Chemical 1
therapy O 0
. O 0

CONCLUSION O 0
: O 0
Pericarditis B-Disease 1
may O 0
be O 0
the O 0
initial O 0
manifestation O 0
of O 0
drug O 0
- O 0
induced O 0
vasculitis B-Disease 1
attributable O 0
to O 0
propylthio B-Chemical 1
- I-Chemical 1
uracil I-Chemical 1
therapy O 0
. O 0

Repeated O 0
transient O 0
anuria B-Disease 1
following O 0
losartan B-Chemical 1
administration O 0
in O 0
a O 0
patient O 0
with O 0
a O 0
solitary O 0
kidney O 0
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
70 O 0
- O 0
year O 0
- O 0
old O 0
hypertensive B-Disease 1
man O 0
with O 0
a O 0
solitary O 0
kidney O 0
and O 0
chronic B-Disease 1
renal I-Disease 1
insufficiency I-Disease 1
who O 0
developed O 0
two O 0
episodes O 0
of O 0
transient O 0
anuria B-Disease 1
after O 0
losartan B-Chemical 1
administration O 0
. O 0

He O 0
was O 0
hospitalized O 0
for O 0
a O 0
myocardial B-Disease 1
infarction I-Disease 1
with O 0
pulmonary B-Disease 1
edema I-Disease 1
, O 0
treated O 0
with O 0
high O 0
- O 0
dose O 0
diuretics O 0
. O 0

Due O 0
to O 0
severe O 0
systolic B-Disease 1
dysfunction I-Disease 1
losartan B-Chemical 1
was O 0
prescribed O 0
. O 0

Surprisingly O 0
, O 0
the O 0
first O 0
dose O 0
of O 0
50 O 0
mg O 0
of O 0
losartan B-Chemical 1
resulted O 0
in O 0
a O 0
sudden O 0
anuria B-Disease 1
, O 0
which O 0
lasted O 0
eight O 0
hours O 0
despite O 0
high O 0
- O 0
dose O 0
furosemide B-Chemical 1
and O 0
amine B-Chemical 1
infusion O 0
. O 0

One O 0
week O 0
later O 0
, O 0
by O 0
mistake O 0
, O 0
losartan B-Chemical 1
was O 0
prescribed O 0
again O 0
and O 0
after O 0
the O 0
second O 0
dose O 0
of O 0
50 O 0
mg O 0
, O 0
the O 0
patient O 0
developed O 0
a O 0
second O 0
episode O 0
of O 0
transient O 0
anuria B-Disease 1
lasting O 0
10 O 0
hours O 0
. O 0

During O 0
these O 0
two O 0
episodes O 0
, O 0
his O 0
blood O 0
pressure O 0
diminished O 0
but O 0
no O 0
severe O 0
hypotension B-Disease 1
was O 0
noted O 0
. O 0

Ultimately O 0
, O 0
an O 0
arteriography O 0
showed O 0
a O 0
70 O 0
- O 0
80 O 0
% O 0
renal B-Disease 1
artery I-Disease 1
stenosis I-Disease 1
. O 0

In O 0
this O 0
patient O 0
, O 0
renal B-Disease 1
artery I-Disease 1
stenosis I-Disease 1
combined O 0
with O 0
heart B-Disease 1
failure I-Disease 1
and O 0
diuretic O 0
therapy O 0
certainly O 0
resulted O 0
in O 0
a O 0
strong O 0
activation O 0
of O 0
the O 0
renin O 0
- O 0
angiotensin B-Chemical 1
system O 0
( O 0
RAS O 0
) O 0
. O 0

Under O 0
such O 0
conditions O 0
, O 0
angiotensin B-Chemical 1
II I-Chemical 1
receptor O 0
blockade O 0
by O 0
losartan B-Chemical 1
probably O 0
induced O 0
a O 0
critical O 0
fall O 0
in O 0
glomerular O 0
filtration O 0
pressure O 0
. O 0

This O 0
case O 0
report O 0
highlights O 0
the O 0
fact O 0
that O 0
the O 0
angiotensin B-Chemical 1
II I-Chemical 1
receptor O 0
antagonist O 0
losartan B-Chemical 1
can O 0
cause O 0
serious O 0
unexpected O 0
complications O 0
in O 0
patients O 0
with O 0
renovascular B-Disease 1
disease I-Disease 1
and O 0
should O 0
be O 0
used O 0
with O 0
extreme O 0
caution O 0
in O 0
this O 0
setting O 0
. O 0

Calcineurin O 0
- O 0
inhibitor O 0
induced O 0
pain B-Disease 1
syndrome O 0
( O 0
CIPS B-Disease 1
) O 0
: O 0
a O 0
severe O 0
disabling O 0
complication O 0
after O 0
organ O 0
transplantation O 0
. O 0

Bone O 0
pain B-Disease 1
after O 0
transplantation O 0
is O 0
a O 0
frequent O 0
complication O 0
that O 0
can O 0
be O 0
caused O 0
by O 0
several O 0
diseases O 0
. O 0

Treatment O 0
strategies O 0
depend O 0
on O 0
the O 0
correct O 0
diagnosis O 0
of O 0
the O 0
pain B-Disease 1
. O 0

Nine O 0
patients O 0
with O 0
severe O 0
pain B-Disease 1
in O 0
their O 0
feet O 0
, O 0
which O 0
was O 0
registered O 0
after O 0
transplantation O 0
, O 0
were O 0
investigated O 0
. O 0

Bone O 0
scans O 0
showed O 0
an O 0
increased O 0
tracer O 0
uptake O 0
of O 0
the O 0
foot O 0
bones O 0
. O 0

Magnetic O 0
resonance O 0
imaging O 0
demonstrated O 0
bone B-Disease 1
marrow I-Disease 1
oedema I-Disease 1
in O 0
the O 0
painful O 0
bones O 0
. O 0

Pain B-Disease 1
was O 0
not O 0
explained O 0
by O 0
other O 0
diseases O 0
causing O 0
foot O 0
pain B-Disease 1
, O 0
like O 0
reflex B-Disease 1
sympathetic I-Disease 1
dystrophy I-Disease 1
, O 0
polyneuropathy B-Disease 1
, O 0
Morton B-Disease 1
' I-Disease 1
s I-Disease 1
neuralgia I-Disease 1
, O 0
gout B-Disease 1
, O 0
osteoporosis B-Disease 1
, O 0
avascular B-Disease 1
necrosis I-Disease 1
, O 0
intermittent B-Disease 1
claudication I-Disease 1
, O 0
orthopaedic O 0
foot B-Disease 1
deformities I-Disease 1
, O 0
stress B-Disease 1
fractures I-Disease 1
, O 0
and O 0
hyperparathyroidism B-Disease 1
. O 0

The O 0
reduction O 0
of O 0
cyclosporine B-Chemical 1
- O 0
or O 0
tacrolimus B-Chemical 1
trough O 0
levels O 0
and O 0
the O 0
administration O 0
of O 0
calcium B-Chemical 1
channel O 0
blockers O 0
led O 0
to O 0
relief O 0
of O 0
pain B-Disease 1
. O 0

The O 0
Calcineurin O 0
- O 0
inhibitor O 0
Induced O 0
Pain B-Disease 1
Syndrome O 0
( O 0
CIPS B-Disease 1
) O 0
is O 0
a O 0
rare O 0
but O 0
severe O 0
side O 0
effect O 0
of O 0
cyclosporine B-Chemical 1
or O 0
tacrolimus B-Chemical 1
and O 0
is O 0
accurately O 0
diagnosed O 0
by O 0
its O 0
typical O 0
presentation O 0
, O 0
magnetic O 0
resonance O 0
imaging O 0
and O 0
bone O 0
scans O 0
. O 0

Incorrect O 0
diagnosis O 0
of O 0
the O 0
syndrome O 0
will O 0
lead O 0
to O 0
a O 0
significant O 0
reduction O 0
of O 0
life O 0
quality O 0
in O 0
patients O 0
suffering O 0
from O 0
CIPS B-Disease 1
. O 0

Brain O 0
natriuretic O 0
peptide O 0
is O 0
a O 0
predictor O 0
of O 0
anthracycline B-Chemical 1
- O 0
induced O 0
cardiotoxicity B-Disease 1
. O 0

Anthracyclines B-Chemical 1
are O 0
effective O 0
antineoplastic O 0
drugs O 0
, O 0
but O 0
they O 0
frequently O 0
cause O 0
dose O 0
- O 0
related O 0
cardiotoxicity B-Disease 1
. O 0

The O 0
cardiotoxicity B-Disease 1
of O 0
conventional O 0
anthracycline B-Chemical 1
therapy O 0
highlights O 0
a O 0
need O 0
to O 0
search O 0
for O 0
methods O 0
that O 0
are O 0
highly O 0
sensitive O 0
and O 0
capable O 0
of O 0
predicting O 0
cardiac B-Disease 1
dysfunction I-Disease 1
. O 0

We O 0
measured O 0
the O 0
plasma O 0
level O 0
of O 0
brain O 0
natriuretic O 0
peptide O 0
( O 0
BNP O 0
) O 0
to O 0
determine O 0
whether O 0
BNP O 0
might O 0
serve O 0
as O 0
a O 0
simple O 0
diagnostic O 0
indicator O 0
of O 0
anthracycline B-Chemical 1
- O 0
induced O 0
cardiotoxicity B-Disease 1
in O 0
patients O 0
with O 0
acute B-Disease 1
leukemia I-Disease 1
treated O 0
with O 0
a O 0
daunorubicin B-Chemical 1
( O 0
DNR B-Chemical 1
) O 0
- O 0
containing O 0
regimen O 0
. O 0

Thirteen O 0
patients O 0
with O 0
acute B-Disease 1
leukemia I-Disease 1
were O 0
treated O 0
with O 0
a O 0
DNR B-Chemical 1
- O 0
containing O 0
regimen O 0
. O 0

Cardiac O 0
functions O 0
were O 0
evaluated O 0
with O 0
radionuclide O 0
angiography O 0
before O 0
chemotherapies O 0
. O 0

The O 0
plasma O 0
levels O 0
of O 0
atrial O 0
natriuretic O 0
peptide O 0
( O 0
ANP O 0
) O 0
and O 0
BNP O 0
were O 0
measured O 0
at O 0
the O 0
time O 0
of O 0
radionuclide O 0
angiography O 0
. O 0

Three O 0
patients O 0
developed O 0
congestive B-Disease 1
heart I-Disease 1
failure I-Disease 1
after O 0
the O 0
completion O 0
of O 0
chemotherapy O 0
. O 0

Five O 0
patients O 0
were O 0
diagnosed O 0
as O 0
having O 0
subclinical O 0
heart B-Disease 1
failure I-Disease 1
after O 0
the O 0
completion O 0
of O 0
chemotherapy O 0
. O 0

The O 0
plasma O 0
levels O 0
of O 0
BNP O 0
in O 0
all O 0
the O 0
patients O 0
with O 0
clinical O 0
and O 0
subclinical O 0
heart B-Disease 1
failure I-Disease 1
increased O 0
above O 0
the O 0
normal O 0
limit O 0
( O 0
40 O 0
pg O 0
/ O 0
ml O 0
) O 0
before O 0
the O 0
detection O 0
of O 0
clinical O 0
or O 0
subclinical O 0
heart B-Disease 1
failure I-Disease 1
by O 0
radionuclide O 0
angiography O 0
. O 0

On O 0
the O 0
other O 0
hand O 0
, O 0
BNP O 0
did O 0
not O 0
increase O 0
in O 0
the O 0
patients O 0
without O 0
heart B-Disease 1
failure I-Disease 1
given O 0
DNR B-Chemical 1
, O 0
even O 0
at O 0
more O 0
than O 0
700 O 0
mg O 0
/ O 0
m O 0
( O 0
2 O 0
) O 0
. O 0

The O 0
plasma O 0
level O 0
of O 0
ANP O 0
did O 0
not O 0
always O 0
increase O 0
in O 0
all O 0
the O 0
patients O 0
with O 0
clinical O 0
and O 0
subclinical O 0
heart B-Disease 1
failure I-Disease 1
. O 0

These O 0
preliminary O 0
results O 0
suggest O 0
that O 0
BNP O 0
may O 0
be O 0
useful O 0
as O 0
an O 0
early O 0
and O 0
sensitive O 0
indicator O 0
of O 0
anthracycline B-Chemical 1
- O 0
induced O 0
cardiotoxicity B-Disease 1
. O 0

Nephrotoxicity B-Disease 1
of O 0
combined O 0
cephalothin B-Chemical 1
- O 0
gentamicin B-Chemical 1
regimen O 0
. O 0

Two O 0
patients O 0
developed O 0
acute B-Disease 1
tubular I-Disease 1
necrosis I-Disease 1
, O 0
characterized O 0
clinically O 0
by O 0
acute O 0
oliguric B-Disease 1
renal I-Disease 1
failure I-Disease 1
, O 0
while O 0
they O 0
were O 0
receiving O 0
a O 0
combination O 0
of O 0
cephalothin B-Chemical 1
sodium I-Chemical 1
and O 0
gentamicin B-Chemical 1
sulfate I-Chemical 1
therapy O 0
. O 0

Patients O 0
who O 0
are O 0
given O 0
this O 0
drug O 0
regimen O 0
should O 0
be O 0
observed O 0
very O 0
carefully O 0
for O 0
early O 0
signs O 0
of O 0
nephrotoxicity B-Disease 1
. O 0

High O 0
doses O 0
of O 0
this O 0
antibiotic O 0
combination O 0
should O 0
be O 0
avoided O 0
especially O 0
in O 0
elderly O 0
patients O 0
. O 0

Patients O 0
with O 0
renal B-Disease 1
insufficiency I-Disease 1
should O 0
not O 0
be O 0
given O 0
this O 0
regimen O 0
. O 0

In O 0
vivo O 0
protection O 0
of O 0
dna O 0
damage O 0
associated O 0
apoptotic O 0
and O 0
necrotic B-Disease 1
cell O 0
deaths O 0
during O 0
acetaminophen B-Chemical 1
- O 0
induced O 0
nephrotoxicity B-Disease 1
, O 0
amiodarone B-Chemical 1
- O 0
induced O 0
lung B-Disease 1
toxicity I-Disease 1
and O 0
doxorubicin B-Chemical 1
- O 0
induced O 0
cardiotoxicity B-Disease 1
by O 0
a O 0
novel O 0
IH636 B-Chemical 1
grape I-Chemical 1
seed I-Chemical 1
proanthocyanidin I-Chemical 1
extract I-Chemical 1
. O 0

Grape B-Chemical 1
seed I-Chemical 1
extract I-Chemical 1
, O 0
primarily O 0
a O 0
mixture O 0
of O 0
proanthocyanidins B-Chemical 1
, O 0
has O 0
been O 0
shown O 0
to O 0
modulate O 0
a O 0
wide O 0
- O 0
range O 0
of O 0
biological O 0
, O 0
pharmacological O 0
and O 0
toxicological O 0
effects O 0
which O 0
are O 0
mainly O 0
cytoprotective O 0
. O 0

This O 0
study O 0
assessed O 0
the O 0
ability O 0
of O 0
IH636 B-Chemical 1
grape I-Chemical 1
seed I-Chemical 1
proanthocyanidin I-Chemical 1
extract I-Chemical 1
( O 0
GSPE B-Chemical 1
) O 0
to O 0
prevent O 0
acetaminophen B-Chemical 1
( O 0
AAP B-Chemical 1
) O 0
- O 0
induced O 0
nephrotoxicity B-Disease 1
, O 0
amiodarone B-Chemical 1
( O 0
AMI B-Chemical 1
) O 0
- O 0
induced O 0
lung B-Disease 1
toxicity I-Disease 1
, O 0
and O 0
doxorubicin B-Chemical 1
( O 0
DOX B-Chemical 1
) O 0
- O 0
induced O 0
cardiotoxicity B-Disease 1
in O 0
mice O 0
. O 0

Experimental O 0
design O 0
consisted O 0
of O 0
four O 0
groups O 0
: O 0
control O 0
( O 0
vehicle O 0
alone O 0
) O 0
, O 0
GSPE B-Chemical 1
alone O 0
, O 0
drug O 0
alone O 0
and O 0
GSPE B-Chemical 1
+ O 0
drug O 0
. O 0

For O 0
the O 0
cytoprotection O 0
study O 0
, O 0
animals O 0
were O 0
orally O 0
gavaged O 0
100 O 0
mg O 0
/ O 0
Kg O 0
GSPE B-Chemical 1
for O 0
7 O 0
- O 0
10 O 0
days O 0
followed O 0
by O 0
i O 0
. O 0
p O 0
. O 0
injections O 0
of O 0
organ O 0
specific O 0
three O 0
drugs O 0
( O 0
AAP B-Chemical 1
: O 0
500 O 0
mg O 0
/ O 0
Kg O 0
for O 0
24 O 0
h O 0
; O 0
AMI B-Chemical 1
: O 0
50 O 0
mg O 0
/ O 0
Kg O 0
/ O 0
day O 0
for O 0
four O 0
days O 0
; O 0
DOX B-Chemical 1
: O 0
20 O 0
mg O 0
/ O 0
Kg O 0
for O 0
48 O 0
h O 0
) O 0
. O 0

Parameters O 0
of O 0
study O 0
included O 0
analysis O 0
of O 0
serum O 0
chemistry O 0
( O 0
ALT O 0
, O 0
BUN O 0
and O 0
CPK O 0
) O 0
, O 0
and O 0
orderly O 0
fragmentation O 0
of O 0
genomic O 0
DNA O 0
( O 0
both O 0
endonuclease O 0
- O 0
dependent O 0
and O 0
independent O 0
) O 0
in O 0
addition O 0
to O 0
microscopic O 0
evaluation O 0
of O 0
damage O 0
and O 0
/ O 0
or O 0
protection O 0
in O 0
corresponding O 0
PAS O 0
stained O 0
tissues O 0
. O 0

Results O 0
indicate O 0
that O 0
GSPE B-Chemical 1
preexposure O 0
prior O 0
to O 0
AAP B-Chemical 1
, O 0
AMI B-Chemical 1
and O 0
DOX B-Chemical 1
, O 0
provided O 0
near O 0
complete O 0
protection O 0
in O 0
terms O 0
of O 0
serum O 0
chemistry O 0
changes O 0
( O 0
ALT O 0
, O 0
BUN O 0
and O 0
CPK O 0
) O 0
, O 0
and O 0
significantly O 0
reduced O 0
DNA O 0
fragmentation O 0
. O 0

Histopathological O 0
examination O 0
of O 0
kidney O 0
, O 0
heart O 0
and O 0
lung O 0
sections O 0
revealed O 0
moderate O 0
to O 0
massive O 0
tissue B-Disease 1
damage I-Disease 1
with O 0
a O 0
variety O 0
of O 0
morphological O 0
aberrations O 0
by O 0
all O 0
the O 0
three O 0
drugs O 0
in O 0
the O 0
absence O 0
of O 0
GSPE B-Chemical 1
preexposure O 0
than O 0
in O 0
its O 0
presence O 0
. O 0

GSPE B-Chemical 1
+ O 0
drug O 0
exposed O 0
tissues O 0
exhibited O 0
minor O 0
residual O 0
damage O 0
or O 0
near O 0
total O 0
recovery O 0
. O 0

Additionally O 0
, O 0
histopathological O 0
alterations O 0
mirrored O 0
both O 0
serum O 0
chemistry O 0
changes O 0
and O 0
the O 0
pattern O 0
of O 0
DNA O 0
fragmentation O 0
. O 0

Interestingly O 0
, O 0
all O 0
the O 0
drugs O 0
, O 0
such O 0
as O 0
, O 0
AAP B-Chemical 1
, O 0
AMI B-Chemical 1
and O 0
DOX B-Chemical 1
induced O 0
apoptotic O 0
death O 0
in O 0
addition O 0
to O 0
necrosis B-Disease 1
in O 0
the O 0
respective O 0
organs O 0
which O 0
was O 0
very O 0
effectively O 0
blocked O 0
by O 0
GSPE B-Chemical 1
. O 0

Since O 0
AAP B-Chemical 1
, O 0
AMI B-Chemical 1
and O 0
DOX B-Chemical 1
undergo O 0
biotransformation O 0
and O 0
are O 0
known O 0
to O 0
produce O 0
damaging O 0
radicals O 0
in O 0
vivo O 0
, O 0
the O 0
protection O 0
by O 0
GSPE B-Chemical 1
may O 0
be O 0
linked O 0
to O 0
both O 0
inhibition O 0
of O 0
metabolism O 0
and O 0
/ O 0
or O 0
detoxification O 0
of O 0
cytotoxic O 0
radicals O 0
. O 0

In O 0
addition O 0
, O 0
its O 0
' O 0
presumed O 0
contribution O 0
to O 0
DNA O 0
repair O 0
may O 0
be O 0
another O 0
important O 0
attribute O 0
, O 0
which O 0
played O 0
a O 0
role O 0
in O 0
the O 0
chemoprevention O 0
process O 0
. O 0

Additionally O 0
, O 0
this O 0
may O 0
have O 0
been O 0
the O 0
first O 0
report O 0
on O 0
AMI B-Chemical 1
- O 0
induced O 0
apoptotic O 0
death O 0
in O 0
the O 0
lung O 0
tissue O 0
. O 0

Taken O 0
together O 0
, O 0
these O 0
events O 0
undoubtedly O 0
establish O 0
GSPE B-Chemical 1
' O 0
s O 0
abundant O 0
bioavailability O 0
, O 0
and O 0
the O 0
power O 0
to O 0
defend O 0
multiple O 0
target O 0
organs O 0
from O 0
toxic O 0
assaults O 0
induced O 0
by O 0
structurally O 0
diverse O 0
and O 0
functionally O 0
different O 0
entities O 0
in O 0
vivo O 0
. O 0

Antidepressant B-Chemical 1
- O 0
induced O 0
mania B-Disease 1
in O 0
bipolar B-Disease 1
patients O 0
: O 0
identification O 0
of O 0
risk O 0
factors O 0
. O 0

BACKGROUND O 0
: O 0
Concerns O 0
about O 0
possible O 0
risks O 0
of O 0
switching O 0
to O 0
mania B-Disease 1
associated O 0
with O 0
antidepressants B-Chemical 1
continue O 0
to O 0
interfere O 0
with O 0
the O 0
establishment O 0
of O 0
an O 0
optimal O 0
treatment O 0
paradigm O 0
for O 0
bipolar B-Disease 1
depression I-Disease 1
. O 0

METHOD O 0
: O 0
The O 0
response O 0
of O 0
44 O 0
patients O 0
meeting O 0
DSM O 0
- O 0
IV O 0
criteria O 0
for O 0
bipolar B-Disease 1
disorder I-Disease 1
to O 0
naturalistic O 0
treatment O 0
was O 0
assessed O 0
for O 0
at O 0
least O 0
6 O 0
weeks O 0
using O 0
the O 0
Montgomery O 0
- O 0
Asberg O 0
Depression O 0
Rating O 0
Scale O 0
and O 0
the O 0
Bech O 0
- O 0
Rafaelson O 0
Mania O 0
Rating O 0
Scale O 0
. O 0

Patients O 0
who O 0
experienced O 0
a O 0
manic B-Disease 1
or O 0
hypomanic B-Disease 1
switch O 0
were O 0
compared O 0
with O 0
those O 0
who O 0
did O 0
not O 0
on O 0
several O 0
variables O 0
including O 0
age O 0
, O 0
sex O 0
, O 0
diagnosis O 0
( O 0
DSM B-Disease 1
- I-Disease 1
IV I-Disease 1
bipolar I-Disease 1
I I-Disease 1
vs O 0
. O 0
bipolar B-Disease 1
II I-Disease 1
) O 0
, O 0
number O 0
of O 0
previous O 0
manic B-Disease 1
episodes O 0
, O 0
type O 0
of O 0
antidepressant B-Chemical 1
therapy O 0
used O 0
( O 0
electroconvulsive O 0
therapy O 0
vs O 0
. O 0
antidepressant B-Chemical 1
drugs O 0
and O 0
, O 0
more O 0
particularly O 0
, O 0
selective O 0
serotonin B-Chemical 1
reuptake I-Chemical 1
inhibitors I-Chemical 1
[ O 0
SSRIs B-Chemical 1
] O 0
) O 0
, O 0
use O 0
and O 0
type O 0
of O 0
mood O 0
stabilizers O 0
( O 0
lithium B-Chemical 1
vs O 0
. O 0
anticonvulsants O 0
) O 0
, O 0
and O 0
temperament O 0
of O 0
the O 0
patient O 0
, O 0
assessed O 0
during O 0
a O 0
normothymic O 0
period O 0
using O 0
the O 0
hyperthymia O 0
component O 0
of O 0
the O 0
Semi O 0
- O 0
structured O 0
Affective O 0
Temperament O 0
Interview O 0
. O 0

RESULTS O 0
: O 0
Switches O 0
to O 0
hypomania B-Disease 1
or O 0
mania B-Disease 1
occurred O 0
in O 0
27 O 0
% O 0
of O 0
all O 0
patients O 0
( O 0
N O 0
= O 0
12 O 0
) O 0
( O 0
and O 0
in O 0
24 O 0
% O 0
of O 0
the O 0
subgroup O 0
of O 0
patients O 0
treated O 0
with O 0
SSRIs B-Chemical 1
[ O 0
8 O 0
/ O 0
33 O 0
] O 0
) O 0
; O 0
16 O 0
% O 0
( O 0
N O 0
= O 0
7 O 0
) O 0
experienced O 0
manic B-Disease 1
episodes O 0
, O 0
and O 0
11 O 0
% O 0
( O 0
N O 0
= O 0
5 O 0
) O 0
experienced O 0
hypomanic B-Disease 1
episodes O 0
. O 0

Sex O 0
, O 0
age O 0
, O 0
diagnosis O 0
( O 0
bipolar B-Disease 1
I I-Disease 1
vs O 0
. O 0
bipolar B-Disease 1
II I-Disease 1
) O 0
, O 0
and O 0
additional O 0
treatment O 0
did O 0
not O 0
affect O 0
the O 0
risk O 0
of O 0
switching O 0
. O 0

The O 0
incidence O 0
of O 0
mood O 0
switches O 0
seemed O 0
not O 0
to O 0
differ O 0
between O 0
patients O 0
receiving O 0
an O 0
anticonvulsant O 0
and O 0
those O 0
receiving O 0
no O 0
mood O 0
stabilizer O 0
. O 0

In O 0
contrast O 0
, O 0
mood O 0
switches O 0
were O 0
less O 0
frequent O 0
in O 0
patients O 0
receiving O 0
lithium B-Chemical 1
( O 0
15 O 0
% O 0
, O 0
4 O 0
/ O 0
26 O 0
) O 0
than O 0
in O 0
patients O 0
not O 0
treated O 0
with O 0
lithium B-Chemical 1
( O 0
44 O 0
% O 0
, O 0
8 O 0
/ O 0
18 O 0
; O 0
p O 0
= O 0
. O 0
04 O 0
) O 0
. O 0

The O 0
number O 0
of O 0
previous O 0
manic B-Disease 1
episodes O 0
did O 0
not O 0
affect O 0
the O 0
probability O 0
of O 0
switching O 0
, O 0
whereas O 0
a O 0
high O 0
score O 0
on O 0
the O 0
hyperthymia O 0
component O 0
of O 0
the O 0
Semistructured O 0
Affective O 0
Temperament O 0
Interview O 0
was O 0
associated O 0
with O 0
a O 0
greater O 0
risk O 0
of O 0
switching O 0
( O 0
p O 0
= O 0
. O 0
008 O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
The O 0
frequency O 0
of O 0
mood O 0
switching O 0
associated O 0
with O 0
acute O 0
antidepressant B-Chemical 1
therapy O 0
may O 0
be O 0
reduced O 0
by O 0
lithium B-Chemical 1
treatment O 0
. O 0

Particular O 0
attention O 0
should O 0
be O 0
paid O 0
to O 0
patients O 0
with O 0
a O 0
hyperthymic O 0
temperament O 0
, O 0
who O 0
have O 0
a O 0
greater O 0
risk O 0
of O 0
mood O 0
switches O 0
. O 0

Peritubular O 0
capillary O 0
basement O 0
membrane O 0
reduplication O 0
in O 0
allografts O 0
and O 0
native O 0
kidney B-Disease 1
disease I-Disease 1
: O 0
a O 0
clinicopathologic O 0
study O 0
of O 0
278 O 0
consecutive O 0
renal O 0
specimens O 0
. O 0

BACKGROUND O 0
: O 0
An O 0
association O 0
has O 0
been O 0
found O 0
between O 0
transplant B-Disease 1
glomerulopathy I-Disease 1
( O 0
TG B-Disease 1
) O 0
and O 0
reduplication O 0
of O 0
peritubular O 0
capillary O 0
basement O 0
membranes O 0
( O 0
PTCR O 0
) O 0
. O 0

Although O 0
such O 0
an O 0
association O 0
is O 0
of O 0
practical O 0
and O 0
theoretical O 0
importance O 0
, O 0
only O 0
one O 0
prospective O 0
study O 0
has O 0
tried O 0
to O 0
confirm O 0
it O 0
. O 0

METHODS O 0
: O 0
We O 0
examined O 0
278 O 0
consecutive O 0
renal O 0
specimens O 0
( O 0
from O 0
135 O 0
transplants O 0
and O 0
143 O 0
native O 0
kidneys O 0
) O 0
for O 0
ultrastructural O 0
evidence O 0
of O 0
PTCR O 0
. O 0

In O 0
addition O 0
to O 0
renal O 0
allografts O 0
with O 0
TG B-Disease 1
, O 0
we O 0
also O 0
examined O 0
grafts O 0
with O 0
acute O 0
rejection O 0
, O 0
recurrent O 0
glomerulonephritis B-Disease 1
, O 0
chronic B-Disease 1
allograft I-Disease 1
nephropathy I-Disease 1
and O 0
stable O 0
grafts O 0
( O 0
" O 0
protocol O 0
biopsies O 0
" O 0
) O 0
. O 0

Native O 0
kidney O 0
specimens O 0
included O 0
a O 0
wide O 0
range O 0
of O 0
glomerulopathies B-Disease 1
as O 0
well O 0
as O 0
cases O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
, O 0
malignant B-Disease 1
hypertension I-Disease 1
, O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
, O 0
and O 0
acute B-Disease 1
tubular I-Disease 1
necrosis I-Disease 1
. O 0

RESULTS O 0
: O 0
We O 0
found O 0
PTCR O 0
in O 0
14 O 0
of O 0
15 O 0
cases O 0
of O 0
TG B-Disease 1
, O 0
in O 0
7 O 0
transplant O 0
biopsy O 0
specimens O 0
without O 0
TG B-Disease 1
, O 0
and O 0
in O 0
13 O 0
of O 0
143 O 0
native O 0
kidney O 0
biopsy O 0
specimens O 0
. O 0

These O 0
13 O 0
included O 0
cases O 0
of O 0
malignant B-Disease 1
hypertension I-Disease 1
, O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
, O 0
lupus B-Disease 1
nephritis I-Disease 1
, O 0
Henoch B-Disease 1
- I-Disease 1
Schonlein I-Disease 1
nephritis I-Disease 1
, O 0
crescentic O 0
glomerulonephritis B-Disease 1
, O 0
and O 0
cocaine B-Chemical 1
- O 0
related O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
. O 0

Mild O 0
PTCR O 0
in O 0
allografts O 0
without O 0
TG B-Disease 1
did O 0
not O 0
predict O 0
renal B-Disease 1
failure I-Disease 1
or O 0
significant O 0
proteinuria B-Disease 1
after O 0
follow O 0
- O 0
up O 0
periods O 0
of O 0
between O 0
3 O 0
months O 0
and O 0
1 O 0
year O 0
. O 0

CONCLUSIONS O 0
: O 0
We O 0
conclude O 0
that O 0
in O 0
transplants O 0
, O 0
there O 0
is O 0
a O 0
strong O 0
association O 0
between O 0
well O 0
- O 0
developed O 0
PTCR O 0
and O 0
TG B-Disease 1
, O 0
while O 0
the O 0
significance O 0
of O 0
mild O 0
PTCR O 0
and O 0
its O 0
predictive O 0
value O 0
in O 0
the O 0
absence O 0
of O 0
TG B-Disease 1
is O 0
unclear O 0
. O 0

PTCR O 0
also O 0
occurs O 0
in O 0
certain O 0
native O 0
kidney B-Disease 1
diseases I-Disease 1
, O 0
though O 0
the O 0
association O 0
is O 0
not O 0
as O 0
strong O 0
as O 0
that O 0
for O 0
TG B-Disease 1
. O 0

We O 0
suggest O 0
that O 0
repeated O 0
endothelial B-Disease 1
injury I-Disease 1
, O 0
including O 0
immunologic B-Disease 1
injury I-Disease 1
, O 0
may O 0
be O 0
the O 0
cause O 0
of O 0
this O 0
lesion O 0
both O 0
in O 0
allografts O 0
and O 0
native O 0
kidneys O 0
. O 0

Caffeine B-Chemical 1
- O 0
induced O 0
cardiac B-Disease 1
arrhythmia I-Disease 1
: O 0
an O 0
unrecognised O 0
danger O 0
of O 0
healthfood O 0
products O 0
. O 0

We O 0
describe O 0
a O 0
25 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
with O 0
pre O 0
- O 0
existing O 0
mitral B-Disease 1
valve I-Disease 1
prolapse I-Disease 1
who O 0
developed O 0
intractable O 0
ventricular B-Disease 1
fibrillation I-Disease 1
after O 0
consuming O 0
a O 0
" O 0
natural O 0
energy O 0
" O 0
guarana O 0
health O 0
drink O 0
containing O 0
a O 0
high O 0
concentration O 0
of O 0
caffeine B-Chemical 1
. O 0

This O 0
case O 0
highlights O 0
the O 0
need O 0
for O 0
adequate O 0
labelling O 0
and O 0
regulation O 0
of O 0
such O 0
products O 0
. O 0

Conformationally O 0
restricted O 0
analogs O 0
of O 0
BD1008 B-Chemical 1
and O 0
an O 0
antisense O 0
oligodeoxynucleotide B-Chemical 1
targeting O 0
sigma1 O 0
receptors O 0
produce O 0
anti O 0
- O 0
cocaine B-Chemical 1
effects O 0
in O 0
mice O 0
. O 0

Cocaine B-Chemical 1
' O 0
s O 0
ability O 0
to O 0
interact O 0
with O 0
sigma O 0
receptors O 0
suggests O 0
that O 0
these O 0
proteins O 0
mediate O 0
some O 0
of O 0
its O 0
behavioral O 0
effects O 0
. O 0

Therefore O 0
, O 0
three O 0
novel O 0
sigma O 0
receptor O 0
ligands O 0
with O 0
antagonist O 0
activity O 0
were O 0
evaluated O 0
in O 0
Swiss O 0
Webster O 0
mice O 0
: O 0
BD1018 B-Chemical 1
( O 0
3S B-Chemical 1
- I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
[ I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
3 I-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dichlorophenyl I-Chemical 1
) I-Chemical 1
ethyl I-Chemical 1
] I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
diazabicyclo I-Chemical 1
[ I-Chemical 1
4 I-Chemical 1
. I-Chemical 1
3 I-Chemical 1
. I-Chemical 1
0 I-Chemical 1
] I-Chemical 1
nonane I-Chemical 1
) O 0
, O 0
BD1063 B-Chemical 1
( O 0
1 B-Chemical 1
- I-Chemical 1
[ I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
3 I-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dichlorophenyl I-Chemical 1
) I-Chemical 1
ethyl I-Chemical 1
] I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
methylpiperazine I-Chemical 1
) O 0
, O 0
and O 0
LR132 B-Chemical 1
( O 0
1R O 0
, O 0
2S O 0
- O 0
( O 0
+ O 0
) O 0
- O 0
cis O 0
- O 0
N O 0
- O 0
[ O 0
2 O 0
- O 0
( O 0
3 O 0
, O 0
4 O 0
- O 0
dichlorophenyl O 0
) O 0
ethyl O 0
] O 0
- O 0
2 O 0
- O 0
( O 0
1 O 0
- O 0
pyrrolidinyl O 0
) O 0
cyclohexylamine O 0
) O 0
. O 0

Competition O 0
binding O 0
assays O 0
demonstrated O 0
that O 0
all O 0
three O 0
compounds O 0
have O 0
high O 0
affinities O 0
for O 0
sigma1 O 0
receptors O 0
. O 0

The O 0
three O 0
compounds O 0
vary O 0
in O 0
their O 0
affinities O 0
for O 0
sigma2 O 0
receptors O 0
and O 0
exhibit O 0
negligible O 0
affinities O 0
for O 0
dopamine B-Chemical 1
, O 0
opioid O 0
, O 0
GABA B-Chemical 1
( O 0
A O 0
) O 0
and O 0
NMDA B-Chemical 1
receptors O 0
. O 0

In O 0
behavioral O 0
studies O 0
, O 0
pre O 0
- O 0
treatment O 0
of O 0
mice O 0
with O 0
BD1018 B-Chemical 1
, O 0
BD1063 B-Chemical 1
, O 0
or O 0
LR132 B-Chemical 1
significantly O 0
attenuated O 0
cocaine B-Chemical 1
- O 0
induced O 0
convulsions B-Disease 1
and O 0
lethality O 0
. O 0

Moreover O 0
, O 0
post O 0
- O 0
treatment O 0
with O 0
LR132 B-Chemical 1
prevented O 0
cocaine B-Chemical 1
- O 0
induced O 0
lethality O 0
in O 0
a O 0
significant O 0
proportion O 0
of O 0
animals O 0
. O 0

In O 0
contrast O 0
to O 0
the O 0
protection O 0
provided O 0
by O 0
the O 0
putative O 0
antagonists O 0
, O 0
the O 0
well O 0
- O 0
characterized O 0
sigma O 0
receptor O 0
agonist O 0
di B-Chemical 1
- I-Chemical 1
o I-Chemical 1
- I-Chemical 1
tolylguanidine I-Chemical 1
( O 0
DTG B-Chemical 1
) O 0
and O 0
the O 0
novel O 0
sigma O 0
receptor O 0
agonist O 0
BD1031 B-Chemical 1
( O 0
3R B-Chemical 1
- I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
[ I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
3 I-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dichlorophenyl I-Chemical 1
) I-Chemical 1
ethyl I-Chemical 1
] I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
diazabicyclo I-Chemical 1
[ I-Chemical 1
4 I-Chemical 1
. I-Chemical 1
3 I-Chemical 1
. I-Chemical 1
0 I-Chemical 1
] I-Chemical 1
nonane I-Chemical 1
) O 0
each O 0
worsened O 0
the O 0
behavioral O 0
toxicity B-Disease 1
of O 0
cocaine B-Chemical 1
. O 0

At O 0
doses O 0
where O 0
alone O 0
, O 0
they O 0
produced O 0
no O 0
significant O 0
effects O 0
on O 0
locomotion O 0
, O 0
BD1018 B-Chemical 1
, O 0
BD1063 B-Chemical 1
and O 0
LR132 B-Chemical 1
significantly O 0
attenuated O 0
the O 0
locomotor O 0
stimulatory O 0
effects O 0
of O 0
cocaine B-Chemical 1
. O 0

To O 0
further O 0
validate O 0
the O 0
hypothesis O 0
that O 0
the O 0
anti O 0
- O 0
cocaine B-Chemical 1
effects O 0
of O 0
the O 0
novel O 0
ligands O 0
involved O 0
antagonism O 0
of O 0
sigma O 0
receptors O 0
, O 0
an O 0
antisense O 0
oligodeoxynucleotide B-Chemical 1
against O 0
sigma1 O 0
receptors O 0
was O 0
also O 0
shown O 0
to O 0
significantly O 0
attenuate O 0
the O 0
convulsive B-Disease 1
and O 0
locomotor O 0
stimulatory O 0
effects O 0
of O 0
cocaine B-Chemical 1
. O 0

Together O 0
, O 0
the O 0
data O 0
suggests O 0
that O 0
functional O 0
antagonism O 0
of O 0
sigma O 0
receptors O 0
is O 0
capable O 0
of O 0
attenuating O 0
a O 0
number O 0
of O 0
cocaine B-Chemical 1
- O 0
induced O 0
behaviors O 0
. O 0

Ranitidine B-Chemical 1
- O 0
induced O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
in O 0
a O 0
cadaveric O 0
renal O 0
allograft O 0
. O 0

Ranitidine B-Chemical 1
frequently O 0
is O 0
used O 0
for O 0
preventing O 0
peptic O 0
ulceration O 0
after O 0
renal O 0
transplantation O 0
. O 0

This O 0
drug O 0
occasionally O 0
has O 0
been O 0
associated O 0
with O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
in O 0
native O 0
kidneys O 0
. O 0

There O 0
are O 0
no O 0
similar O 0
reports O 0
with O 0
renal O 0
transplantation O 0
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
ranitidine B-Chemical 1
- O 0
induced O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
in O 0
a O 0
recipient O 0
of O 0
a O 0
cadaveric O 0
renal O 0
allograft O 0
presenting O 0
with O 0
acute O 0
allograft O 0
dysfunction O 0
within O 0
48 O 0
hours O 0
of O 0
exposure O 0
to O 0
the O 0
drug O 0
. O 0

The O 0
biopsy O 0
specimen O 0
showed O 0
pathognomonic O 0
features O 0
, O 0
including O 0
eosinophilic O 0
infiltration O 0
of O 0
the O 0
interstitial O 0
compartment O 0
. O 0

Allograft O 0
function O 0
improved O 0
rapidly O 0
and O 0
returned O 0
to O 0
baseline O 0
after O 0
stopping O 0
the O 0
drug O 0
. O 0

Liver B-Disease 1
disease I-Disease 1
caused O 0
by O 0
propylthiouracil B-Chemical 1
. O 0

This O 0
report O 0
presents O 0
the O 0
clinical O 0
, O 0
laboratory O 0
, O 0
and O 0
light O 0
and O 0
electron O 0
microscopic O 0
observations O 0
on O 0
a O 0
patient O 0
with O 0
chronic B-Disease 1
active I-Disease 1
( I-Disease 1
aggressive I-Disease 1
) I-Disease 1
hepatitis I-Disease 1
caused O 0
by O 0
the O 0
administration O 0
of O 0
propylthiouracil B-Chemical 1
. O 0

This O 0
is O 0
an O 0
addition O 0
to O 0
the O 0
list O 0
of O 0
drugs O 0
that O 0
must O 0
be O 0
considered O 0
in O 0
the O 0
evaluation O 0
of O 0
chronic O 0
liver B-Disease 1
disease I-Disease 1
. O 0

Withdrawal B-Disease 1
- I-Disease 1
emergent I-Disease 1
rabbit I-Disease 1
syndrome I-Disease 1
during O 0
dose O 0
reduction O 0
of O 0
risperidone B-Chemical 1
. O 0

Rabbit B-Disease 1
syndrome I-Disease 1
( O 0
RS B-Disease 1
) O 0
is O 0
a O 0
rare O 0
extrapyramidal O 0
side O 0
effect O 0
caused O 0
by O 0
prolonged O 0
neuroleptic O 0
medication O 0
. O 0

Here O 0
we O 0
present O 0
a O 0
case O 0
of O 0
withdrawal B-Disease 1
- I-Disease 1
emergent I-Disease 1
RS I-Disease 1
, O 0
which O 0
is O 0
the O 0
first O 0
of O 0
its O 0
kind O 0
to O 0
be O 0
reported O 0
. O 0

The O 0
patient O 0
developed O 0
RS B-Disease 1
during O 0
dose O 0
reduction O 0
of O 0
risperidone B-Chemical 1
. O 0

The O 0
symptom O 0
was O 0
treated O 0
successfully O 0
with O 0
trihexyphenidyl B-Chemical 1
anticholinergic O 0
therapy O 0
. O 0

The O 0
underlying O 0
mechanism O 0
of O 0
withdrawal B-Disease 1
- I-Disease 1
emergent I-Disease 1
RS I-Disease 1
in O 0
the O 0
present O 0
case O 0
may O 0
have O 0
been O 0
related O 0
to O 0
the O 0
pharmacological O 0
profile O 0
of O 0
risperidone B-Chemical 1
, O 0
a O 0
serotonin B-Chemical 1
- O 0
dopamine B-Chemical 1
antagonist O 0
, O 0
suggesting O 0
the O 0
pathophysiologic O 0
influence O 0
of O 0
the O 0
serotonin B-Chemical 1
system O 0
in O 0
the O 0
development O 0
of O 0
RS B-Disease 1
. O 0

Pharmacokinetic O 0
/ O 0
pharmacodynamic O 0
assessment O 0
of O 0
the O 0
effects O 0
of O 0
E4031 B-Chemical 1
, O 0
cisapride B-Chemical 1
, O 0
terfenadine B-Chemical 1
and O 0
terodiline B-Chemical 1
on O 0
monophasic O 0
action O 0
potential O 0
duration O 0
in O 0
dog O 0
. O 0

1 O 0
. O 0

Torsades B-Disease 1
de I-Disease 1
pointes I-Disease 1
( O 0
TDP B-Disease 1
) O 0
is O 0
a O 0
potentially O 0
fatal O 0
ventricular B-Disease 1
tachycardia I-Disease 1
associated O 0
with O 0
increases O 0
in O 0
QT O 0
interval O 0
and O 0
monophasic O 0
action O 0
potential O 0
duration O 0
( O 0
MAPD O 0
) O 0
. O 0

TDP B-Disease 1
is O 0
a O 0
side O 0
- O 0
effect O 0
that O 0
has O 0
led O 0
to O 0
withdrawal O 0
of O 0
several O 0
drugs O 0
from O 0
the O 0
market O 0
( O 0
e O 0
. O 0
g O 0
. O 0
terfenadine B-Chemical 1
and O 0
terodiline B-Chemical 1
) O 0
. O 0

2 O 0
. O 0

The O 0
potential O 0
of O 0
compounds O 0
to O 0
cause O 0
TDP B-Disease 1
was O 0
evaluated O 0
by O 0
monitoring O 0
their O 0
effects O 0
on O 0
MAPD O 0
in O 0
dog O 0
. O 0

Four O 0
compounds O 0
known O 0
to O 0
increase O 0
QT O 0
interval O 0
and O 0
cause O 0
TDP B-Disease 1
were O 0
investigated O 0
: O 0
terfenadine B-Chemical 1
, O 0
terodiline B-Chemical 1
, O 0
cisapride B-Chemical 1
and O 0
E4031 B-Chemical 1
. O 0

On O 0
the O 0
basis O 0
that O 0
only O 0
free O 0
drug O 0
in O 0
the O 0
systemic O 0
circulation O 0
will O 0
elicit O 0
a O 0
pharmacological O 0
response O 0
target O 0
, O 0
free O 0
concentrations O 0
in O 0
plasma O 0
were O 0
selected O 0
to O 0
mimic O 0
the O 0
free O 0
drug O 0
exposures O 0
in O 0
man O 0
. O 0

Infusion O 0
regimens O 0
were O 0
designed O 0
that O 0
rapidly O 0
achieved O 0
and O 0
maintained O 0
target O 0
- O 0
free O 0
concentrations O 0
of O 0
these O 0
drugs O 0
in O 0
plasma O 0
and O 0
data O 0
on O 0
the O 0
relationship O 0
between O 0
free O 0
concentration O 0
and O 0
changes O 0
in O 0
MAPD O 0
were O 0
obtained O 0
for O 0
these O 0
compounds O 0
. O 0

3 O 0
. O 0

These O 0
data O 0
indicate O 0
that O 0
the O 0
free O 0
ED50 O 0
in O 0
plasma O 0
for O 0
terfenadine B-Chemical 1
( O 0
1 O 0
. O 0
9 O 0
nM O 0
) O 0
, O 0
terodiline B-Chemical 1
( O 0
76 O 0
nM O 0
) O 0
, O 0
cisapride B-Chemical 1
( O 0
11 O 0
nM O 0
) O 0
and O 0
E4031 B-Chemical 1
( O 0
1 O 0
. O 0
9 O 0
nM O 0
) O 0
closely O 0
correlate O 0
with O 0
the O 0
free O 0
concentration O 0
in O 0
man O 0
causing O 0
QT O 0
effects O 0
. O 0

For O 0
compounds O 0
that O 0
have O 0
shown O 0
TDP B-Disease 1
in O 0
the O 0
clinic O 0
( O 0
terfenadine B-Chemical 1
, O 0
terodiline B-Chemical 1
, O 0
cisapride B-Chemical 1
) O 0
there O 0
is O 0
little O 0
differentiation O 0
between O 0
the O 0
dog O 0
ED50 O 0
and O 0
the O 0
efficacious O 0
free O 0
plasma O 0
concentrations O 0
in O 0
man O 0
( O 0
< O 0
10 O 0
- O 0
fold O 0
) O 0
reflecting O 0
their O 0
limited O 0
safety O 0
margins O 0
. O 0

These O 0
data O 0
underline O 0
the O 0
need O 0
to O 0
maximize O 0
the O 0
therapeutic O 0
ratio O 0
with O 0
respect O 0
to O 0
TDP B-Disease 1
in O 0
potential O 0
development O 0
candidates O 0
and O 0
the O 0
importance O 0
of O 0
using O 0
free O 0
drug O 0
concentrations O 0
in O 0
pharmacokinetic O 0
/ O 0
pharmacodynamic O 0
studies O 0
. O 0

Bladder O 0
retention B-Disease 1
of I-Disease 1
urine I-Disease 1
as O 0
a O 0
result O 0
of O 0
continuous O 0
intravenous O 0
infusion O 0
of O 0
fentanyl B-Chemical 1
: O 0
2 O 0
case O 0
reports O 0
. O 0

Sedation O 0
has O 0
been O 0
commonly O 0
used O 0
in O 0
the O 0
neonate O 0
to O 0
decrease O 0
the O 0
stress O 0
and O 0
pain B-Disease 1
from O 0
the O 0
noxious O 0
stimuli O 0
and O 0
invasive O 0
procedures O 0
in O 0
the O 0
neonatal O 0
intensive O 0
care O 0
unit O 0
, O 0
as O 0
well O 0
as O 0
to O 0
facilitate O 0
synchrony O 0
between O 0
ventilator O 0
and O 0
spontaneous O 0
breaths O 0
. O 0

Fentanyl B-Chemical 1
, O 0
an O 0
opioid O 0
analgesic O 0
, O 0
is O 0
frequently O 0
used O 0
in O 0
the O 0
neonatal O 0
intensive O 0
care O 0
unit O 0
setting O 0
for O 0
these O 0
very O 0
purposes O 0
. O 0

Various O 0
reported O 0
side O 0
effects O 0
of O 0
fentanyl B-Chemical 1
administration O 0
include O 0
chest B-Disease 1
wall I-Disease 1
rigidity I-Disease 1
, O 0
hypotension B-Disease 1
, O 0
respiratory B-Disease 1
depression I-Disease 1
, O 0
and O 0
bradycardia B-Disease 1
. O 0

Here O 0
, O 0
2 O 0
cases O 0
of O 0
urinary B-Disease 1
bladder I-Disease 1
retention I-Disease 1
leading O 0
to O 0
renal O 0
pelvocalyceal O 0
dilatation O 0
mimicking O 0
hydronephrosis B-Disease 1
as O 0
a O 0
result O 0
of O 0
continuous O 0
infusion O 0
of O 0
fentanyl B-Chemical 1
are O 0
reported O 0
. O 0

Fatal O 0
myeloencephalopathy B-Disease 1
due O 0
to O 0
accidental O 0
intrathecal O 0
vincristin B-Chemical 1
administration O 0
: O 0
a O 0
report O 0
of O 0
two O 0
cases O 0
. O 0

We O 0
report O 0
on O 0
two O 0
fatal O 0
cases O 0
of O 0
accidental O 0
intrathecal O 0
vincristine B-Chemical 1
instillation O 0
in O 0
a O 0
5 O 0
- O 0
year O 0
old O 0
girl O 0
with O 0
recurrent O 0
acute B-Disease 1
lymphoblastic I-Disease 1
leucemia I-Disease 1
and O 0
a O 0
57 O 0
- O 0
year O 0
old O 0
man O 0
with O 0
lymphoblastic B-Disease 1
lymphoma I-Disease 1
. O 0

The O 0
girl O 0
died O 0
seven O 0
days O 0
, O 0
the O 0
man O 0
four O 0
weeks O 0
after O 0
intrathecal O 0
injection O 0
of O 0
vincristine B-Chemical 1
. O 0

Clinically O 0
, O 0
the O 0
onset O 0
was O 0
characterized O 0
by O 0
the O 0
signs O 0
of O 0
opistothonus B-Disease 1
, I-Disease 1
sensory I-Disease 1
and I-Disease 1
motor I-Disease 1
dysfunction I-Disease 1
and O 0
ascending O 0
paralysis B-Disease 1
. O 0

Histological O 0
and O 0
immunohistochemical O 0
investigations O 0
( O 0
HE O 0
- O 0
LFB O 0
, O 0
CD O 0
- O 0
68 O 0
, O 0
Neurofilament O 0
) O 0
revealed O 0
degeneration B-Disease 1
of I-Disease 1
myelin I-Disease 1
and I-Disease 1
axons I-Disease 1
as O 0
well O 0
as O 0
pseudocystic B-Disease 1
transformation I-Disease 1
in O 0
areas O 0
exposed O 0
to O 0
vincristine B-Chemical 1
, O 0
accompanied O 0
by O 0
secondary O 0
changes O 0
with O 0
numerous O 0
prominent O 0
macrophages O 0
. O 0

The O 0
clinical O 0
course O 0
and O 0
histopathological O 0
results O 0
of O 0
the O 0
two O 0
cases O 0
are O 0
presented O 0
. O 0

A O 0
review O 0
of O 0
all O 0
reported O 0
cases O 0
in O 0
the O 0
literature O 0
is O 0
given O 0
. O 0

A O 0
better O 0
controlled O 0
regimen O 0
for O 0
administering O 0
vincristine B-Chemical 1
and O 0
intrathecal O 0
chemotherapy O 0
is O 0
recommended O 0
. O 0

Palpebral B-Disease 1
twitching I-Disease 1
in O 0
a O 0
depressed B-Disease 1
adolescent O 0
on O 0
citalopram B-Chemical 1
. O 0

Current O 0
estimates O 0
suggest O 0
that O 0
between O 0
0 O 0
. O 0
4 O 0
% O 0
and O 0
8 O 0
. O 0
3 O 0
% O 0
of O 0
children O 0
and O 0
adolescents O 0
are O 0
affected O 0
by O 0
major B-Disease 1
depression I-Disease 1
. O 0

We O 0
report O 0
a O 0
favorable O 0
response O 0
to O 0
treatment O 0
with O 0
citalopram B-Chemical 1
by O 0
a O 0
15 O 0
- O 0
year O 0
- O 0
old O 0
boy O 0
with O 0
major B-Disease 1
depression I-Disease 1
who O 0
exhibited O 0
palpebral B-Disease 1
twitching I-Disease 1
during O 0
his O 0
first O 0
2 O 0
weeks O 0
of O 0
treatment O 0
. O 0

This O 0
may O 0
have O 0
been O 0
a O 0
side O 0
effect O 0
of O 0
citalopram B-Chemical 1
as O 0
it O 0
remitted O 0
with O 0
redistribution O 0
of O 0
doses O 0
. O 0

The O 0
3 O 0
- O 0
week O 0
sulphasalazine B-Chemical 1
syndrome O 0
strikes O 0
again O 0
. O 0

A O 0
34 O 0
- O 0
year O 0
- O 0
old O 0
lady O 0
developed O 0
a O 0
constellation O 0
of O 0
dermatitis B-Disease 1
, O 0
fever B-Disease 1
, O 0
lymphadenopathy B-Disease 1
and O 0
hepatitis B-Disease 1
, O 0
beginning O 0
on O 0
the O 0
17th O 0
day O 0
of O 0
a O 0
course O 0
of O 0
oral O 0
sulphasalazine B-Chemical 1
for O 0
sero O 0
- O 0
negative O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
. O 0

Cervical O 0
and O 0
inguinal O 0
lymph O 0
node O 0
biopsies O 0
showed O 0
the O 0
features O 0
of O 0
severe O 0
necrotising O 0
lymphadenitis B-Disease 1
, O 0
associated O 0
with O 0
erythrophagocytosis O 0
and O 0
prominent O 0
eosinophilic O 0
infiltrates O 0
, O 0
without O 0
viral O 0
inclusion O 0
bodies O 0
, O 0
suggestive O 0
of O 0
an O 0
adverse B-Disease 1
drug I-Disease 1
reaction I-Disease 1
. O 0
A O 0
week O 0
later O 0
, O 0
fulminant O 0
drug B-Disease 1
- I-Disease 1
induced I-Disease 1
hepatitis I-Disease 1
, O 0
associated O 0
with O 0
the O 0
presence O 0
of O 0
anti O 0
- O 0
nuclear O 0
autoantibodies O 0
( O 0
but O 0
not O 0
with O 0
other O 0
markers O 0
of O 0
autoimmunity B-Disease 1
) O 0
, O 0
and O 0
accompanied O 0
by O 0
multi B-Disease 1
- I-Disease 1
organ I-Disease 1
failure I-Disease 1
and O 0
sepsis B-Disease 1
, O 0
supervened O 0
. O 0

She O 0
subsequently O 0
died O 0
some O 0
5 O 0
weeks O 0
after O 0
the O 0
commencement O 0
of O 0
her O 0
drug O 0
therapy O 0
. O 0
Post O 0
- O 0
mortem O 0
examination O 0
showed O 0
evidence O 0
of O 0
massive B-Disease 1
hepatocellular I-Disease 1
necrosis I-Disease 1
, O 0
acute O 0
hypersensitivity O 0
myocarditis B-Disease 1
, O 0
focal O 0
acute O 0
tubulo O 0
- O 0
interstitial O 0
nephritis B-Disease 1
and O 0
extensive O 0
bone B-Disease 1
marrow I-Disease 1
necrosis I-Disease 1
, O 0
with O 0
no O 0
evidence O 0
of O 0
malignancy B-Disease 1
. O 0

It O 0
is O 0
thought O 0
that O 0
the O 0
clinico O 0
- O 0
pathological O 0
features O 0
and O 0
chronology O 0
of O 0
this O 0
case O 0
bore O 0
the O 0
hallmarks O 0
of O 0
the O 0
so O 0
- O 0
called O 0
" O 0
3 O 0
- O 0
week O 0
sulphasalazine B-Chemical 1
syndrome O 0
" O 0
, O 0
a O 0
rare O 0
, O 0
but O 0
often O 0
fatal O 0
, O 0
immunoallergic O 0
reaction O 0
to O 0
sulphasalazine B-Chemical 1
. O 0

Intravenous O 0
administration O 0
of O 0
prochlorperazine B-Chemical 1
by O 0
15 O 0
- O 0
minute O 0
infusion O 0
versus O 0
2 O 0
- O 0
minute O 0
bolus O 0
does O 0
not O 0
affect O 0
the O 0
incidence O 0
of O 0
akathisia B-Disease 1
: O 0
a O 0
prospective O 0
, O 0
randomized O 0
, O 0
controlled O 0
trial O 0
. O 0

STUDY O 0
OBJECTIVE O 0
: O 0
We O 0
sought O 0
to O 0
compare O 0
the O 0
rate O 0
of O 0
akathisia B-Disease 1
after O 0
administration O 0
of O 0
intravenous O 0
prochlorperazine B-Chemical 1
as O 0
a O 0
2 O 0
- O 0
minute O 0
bolus O 0
or O 0
15 O 0
- O 0
minute O 0
infusion O 0
. O 0

METHODS O 0
: O 0
We O 0
conducted O 0
a O 0
prospective O 0
, O 0
randomized O 0
, O 0
double O 0
- O 0
blind O 0
study O 0
in O 0
the O 0
emergency O 0
department O 0
of O 0
a O 0
central O 0
- O 0
city O 0
teaching O 0
hospital O 0
. O 0

Patients O 0
aged O 0
18 O 0
years O 0
or O 0
older O 0
treated O 0
with O 0
prochlorperazine B-Chemical 1
for O 0
headache B-Disease 1
, O 0
nausea B-Disease 1
, O 0
or O 0
vomiting B-Disease 1
were O 0
eligible O 0
for O 0
inclusion O 0
. O 0

Study O 0
participants O 0
were O 0
randomized O 0
to O 0
receive O 0
10 O 0
mg O 0
of O 0
prochlorperazine B-Chemical 1
administered O 0
intravenously O 0
by O 0
means O 0
of O 0
2 O 0
- O 0
minute O 0
push O 0
( O 0
bolus O 0
group O 0
) O 0
or O 0
10 O 0
mg O 0
diluted O 0
in O 0
50 O 0
mL O 0
of O 0
normal O 0
saline O 0
solution O 0
administered O 0
by O 0
means O 0
of O 0
intravenous O 0
infusion O 0
during O 0
a O 0
15 O 0
- O 0
minute O 0
period O 0
( O 0
infusion O 0
group O 0
) O 0
. O 0

The O 0
main O 0
outcome O 0
was O 0
the O 0
number O 0
of O 0
study O 0
participants O 0
experiencing O 0
akathisia B-Disease 1
within O 0
60 O 0
minutes O 0
of O 0
administration O 0
. O 0

Akathisia O 0
was O 0
defined O 0
as O 0
either O 0
a O 0
spontaneous O 0
report O 0
of O 0
restlessness O 0
or O 0
agitation B-Disease 1
or O 0
a O 0
change O 0
of O 0
2 O 0
or O 0
more O 0
in O 0
the O 0
patient O 0
- O 0
reported O 0
akathisia B-Disease 1
rating O 0
scale O 0
and O 0
a O 0
change O 0
of O 0
at O 0
least O 0
1 O 0
in O 0
the O 0
investigator O 0
- O 0
observed O 0
akathisia B-Disease 1
rating O 0
scale O 0
. O 0

The O 0
intensity O 0
of O 0
headache B-Disease 1
and O 0
nausea B-Disease 1
was O 0
measured O 0
with O 0
a O 0
100 O 0
- O 0
mm O 0
visual O 0
analog O 0
scale O 0
. O 0

RESULTS O 0
: O 0
One O 0
hundred O 0
patients O 0
were O 0
enrolled O 0
. O 0

One O 0
study O 0
participant O 0
was O 0
excluded O 0
after O 0
protocol O 0
violation O 0
. O 0

Seventy O 0
- O 0
three O 0
percent O 0
( O 0
73 O 0
/ O 0
99 O 0
) O 0
of O 0
the O 0
study O 0
participants O 0
were O 0
treated O 0
for O 0
headache B-Disease 1
and O 0
70 O 0
% O 0
( O 0
70 O 0
/ O 0
99 O 0
) O 0
for O 0
nausea B-Disease 1
. O 0

In O 0
the O 0
bolus O 0
group O 0
, O 0
26 O 0
. O 0
0 O 0
% O 0
( O 0
13 O 0
/ O 0
50 O 0
) O 0
had O 0
akathisia B-Disease 1
compared O 0
with O 0
32 O 0
. O 0
7 O 0
% O 0
( O 0
16 O 0
/ O 0
49 O 0
) O 0
in O 0
the O 0
infusion O 0
group O 0
( O 0
Delta O 0
= O 0
- O 0
6 O 0
. O 0
7 O 0
% O 0
; O 0
95 O 0
% O 0
confidence O 0
interval O 0
[ O 0
CI O 0
] O 0
- O 0
24 O 0
. O 0
6 O 0
% O 0
to O 0
11 O 0
. O 0
2 O 0
% O 0
) O 0
. O 0

The O 0
difference O 0
between O 0
the O 0
bolus O 0
and O 0
infusion O 0
groups O 0
in O 0
the O 0
percentage O 0
of O 0
participants O 0
who O 0
saw O 0
a O 0
50 O 0
% O 0
reduction O 0
in O 0
their O 0
headache B-Disease 1
intensity O 0
within O 0
30 O 0
minutes O 0
was O 0
11 O 0
. O 0
8 O 0
% O 0
( O 0
95 O 0
% O 0
CI O 0
- O 0
9 O 0
. O 0
6 O 0
% O 0
to O 0
33 O 0
. O 0
3 O 0
% O 0
) O 0
. O 0

The O 0
difference O 0
in O 0
the O 0
percentage O 0
of O 0
patients O 0
with O 0
a O 0
50 O 0
% O 0
reduction O 0
in O 0
their O 0
nausea B-Disease 1
was O 0
12 O 0
. O 0
6 O 0
% O 0
( O 0
95 O 0
% O 0
CI O 0
- O 0
4 O 0
. O 0
6 O 0
% O 0
to O 0
29 O 0
. O 0
8 O 0
% O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
A O 0
50 O 0
% O 0
reduction O 0
in O 0
the O 0
incidence O 0
of O 0
akathisia B-Disease 1
when O 0
prochlorperazine B-Chemical 1
was O 0
administered O 0
by O 0
means O 0
of O 0
15 O 0
- O 0
minute O 0
intravenous O 0
infusion O 0
versus O 0
a O 0
2 O 0
- O 0
minute O 0
intravenous O 0
push O 0
was O 0
not O 0
detected O 0
. O 0

The O 0
efficacy O 0
of O 0
prochlorperazine B-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
headache B-Disease 1
and O 0
nausea B-Disease 1
likewise O 0
did O 0
not O 0
appear O 0
to O 0
be O 0
affected O 0
by O 0
the O 0
rate O 0
of O 0
administration O 0
, O 0
although O 0
no O 0
formal O 0
statistical O 0
comparisons O 0
were O 0
made O 0
. O 0

Combined O 0
antiretroviral O 0
therapy O 0
causes O 0
cardiomyopathy B-Disease 1
and O 0
elevates O 0
plasma O 0
lactate B-Chemical 1
in O 0
transgenic O 0
AIDS B-Disease 1
mice O 0
. O 0

Highly O 0
active O 0
antiretroviral O 0
therapy O 0
( O 0
HAART O 0
) O 0
is O 0
implicated O 0
in O 0
cardiomyopathy B-Disease 1
( O 0
CM B-Disease 1
) O 0
and O 0
in O 0
elevated O 0
plasma O 0
lactate B-Chemical 1
( O 0
LA B-Chemical 1
) O 0
in O 0
AIDS B-Disease 1
through O 0
mechanisms O 0
of O 0
mitochondrial B-Disease 1
dysfunction I-Disease 1
. O 0

To O 0
determine O 0
mitochondrial O 0
events O 0
from O 0
HAART O 0
in O 0
vivo O 0
, O 0
8 O 0
- O 0
week O 0
- O 0
old O 0
hemizygous O 0
transgenic O 0
AIDS B-Disease 1
mice O 0
( O 0
NL4 O 0
- O 0
3Delta O 0
gag O 0
/ O 0
pol O 0
; O 0
TG O 0
) O 0
and O 0
wild O 0
- O 0
type O 0
FVB O 0
/ O 0
n O 0
littermates O 0
were O 0
treated O 0
with O 0
the O 0
HAART O 0
combination O 0
of O 0
zidovudine B-Chemical 1
, O 0
lamivudine B-Chemical 1
, O 0
and O 0
indinavir B-Chemical 1
or O 0
vehicle O 0
control O 0
for O 0
10 O 0
days O 0
or O 0
35 O 0
days O 0
. O 0

At O 0
termination O 0
of O 0
the O 0
experiments O 0
, O 0
mice O 0
underwent O 0
echocardiography O 0
, O 0
quantitation O 0
of O 0
abundance O 0
of O 0
molecular O 0
markers O 0
of O 0
CM B-Disease 1
( O 0
ventricular O 0
mRNA O 0
encoding O 0
atrial O 0
natriuretic O 0
factor O 0
[ O 0
ANF O 0
] O 0
and O 0
sarcoplasmic O 0
calcium B-Chemical 1
ATPase O 0
[ O 0
SERCA2 O 0
] O 0
) O 0
, O 0
and O 0
determination O 0
of O 0
plasma O 0
LA B-Chemical 1
. O 0

Myocardial O 0
histologic O 0
features O 0
were O 0
analyzed O 0
semiquantitatively O 0
and O 0
results O 0
were O 0
confirmed O 0
by O 0
transmission O 0
electron O 0
microscopy O 0
. O 0

After O 0
35 O 0
days O 0
in O 0
the O 0
TG O 0
+ O 0
HAART O 0
cohort O 0
, O 0
left O 0
ventricular O 0
mass O 0
increased O 0
160 O 0
% O 0
by O 0
echocardiography O 0
. O 0

Molecularly O 0
, O 0
ANF O 0
mRNA O 0
increased O 0
250 O 0
% O 0
and O 0
SERCA2 O 0
mRNA O 0
decreased O 0
57 O 0
% O 0
. O 0

Biochemically O 0
, O 0
LA B-Chemical 1
was O 0
elevated O 0
( O 0
8 O 0
. O 0
5 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
0 O 0
mM O 0
) O 0
. O 0

Pathologically O 0
, O 0
granular O 0
cytoplasmic O 0
changes O 0
were O 0
found O 0
in O 0
cardiac O 0
myocytes O 0
, O 0
indicating O 0
enlarged O 0
, O 0
damaged O 0
mitochondria O 0
. O 0

Findings O 0
were O 0
confirmed O 0
ultrastructurally O 0
. O 0

No O 0
changes O 0
were O 0
found O 0
in O 0
other O 0
cohorts O 0
. O 0

After O 0
10 O 0
days O 0
, O 0
only O 0
ANF O 0
was O 0
elevated O 0
, O 0
and O 0
only O 0
in O 0
the O 0
TG O 0
+ O 0
HAART O 0
cohort O 0
. O 0

Results O 0
show O 0
that O 0
cumulative O 0
HAART O 0
caused O 0
mitochondrial O 0
CM B-Disease 1
with O 0
elevated O 0
LA B-Chemical 1
in O 0
AIDS B-Disease 1
transgenic O 0
mice O 0
. O 0

A O 0
Phase O 0
II O 0
trial O 0
of O 0
cisplatin B-Chemical 1
plus O 0
WR B-Chemical 1
- I-Chemical 1
2721 I-Chemical 1
( O 0
amifostine B-Chemical 1
) O 0
for O 0
metastatic O 0
breast B-Disease 1
carcinoma I-Disease 1
: O 0
an O 0
Eastern O 0
Cooperative O 0
Oncology O 0
Group O 0
Study O 0
( O 0
E8188 O 0
) O 0
. O 0

BACKGROUND O 0
: O 0
Cisplatin B-Chemical 1
has O 0
minimal O 0
antitumor O 0
activity O 0
when O 0
used O 0
as O 0
second O 0
- O 0
or O 0
third O 0
- O 0
line O 0
treatment O 0
of O 0
metastatic O 0
breast B-Disease 1
carcinoma I-Disease 1
. O 0

Older O 0
reports O 0
suggest O 0
an O 0
objective O 0
response O 0
rate O 0
of O 0
8 O 0
% O 0
when O 0
60 O 0
- O 0
120 O 0
mg O 0
/ O 0
m2 O 0
of O 0
cisplatin B-Chemical 1
is O 0
administered O 0
every O 0
3 O 0
- O 0
4 O 0
weeks O 0
. O 0

Although O 0
a O 0
dose O 0
- O 0
response O 0
effect O 0
has O 0
been O 0
observed O 0
with O 0
cisplatin B-Chemical 1
, O 0
the O 0
dose O 0
- O 0
limiting O 0
toxicities B-Disease 1
associated O 0
with O 0
cisplatin B-Chemical 1
( O 0
e O 0
. O 0
g O 0
. O 0
, O 0
nephrotoxicity B-Disease 1
, O 0
ototoxicity B-Disease 1
, O 0
and O 0
neurotoxicity B-Disease 1
) O 0
have O 0
limited O 0
its O 0
use O 0
as O 0
a O 0
treatment O 0
for O 0
breast B-Disease 1
carcinoma I-Disease 1
. O 0

WR B-Chemical 1
- I-Chemical 1
2721 I-Chemical 1
or O 0
amifostine B-Chemical 1
initially O 0
was O 0
developed O 0
to O 0
protect O 0
military O 0
personnel O 0
in O 0
the O 0
event O 0
of O 0
nuclear O 0
war O 0
. O 0

Amifostine B-Chemical 1
subsequently O 0
was O 0
shown O 0
to O 0
protect O 0
normal O 0
tissues O 0
from O 0
the O 0
toxic O 0
effects O 0
of O 0
alkylating B-Chemical 1
agents I-Chemical 1
and O 0
cisplatin B-Chemical 1
without O 0
decreasing O 0
the O 0
antitumor O 0
effect O 0
of O 0
the O 0
chemotherapy O 0
. O 0

Early O 0
trials O 0
of O 0
cisplatin B-Chemical 1
and O 0
amifostine B-Chemical 1
also O 0
suggested O 0
that O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
cisplatin B-Chemical 1
- O 0
induced O 0
nephrotoxicity B-Disease 1
, O 0
ototoxicity B-Disease 1
, O 0
and O 0
neuropathy B-Disease 1
were O 0
reduced O 0
. O 0

METHODS O 0
: O 0
A O 0
Phase O 0
II O 0
study O 0
of O 0
the O 0
combination O 0
of O 0
cisplatin B-Chemical 1
plus O 0
amifostine B-Chemical 1
was O 0
conducted O 0
in O 0
patients O 0
with O 0
progressive O 0
metastatic O 0
breast B-Disease 1
carcinoma I-Disease 1
who O 0
had O 0
received O 0
one O 0
, O 0
but O 0
not O 0
more O 0
than O 0
one O 0
, O 0
chemotherapy O 0
regimen O 0
for O 0
metastatic O 0
disease O 0
. O 0

Patients O 0
received O 0
amifostine B-Chemical 1
, O 0
910 O 0
mg O 0
/ O 0
m2 O 0
intravenously O 0
over O 0
15 O 0
minutes O 0
. O 0

After O 0
completion O 0
of O 0
the O 0
amifostine B-Chemical 1
infusion O 0
, O 0
cisplatin B-Chemical 1
120 O 0
mg O 0
/ O 0
m2 O 0
was O 0
administered O 0
over O 0
30 O 0
minutes O 0
. O 0

Intravenous O 0
hydration O 0
and O 0
mannitol B-Chemical 1
was O 0
administered O 0
before O 0
and O 0
after O 0
cisplatin B-Chemical 1
. O 0

Treatment O 0
was O 0
administered O 0
every O 0
3 O 0
weeks O 0
until O 0
disease O 0
progression O 0
. O 0

RESULTS O 0
: O 0
Forty O 0
- O 0
four O 0
patients O 0
were O 0
enrolled O 0
in O 0
the O 0
study O 0
of O 0
which O 0
7 O 0
( O 0
16 O 0
% O 0
) O 0
were O 0
ineligible O 0
. O 0

A O 0
median O 0
of O 0
2 O 0
cycles O 0
of O 0
therapy O 0
was O 0
administered O 0
to O 0
the O 0
37 O 0
eligible O 0
patients O 0
. O 0

Six O 0
partial O 0
responses O 0
were O 0
observed O 0
for O 0
an O 0
overall O 0
response O 0
rate O 0
of O 0
16 O 0
% O 0
. O 0

Most O 0
patients O 0
( O 0
57 O 0
% O 0
) O 0
stopped O 0
treatment O 0
because O 0
of O 0
disease O 0
progression O 0
. O 0

Neurologic B-Disease 1
toxicity I-Disease 1
was O 0
reported O 0
in O 0
52 O 0
% O 0
of O 0
patients O 0
. O 0

Seven O 0
different O 0
life O 0
- O 0
threatening O 0
toxicities B-Disease 1
were O 0
observed O 0
in O 0
patients O 0
while O 0
receiving O 0
treatment O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
combination O 0
of O 0
cisplatin B-Chemical 1
and O 0
amifostine B-Chemical 1
in O 0
this O 0
study O 0
resulted O 0
in O 0
an O 0
overall O 0
response O 0
rate O 0
of O 0
16 O 0
% O 0
. O 0

Neither O 0
a O 0
tumor B-Disease 1
- O 0
protective O 0
effect O 0
nor O 0
reduced O 0
toxicity B-Disease 1
to O 0
normal O 0
tissues O 0
was O 0
observed O 0
with O 0
the O 0
addition O 0
of O 0
amifostine B-Chemical 1
to O 0
cisplatin B-Chemical 1
in O 0
this O 0
trial O 0
. O 0

Oral B-Chemical 1
contraceptives I-Chemical 1
and O 0
the O 0
risk O 0
of O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

BACKGROUND O 0
: O 0
An O 0
association O 0
between O 0
the O 0
use O 0
of O 0
oral B-Chemical 1
contraceptives I-Chemical 1
and O 0
the O 0
risk O 0
of O 0
myocardial B-Disease 1
infarction I-Disease 1
has O 0
been O 0
found O 0
in O 0
some O 0
, O 0
but O 0
not O 0
all O 0
, O 0
studies O 0
. O 0

We O 0
investigated O 0
this O 0
association O 0
, O 0
according O 0
to O 0
the O 0
type O 0
of O 0
progestagen B-Chemical 1
included O 0
in O 0
third O 0
- O 0
generation O 0
( O 0
i O 0
. O 0
e O 0
. O 0
, O 0
desogestrel B-Chemical 1
or O 0
gestodene B-Chemical 1
) O 0
and O 0
second O 0
- O 0
generation O 0
( O 0
i O 0
. O 0
e O 0
. O 0
, O 0
levonorgestrel B-Chemical 1
) O 0
oral B-Chemical 1
contraceptives I-Chemical 1
, O 0
the O 0
dose O 0
of O 0
estrogen B-Chemical 1
, O 0
and O 0
the O 0
presence O 0
or O 0
absence O 0
of O 0
prothrombotic O 0
mutations O 0
METHODS O 0
: O 0
In O 0
a O 0
nationwide O 0
, O 0
population O 0
- O 0
based O 0
, O 0
case O 0
- O 0
control O 0
study O 0
, O 0
we O 0
identified O 0
and O 0
enrolled O 0
248 O 0
women O 0
18 O 0
through O 0
49 O 0
years O 0
of O 0
age O 0
who O 0
had O 0
had O 0
a O 0
first O 0
myocardial B-Disease 1
infarction I-Disease 1
between O 0
1990 O 0
and O 0
1995 O 0
and O 0
925 O 0
control O 0
women O 0
who O 0
had O 0
not O 0
had O 0
a O 0
myocardial B-Disease 1
infarction I-Disease 1
and O 0
who O 0
were O 0
matched O 0
for O 0
age O 0
, O 0
calendar O 0
year O 0
of O 0
the O 0
index O 0
event O 0
, O 0
and O 0
area O 0
of O 0
residence O 0
. O 0

Subjects O 0
supplied O 0
information O 0
on O 0
oral B-Chemical 1
- I-Chemical 1
contraceptive I-Chemical 1
use O 0
and O 0
major O 0
cardiovascular O 0
risk O 0
factors O 0
. O 0

An O 0
analysis O 0
for O 0
factor O 0
V O 0
Leiden O 0
and O 0
the O 0
G20210A O 0
mutation O 0
in O 0
the O 0
prothrombin O 0
gene O 0
was O 0
conducted O 0
in O 0
217 O 0
patients O 0
and O 0
763 O 0
controls O 0
RESULTS O 0
: O 0
The O 0
odds O 0
ratio O 0
for O 0
myocardial B-Disease 1
infarction I-Disease 1
among O 0
women O 0
who O 0
used O 0
any O 0
type O 0
of O 0
combined O 0
oral B-Chemical 1
contraceptive I-Chemical 1
, O 0
as O 0
compared O 0
with O 0
nonusers O 0
, O 0
was O 0
2 O 0
. O 0
0 O 0
( O 0
95 O 0
percent O 0
confidence O 0
interval O 0
, O 0
1 O 0
. O 0
5 O 0
to O 0
2 O 0
. O 0
8 O 0
) O 0
. O 0

The O 0
adjusted O 0
odds O 0
ratio O 0
was O 0
2 O 0
. O 0
5 O 0
( O 0
95 O 0
percent O 0
confidence O 0
interval O 0
, O 0
1 O 0
. O 0
5 O 0
to O 0
4 O 0
. O 0
1 O 0
) O 0
among O 0
women O 0
who O 0
used O 0
second O 0
- O 0
generation O 0
oral B-Chemical 1
contraceptives I-Chemical 1
and O 0
1 O 0
. O 0
3 O 0
( O 0
95 O 0
percent O 0
confidence O 0
interval O 0
, O 0
0 O 0
. O 0
7 O 0
to O 0
2 O 0
. O 0
5 O 0
) O 0
among O 0
those O 0
who O 0
used O 0
third O 0
- O 0
generation O 0
oral B-Chemical 1
contraceptives I-Chemical 1
. O 0

Among O 0
women O 0
who O 0
used O 0
oral B-Chemical 1
contraceptives I-Chemical 1
, O 0
the O 0
odds O 0
ratio O 0
was O 0
2 O 0
. O 0
1 O 0
( O 0
95 O 0
percent O 0
confidence O 0
interval O 0
, O 0
1 O 0
. O 0
5 O 0
to O 0
3 O 0
. O 0
0 O 0
) O 0
for O 0
those O 0
without O 0
a O 0
prothrombotic O 0
mutation O 0
and O 0
1 O 0
. O 0
9 O 0
( O 0
95 O 0
percent O 0
confidence O 0
interval O 0
, O 0
0 O 0
. O 0
6 O 0
to O 0
5 O 0
. O 0
5 O 0
) O 0
for O 0
those O 0
with O 0
a O 0
mutation O 0
CONCLUSIONS O 0
: O 0
The O 0
risk O 0
of O 0
myocardial B-Disease 1
infarction I-Disease 1
was O 0
increased O 0
among O 0
women O 0
who O 0
used O 0
second O 0
- O 0
generation O 0
oral B-Chemical 1
contraceptives I-Chemical 1
. O 0

The O 0
results O 0
with O 0
respect O 0
to O 0
the O 0
use O 0
of O 0
third O 0
- O 0
generation O 0
oral B-Chemical 1
contraceptives I-Chemical 1
were O 0
inconclusive O 0
but O 0
suggested O 0
that O 0
the O 0
risk O 0
was O 0
lower O 0
than O 0
the O 0
risk O 0
associated O 0
with O 0
second O 0
- O 0
generation O 0
oral B-Chemical 1
contraceptives I-Chemical 1
. O 0

The O 0
risk O 0
of O 0
myocardial B-Disease 1
infarction I-Disease 1
was O 0
similar O 0
among O 0
women O 0
who O 0
used O 0
oral B-Chemical 1
contraceptives I-Chemical 1
whether O 0
or O 0
not O 0
they O 0
had O 0
a O 0
prothrombotic O 0
mutation O 0
. O 0

End B-Disease 1
- I-Disease 1
stage I-Disease 1
renal I-Disease 1
disease I-Disease 1
( O 0
ESRD B-Disease 1
) O 0
after O 0
orthotopic O 0
liver O 0
transplantation O 0
( O 0
OLTX O 0
) O 0
using O 0
calcineurin O 0
- O 0
based O 0
immunotherapy O 0
: O 0
risk O 0
of O 0
development O 0
and O 0
treatment O 0
. O 0

BACKGROUND O 0
: O 0
The O 0
calcineurin O 0
inhibitors O 0
cyclosporine B-Chemical 1
and O 0
tacrolimus B-Chemical 1
are O 0
both O 0
known O 0
to O 0
be O 0
nephrotoxic B-Disease 1
. O 0

Their O 0
use O 0
in O 0
orthotopic O 0
liver O 0
transplantation O 0
( O 0
OLTX O 0
) O 0
has O 0
dramatically O 0
improved O 0
success O 0
rates O 0
. O 0

Recently O 0
, O 0
however O 0
, O 0
we O 0
have O 0
had O 0
an O 0
increase O 0
of O 0
patients O 0
who O 0
are O 0
presenting O 0
after O 0
OLTX O 0
with O 0
end B-Disease 1
- I-Disease 1
stage I-Disease 1
renal I-Disease 1
disease I-Disease 1
( O 0
ESRD B-Disease 1
) O 0
. O 0

This O 0
retrospective O 0
study O 0
examines O 0
the O 0
incidence O 0
and O 0
treatment O 0
of O 0
ESRD B-Disease 1
and O 0
chronic B-Disease 1
renal I-Disease 1
failure I-Disease 1
( O 0
CRF B-Disease 1
) O 0
in O 0
OLTX O 0
patients O 0
. O 0

METHODS O 0
: O 0
Patients O 0
receiving O 0
an O 0
OLTX O 0
only O 0
from O 0
June O 0
1985 O 0
through O 0
December O 0
of O 0
1994 O 0
who O 0
survived O 0
6 O 0
months O 0
postoperatively O 0
were O 0
studied O 0
( O 0
n O 0
= O 0
834 O 0
) O 0
. O 0

Our O 0
prospectively O 0
collected O 0
database O 0
was O 0
the O 0
source O 0
of O 0
information O 0
. O 0

Patients O 0
were O 0
divided O 0
into O 0
three O 0
groups O 0
: O 0
Controls O 0
, O 0
no O 0
CRF B-Disease 1
or O 0
ESRD B-Disease 1
, O 0
n O 0
= O 0
748 O 0
; O 0
CRF B-Disease 1
, O 0
sustained O 0
serum O 0
creatinine B-Chemical 1
> O 0
2 O 0
. O 0
5 O 0
mg O 0
/ O 0
dl O 0
, O 0
n O 0
= O 0
41 O 0
; O 0
and O 0
ESRD B-Disease 1
, O 0
n O 0
= O 0
45 O 0
. O 0

Groups O 0
were O 0
compared O 0
for O 0
preoperative O 0
laboratory O 0
variables O 0
, O 0
diagnosis O 0
, O 0
postoperative O 0
variables O 0
, O 0
survival O 0
, O 0
type O 0
of O 0
ESRD B-Disease 1
therapy O 0
, O 0
and O 0
survival O 0
from O 0
onset O 0
of O 0
ESRD B-Disease 1
. O 0

RESULTS O 0
: O 0
At O 0
13 O 0
years O 0
after O 0
OLTX O 0
, O 0
the O 0
incidence O 0
of O 0
severe O 0
renal B-Disease 1
dysfunction I-Disease 1
was O 0
18 O 0
. O 0
1 O 0
% O 0
( O 0
CRF B-Disease 1
8 O 0
. O 0
6 O 0
% O 0
and O 0
ESRD B-Disease 1
9 O 0
. O 0
5 O 0
% O 0
) O 0
. O 0

Compared O 0
with O 0
control O 0
patients O 0
, O 0
CRF B-Disease 1
and O 0
ESRD B-Disease 1
patients O 0
had O 0
higher O 0
preoperative O 0
serum O 0
creatinine B-Chemical 1
levels O 0
, O 0
a O 0
greater O 0
percentage O 0
of O 0
patients O 0
with O 0
hepatorenal B-Disease 1
syndrome I-Disease 1
, O 0
higher O 0
percentage O 0
requirement O 0
for O 0
dialysis O 0
in O 0
the O 0
first O 0
3 O 0
months O 0
postoperatively O 0
, O 0
and O 0
a O 0
higher O 0
1 O 0
- O 0
year O 0
serum O 0
creatinine B-Chemical 1
. O 0

Multivariate O 0
stepwise O 0
logistic O 0
regression O 0
analysis O 0
using O 0
preoperative O 0
and O 0
postoperative O 0
variables O 0
identified O 0
that O 0
an O 0
increase O 0
of O 0
serum O 0
creatinine B-Chemical 1
compared O 0
with O 0
average O 0
at O 0
1 O 0
year O 0
, O 0
3 O 0
months O 0
, O 0
and O 0
4 O 0
weeks O 0
postoperatively O 0
were O 0
independent O 0
risk O 0
factors O 0
for O 0
the O 0
development O 0
of O 0
CRF B-Disease 1
or O 0
ESRD B-Disease 1
with O 0
odds O 0
ratios O 0
of O 0
2 O 0
. O 0
6 O 0
, O 0
2 O 0
. O 0
2 O 0
, O 0
and O 0
1 O 0
. O 0
6 O 0
, O 0
respectively O 0
. O 0

Overall O 0
survival O 0
from O 0
the O 0
time O 0
of O 0
OLTX O 0
was O 0
not O 0
significantly O 0
different O 0
among O 0
groups O 0
, O 0
but O 0
by O 0
year O 0
13 O 0
, O 0
the O 0
survival O 0
of O 0
the O 0
patients O 0
who O 0
had O 0
ESRD B-Disease 1
was O 0
only O 0
28 O 0
. O 0
2 O 0
% O 0
compared O 0
with O 0
54 O 0
. O 0
6 O 0
% O 0
in O 0
the O 0
control O 0
group O 0
. O 0

Patients O 0
developing O 0
ESRD B-Disease 1
had O 0
a O 0
6 O 0
- O 0
year O 0
survival O 0
after O 0
onset O 0
of O 0
ESRD B-Disease 1
of O 0
27 O 0
% O 0
for O 0
the O 0
patients O 0
receiving O 0
hemodialysis O 0
versus O 0
71 O 0
. O 0
4 O 0
% O 0
for O 0
the O 0
patients O 0
developing O 0
ESRD B-Disease 1
who O 0
subsequently O 0
received O 0
kidney O 0
transplants O 0
. O 0

CONCLUSIONS O 0
: O 0
Patients O 0
who O 0
are O 0
more O 0
than O 0
10 O 0
years O 0
post O 0
- O 0
OLTX O 0
have O 0
CRF B-Disease 1
and O 0
ESRD B-Disease 1
at O 0
a O 0
high O 0
rate O 0
. O 0

The O 0
development O 0
of O 0
ESRD B-Disease 1
decreases O 0
survival O 0
, O 0
particularly O 0
in O 0
those O 0
patients O 0
treated O 0
with O 0
dialysis O 0
only O 0
. O 0

Patients O 0
who O 0
develop O 0
ESRD B-Disease 1
have O 0
a O 0
higher O 0
preoperative O 0
and O 0
1 O 0
- O 0
year O 0
serum O 0
creatinine B-Chemical 1
and O 0
are O 0
more O 0
likely O 0
to O 0
have O 0
hepatorenal B-Disease 1
syndrome I-Disease 1
. O 0

However O 0
, O 0
an O 0
increase O 0
of O 0
serum O 0
creatinine B-Chemical 1
at O 0
various O 0
times O 0
postoperatively O 0
is O 0
more O 0
predictive O 0
of O 0
the O 0
development O 0
of O 0
CRF B-Disease 1
or O 0
ESRD B-Disease 1
. O 0

New O 0
strategies O 0
for O 0
long O 0
- O 0
term O 0
immunosuppression O 0
may O 0
be O 0
needed O 0
to O 0
decrease O 0
this O 0
complication O 0
. O 0

Epileptic B-Disease 1
seizures I-Disease 1
following O 0
cortical O 0
application O 0
of O 0
fibrin O 0
sealants O 0
containing O 0
tranexamic B-Chemical 1
acid I-Chemical 1
in O 0
rats O 0
. O 0

BACKGROUND O 0
: O 0
Fibrin O 0
sealants O 0
( O 0
FS O 0
) O 0
derived O 0
from O 0
human O 0
plasma O 0
are O 0
frequently O 0
used O 0
in O 0
neurosurgery O 0
. O 0

In O 0
order O 0
to O 0
increase O 0
clot O 0
stability O 0
, O 0
FS O 0
typically O 0
contain O 0
aprotinin O 0
, O 0
a O 0
natural O 0
fibrinolysis O 0
inhibitor O 0
. O 0

Recently O 0
, O 0
synthetic O 0
fibrinolysis O 0
inhibitors O 0
such O 0
as O 0
tranexamic B-Chemical 1
acid I-Chemical 1
( O 0
tAMCA B-Chemical 1
) O 0
have O 0
been O 0
considered O 0
as O 0
substitutes O 0
for O 0
aprotinin O 0
. O 0

However O 0
, O 0
tAMCA B-Chemical 1
has O 0
been O 0
shown O 0
to O 0
cause O 0
epileptic B-Disease 1
seizures I-Disease 1
. O 0

We O 0
wanted O 0
to O 0
study O 0
whether O 0
tAMCA B-Chemical 1
retains O 0
its O 0
convulsive B-Disease 1
action O 0
if O 0
incorporated O 0
into O 0
a O 0
FS O 0
. O 0

METHOD O 0
: O 0
FS O 0
containing O 0
aprotinin O 0
or O 0
different O 0
concentrations O 0
of O 0
tAMCA B-Chemical 1
( O 0
0 O 0
. O 0
5 O 0
- O 0
47 O 0
. O 0
5 O 0
mg O 0
/ O 0
ml O 0
) O 0
were O 0
applied O 0
to O 0
the O 0
pial O 0
surface O 0
of O 0
the O 0
cortex O 0
of O 0
anaesthetized O 0
rats O 0
. O 0

The O 0
response O 0
of O 0
the O 0
animals O 0
was O 0
evaluated O 0
using O 0
electroencephalography O 0
and O 0
by O 0
monitoring O 0
the O 0
clinical O 0
behaviour O 0
during O 0
and O 0
after O 0
recovery O 0
from O 0
anaesthesia O 0
. O 0

FINDINGS O 0
: O 0
FS O 0
containing O 0
tAMCA B-Chemical 1
caused O 0
paroxysmal O 0
brain O 0
activity O 0
which O 0
was O 0
associated O 0
with O 0
distinct O 0
convulsive B-Disease 1
behaviours O 0
. O 0

The O 0
degree O 0
of O 0
these O 0
seizures B-Disease 1
increased O 0
with O 0
increasing O 0
concentration O 0
of O 0
tAMCA B-Chemical 1
. O 0

Thus O 0
, O 0
FS O 0
containing O 0
47 O 0
. O 0
5 O 0
mg O 0
/ O 0
ml O 0
tAMCA B-Chemical 1
evoked O 0
generalized B-Disease 1
seizures I-Disease 1
in O 0
all O 0
tested O 0
rats O 0
( O 0
n O 0
= O 0
6 O 0
) O 0
while O 0
the O 0
lowest O 0
concentration O 0
of O 0
tAMCA B-Chemical 1
( O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
ml O 0
) O 0
only O 0
evoked O 0
brief O 0
episodes O 0
of O 0
jerk O 0
- O 0
correlated O 0
convulsive B-Disease 1
potentials O 0
in O 0
1 O 0
of O 0
6 O 0
rats O 0
. O 0

In O 0
contrast O 0
, O 0
FS O 0
containing O 0
aprotinin O 0
did O 0
not O 0
evoke O 0
any O 0
paroxysmal O 0
activity O 0
. O 0

INTERPRETATION O 0
: O 0
Tranexamic B-Chemical 1
acid I-Chemical 1
retains O 0
its O 0
convulsive B-Disease 1
action O 0
within O 0
FS O 0
. O 0

Thus O 0
, O 0
use O 0
of O 0
FS O 0
containing O 0
tAMCA B-Chemical 1
for O 0
surgery O 0
within O 0
or O 0
close O 0
to O 0
the O 0
CNS O 0
may O 0
pose O 0
a O 0
substantial O 0
risk O 0
to O 0
the O 0
patient O 0
. O 0

Sequential O 0
observations O 0
of O 0
exencephaly B-Disease 1
and O 0
subsequent O 0
morphological O 0
changes O 0
by O 0
mouse O 0
exo O 0
utero O 0
development O 0
system O 0
: O 0
analysis O 0
of O 0
the O 0
mechanism O 0
of O 0
transformation O 0
from O 0
exencephaly B-Disease 1
to O 0
anencephaly B-Disease 1
. O 0

Anencephaly B-Disease 1
has O 0
been O 0
suggested O 0
to O 0
develop O 0
from O 0
exencephaly B-Disease 1
; O 0
however O 0
, O 0
there O 0
is O 0
little O 0
direct O 0
experimental O 0
evidence O 0
to O 0
support O 0
this O 0
, O 0
and O 0
the O 0
mechanism O 0
of O 0
transformation O 0
remains O 0
unclear O 0
. O 0

We O 0
examined O 0
this O 0
theory O 0
using O 0
the O 0
exo O 0
utero O 0
development O 0
system O 0
that O 0
allows O 0
direct O 0
and O 0
sequential O 0
observations O 0
of O 0
mid O 0
- O 0
to O 0
late O 0
- O 0
gestation O 0
mouse O 0
embryos O 0
. O 0

We O 0
observed O 0
the O 0
exencephaly B-Disease 1
induced O 0
by O 0
5 B-Chemical 1
- I-Chemical 1
azacytidine I-Chemical 1
at O 0
embryonic O 0
day O 0
13 O 0
. O 0
5 O 0
( O 0
E13 O 0
. O 0
5 O 0
) O 0
, O 0
let O 0
the O 0
embryos O 0
develop O 0
exo O 0
utero O 0
until O 0
E18 O 0
. O 0
5 O 0
, O 0
and O 0
re O 0
- O 0
observed O 0
the O 0
same O 0
embryos O 0
at O 0
E18 O 0
. O 0
5 O 0
. O 0

We O 0
confirmed O 0
several O 0
cases O 0
of O 0
transformation O 0
from O 0
exencephaly B-Disease 1
to O 0
anencephaly B-Disease 1
. O 0

However O 0
, O 0
in O 0
many O 0
cases O 0
, O 0
the O 0
exencephalic B-Disease 1
brain O 0
tissue O 0
was O 0
preserved O 0
with O 0
more O 0
or O 0
less O 0
reduction O 0
during O 0
this O 0
period O 0
. O 0

To O 0
analyze O 0
the O 0
transformation O 0
patterns O 0
, O 0
we O 0
classified O 0
the O 0
exencephaly B-Disease 1
by O 0
size O 0
and O 0
shape O 0
of O 0
the O 0
exencephalic B-Disease 1
tissue O 0
into O 0
several O 0
types O 0
at O 0
E13 O 0
. O 0
5 O 0
and O 0
E18 O 0
. O 0
5 O 0
. O 0

It O 0
was O 0
found O 0
that O 0
the O 0
transformation O 0
of O 0
exencephalic B-Disease 1
tissue O 0
was O 0
not O 0
simply O 0
size O 0
- O 0
dependent O 0
, O 0
and O 0
all O 0
cases O 0
of O 0
anencephaly B-Disease 1
at O 0
E18 O 0
. O 0
5 O 0
resulted O 0
from O 0
embryos O 0
with O 0
a O 0
large O 0
amount O 0
of O 0
exencephalic B-Disease 1
tissue O 0
at O 0
E13 O 0
. O 0
5 O 0
. O 0

Microscopic O 0
observation O 0
showed O 0
the O 0
configuration O 0
of O 0
exencephaly B-Disease 1
at O 0
E13 O 0
. O 0
5 O 0
, O 0
frequent O 0
hemorrhaging B-Disease 1
and O 0
detachment O 0
of O 0
the O 0
neural O 0
plate O 0
from O 0
surface O 0
ectoderm O 0
in O 0
the O 0
exencephalic B-Disease 1
head O 0
at O 0
E15 O 0
. O 0
5 O 0
, O 0
and O 0
multiple O 0
modes O 0
of O 0
reduction O 0
in O 0
the O 0
exencephalic B-Disease 1
tissue O 0
at O 0
E18 O 0
. O 0
5 O 0
. O 0

From O 0
observations O 0
of O 0
the O 0
vasculature O 0
, O 0
altered O 0
distribution O 0
patterns O 0
of O 0
vessels O 0
were O 0
identified O 0
in O 0
the O 0
exencephalic B-Disease 1
head O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
overgrowth O 0
of O 0
the O 0
exencephalic B-Disease 1
neural O 0
tissue O 0
causes O 0
the O 0
altered O 0
distribution O 0
patterns O 0
of O 0
vessels O 0
, O 0
subsequent O 0
peripheral O 0
circulatory B-Disease 1
failure I-Disease 1
and O 0
/ O 0
or O 0
hemorrhaging B-Disease 1
in O 0
various O 0
parts O 0
of O 0
the O 0
exencephalic B-Disease 1
head O 0
, O 0
leading O 0
to O 0
the O 0
multiple O 0
modes O 0
of O 0
tissue O 0
reduction O 0
during O 0
transformation O 0
from O 0
exencephaly B-Disease 1
to O 0
anencephaly B-Disease 1
. O 0

99mTc B-Chemical 1
- I-Chemical 1
glucarate I-Chemical 1
for O 0
detection O 0
of O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

Infarct B-Disease 1
- O 0
avid O 0
radiopharmaceuticals O 0
are O 0
necessary O 0
for O 0
rapid O 0
and O 0
timely O 0
diagnosis O 0
of O 0
acute O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

The O 0
animal O 0
model O 0
used O 0
to O 0
produce O 0
infarction B-Disease 1
implies O 0
artery O 0
ligation O 0
but O 0
chemical O 0
induction O 0
can O 0
be O 0
easily O 0
obtained O 0
with O 0
isoproterenol B-Chemical 1
. O 0

A O 0
new O 0
infarct B-Disease 1
- O 0
avid O 0
radiopharmaceutical O 0
based O 0
on O 0
glucaric B-Chemical 1
acid I-Chemical 1
was O 0
prepared O 0
in O 0
the O 0
hospital O 0
radiopharmacy O 0
of O 0
the O 0
INCMNSZ O 0
. O 0

99mTc B-Chemical 1
- I-Chemical 1
glucarate I-Chemical 1
was O 0
easy O 0
to O 0
prepare O 0
, O 0
stable O 0
for O 0
96 O 0
h O 0
and O 0
was O 0
used O 0
to O 0
study O 0
its O 0
biodistribution O 0
in O 0
rats O 0
with O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
acute O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

Histological O 0
studies O 0
demonstrated O 0
that O 0
the O 0
rats O 0
developed O 0
an O 0
infarct B-Disease 1
18 O 0
h O 0
after O 0
isoproterenol B-Chemical 1
administration O 0
. O 0

The O 0
rat O 0
biodistribution O 0
studies O 0
showed O 0
a O 0
rapid O 0
blood O 0
clearance O 0
via O 0
the O 0
kidneys O 0
. O 0

Thirty O 0
minutes O 0
after O 0
99mTc B-Chemical 1
- I-Chemical 1
glucarate I-Chemical 1
administration O 0
the O 0
standardised O 0
heart O 0
uptake O 0
value O 0
S O 0
( O 0
h O 0
) O 0
UV O 0
was O 0
4 O 0
. O 0
7 O 0
in O 0
infarcted O 0
rat O 0
heart O 0
which O 0
is O 0
six O 0
times O 0
more O 0
than O 0
in O 0
normal O 0
rats O 0
. O 0

ROIs O 0
drawn O 0
over O 0
the O 0
gamma O 0
camera O 0
images O 0
showed O 0
a O 0
ratio O 0
of O 0
4 O 0
. O 0
4 O 0
. O 0

The O 0
high O 0
image O 0
quality O 0
suggests O 0
that O 0
high O 0
contrast O 0
images O 0
can O 0
be O 0
obtained O 0
in O 0
humans O 0
and O 0
the O 0
96 O 0
h O 0
stability O 0
makes O 0
it O 0
an O 0
ideal O 0
agent O 0
to O 0
detect O 0
, O 0
in O 0
patients O 0
, O 0
early O 0
cardiac B-Disease 1
infarction I-Disease 1
. O 0

Bupropion B-Chemical 1
( O 0
Zyban B-Chemical 1
) O 0
toxicity B-Disease 1
. O 0

Bupropion B-Chemical 1
is O 0
a O 0
monocyclic O 0
antidepressant B-Chemical 1
structurally O 0
related O 0
to O 0
amphetamine B-Chemical 1
. O 0

Zyban B-Chemical 1
, O 0
a O 0
sustained O 0
- O 0
release O 0
formulation O 0
of O 0
bupropion B-Chemical 1
hydrochloride I-Chemical 1
, O 0
was O 0
recently O 0
released O 0
in O 0
Ireland O 0
, O 0
as O 0
a O 0
smoking O 0
cessation O 0
aid O 0
. O 0

In O 0
the O 0
initial O 0
6 O 0
months O 0
since O 0
it O 0
' O 0
s O 0
introduction O 0
, O 0
12 O 0
overdose B-Disease 1
cases O 0
have O 0
been O 0
reported O 0
to O 0
The O 0
National O 0
Poisons O 0
Information O 0
Centre O 0
. O 0

8 O 0
patients O 0
developed O 0
symptoms O 0
of O 0
toxicity B-Disease 1
. O 0

Common O 0
features O 0
included O 0
tachycardia B-Disease 1
, O 0
drowsiness O 0
, O 0
hallucinations B-Disease 1
and O 0
convulsions B-Disease 1
. O 0

Two O 0
patients O 0
developed O 0
severe O 0
cardiac B-Disease 1
arrhythmias I-Disease 1
, O 0
including O 0
one O 0
patient O 0
who O 0
was O 0
resuscitated O 0
following O 0
a O 0
cardiac B-Disease 1
arrest I-Disease 1
. O 0

All O 0
patients O 0
recovered O 0
without O 0
sequelae O 0
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
a O 0
31 O 0
year O 0
old O 0
female O 0
who O 0
required O 0
admission O 0
to O 0
the O 0
Intensive O 0
Care O 0
Unit O 0
for O 0
ventilation O 0
and O 0
full O 0
supportive O 0
therapy O 0
, O 0
following O 0
ingestion O 0
of O 0
13 O 0
. O 0
5g O 0
bupropion B-Chemical 1
. O 0

Recurrent O 0
seizures B-Disease 1
were O 0
treated O 0
with O 0
diazepam B-Chemical 1
and O 0
broad O 0
complex O 0
tachycardia B-Disease 1
was O 0
successfully O 0
treated O 0
with O 0
adenosine B-Chemical 1
. O 0

Zyban B-Chemical 1
caused O 0
significant O 0
neurological B-Disease 1
and I-Disease 1
cardiovascular I-Disease 1
toxicity I-Disease 1
in O 0
overdose B-Disease 1
. O 0

The O 0
potential O 0
toxic O 0
effects O 0
should O 0
be O 0
considered O 0
when O 0
prescribing O 0
it O 0
as O 0
a O 0
smoking O 0
cessation O 0
aid O 0
. O 0

GLEPP1 O 0
receptor O 0
tyrosine B-Chemical 1
phosphatase O 0
( O 0
Ptpro O 0
) O 0
in O 0
rat O 0
PAN B-Chemical 1
nephrosis B-Disease 1
. O 0

A O 0
marker O 0
of O 0
acute O 0
podocyte O 0
injury O 0
. O 0

Glomerular O 0
epithelial O 0
protein O 0
1 O 0
( O 0
GLEPP1 O 0
) O 0
is O 0
a O 0
podocyte O 0
receptor O 0
membrane O 0
protein O 0
tyrosine B-Chemical 1
phosphatase O 0
located O 0
on O 0
the O 0
apical O 0
cell O 0
membrane O 0
of O 0
visceral O 0
glomerular O 0
epithelial O 0
cell O 0
and O 0
foot O 0
processes O 0
. O 0

This O 0
receptor O 0
plays O 0
a O 0
role O 0
in O 0
regulating O 0
the O 0
structure O 0
and O 0
function O 0
of O 0
podocyte O 0
foot O 0
process O 0
. O 0

To O 0
better O 0
understand O 0
the O 0
utility O 0
of O 0
GLEPP1 O 0
as O 0
a O 0
marker O 0
of O 0
glomerular B-Disease 1
injury I-Disease 1
, O 0
the O 0
amount O 0
and O 0
distribution O 0
of O 0
GLEPP1 O 0
protein O 0
and O 0
mRNA O 0
were O 0
examined O 0
by O 0
immunohistochemistry O 0
, O 0
Western O 0
blot O 0
and O 0
RNase O 0
protection O 0
assay O 0
in O 0
a O 0
model O 0
of O 0
podocyte O 0
injury O 0
in O 0
the O 0
rat O 0
. O 0

Puromycin B-Chemical 1
aminonucleoside I-Chemical 1
nephrosis B-Disease 1
was O 0
induced O 0
by O 0
single O 0
intraperitoneal O 0
injection O 0
of O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
( O 0
PAN B-Chemical 1
, O 0
20 O 0
mg O 0
/ O 0
100g O 0
BW O 0
) O 0
. O 0

Tissues O 0
were O 0
analyzed O 0
at O 0
0 O 0
, O 0
5 O 0
, O 0
7 O 0
, O 0
11 O 0
, O 0
21 O 0
, O 0
45 O 0
, O 0
80 O 0
and O 0
126 O 0
days O 0
after O 0
PAN B-Chemical 1
injection O 0
so O 0
as O 0
to O 0
include O 0
both O 0
the O 0
acute O 0
phase O 0
of O 0
proteinuria B-Disease 1
associated O 0
with O 0
foot O 0
process O 0
effacement O 0
( O 0
days O 0
5 O 0
- O 0
11 O 0
) O 0
and O 0
the O 0
chronic O 0
phase O 0
of O 0
proteinuria B-Disease 1
associated O 0
with O 0
glomerulosclerosis B-Disease 1
( O 0
days O 0
45 O 0
- O 0
126 O 0
) O 0
. O 0

At O 0
day O 0
5 O 0
, O 0
GLEPP1 O 0
protein O 0
and O 0
mRNA O 0
were O 0
reduced O 0
from O 0
the O 0
normal O 0
range O 0
( O 0
265 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
79 O 0
. O 0
6 O 0
x O 0
10 O 0
( O 0
6 O 0
) O 0
moles O 0
/ O 0
glomerulus O 0
and O 0
100 O 0
% O 0
) O 0
to O 0
15 O 0
% O 0
of O 0
normal O 0
( O 0
41 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
4 O 0
. O 0
8 O 0
x O 0
10 O 0
( O 0
6 O 0
) O 0
moles O 0
/ O 0
glomerulus O 0
, O 0
p O 0
< O 0
0 O 0
. O 0
005 O 0
) O 0
. O 0

This O 0
occurred O 0
in O 0
association O 0
with O 0
an O 0
increase O 0
in O 0
urinary O 0
protein O 0
content O 0
from O 0
1 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
1 O 0
to O 0
99 O 0
. O 0
0 O 0
+ O 0
/ O 0
- O 0
61 O 0
mg O 0
/ O 0
day O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

In O 0
contrast O 0
, O 0
podocalyxin O 0
did O 0
not O 0
change O 0
significantly O 0
at O 0
this O 0
time O 0
. O 0

By O 0
day O 0
11 O 0
, O 0
GLEPP1 O 0
protein O 0
and O 0
mRNA O 0
had O 0
begun O 0
to O 0
return O 0
towards O 0
baseline O 0
. O 0

By O 0
day O 0
45 O 0
- O 0
126 O 0
, O 0
at O 0
a O 0
time O 0
when O 0
glomerular O 0
scarring O 0
was O 0
present O 0
, O 0
GLEPP1 O 0
was O 0
absent O 0
from O 0
glomerulosclerotic O 0
areas O 0
although O 0
the O 0
total O 0
glomerular O 0
content O 0
of O 0
GLEPP1 O 0
was O 0
not O 0
different O 0
from O 0
normal O 0
. O 0

We O 0
conclude O 0
that O 0
GLEPP1 O 0
expression O 0
, O 0
unlike O 0
podocalyxin O 0
, O 0
reflects O 0
podocyte O 0
injury O 0
induced O 0
by O 0
PAN B-Chemical 1
. O 0

GLEPP1 O 0
expression O 0
may O 0
be O 0
a O 0
useful O 0
marker O 0
of O 0
podocyte O 0
injury O 0
. O 0

Antithymocyte B-Chemical 1
globulin I-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
D B-Chemical 1
- I-Chemical 1
penicillamine I-Chemical 1
- O 0
induced O 0
aplastic B-Disease 1
anemia I-Disease 1
. O 0

A O 0
patient O 0
who O 0
received O 0
antithymocyte B-Chemical 1
globulin I-Chemical 1
therapy O 0
for O 0
aplastic B-Disease 1
anemia I-Disease 1
due O 0
to O 0
D B-Chemical 1
- I-Chemical 1
penicillamine I-Chemical 1
therapy O 0
is O 0
described O 0
. O 0

Bone O 0
marrow O 0
recovery O 0
and O 0
peripheral O 0
blood O 0
recovery O 0
were O 0
complete O 0
1 O 0
month O 0
and O 0
3 O 0
months O 0
, O 0
respectively O 0
, O 0
after O 0
treatment O 0
, O 0
and O 0
blood O 0
transfusion O 0
or O 0
other O 0
therapies O 0
were O 0
not O 0
necessary O 0
in O 0
a O 0
follow O 0
- O 0
up O 0
period O 0
of O 0
more O 0
than O 0
2 O 0
years O 0
. O 0

Use O 0
of O 0
antithymocyte B-Chemical 1
globulin I-Chemical 1
may O 0
be O 0
the O 0
optimal O 0
treatment O 0
of O 0
D B-Chemical 1
- I-Chemical 1
penicillamine I-Chemical 1
- O 0
induced O 0
aplastic B-Disease 1
anemia I-Disease 1
. O 0

Metamizol B-Chemical 1
potentiates O 0
morphine B-Chemical 1
antinociception O 0
but O 0
not O 0
constipation B-Disease 1
after O 0
chronic O 0
treatment O 0
. O 0

This O 0
work O 0
evaluates O 0
the O 0
antinociceptive O 0
and O 0
constipating B-Disease 1
effects O 0
of O 0
the O 0
combination O 0
of O 0
3 O 0
. O 0
2 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
morphine B-Chemical 1
with O 0
177 O 0
. O 0
8 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
metamizol B-Chemical 1
in O 0
acutely O 0
and O 0
chronically O 0
treated O 0
( O 0
once O 0
a O 0
day O 0
for O 0
12 O 0
days O 0
) O 0
rats O 0
. O 0

On O 0
the O 0
13th O 0
day O 0
, O 0
antinociceptive O 0
effects O 0
were O 0
assessed O 0
using O 0
a O 0
model O 0
of O 0
inflammatory O 0
nociception O 0
, O 0
pain B-Disease 1
- O 0
induced O 0
functional O 0
impairment O 0
model O 0
, O 0
and O 0
the O 0
charcoal B-Chemical 1
meal O 0
test O 0
was O 0
used O 0
to O 0
evaluate O 0
the O 0
intestinal O 0
transit O 0
. O 0

Simultaneous O 0
administration O 0
of O 0
morphine B-Chemical 1
with O 0
metamizol B-Chemical 1
resulted O 0
in O 0
a O 0
markedly O 0
antinociceptive O 0
potentiation O 0
and O 0
an O 0
increasing O 0
of O 0
the O 0
duration O 0
of O 0
action O 0
after O 0
a O 0
single O 0
( O 0
298 O 0
+ O 0
/ O 0
- O 0
7 O 0
vs O 0
. O 0
139 O 0
+ O 0
/ O 0
- O 0
36 O 0
units O 0
area O 0
( O 0
ua O 0
) O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
and O 0
repeated O 0
administration O 0
( O 0
280 O 0
+ O 0
/ O 0
- O 0
17 O 0
vs O 0
. O 0
131 O 0
+ O 0
/ O 0
- O 0
22 O 0
ua O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

Antinociceptive O 0
effect O 0
of O 0
morphine B-Chemical 1
was O 0
reduced O 0
in O 0
chronically O 0
treated O 0
rats O 0
( O 0
39 O 0
+ O 0
/ O 0
- O 0
10 O 0
vs O 0
. O 0
18 O 0
+ O 0
/ O 0
- O 0
5 O 0
au O 0
) O 0
while O 0
the O 0
combination O 0
- O 0
induced O 0
antinociception O 0
was O 0
remained O 0
similar O 0
as O 0
an O 0
acute O 0
treatment O 0
( O 0
298 O 0
+ O 0
/ O 0
- O 0
7 O 0
vs O 0
. O 0
280 O 0
+ O 0
/ O 0
- O 0
17 O 0
au O 0
) O 0
. O 0

Acute O 0
antinociceptive O 0
effects O 0
of O 0
the O 0
combination O 0
were O 0
partially O 0
prevented O 0
by O 0
3 O 0
. O 0
2 O 0
mg O 0
/ O 0
kg O 0
naloxone B-Chemical 1
s O 0
. O 0
c O 0
. O 0

( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
suggesting O 0
the O 0
partial O 0
involvement O 0
of O 0
the O 0
opioidergic O 0
system O 0
in O 0
the O 0
synergism O 0
observed O 0
. O 0

In O 0
independent O 0
groups O 0
, O 0
morphine B-Chemical 1
inhibited O 0
the O 0
intestinal O 0
transit O 0
in O 0
48 O 0
+ O 0
/ O 0
- O 0
4 O 0
% O 0
and O 0
38 O 0
+ O 0
/ O 0
- O 0
4 O 0
% O 0
after O 0
acute O 0
and O 0
chronic O 0
treatment O 0
, O 0
respectively O 0
, O 0
suggesting O 0
that O 0
tolerance O 0
did O 0
not O 0
develop O 0
to O 0
the O 0
constipating B-Disease 1
effects O 0
. O 0

The O 0
combination O 0
inhibited O 0
intestinal O 0
transit O 0
similar O 0
to O 0
that O 0
produced O 0
by O 0
morphine B-Chemical 1
regardless O 0
of O 0
the O 0
time O 0
of O 0
treatment O 0
, O 0
suggesting O 0
that O 0
metamizol B-Chemical 1
did O 0
not O 0
potentiate O 0
morphine B-Chemical 1
- O 0
induced O 0
constipation B-Disease 1
. O 0

These O 0
findings O 0
show O 0
a O 0
significant O 0
interaction O 0
between O 0
morphine B-Chemical 1
and O 0
metamizol B-Chemical 1
in O 0
chronically O 0
treated O 0
rats O 0
, O 0
suggesting O 0
that O 0
this O 0
combination O 0
could O 0
be O 0
useful O 0
for O 0
the O 0
treatment O 0
of O 0
chronic B-Disease 1
pain I-Disease 1
. O 0

Ifosfamide B-Chemical 1
encephalopathy B-Disease 1
presenting O 0
with O 0
asterixis B-Disease 1
. O 0

CNS O 0
toxic O 0
effects O 0
of O 0
the O 0
antineoplastic O 0
agent O 0
ifosfamide B-Chemical 1
( O 0
IFX B-Chemical 1
) O 0
are O 0
frequent O 0
and O 0
include O 0
a O 0
variety O 0
of O 0
neurological O 0
symptoms O 0
that O 0
can O 0
limit O 0
drug O 0
use O 0
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
a O 0
51 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
who O 0
developed O 0
severe O 0
, O 0
disabling O 0
negative O 0
myoclonus B-Disease 1
of O 0
the O 0
upper O 0
and O 0
lower O 0
extremities O 0
after O 0
the O 0
infusion O 0
of O 0
ifosfamide B-Chemical 1
for O 0
plasmacytoma B-Disease 1
. O 0

He O 0
was O 0
awake O 0
, O 0
revealed O 0
no O 0
changes O 0
of O 0
mental O 0
status O 0
and O 0
at O 0
rest O 0
there O 0
were O 0
no O 0
further O 0
motor O 0
symptoms O 0
. O 0

Cranial O 0
magnetic O 0
resonance O 0
imaging O 0
and O 0
extensive O 0
laboratory O 0
studies O 0
failed O 0
to O 0
reveal O 0
structural B-Disease 1
lesions I-Disease 1
of I-Disease 1
the I-Disease 1
brain I-Disease 1
and O 0
metabolic B-Disease 1
abnormalities I-Disease 1
. O 0

An O 0
electroencephalogram O 0
showed O 0
continuous O 0
, O 0
generalized O 0
irregular O 0
slowing O 0
with O 0
admixed O 0
periodic O 0
triphasic O 0
waves O 0
indicating O 0
symptomatic O 0
encephalopathy B-Disease 1
. O 0

The O 0
administration O 0
of O 0
ifosfamide B-Chemical 1
was O 0
discontinued O 0
and O 0
within O 0
12 O 0
h O 0
the O 0
asterixis B-Disease 1
resolved O 0
completely O 0
. O 0

In O 0
the O 0
patient O 0
described O 0
, O 0
the O 0
presence O 0
of O 0
asterixis B-Disease 1
during O 0
infusion O 0
of O 0
ifosfamide B-Chemical 1
, O 0
normal O 0
laboratory O 0
findings O 0
and O 0
imaging O 0
studies O 0
and O 0
the O 0
resolution O 0
of O 0
symptoms O 0
following O 0
the O 0
discontinuation O 0
of O 0
the O 0
drug O 0
suggest O 0
that O 0
negative O 0
myoclonus B-Disease 1
is O 0
associated O 0
with O 0
the O 0
use O 0
of O 0
IFX B-Chemical 1
. O 0

Antagonism O 0
between O 0
interleukin O 0
3 O 0
and O 0
erythropoietin O 0
in O 0
mice O 0
with O 0
azidothymidine B-Chemical 1
- O 0
induced O 0
anemia B-Disease 1
and O 0
in O 0
bone O 0
marrow O 0
endothelial O 0
cells O 0
. O 0

Azidothymidine B-Chemical 1
( O 0
AZT B-Chemical 1
) O 0
- O 0
induced O 0
anemia B-Disease 1
in O 0
mice O 0
can O 0
be O 0
reversed O 0
by O 0
the O 0
administration O 0
of O 0
IGF O 0
- O 0
IL O 0
- O 0
3 O 0
( O 0
fusion O 0
protein O 0
of O 0
insulin O 0
- O 0
like O 0
growth O 0
factor O 0
II O 0
( O 0
IGF O 0
II O 0
) O 0
and O 0
interleukin O 0
3 O 0
) O 0
. O 0

Although O 0
interleukin O 0
3 O 0
( O 0
IL O 0
- O 0
3 O 0
) O 0
and O 0
erythropoietin O 0
( O 0
EPO O 0
) O 0
are O 0
known O 0
to O 0
act O 0
synergistically O 0
on O 0
hematopoietic O 0
cell O 0
proliferation O 0
in O 0
vitro O 0
, O 0
injection O 0
of O 0
IGF O 0
- O 0
IL O 0
- O 0
3 O 0
and O 0
EPO O 0
in O 0
AZT B-Chemical 1
- O 0
treated O 0
mice O 0
resulted O 0
in O 0
a O 0
reduction O 0
of O 0
red O 0
cells O 0
and O 0
an O 0
increase O 0
of O 0
plasma O 0
EPO O 0
levels O 0
as O 0
compared O 0
to O 0
animals O 0
treated O 0
with O 0
IGF O 0
- O 0
IL O 0
- O 0
3 O 0
or O 0
EPO O 0
alone O 0
. O 0

We O 0
tested O 0
the O 0
hypothesis O 0
that O 0
the O 0
antagonistic O 0
effect O 0
of O 0
IL O 0
- O 0
3 O 0
and O 0
EPO O 0
on O 0
erythroid O 0
cells O 0
may O 0
be O 0
mediated O 0
by O 0
endothelial O 0
cells O 0
. O 0

Bovine O 0
liver O 0
erythroid O 0
cells O 0
were O 0
cultured O 0
on O 0
monolayers O 0
of O 0
human O 0
bone O 0
marrow O 0
endothelial O 0
cells O 0
previously O 0
treated O 0
with O 0
EPO O 0
and O 0
IGF O 0
- O 0
IL O 0
- O 0
3 O 0
. O 0

There O 0
was O 0
a O 0
significant O 0
reduction O 0
of O 0
thymidine B-Chemical 1
incorporation O 0
into O 0
both O 0
erythroid O 0
and O 0
endothelial O 0
cells O 0
in O 0
cultures O 0
pre O 0
- O 0
treated O 0
with O 0
IGF O 0
- O 0
IL O 0
- O 0
3 O 0
and O 0
EPO O 0
. O 0

Endothelial O 0
cell O 0
culture O 0
supernatants O 0
separated O 0
by O 0
ultrafiltration O 0
and O 0
ultracentrifugation O 0
from O 0
cells O 0
treated O 0
with O 0
EPO O 0
and O 0
IL O 0
- O 0
3 O 0
significantly O 0
reduced O 0
thymidine B-Chemical 1
incorporation O 0
into O 0
erythroid O 0
cells O 0
as O 0
compared O 0
to O 0
identical O 0
fractions O 0
obtained O 0
from O 0
the O 0
media O 0
of O 0
cells O 0
cultured O 0
with O 0
EPO O 0
alone O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
endothelial O 0
cells O 0
treated O 0
simultaneously O 0
with O 0
EPO O 0
and O 0
IL O 0
- O 0
3 O 0
have O 0
a O 0
negative O 0
effect O 0
on O 0
erythroid O 0
cell O 0
production O 0
. O 0

The O 0
relationship O 0
between O 0
hippocampal O 0
acetylcholine B-Chemical 1
release O 0
and O 0
cholinergic O 0
convulsant O 0
sensitivity O 0
in O 0
withdrawal O 0
seizure B-Disease 1
- O 0
prone O 0
and O 0
withdrawal O 0
seizure B-Disease 1
- O 0
resistant O 0
selected O 0
mouse O 0
lines O 0
. O 0

BACKGROUND O 0
: O 0
The O 0
septo O 0
- O 0
hippocampal O 0
cholinergic O 0
pathway O 0
has O 0
been O 0
implicated O 0
in O 0
epileptogenesis O 0
, O 0
and O 0
genetic O 0
factors O 0
influence O 0
the O 0
response O 0
to O 0
cholinergic O 0
agents O 0
, O 0
but O 0
limited O 0
data O 0
are O 0
available O 0
on O 0
cholinergic O 0
involvement O 0
in O 0
alcohol B-Chemical 1
withdrawal O 0
severity O 0
. O 0

Thus O 0
, O 0
the O 0
relationship O 0
between O 0
cholinergic O 0
activity O 0
and O 0
responsiveness O 0
and O 0
alcohol B-Chemical 1
withdrawal O 0
was O 0
investigated O 0
in O 0
a O 0
genetic O 0
animal O 0
model O 0
of O 0
ethanol B-Chemical 1
withdrawal O 0
severity O 0
. O 0

METHODS O 0
: O 0
Cholinergic O 0
convulsant O 0
sensitivity O 0
was O 0
examined O 0
in O 0
alcohol B-Chemical 1
- O 0
na O 0
ve O 0
Withdrawal O 0
Seizure B-Disease 1
- O 0
Prone O 0
( O 0
WSP O 0
) O 0
and O 0
- O 0
Resistant O 0
( O 0
WSR O 0
) O 0
mice O 0
. O 0

Animals O 0
were O 0
administered O 0
nicotine B-Chemical 1
, O 0
carbachol B-Chemical 1
, O 0
or O 0
neostigmine B-Chemical 1
via O 0
timed O 0
tail O 0
vein O 0
infusion O 0
, O 0
and O 0
the O 0
latencies O 0
to O 0
onset O 0
of O 0
tremor B-Disease 1
and O 0
clonus O 0
were O 0
recorded O 0
and O 0
converted O 0
to O 0
threshold O 0
dose O 0
. O 0

We O 0
also O 0
used O 0
microdialysis O 0
to O 0
measure O 0
basal O 0
and O 0
potassium B-Chemical 1
- O 0
stimulated O 0
acetylcholine B-Chemical 1
( O 0
ACh B-Chemical 1
) O 0
release O 0
in O 0
the O 0
CA1 O 0
region O 0
of O 0
the O 0
hippocampus O 0
. O 0

Potassium B-Chemical 1
was O 0
applied O 0
by O 0
reverse O 0
dialysis O 0
twice O 0
, O 0
separated O 0
by O 0
75 O 0
min O 0
. O 0

Hippocampal O 0
ACh B-Chemical 1
also O 0
was O 0
measured O 0
during O 0
testing O 0
for O 0
handling O 0
- O 0
induced O 0
convulsions B-Disease 1
. O 0

RESULTS O 0
: O 0
Sensitivity O 0
to O 0
several O 0
convulsion B-Disease 1
endpoints O 0
induced O 0
by O 0
nicotine B-Chemical 1
, O 0
carbachol B-Chemical 1
, O 0
and O 0
neostigmine B-Chemical 1
were O 0
significantly O 0
greater O 0
in O 0
WSR O 0
versus O 0
WSP O 0
mice O 0
. O 0

In O 0
microdialysis O 0
experiments O 0
, O 0
the O 0
lines O 0
did O 0
not O 0
differ O 0
in O 0
basal O 0
release O 0
of O 0
ACh B-Chemical 1
, O 0
and O 0
50 O 0
mM O 0
KCl B-Chemical 1
increased O 0
ACh B-Chemical 1
output O 0
in O 0
both O 0
lines O 0
of O 0
mice O 0
. O 0

However O 0
, O 0
the O 0
increase O 0
in O 0
release O 0
of O 0
ACh B-Chemical 1
produced O 0
by O 0
the O 0
first O 0
application O 0
of O 0
KCl B-Chemical 1
was O 0
2 O 0
- O 0
fold O 0
higher O 0
in O 0
WSP O 0
versus O 0
WSR O 0
mice O 0
. O 0

When O 0
hippocampal O 0
ACh B-Chemical 1
was O 0
measured O 0
during O 0
testing O 0
for O 0
handling O 0
- O 0
induced O 0
convulsions B-Disease 1
, O 0
extracellular O 0
ACh B-Chemical 1
was O 0
significantly O 0
elevated O 0
( O 0
192 O 0
% O 0
) O 0
in O 0
WSP O 0
mice O 0
, O 0
but O 0
was O 0
nonsignificantly O 0
elevated O 0
( O 0
59 O 0
% O 0
) O 0
in O 0
WSR O 0
mice O 0
. O 0

CONCLUSIONS O 0
: O 0
These O 0
results O 0
suggest O 0
that O 0
differences O 0
in O 0
cholinergic O 0
activity O 0
and O 0
postsynaptic O 0
sensitivity O 0
to O 0
cholinergic O 0
convulsants B-Disease 1
may O 0
be O 0
associated O 0
with O 0
ethanol B-Chemical 1
withdrawal O 0
severity O 0
and O 0
implicate O 0
cholinergic O 0
mechanisms O 0
in O 0
alcohol B-Chemical 1
withdrawal O 0
. O 0

Specifically O 0
, O 0
WSP O 0
mice O 0
may O 0
have O 0
lower O 0
sensitivity O 0
to O 0
cholinergic O 0
convulsants B-Disease 1
compared O 0
with O 0
WSR O 0
because O 0
of O 0
postsynaptic O 0
receptor O 0
desensitization O 0
brought O 0
on O 0
by O 0
higher O 0
activity O 0
of O 0
cholinergic O 0
neurons O 0
. O 0

Capsaicin B-Chemical 1
- O 0
induced O 0
muscle B-Disease 1
pain I-Disease 1
alters O 0
the O 0
excitability O 0
of O 0
the O 0
human O 0
jaw O 0
- O 0
stretch O 0
reflex O 0
. O 0

The O 0
pathophysiology O 0
of O 0
painful O 0
temporomandibular B-Disease 1
disorders I-Disease 1
is O 0
not O 0
fully O 0
understood O 0
, O 0
but O 0
evidence O 0
suggests O 0
that O 0
muscle B-Disease 1
pain I-Disease 1
modulates O 0
motor O 0
function O 0
in O 0
characteristic O 0
ways O 0
. O 0

This O 0
study O 0
tested O 0
the O 0
hypothesis O 0
that O 0
activation O 0
of O 0
nociceptive B-Disease 1
muscle I-Disease 1
afferent O 0
fibers O 0
would O 0
be O 0
linked O 0
to O 0
an O 0
increased O 0
excitability O 0
of O 0
the O 0
human O 0
jaw O 0
- O 0
stretch O 0
reflex O 0
and O 0
whether O 0
this O 0
process O 0
would O 0
be O 0
sensitive O 0
to O 0
length O 0
and O 0
velocity O 0
of O 0
the O 0
stretch O 0
. O 0

Capsaicin B-Chemical 1
( O 0
10 O 0
micro O 0
g O 0
) O 0
was O 0
injected O 0
into O 0
the O 0
masseter O 0
muscle O 0
to O 0
induce O 0
pain B-Disease 1
in O 0
11 O 0
healthy O 0
volunteers O 0
. O 0

Short O 0
- O 0
latency O 0
reflex O 0
responses O 0
were O 0
evoked O 0
in O 0
the O 0
masseter O 0
and O 0
temporalis O 0
muscles O 0
by O 0
a O 0
stretch O 0
device O 0
with O 0
different O 0
velocities O 0
and O 0
displacements O 0
before O 0
, O 0
during O 0
, O 0
and O 0
after O 0
the O 0
pain B-Disease 1
. O 0

The O 0
normalized O 0
reflex O 0
amplitude O 0
increased O 0
with O 0
an O 0
increase O 0
in O 0
velocity O 0
at O 0
a O 0
given O 0
displacement O 0
, O 0
but O 0
remained O 0
constant O 0
with O 0
different O 0
displacements O 0
at O 0
a O 0
given O 0
velocity O 0
. O 0

The O 0
normalized O 0
reflex O 0
amplitude O 0
was O 0
significantly O 0
higher O 0
during O 0
pain B-Disease 1
, O 0
but O 0
only O 0
at O 0
faster O 0
stretches O 0
in O 0
the O 0
painful B-Disease 1
muscle I-Disease 1
. O 0

Increased O 0
sensitivity O 0
of O 0
the O 0
fusimotor O 0
system O 0
during O 0
acute O 0
muscle B-Disease 1
pain I-Disease 1
could O 0
be O 0
one O 0
likely O 0
mechanism O 0
to O 0
explain O 0
the O 0
findings O 0
. O 0

Effects O 0
of O 0
5 O 0
- O 0
HT1B O 0
receptor O 0
ligands O 0
microinjected O 0
into O 0
the O 0
accumbal O 0
shell O 0
or O 0
core O 0
on O 0
the O 0
cocaine B-Chemical 1
- O 0
induced O 0
locomotor B-Disease 1
hyperactivity I-Disease 1
in O 0
rats O 0
. O 0

The O 0
present O 0
study O 0
was O 0
designed O 0
to O 0
examine O 0
the O 0
effect O 0
of O 0
5 O 0
- O 0
HT1B O 0
receptor O 0
ligands O 0
microinjected O 0
into O 0
the O 0
subregions O 0
of O 0
the O 0
nucleus O 0
accumbens O 0
( O 0
the O 0
shell O 0
and O 0
the O 0
core O 0
) O 0
on O 0
the O 0
locomotor B-Disease 1
hyperactivity I-Disease 1
induced O 0
by O 0
cocaine B-Chemical 1
in O 0
rats O 0
. O 0

Male O 0
Wistar O 0
rats O 0
were O 0
implanted O 0
bilaterally O 0
with O 0
cannulae O 0
into O 0
the O 0
accumbens O 0
shell O 0
or O 0
core O 0
, O 0
and O 0
then O 0
were O 0
locally O 0
injected O 0
with O 0
GR B-Chemical 1
55562 I-Chemical 1
( O 0
an O 0
antagonist O 0
of O 0
5 O 0
- O 0
HT1B O 0
receptors O 0
) O 0
or O 0
CP B-Chemical 1
93129 I-Chemical 1
( O 0
an O 0
agonist O 0
of O 0
5 O 0
- O 0
HT1B O 0
receptors O 0
) O 0
. O 0

Given O 0
alone O 0
to O 0
any O 0
accumbal O 0
subregion O 0
, O 0
GR B-Chemical 1
55562 I-Chemical 1
( O 0
0 O 0
. O 0
1 O 0
- O 0
10 O 0
microg O 0
/ O 0
side O 0
) O 0
or O 0
CP B-Chemical 1
93129 I-Chemical 1
( O 0
0 O 0
. O 0
1 O 0
- O 0
10 O 0
microg O 0
/ O 0
side O 0
) O 0
did O 0
not O 0
change O 0
basal O 0
locomotor O 0
activity O 0
. O 0

Systemic O 0
cocaine B-Chemical 1
( O 0
10 O 0
mg O 0
/ O 0
kg O 0
) O 0
significantly O 0
increased O 0
the O 0
locomotor O 0
activity O 0
of O 0
rats O 0
. O 0

GR B-Chemical 1
55562 I-Chemical 1
( O 0
0 O 0
. O 0
1 O 0
- O 0
10 O 0
microg O 0
/ O 0
side O 0
) O 0
, O 0
administered O 0
intra O 0
- O 0
accumbens O 0
shell O 0
prior O 0
to O 0
cocaine B-Chemical 1
, O 0
dose O 0
- O 0
dependently O 0
attenuated O 0
the O 0
psychostimulant O 0
- O 0
induced O 0
locomotor B-Disease 1
hyperactivity I-Disease 1
. O 0

Such O 0
attenuation O 0
was O 0
not O 0
found O 0
in O 0
animals O 0
which O 0
had O 0
been O 0
injected O 0
with O 0
GR B-Chemical 1
55562 I-Chemical 1
into O 0
the O 0
accumbens O 0
core O 0
. O 0

When O 0
injected O 0
into O 0
the O 0
accumbens O 0
shell O 0
( O 0
but O 0
not O 0
the O 0
core O 0
) O 0
before O 0
cocaine B-Chemical 1
, O 0
CP B-Chemical 1
93129 I-Chemical 1
( O 0
0 O 0
. O 0
1 O 0
- O 0
10 O 0
microg O 0
/ O 0
side O 0
) O 0
enhanced O 0
the O 0
locomotor O 0
response O 0
to O 0
cocaine B-Chemical 1
; O 0
the O 0
maximum O 0
effect O 0
being O 0
observed O 0
after O 0
10 O 0
microg O 0
/ O 0
side O 0
of O 0
the O 0
agonist O 0
. O 0

The O 0
later O 0
enhancement O 0
was O 0
attenuated O 0
after O 0
intra O 0
- O 0
accumbens O 0
shell O 0
treatment O 0
with O 0
GR B-Chemical 1
55562 I-Chemical 1
( O 0
1 O 0
microg O 0
/ O 0
side O 0
) O 0
. O 0

Our O 0
findings O 0
indicate O 0
that O 0
cocaine B-Chemical 1
induced O 0
hyperlocomotion B-Disease 1
is O 0
modified O 0
by O 0
5 O 0
- O 0
HT1B O 0
receptor O 0
ligands O 0
microinjected O 0
into O 0
the O 0
accumbens O 0
shell O 0
, O 0
but O 0
not O 0
core O 0
, O 0
this O 0
modification O 0
consisting O 0
in O 0
inhibitory O 0
and O 0
facilitatory O 0
effects O 0
of O 0
the O 0
5 O 0
- O 0
HT1B O 0
receptor O 0
antagonist O 0
( O 0
GR B-Chemical 1
55562 I-Chemical 1
) O 0
and O 0
agonist O 0
( O 0
CP B-Chemical 1
93129 I-Chemical 1
) O 0
, O 0
respectively O 0
. O 0

In O 0
other O 0
words O 0
, O 0
the O 0
present O 0
results O 0
suggest O 0
that O 0
the O 0
accumbal O 0
shell O 0
5 O 0
- O 0
HT1B O 0
receptors O 0
play O 0
a O 0
permissive O 0
role O 0
in O 0
the O 0
behavioural O 0
response O 0
to O 0
the O 0
psychostimulant O 0
. O 0

Cocaine B-Chemical 1
related O 0
chest B-Disease 1
pain I-Disease 1
: O 0
are O 0
we O 0
seeing O 0
the O 0
tip O 0
of O 0
an O 0
iceberg O 0
? O 0

The O 0
recreational O 0
use O 0
of O 0
cocaine B-Chemical 1
is O 0
on O 0
the O 0
increase O 0
. O 0

The O 0
emergency O 0
nurse O 0
ought O 0
to O 0
be O 0
familiar O 0
with O 0
some O 0
of O 0
the O 0
cardiovascular O 0
consequences O 0
of O 0
cocaine B-Chemical 1
use O 0
. O 0

In O 0
particular O 0
, O 0
the O 0
tendency O 0
of O 0
cocaine B-Chemical 1
to O 0
produce O 0
chest B-Disease 1
pain I-Disease 1
ought O 0
to O 0
be O 0
in O 0
the O 0
mind O 0
of O 0
the O 0
emergency O 0
nurse O 0
when O 0
faced O 0
with O 0
a O 0
young O 0
victim O 0
of O 0
chest B-Disease 1
pain I-Disease 1
who O 0
is O 0
otherwise O 0
at O 0
low O 0
risk O 0
. O 0

The O 0
mechanism O 0
of O 0
chest B-Disease 1
pain I-Disease 1
related O 0
to O 0
cocaine B-Chemical 1
use O 0
is O 0
discussed O 0
and O 0
treatment O 0
dilemmas O 0
are O 0
discussed O 0
. O 0

Finally O 0
, O 0
moral O 0
issues O 0
relating O 0
to O 0
the O 0
testing O 0
of O 0
potential O 0
cocaine B-Chemical 1
users O 0
will O 0
be O 0
addressed O 0
. O 0

Crossover O 0
comparison O 0
of O 0
efficacy O 0
and O 0
preference O 0
for O 0
rizatriptan B-Chemical 1
10 O 0
mg O 0
versus O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
in O 0
migraine B-Disease 1
. O 0

Rizatriptan B-Chemical 1
is O 0
a O 0
selective O 0
5 B-Chemical 1
- I-Chemical 1
HT I-Chemical 1
( O 0
1B O 0
/ O 0
1D O 0
) O 0
receptor O 0
agonist O 0
with O 0
rapid O 0
oral O 0
absorption O 0
and O 0
early O 0
onset O 0
of O 0
action O 0
in O 0
the O 0
acute O 0
treatment O 0
of O 0
migraine B-Disease 1
. O 0

This O 0
randomized O 0
double O 0
- O 0
blind O 0
crossover O 0
outpatient O 0
study O 0
assessed O 0
the O 0
preference O 0
for O 0
1 O 0
rizatriptan B-Chemical 1
10 O 0
mg O 0
tablet O 0
to O 0
2 O 0
ergotamine B-Chemical 1
1 O 0
mg O 0
/ O 0
caffeine B-Chemical 1
100 O 0
mg O 0
tablets O 0
in O 0
439 O 0
patients O 0
treating O 0
a O 0
single O 0
migraine B-Disease 1
attack O 0
with O 0
each O 0
therapy O 0
. O 0

Of O 0
patients O 0
expressing O 0
a O 0
preference O 0
( O 0
89 O 0
. O 0
1 O 0
% O 0
) O 0
, O 0
more O 0
than O 0
twice O 0
as O 0
many O 0
preferred O 0
rizatriptan B-Chemical 1
to O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
( O 0
69 O 0
. O 0
9 O 0
vs O 0
. O 0
30 O 0
. O 0
1 O 0
% O 0
, O 0
p O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

Faster O 0
relief O 0
of O 0
headache B-Disease 1
was O 0
the O 0
most O 0
important O 0
reason O 0
for O 0
preference O 0
, O 0
cited O 0
by O 0
67 O 0
. O 0
3 O 0
% O 0
of O 0
patients O 0
preferring O 0
rizatriptan B-Chemical 1
and O 0
54 O 0
. O 0
2 O 0
% O 0
of O 0
patients O 0
who O 0
preferred O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
. O 0

The O 0
co O 0
- O 0
primary O 0
endpoint O 0
of O 0
being O 0
pain B-Disease 1
free O 0
at O 0
2 O 0
h O 0
was O 0
also O 0
in O 0
favor O 0
of O 0
rizatriptan B-Chemical 1
. O 0

Forty O 0
- O 0
nine O 0
percent O 0
of O 0
patients O 0
were O 0
pain B-Disease 1
free O 0
2 O 0
h O 0
after O 0
rizatriptan B-Chemical 1
, O 0
compared O 0
with O 0
24 O 0
. O 0
3 O 0
% O 0
treated O 0
with O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
( O 0
p O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
rizatriptan B-Chemical 1
being O 0
superior O 0
within O 0
1 O 0
h O 0
of O 0
treatment O 0
. O 0

Headache B-Disease 1
relief O 0
at O 0
2 O 0
h O 0
was O 0
75 O 0
. O 0
9 O 0
% O 0
for O 0
rizatriptan B-Chemical 1
and O 0
47 O 0
. O 0
3 O 0
% O 0
for O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
( O 0
p O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
with O 0
rizatriptan B-Chemical 1
being O 0
superior O 0
to O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
within O 0
30 O 0
min O 0
of O 0
dosing O 0
. O 0

Almost O 0
36 O 0
% O 0
of O 0
patients O 0
taking O 0
rizatriptan B-Chemical 1
were O 0
pain B-Disease 1
free O 0
at O 0
2 O 0
h O 0
and O 0
had O 0
no O 0
recurrence O 0
or O 0
need O 0
for O 0
additional O 0
medication O 0
within O 0
24 O 0
h O 0
, O 0
compared O 0
to O 0
20 O 0
% O 0
of O 0
patients O 0
on O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
( O 0
p O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

Rizatriptan B-Chemical 1
was O 0
also O 0
superior O 0
to O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
in O 0
the O 0
proportions O 0
of O 0
patients O 0
with O 0
no O 0
nausea B-Disease 1
, O 0
vomiting B-Disease 1
, O 0
phonophobia B-Disease 1
or O 0
photophobia B-Disease 1
and O 0
for O 0
patients O 0
with O 0
normal O 0
function O 0
2 O 0
h O 0
after O 0
drug O 0
intake O 0
( O 0
p O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

More O 0
patients O 0
were O 0
( O 0
completely O 0
, O 0
very O 0
or O 0
somewhat O 0
) O 0
satisfied O 0
2 O 0
h O 0
after O 0
treatment O 0
with O 0
rizatriptan B-Chemical 1
( O 0
69 O 0
. O 0
8 O 0
% O 0
) O 0
than O 0
at O 0
2 O 0
h O 0
after O 0
treatment O 0
with O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
( O 0
38 O 0
. O 0
6 O 0
% O 0
, O 0
p O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

Recurrence O 0
rates O 0
were O 0
31 O 0
. O 0
4 O 0
% O 0
with O 0
rizatriptan B-Chemical 1
and O 0
15 O 0
. O 0
3 O 0
% O 0
with O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
. O 0

Both O 0
active O 0
treatments O 0
were O 0
well O 0
tolerated O 0
. O 0

The O 0
most O 0
common O 0
adverse O 0
events O 0
( O 0
incidence O 0
> O 0
or O 0
= O 0
5 O 0
% O 0
in O 0
one O 0
group O 0
) O 0
after O 0
rizatriptan B-Chemical 1
and O 0
ergotamine B-Chemical 1
/ O 0
caffeine B-Chemical 1
, O 0
respectively O 0
, O 0
were O 0
dizziness B-Disease 1
( O 0
6 O 0
. O 0
7 O 0
and O 0
5 O 0
. O 0
3 O 0
% O 0
) O 0
, O 0
nausea B-Disease 1
( O 0
4 O 0
. O 0
2 O 0
and O 0
8 O 0
. O 0
5 O 0
% O 0
) O 0
and O 0
somnolence B-Disease 1
( O 0
5 O 0
. O 0
5 O 0
and O 0
2 O 0
. O 0
3 O 0
% O 0
) O 0
. O 0

Severe O 0
ocular B-Disease 1
and I-Disease 1
orbital I-Disease 1
toxicity I-Disease 1
after O 0
intracarotid O 0
injection O 0
of O 0
carboplatin B-Chemical 1
for O 0
recurrent O 0
glioblastomas B-Disease 1
. O 0

BACKGROUND O 0
: O 0
Glioblastoma B-Disease 1
is O 0
a O 0
malignant B-Disease 1
tumor I-Disease 1
that O 0
occurs O 0
in O 0
the O 0
cerebrum O 0
during O 0
adulthood O 0
. O 0

With O 0
current O 0
treatment O 0
regimens O 0
including O 0
combined O 0
surgery O 0
, O 0
radiation O 0
and O 0
chemotherapy O 0
, O 0
the O 0
average O 0
life O 0
expectancy O 0
of O 0
the O 0
patients O 0
is O 0
limited O 0
to O 0
approximately O 0
1 O 0
year O 0
. O 0

Therefore O 0
, O 0
patients O 0
with O 0
glioblastoma B-Disease 1
sometimes O 0
have O 0
intracarotid O 0
injection O 0
of O 0
carcinostatics O 0
added O 0
to O 0
the O 0
treatment O 0
regimen O 0
. O 0

Generally O 0
, O 0
carboplatin B-Chemical 1
is O 0
said O 0
to O 0
have O 0
milder O 0
side O 0
effects O 0
than O 0
cisplatin B-Chemical 1
, O 0
whose O 0
ocular B-Disease 1
and I-Disease 1
orbital I-Disease 1
toxicity I-Disease 1
are O 0
well O 0
known O 0
. O 0

However O 0
, O 0
we O 0
experienced O 0
a O 0
case O 0
of O 0
severe O 0
ocular B-Disease 1
and I-Disease 1
orbital I-Disease 1
toxicity I-Disease 1
after O 0
intracarotid O 0
injection O 0
of O 0
carboplatin B-Chemical 1
, O 0
which O 0
is O 0
infrequently O 0
reported O 0
. O 0

CASE O 0
: O 0
A O 0
58 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
received O 0
an O 0
intracarotid O 0
injection O 0
of O 0
carboplatin B-Chemical 1
for O 0
recurrent O 0
glioblastomas B-Disease 1
in O 0
his O 0
left O 0
temporal O 0
lobe O 0
. O 0

He O 0
complained O 0
of O 0
pain B-Disease 1
and I-Disease 1
visual I-Disease 1
disturbance I-Disease 1
in I-Disease 1
the I-Disease 1
ipsilateral I-Disease 1
eye I-Disease 1
30 O 0
h O 0
after O 0
the O 0
injection O 0
. O 0

Various O 0
ocular O 0
symptoms O 0
and O 0
findings O 0
caused O 0
by O 0
carboplatin B-Chemical 1
toxicity B-Disease 1
were O 0
seen O 0
. O 0

RESULTS O 0
: O 0
He O 0
was O 0
treated O 0
with O 0
intravenous O 0
administration O 0
of O 0
corticosteroids O 0
and O 0
glycerin B-Chemical 1
for O 0
6 O 0
days O 0
after O 0
the O 0
injection O 0
. O 0

Although O 0
the O 0
intraocular O 0
pressure O 0
elevation O 0
caused O 0
by O 0
secondary O 0
acute O 0
angle O 0
- O 0
closure O 0
glaucoma B-Disease 1
decreased O 0
and O 0
ocular B-Disease 1
pain I-Disease 1
diminished O 0
, O 0
inexorable O 0
papilledema B-Disease 1
and O 0
exudative O 0
retinal B-Disease 1
detachment I-Disease 1
continued O 0
for O 0
3 O 0
weeks O 0
. O 0

Finally O 0
, O 0
6 O 0
weeks O 0
later O 0
, O 0
diffuse O 0
chorioretinal B-Disease 1
atrophy I-Disease 1
with O 0
optic B-Disease 1
atrophy I-Disease 1
occurred O 0
and O 0
the O 0
vision O 0
in O 0
his O 0
left O 0
eye O 0
was O 0
lost O 0
. O 0

CONCLUSION O 0
: O 0
When O 0
performing O 0
intracarotid O 0
injection O 0
of O 0
carboplatin B-Chemical 1
, O 0
we O 0
must O 0
be O 0
aware O 0
of O 0
its O 0
potentially O 0
blinding O 0
ocular B-Disease 1
toxicity I-Disease 1
. O 0

It O 0
is O 0
recommended O 0
that O 0
further O 0
studies O 0
and O 0
investigations O 0
are O 0
undertaken O 0
in O 0
the O 0
effort O 0
to O 0
minimize O 0
such O 0
severe O 0
side O 0
effects O 0
. O 0

Visual B-Disease 1
hallucinations I-Disease 1
associated O 0
with O 0
zonisamide B-Chemical 1
. O 0

Zonisamide B-Chemical 1
is O 0
a O 0
broad O 0
- O 0
spectrum O 0
antiepileptic O 0
drug O 0
used O 0
to O 0
treat O 0
various O 0
types O 0
of O 0
seizures B-Disease 1
. O 0

Although O 0
visual B-Disease 1
hallucinations I-Disease 1
have O 0
not O 0
been O 0
reported O 0
as O 0
an O 0
adverse O 0
effect O 0
of O 0
this O 0
agent O 0
, O 0
we O 0
describe O 0
three O 0
patients O 0
who O 0
experienced O 0
complex O 0
visual B-Disease 1
hallucinations I-Disease 1
and O 0
altered O 0
mental O 0
status O 0
after O 0
zonisamide B-Chemical 1
treatment O 0
was O 0
begun O 0
or O 0
its O 0
dosage O 0
increased O 0
. O 0

All O 0
three O 0
had O 0
been O 0
diagnosed O 0
earlier O 0
with O 0
epilepsy B-Disease 1
, O 0
and O 0
their O 0
electroencephalogram O 0
( O 0
EEG O 0
) O 0
findings O 0
were O 0
abnormal O 0
. O 0

During O 0
monitoring O 0
, O 0
visual B-Disease 1
hallucinations I-Disease 1
did O 0
not O 0
correlate O 0
with O 0
EEG O 0
readings O 0
, O 0
nor O 0
did O 0
video O 0
recording O 0
capture O 0
any O 0
of O 0
the O 0
described O 0
events O 0
. O 0

None O 0
of O 0
the O 0
patients O 0
had O 0
experienced O 0
visual B-Disease 1
hallucinations I-Disease 1
before O 0
this O 0
event O 0
. O 0

The O 0
only O 0
recent O 0
change O 0
in O 0
their O 0
treatment O 0
was O 0
the O 0
introduction O 0
or O 0
increased O 0
dosage O 0
of O 0
zonisamide B-Chemical 1
. O 0

With O 0
either O 0
discontinuation O 0
or O 0
decreased O 0
dosage O 0
of O 0
the O 0
drug O 0
the O 0
symptoms O 0
disappeared O 0
and O 0
did O 0
not O 0
recur O 0
. O 0

Further O 0
observations O 0
and O 0
reports O 0
will O 0
help O 0
clarify O 0
this O 0
adverse O 0
effect O 0
. O 0

Until O 0
then O 0
, O 0
clinicians O 0
need O 0
to O 0
be O 0
aware O 0
of O 0
this O 0
possible O 0
complication O 0
associated O 0
with O 0
zonisamide B-Chemical 1
. O 0

Anti O 0
- O 0
epileptic B-Disease 1
drugs O 0
- O 0
induced O 0
de O 0
novo O 0
absence B-Disease 1
seizures I-Disease 1
. O 0

The O 0
authors O 0
present O 0
three O 0
patients O 0
with O 0
de O 0
novo O 0
absence B-Disease 1
epilepsy I-Disease 1
after O 0
administration O 0
of O 0
carbamazepine B-Chemical 1
and O 0
vigabatrin B-Chemical 1
. O 0

Despite O 0
the O 0
underlying O 0
diseases O 0
, O 0
the O 0
prognosis O 0
for O 0
drug O 0
- O 0
induced O 0
de O 0
novo O 0
absence B-Disease 1
seizure I-Disease 1
is O 0
good O 0
because O 0
it O 0
subsides O 0
rapidly O 0
after O 0
discontinuing O 0
the O 0
use O 0
of O 0
the O 0
offending O 0
drugs O 0
. O 0

The O 0
gamma B-Chemical 1
- I-Chemical 1
aminobutyric I-Chemical 1
acid I-Chemical 1
- O 0
transmitted O 0
thalamocortical O 0
circuitry O 0
accounts O 0
for O 0
a O 0
major O 0
part O 0
of O 0
the O 0
underlying O 0
neurophysiology O 0
of O 0
the O 0
absence B-Disease 1
epilepsy I-Disease 1
. O 0

Because O 0
drug O 0
- O 0
induced O 0
de O 0
novo O 0
absence B-Disease 1
seizure I-Disease 1
is O 0
rare O 0
, O 0
pro O 0
- O 0
absence O 0
drugs O 0
can O 0
only O 0
be O 0
considered O 0
a O 0
promoting O 0
factor O 0
. O 0

The O 0
underlying O 0
epileptogenecity O 0
of O 0
the O 0
patients O 0
or O 0
the O 0
synergistic O 0
effects O 0
of O 0
the O 0
accompanying O 0
drugs O 0
is O 0
required O 0
to O 0
trigger O 0
the O 0
de O 0
novo O 0
absence B-Disease 1
seizure I-Disease 1
. O 0

The O 0
possibility O 0
of O 0
drug O 0
- O 0
induced O 0
aggravation O 0
should O 0
be O 0
considered O 0
whenever O 0
an O 0
unexpected O 0
increase O 0
in O 0
seizure B-Disease 1
frequency O 0
and O 0
/ O 0
or O 0
new O 0
seizure B-Disease 1
types O 0
appear O 0
following O 0
a O 0
change O 0
in O 0
drug O 0
treatment O 0
. O 0

By O 0
understanding O 0
the O 0
underlying O 0
mechanism O 0
of O 0
absence B-Disease 1
epilepsy I-Disease 1
, O 0
we O 0
can O 0
avoid O 0
the O 0
inappropriate O 0
use O 0
of O 0
anticonvulsants O 0
in O 0
children O 0
with O 0
epilepsy B-Disease 1
and O 0
prevent O 0
drug O 0
- O 0
induced O 0
absence B-Disease 1
seizures I-Disease 1
. O 0

Prenatal O 0
dexamethasone B-Chemical 1
programs O 0
hypertension B-Disease 1
and O 0
renal B-Disease 1
injury I-Disease 1
in O 0
the O 0
rat O 0
. O 0

Dexamethasone O 0
is O 0
frequently O 0
administered O 0
to O 0
the O 0
developing O 0
fetus O 0
to O 0
accelerate O 0
pulmonary O 0
development O 0
. O 0

The O 0
purpose O 0
of O 0
the O 0
present O 0
study O 0
was O 0
to O 0
determine O 0
if O 0
prenatal O 0
dexamethasone B-Chemical 1
programmed O 0
a O 0
progressive O 0
increase B-Disease 1
in I-Disease 1
blood I-Disease 1
pressure I-Disease 1
and O 0
renal B-Disease 1
injury I-Disease 1
in O 0
rats O 0
. O 0

Pregnant O 0
rats O 0
were O 0
given O 0
either O 0
vehicle O 0
or O 0
2 O 0
daily O 0
intraperitoneal O 0
injections O 0
of O 0
dexamethasone B-Chemical 1
( O 0
0 O 0
. O 0
2 O 0
mg O 0
/ O 0
kg O 0
body O 0
weight O 0
) O 0
on O 0
gestational O 0
days O 0
11 O 0
and O 0
12 O 0
, O 0
13 O 0
and O 0
14 O 0
, O 0
15 O 0
and O 0
16 O 0
, O 0
17 O 0
and O 0
18 O 0
, O 0
or O 0
19 O 0
and O 0
20 O 0
. O 0

Offspring O 0
of O 0
rats O 0
administered O 0
dexamethasone B-Chemical 1
on O 0
days O 0
15 O 0
and O 0
16 O 0
gestation O 0
had O 0
a O 0
20 O 0
% O 0
reduction B-Disease 1
in I-Disease 1
glomerular I-Disease 1
number I-Disease 1
compared O 0
with O 0
control O 0
at O 0
6 O 0
to O 0
9 O 0
months O 0
of O 0
age O 0
( O 0
22 O 0
527 O 0
+ O 0
/ O 0
- O 0
509 O 0
versus O 0
28 O 0
050 O 0
+ O 0
/ O 0
- O 0
561 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
which O 0
was O 0
comparable O 0
to O 0
the O 0
percent O 0
reduction O 0
in O 0
glomeruli O 0
measured O 0
at O 0
3 O 0
weeks O 0
of O 0
age O 0
. O 0

Six O 0
- O 0
to O 0
9 O 0
- O 0
month O 0
old O 0
rats O 0
receiving O 0
prenatal O 0
dexamethasone B-Chemical 1
on O 0
days O 0
17 O 0
and O 0
18 O 0
of O 0
gestation O 0
had O 0
a O 0
17 O 0
% O 0
reduction O 0
in O 0
glomeruli O 0
( O 0
23 O 0
380 O 0
+ O 0
/ O 0
- O 0
587 O 0
) O 0
compared O 0
with O 0
control O 0
rats O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Male O 0
rats O 0
that O 0
received O 0
prenatal O 0
dexamethasone B-Chemical 1
on O 0
days O 0
15 O 0
and O 0
16 O 0
, O 0
17 O 0
and O 0
18 O 0
, O 0
and O 0
13 O 0
and O 0
14 O 0
of O 0
gestation O 0
had O 0
elevated B-Disease 1
blood I-Disease 1
pressures I-Disease 1
at O 0
6 O 0
months O 0
of O 0
age O 0
; O 0
the O 0
latter O 0
group O 0
did O 0
not O 0
have O 0
a O 0
reduction B-Disease 1
in I-Disease 1
glomerular I-Disease 1
number I-Disease 1
. O 0

Adult O 0
rats O 0
given O 0
dexamethasone B-Chemical 1
on O 0
days O 0
15 O 0
and O 0
16 O 0
of O 0
gestation O 0
had O 0
more O 0
glomeruli O 0
with O 0
glomerulosclerosis B-Disease 1
than O 0
control O 0
rats O 0
. O 0

This O 0
study O 0
shows O 0
that O 0
prenatal O 0
dexamethasone B-Chemical 1
in O 0
rats O 0
results O 0
in O 0
a O 0
reduction B-Disease 1
in I-Disease 1
glomerular I-Disease 1
number I-Disease 1
, O 0
glomerulosclerosis B-Disease 1
, O 0
and O 0
hypertension B-Disease 1
when O 0
administered O 0
at O 0
specific O 0
points O 0
during O 0
gestation O 0
. O 0

Hypertension B-Disease 1
was O 0
observed O 0
in O 0
animals O 0
that O 0
had O 0
a O 0
reduction O 0
in O 0
glomeruli O 0
as O 0
well O 0
as O 0
in O 0
a O 0
group O 0
that O 0
did O 0
not O 0
have O 0
a O 0
reduction B-Disease 1
in I-Disease 1
glomerular I-Disease 1
number I-Disease 1
, O 0
suggesting O 0
that O 0
a O 0
reduction B-Disease 1
in I-Disease 1
glomerular I-Disease 1
number I-Disease 1
is O 0
not O 0
the O 0
sole O 0
cause O 0
for O 0
the O 0
development O 0
of O 0
hypertension B-Disease 1
. O 0

Kidney O 0
function O 0
and O 0
morphology O 0
after O 0
short O 0
- O 0
term O 0
combination O 0
therapy O 0
with O 0
cyclosporine B-Chemical 1
A I-Chemical 1
, O 0
tacrolimus B-Chemical 1
and O 0
sirolimus B-Chemical 1
in O 0
the O 0
rat O 0
. O 0

BACKGROUND O 0
: O 0
Sirolimus B-Chemical 1
( O 0
SRL B-Chemical 1
) O 0
may O 0
supplement O 0
calcineurin O 0
inhibitors O 0
in O 0
clinical O 0
organ O 0
transplantation O 0
. O 0

These O 0
are O 0
nephrotoxic B-Disease 1
, O 0
but O 0
SRL B-Chemical 1
seems O 0
to O 0
act O 0
differently O 0
displaying O 0
only O 0
minor O 0
nephrotoxic B-Disease 1
effects O 0
, O 0
although O 0
this O 0
question O 0
is O 0
still O 0
open O 0
. O 0

In O 0
a O 0
number O 0
of O 0
treatment O 0
protocols O 0
where O 0
SRL B-Chemical 1
was O 0
combined O 0
with O 0
a O 0
calcineurin O 0
inhibitor O 0
indications O 0
of O 0
a O 0
synergistic O 0
nephrotoxic B-Disease 1
effect O 0
were O 0
described O 0
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
examine O 0
further O 0
the O 0
renal O 0
function O 0
, O 0
including O 0
morphological O 0
analysis O 0
of O 0
the O 0
kidneys O 0
of O 0
male O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
treated O 0
with O 0
either O 0
cyclosporine B-Chemical 1
A I-Chemical 1
( O 0
CsA B-Chemical 1
) O 0
, O 0
tacrolimus B-Chemical 1
( O 0
FK506 B-Chemical 1
) O 0
or O 0
SRL B-Chemical 1
as O 0
monotherapies O 0
or O 0
in O 0
different O 0
combinations O 0
. O 0

METHODS O 0
: O 0
For O 0
a O 0
period O 0
of O 0
2 O 0
weeks O 0
, O 0
CsA B-Chemical 1
15 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
( O 0
given O 0
orally O 0
) O 0
, O 0
FK506 B-Chemical 1
3 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
( O 0
given O 0
orally O 0
) O 0
or O 0
SRL B-Chemical 1
0 O 0
. O 0
4 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
( O 0
given O 0
intraperitoneally O 0
) O 0
was O 0
administered O 0
once O 0
a O 0
day O 0
as O 0
these O 0
doses O 0
have O 0
earlier O 0
been O 0
found O 0
to O 0
achieve O 0
a O 0
significant O 0
immunosuppressive O 0
effect O 0
in O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
. O 0

In O 0
the O 0
' O 0
conscious O 0
catheterized O 0
rat O 0
' O 0
model O 0
, O 0
the O 0
glomerular O 0
filtration O 0
rate O 0
( O 0
GFR O 0
) O 0
was O 0
measured O 0
as O 0
the O 0
clearance O 0
of O 0
Cr O 0
( O 0
EDTA O 0
) O 0
. O 0

The O 0
morphological O 0
analysis O 0
of O 0
the O 0
kidneys O 0
included O 0
a O 0
semi O 0
- O 0
quantitative O 0
scoring O 0
system O 0
analysing O 0
the O 0
degree O 0
of O 0
striped O 0
fibrosis B-Disease 1
, O 0
subcapsular O 0
fibrosis B-Disease 1
and O 0
the O 0
number O 0
of O 0
basophilic O 0
tubules O 0
, O 0
plus O 0
an O 0
additional O 0
stereological O 0
analysis O 0
of O 0
the O 0
total O 0
grade O 0
of O 0
fibrosis B-Disease 1
in O 0
the O 0
cortex O 0
stained O 0
with O 0
Sirius O 0
Red O 0
. O 0

RESULTS O 0
: O 0
CsA B-Chemical 1
, O 0
FK506 B-Chemical 1
and O 0
SRL B-Chemical 1
all O 0
significantly O 0
decreased O 0
the O 0
GFR O 0
. O 0

A O 0
further O 0
deterioration O 0
was O 0
seen O 0
when O 0
CsA B-Chemical 1
was O 0
combined O 0
with O 0
either O 0
FK506 B-Chemical 1
or O 0
SRL B-Chemical 1
, O 0
whereas O 0
the O 0
GFR O 0
remained O 0
unchanged O 0
in O 0
the O 0
group O 0
treated O 0
with O 0
FK506 B-Chemical 1
plus O 0
SRL B-Chemical 1
when O 0
compared O 0
with O 0
treatment O 0
with O 0
any O 0
of O 0
the O 0
single O 0
substances O 0
. O 0

The O 0
morphological O 0
changes O 0
presented O 0
a O 0
similar O 0
pattern O 0
. O 0

The O 0
semi O 0
- O 0
quantitative O 0
scoring O 0
was O 0
significantly O 0
worst O 0
in O 0
the O 0
group O 0
treated O 0
with O 0
CsA B-Chemical 1
plus O 0
SRL B-Chemical 1
( O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
compared O 0
with O 0
controls O 0
) O 0
and O 0
the O 0
analysis O 0
of O 0
the O 0
total O 0
grade O 0
of O 0
fibrosis B-Disease 1
also O 0
showed O 0
the O 0
highest O 0
proportion O 0
in O 0
the O 0
same O 0
group O 0
and O 0
was O 0
significantly O 0
different O 0
from O 0
controls O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
02 O 0
) O 0
. O 0

The O 0
FK506 B-Chemical 1
plus O 0
SRL B-Chemical 1
combination O 0
showed O 0
only O 0
a O 0
marginally O 0
higher O 0
degree O 0
of O 0
fibrosis B-Disease 1
as O 0
compared O 0
with O 0
controls O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
This O 0
rat O 0
study O 0
demonstrated O 0
a O 0
synergistic O 0
nephrotoxic B-Disease 1
effect O 0
of O 0
CsA B-Chemical 1
plus O 0
SRL B-Chemical 1
, O 0
whereas O 0
FK506 B-Chemical 1
plus O 0
SRL B-Chemical 1
was O 0
better O 0
tolerated O 0
. O 0

Evaluation O 0
of O 0
cardiac O 0
troponin O 0
I O 0
and O 0
T O 0
levels O 0
as O 0
markers O 0
of O 0
myocardial B-Disease 1
damage I-Disease 1
in O 0
doxorubicin B-Chemical 1
- O 0
induced O 0
cardiomyopathy B-Disease 1
rats O 0
, O 0
and O 0
their O 0
relationship O 0
with O 0
echocardiographic O 0
and O 0
histological O 0
findings O 0
. O 0

BACKGROUND O 0
: O 0
Cardiac O 0
troponins O 0
I O 0
( O 0
cTnI O 0
) O 0
and O 0
T O 0
( O 0
cTnT O 0
) O 0
have O 0
been O 0
shown O 0
to O 0
be O 0
highly O 0
sensitive O 0
and O 0
specific O 0
markers O 0
of O 0
myocardial B-Disease 1
cell I-Disease 1
injury I-Disease 1
. O 0

We O 0
investigated O 0
the O 0
diagnostic O 0
value O 0
of O 0
cTnI O 0
and O 0
cTnT O 0
for O 0
the O 0
diagnosis O 0
of O 0
myocardial B-Disease 1
damage I-Disease 1
in O 0
a O 0
rat O 0
model O 0
of O 0
doxorubicin B-Chemical 1
( O 0
DOX B-Chemical 1
) O 0
- O 0
induced O 0
cardiomyopathy B-Disease 1
, O 0
and O 0
we O 0
examined O 0
the O 0
relationship O 0
between O 0
serial O 0
cTnI O 0
and O 0
cTnT O 0
with O 0
the O 0
development O 0
of O 0
cardiac B-Disease 1
disorders I-Disease 1
monitored O 0
by O 0
echocardiography O 0
and O 0
histological O 0
examinations O 0
in O 0
this O 0
model O 0
. O 0

METHODS O 0
: O 0
Thirty O 0
- O 0
five O 0
Wistar O 0
rats O 0
were O 0
given O 0
1 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
DOX B-Chemical 1
, O 0
i O 0
. O 0
v O 0
. O 0
, O 0
weekly O 0
for O 0
up O 0
to O 0
8 O 0
weeks O 0
for O 0
a O 0
total O 0
cumulative O 0
dose O 0
of O 0
12 O 0
mg O 0
/ O 0
kg O 0
BW O 0
. O 0

Ten O 0
rats O 0
received O 0
saline O 0
as O 0
a O 0
control O 0
group O 0
. O 0

cTnI O 0
was O 0
measured O 0
with O 0
Access O 0
( O 0
R O 0
) O 0
( O 0
ng O 0
/ O 0
ml O 0
) O 0
and O 0
a O 0
research O 0
immunoassay O 0
( O 0
pg O 0
/ O 0
ml O 0
) O 0
, O 0
and O 0
compared O 0
with O 0
cTnT O 0
, O 0
CK O 0
- O 0
MB O 0
mass O 0
and O 0
CK O 0
. O 0

By O 0
using O 0
transthoracic O 0
echocardiography O 0
, O 0
anterior O 0
and O 0
posterior O 0
wall O 0
thickness O 0
, O 0
LV O 0
diameters O 0
and O 0
LV O 0
fractional O 0
shortening O 0
( O 0
FS O 0
) O 0
were O 0
measured O 0
in O 0
all O 0
rats O 0
before O 0
DOX B-Chemical 1
or O 0
saline O 0
, O 0
and O 0
at O 0
weeks O 0
6 O 0
and O 0
9 O 0
after O 0
treatment O 0
in O 0
all O 0
surviving O 0
rats O 0
. O 0

Histology O 0
was O 0
performed O 0
in O 0
DOX B-Chemical 1
- O 0
rats O 0
at O 0
6 O 0
and O 0
9 O 0
weeks O 0
after O 0
the O 0
last O 0
DOX B-Chemical 1
dose O 0
and O 0
in O 0
all O 0
controls O 0
. O 0

RESULTS O 0
: O 0
Eighteen O 0
of O 0
the O 0
DOX B-Chemical 1
rats O 0
died O 0
prematurely O 0
of O 0
general O 0
toxicity B-Disease 1
during O 0
the O 0
9 O 0
- O 0
week O 0
period O 0
. O 0

End O 0
- O 0
diastolic O 0
( O 0
ED O 0
) O 0
and O 0
end O 0
- O 0
systolic O 0
( O 0
ES O 0
) O 0
LV O 0
diameters O 0
/ O 0
BW O 0
significantly O 0
increased O 0
, O 0
whereas O 0
LV O 0
FS O 0
was O 0
decreased O 0
after O 0
9 O 0
weeks O 0
in O 0
the O 0
DOX B-Chemical 1
group O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

These O 0
parameters O 0
remained O 0
unchanged O 0
in O 0
controls O 0
. O 0

Histological O 0
evaluation O 0
of O 0
hearts O 0
from O 0
all O 0
rats O 0
given O 0
DOX B-Chemical 1
revealed O 0
significant O 0
slight O 0
degrees O 0
of O 0
perivascular O 0
and O 0
interstitial O 0
fibrosis B-Disease 1
. O 0

In O 0
7 O 0
of O 0
the O 0
18 O 0
rats O 0
, O 0
degeneration O 0
and O 0
myocyte O 0
vacuolisation O 0
were O 0
found O 0
. O 0

Only O 0
five O 0
of O 0
the O 0
controls O 0
exhibited O 0
evidence O 0
of O 0
very O 0
slight O 0
perivascular O 0
fibrosis B-Disease 1
. O 0

A O 0
significant O 0
rise O 0
in O 0
cTnT O 0
was O 0
found O 0
in O 0
DOX B-Chemical 1
rats O 0
after O 0
cumulative O 0
doses O 0
of O 0
7 O 0
. O 0
5 O 0
and O 0
12 O 0
mg O 0
/ O 0
kg O 0
in O 0
comparison O 0
with O 0
baseline O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

cTnT O 0
found O 0
in O 0
rats O 0
after O 0
12 O 0
mg O 0
/ O 0
kg O 0
were O 0
significantly O 0
greater O 0
than O 0
that O 0
found O 0
after O 0
7 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
DOX B-Chemical 1
. O 0

Maximal O 0
cTnI O 0
( O 0
pg O 0
/ O 0
ml O 0
) O 0
and O 0
cTnT O 0
levels O 0
were O 0
significantly O 0
increased O 0
in O 0
DOX B-Chemical 1
rats O 0
compared O 0
with O 0
controls O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
006 O 0
, O 0
0 O 0
. O 0
007 O 0
) O 0
. O 0

cTnI O 0
( O 0
ng O 0
/ O 0
ml O 0
) O 0
, O 0
CK O 0
- O 0
MB O 0
mass O 0
and O 0
CK O 0
remained O 0
unchanged O 0
in O 0
DOX B-Chemical 1
rats O 0
compared O 0
with O 0
controls O 0
. O 0

All O 0
markers O 0
remained O 0
stable O 0
in O 0
controls O 0
. O 0

Analysis O 0
of O 0
data O 0
revealed O 0
a O 0
significant O 0
correlation O 0
between O 0
maximal O 0
cTnT O 0
and O 0
ED O 0
and O 0
ES O 0
LV O 0
diameters O 0
/ O 0
BW O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
81 O 0
and O 0
0 O 0
. O 0
65 O 0
; O 0
p O 0
< O 0
0 O 0
. O 0
0001 O 0
) O 0
. O 0

A O 0
significant O 0
relationship O 0
was O 0
observed O 0
between O 0
maximal O 0
cTnT O 0
and O 0
the O 0
extent O 0
of O 0
myocardial O 0
morphological O 0
changes O 0
, O 0
and O 0
between O 0
LV O 0
diameters O 0
/ O 0
BW O 0
and O 0
histological O 0
findings O 0
. O 0

CONCLUSIONS O 0
: O 0
Among O 0
markers O 0
of O 0
ischemic B-Disease 1
injury I-Disease 1
after O 0
DOX B-Chemical 1
in O 0
rats O 0
, O 0
cTnT O 0
showed O 0
the O 0
greatest O 0
ability O 0
to O 0
detect O 0
myocardial B-Disease 1
damage I-Disease 1
assessed O 0
by O 0
echocardiographic O 0
detection O 0
and O 0
histological O 0
changes O 0
. O 0

Although O 0
there O 0
was O 0
a O 0
discrepancy O 0
between O 0
the O 0
amount O 0
of O 0
cTnI O 0
and O 0
cTnT O 0
after O 0
DOX B-Chemical 1
, O 0
probably O 0
due O 0
to O 0
heterogeneity O 0
in O 0
cross O 0
- O 0
reactivities O 0
of O 0
mAbs O 0
to O 0
various O 0
cTnI O 0
and O 0
cTnT O 0
forms O 0
, O 0
it O 0
is O 0
likely O 0
that O 0
cTnT O 0
in O 0
rats O 0
after O 0
DOX B-Chemical 1
indicates O 0
cell O 0
damage O 0
determined O 0
by O 0
the O 0
magnitude O 0
of O 0
injury O 0
induced O 0
and O 0
that O 0
cTnT O 0
should O 0
be O 0
a O 0
useful O 0
marker O 0
for O 0
the O 0
prediction O 0
of O 0
experimentally O 0
induced O 0
cardiotoxicity B-Disease 1
and O 0
possibly O 0
for O 0
cardioprotective O 0
experiments O 0
. O 0

Octreotide B-Chemical 1
- O 0
induced O 0
hypoxemia B-Disease 1
and O 0
pulmonary B-Disease 1
hypertension I-Disease 1
in O 0
premature O 0
neonates O 0
. O 0

The O 0
authors O 0
report O 0
2 O 0
cases O 0
of O 0
premature O 0
neonates O 0
who O 0
had O 0
enterocutaneous O 0
fistula B-Disease 1
complicating O 0
necrotizing B-Disease 1
enterocolitis I-Disease 1
. O 0

Pulmonary B-Disease 1
hypertension I-Disease 1
developed O 0
after O 0
administration O 0
of O 0
a O 0
somatostatin O 0
analogue O 0
, O 0
octreotide B-Chemical 1
, O 0
to O 0
enhance O 0
resolution O 0
of O 0
the O 0
fistula B-Disease 1
. O 0

The O 0
authors O 0
discuss O 0
the O 0
mechanism O 0
of O 0
the O 0
occurrence O 0
of O 0
this O 0
complication O 0
and O 0
recommend O 0
caution O 0
of O 0
its O 0
use O 0
in O 0
high O 0
- O 0
risk O 0
premature O 0
neonates O 0
. O 0

The O 0
risk O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
in O 0
women O 0
prescribed O 0
cyproterone B-Chemical 1
acetate I-Chemical 1
in O 0
combination O 0
with O 0
ethinyl B-Chemical 1
estradiol I-Chemical 1
: O 0
a O 0
nested O 0
cohort O 0
analysis O 0
and O 0
case O 0
- O 0
control O 0
study O 0
. O 0

BACKGROUND O 0
: O 0
Cyproterone B-Chemical 1
acetate I-Chemical 1
combined O 0
with O 0
ethinyl B-Chemical 1
estradiol I-Chemical 1
( O 0
CPA B-Chemical 1
/ O 0
EE B-Chemical 1
) O 0
is O 0
licensed O 0
in O 0
the O 0
UK O 0
for O 0
the O 0
treatment O 0
of O 0
women O 0
with O 0
acne B-Disease 1
and O 0
hirsutism B-Disease 1
and O 0
is O 0
also O 0
a O 0
treatment O 0
option O 0
for O 0
polycystic B-Disease 1
ovary I-Disease 1
syndrome I-Disease 1
( O 0
PCOS B-Disease 1
) O 0
. O 0

Previous O 0
studies O 0
have O 0
demonstrated O 0
an O 0
increased O 0
risk O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
( O 0
VTE B-Disease 1
) O 0
associated O 0
with O 0
CPA B-Chemical 1
/ O 0
EE B-Chemical 1
compared O 0
with O 0
conventional O 0
combined O 0
oral B-Chemical 1
contraceptives I-Chemical 1
( O 0
COCs O 0
) O 0
. O 0

We O 0
believe O 0
the O 0
results O 0
of O 0
those O 0
studies O 0
may O 0
have O 0
been O 0
affected O 0
by O 0
residual O 0
confounding O 0
. O 0

METHODS O 0
: O 0
Using O 0
the O 0
General O 0
Practice O 0
Research O 0
Database O 0
we O 0
conducted O 0
a O 0
cohort O 0
analysis O 0
and O 0
case O 0
- O 0
control O 0
study O 0
nested O 0
within O 0
a O 0
population O 0
of O 0
women O 0
aged O 0
between O 0
15 O 0
and O 0
39 O 0
years O 0
with O 0
acne B-Disease 1
, O 0
hirsutism B-Disease 1
or O 0
PCOS B-Disease 1
to O 0
estimate O 0
the O 0
risk O 0
of O 0
VTE B-Disease 1
associated O 0
with O 0
CPA B-Chemical 1
/ O 0
EE B-Chemical 1
. O 0

RESULTS O 0
: O 0
The O 0
age O 0
- O 0
adjusted O 0
incidence O 0
rate O 0
ratio O 0
for O 0
CPA B-Chemical 1
/ O 0
EE B-Chemical 1
versus O 0
conventional O 0
COCs O 0
was O 0
2 O 0
. O 0
20 O 0
[ O 0
95 O 0
% O 0
confidence O 0
interval O 0
( O 0
CI O 0
) O 0
1 O 0
. O 0
35 O 0
- O 0
3 O 0
. O 0
58 O 0
] O 0
. O 0

Using O 0
as O 0
the O 0
reference O 0
group O 0
women O 0
who O 0
were O 0
not O 0
using O 0
oral O 0
contraception O 0
, O 0
had O 0
no O 0
recent O 0
pregnancy O 0
or O 0
menopausal O 0
symptoms O 0
, O 0
the O 0
case O 0
- O 0
control O 0
analysis O 0
gave O 0
an O 0
adjusted O 0
odds O 0
ratio O 0
( O 0
OR O 0
( O 0
adj O 0
) O 0
) O 0
of O 0
7 O 0
. O 0
44 O 0
( O 0
95 O 0
% O 0
CI O 0
3 O 0
. O 0
67 O 0
- O 0
15 O 0
. O 0
08 O 0
) O 0
for O 0
CPA B-Chemical 1
/ O 0
EE B-Chemical 1
use O 0
compared O 0
with O 0
an O 0
OR O 0
( O 0
adj O 0
) O 0
of O 0
2 O 0
. O 0
58 O 0
( O 0
95 O 0
% O 0
CI O 0
1 O 0
. O 0
60 O 0
- O 0
4 O 0
. O 0
18 O 0
) O 0
for O 0
use O 0
of O 0
conventional O 0
COCs O 0
. O 0

CONCLUSIONS O 0
: O 0
We O 0
have O 0
demonstrated O 0
an O 0
increased O 0
risk O 0
of O 0
VTE B-Disease 1
associated O 0
with O 0
the O 0
use O 0
of O 0
CPA B-Chemical 1
/ O 0
EE B-Chemical 1
in O 0
women O 0
with O 0
acne B-Disease 1
, O 0
hirsutism B-Disease 1
or O 0
PCOS B-Disease 1
although O 0
residual O 0
confounding O 0
by O 0
indication O 0
cannot O 0
be O 0
excluded O 0
. O 0

The O 0
effect O 0
of O 0
treatment O 0
with O 0
gum B-Chemical 1
Arabic I-Chemical 1
on O 0
gentamicin B-Chemical 1
nephrotoxicity B-Disease 1
in O 0
rats O 0
: O 0
a O 0
preliminary O 0
study O 0
. O 0

In O 0
the O 0
present O 0
work O 0
we O 0
assessed O 0
the O 0
effect O 0
of O 0
treatment O 0
of O 0
rats O 0
with O 0
gum B-Chemical 1
Arabic I-Chemical 1
on O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
induced O 0
by O 0
gentamicin B-Chemical 1
( O 0
GM B-Chemical 1
) O 0
nephrotoxicity B-Disease 1
. O 0

Rats O 0
were O 0
treated O 0
with O 0
the O 0
vehicle O 0
( O 0
2 O 0
mL O 0
/ O 0
kg O 0
of O 0
distilled O 0
water O 0
and O 0
5 O 0
% O 0
w O 0
/ O 0
v O 0
cellulose O 0
, O 0
10 O 0
days O 0
) O 0
, O 0
gum B-Chemical 1
Arabic I-Chemical 1
( O 0
2 O 0
mL O 0
/ O 0
kg O 0
of O 0
a O 0
10 O 0
% O 0
w O 0
/ O 0
v O 0
aqueous O 0
suspension O 0
of O 0
gum B-Chemical 1
Arabic I-Chemical 1
powder O 0
, O 0
orally O 0
for O 0
10 O 0
days O 0
) O 0
, O 0
or O 0
gum B-Chemical 1
Arabic I-Chemical 1
concomitantly O 0
with O 0
GM B-Chemical 1
( O 0
80mg O 0
/ O 0
kg O 0
/ O 0
day O 0
intramuscularly O 0
, O 0
during O 0
the O 0
last O 0
six O 0
days O 0
of O 0
the O 0
treatment O 0
period O 0
) O 0
. O 0

Nephrotoxicity B-Disease 1
was O 0
assessed O 0
by O 0
measuring O 0
the O 0
concentrations O 0
of O 0
creatinine B-Chemical 1
and O 0
urea B-Chemical 1
in O 0
the O 0
plasma O 0
and O 0
reduced O 0
glutathione B-Chemical 1
( O 0
GSH B-Chemical 1
) O 0
in O 0
the O 0
kidney O 0
cortex O 0
, O 0
and O 0
by O 0
light O 0
microscopic O 0
examination O 0
of O 0
kidney O 0
sections O 0
. O 0

The O 0
results O 0
indicated O 0
that O 0
concomitant O 0
treatment O 0
with O 0
gum B-Chemical 1
Arabic I-Chemical 1
and O 0
GM B-Chemical 1
significantly O 0
increased O 0
creatinine B-Chemical 1
and O 0
urea B-Chemical 1
by O 0
about O 0
183 O 0
and O 0
239 O 0
% O 0
, O 0
respectively O 0
( O 0
compared O 0
to O 0
432 O 0
and O 0
346 O 0
% O 0
, O 0
respectively O 0
, O 0
in O 0
rats O 0
treated O 0
with O 0
cellulose O 0
and O 0
GM B-Chemical 1
) O 0
, O 0
and O 0
decreased O 0
that O 0
of O 0
cortical O 0
GSH B-Chemical 1
by O 0
21 O 0
% O 0
( O 0
compared O 0
to O 0
27 O 0
% O 0
in O 0
the O 0
cellulose O 0
plus O 0
GM B-Chemical 1
group O 0
) O 0
The O 0
GM B-Chemical 1
- O 0
induced O 0
proximal O 0
tubular B-Disease 1
necrosis I-Disease 1
appeared O 0
to O 0
be O 0
slightly O 0
less O 0
severe O 0
in O 0
rats O 0
given O 0
GM B-Chemical 1
together O 0
with O 0
gum B-Chemical 1
Arabic I-Chemical 1
than O 0
in O 0
those O 0
given O 0
GM B-Chemical 1
and O 0
cellulose O 0
. O 0

It O 0
could O 0
be O 0
inferred O 0
that O 0
gum B-Chemical 1
Arabic I-Chemical 1
treatment O 0
has O 0
induced O 0
a O 0
modest O 0
amelioration O 0
of O 0
some O 0
of O 0
the O 0
histological O 0
and O 0
biochemical O 0
indices O 0
of O 0
GM B-Chemical 1
nephrotoxicity B-Disease 1
. O 0

Further O 0
work O 0
is O 0
warranted O 0
on O 0
the O 0
effect O 0
of O 0
the O 0
treatments O 0
on O 0
renal O 0
functional O 0
aspects O 0
in O 0
models O 0
of O 0
chronic B-Disease 1
renal I-Disease 1
failure I-Disease 1
, O 0
and O 0
on O 0
the O 0
mechanism O 0
( O 0
s O 0
) O 0
involved O 0
. O 0

Increased O 0
frequency O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
with O 0
the O 0
combination O 0
of O 0
docetaxel B-Chemical 1
and O 0
thalidomide B-Chemical 1
in O 0
patients O 0
with O 0
metastatic O 0
androgen O 0
- O 0
independent O 0
prostate B-Disease 1
cancer I-Disease 1
. O 0

STUDY O 0
OBJECTIVE O 0
: O 0
To O 0
evaluate O 0
the O 0
frequency O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
( O 0
VTE B-Disease 1
) O 0
in O 0
patients O 0
with O 0
advanced O 0
androgen O 0
- O 0
independent O 0
prostate B-Disease 1
cancer I-Disease 1
who O 0
were O 0
treated O 0
with O 0
docetaxel B-Chemical 1
alone O 0
or O 0
in O 0
combination O 0
with O 0
thalidomide B-Chemical 1
. O 0

DESIGN O 0
: O 0
Retrospective O 0
analysis O 0
of O 0
a O 0
randomized O 0
phase O 0
II O 0
trial O 0
. O 0

SETTING O 0
: O 0
National O 0
Institutes O 0
of O 0
Health O 0
clinical O 0
research O 0
center O 0
. O 0

PATIENTS O 0
: O 0
Seventy O 0
men O 0
, O 0
aged O 0
50 O 0
- O 0
80 O 0
years O 0
, O 0
with O 0
advanced O 0
androgen O 0
- O 0
independent O 0
prostate B-Disease 1
cancer I-Disease 1
. O 0

INTERVENTION O 0
: O 0
Each O 0
patient O 0
received O 0
either O 0
intravenous O 0
docetaxel B-Chemical 1
30 O 0
mg O 0
/ O 0
m2 O 0
/ O 0
week O 0
for O 0
3 O 0
consecutive O 0
weeks O 0
, O 0
followed O 0
by O 0
1 O 0
week O 0
off O 0
, O 0
or O 0
the O 0
combination O 0
of O 0
continuous O 0
oral O 0
thalidomide B-Chemical 1
200 O 0
mg O 0
every O 0
evening O 0
plus O 0
the O 0
same O 0
docetaxel B-Chemical 1
regimen O 0
. O 0

This O 0
4 O 0
- O 0
week O 0
cycle O 0
was O 0
repeated O 0
until O 0
there O 0
was O 0
evidence O 0
of O 0
excessive O 0
toxicity B-Disease 1
or O 0
disease O 0
progression O 0
. O 0

MEASUREMENTS O 0
AND O 0
MAIN O 0
RESULTS O 0
: O 0
None O 0
of O 0
23 O 0
patients O 0
who O 0
received O 0
docetaxel B-Chemical 1
alone O 0
developed O 0
VTE B-Disease 1
, O 0
whereas O 0
9 O 0
of O 0
47 O 0
patients O 0
( O 0
19 O 0
% O 0
) O 0
who O 0
received O 0
docetaxel B-Chemical 1
plus O 0
thalidomide B-Chemical 1
developed O 0
VTE B-Disease 1
( O 0
p O 0
= O 0
0 O 0
. O 0
025 O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
The O 0
addition O 0
of O 0
thalidomide B-Chemical 1
to O 0
docetaxel B-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
prostate B-Disease 1
cancer I-Disease 1
significantly O 0
increases O 0
the O 0
frequency O 0
of O 0
VTE B-Disease 1
. O 0

Clinicians O 0
should O 0
be O 0
aware O 0
of O 0
this O 0
potential O 0
complication O 0
when O 0
adding O 0
thalidomide B-Chemical 1
to O 0
chemotherapeutic O 0
regimens O 0
. O 0

Ticlopidine B-Chemical 1
- O 0
induced O 0
cholestatic B-Disease 1
hepatitis I-Disease 1
. O 0

OBJECTIVE O 0
: O 0
To O 0
report O 0
2 O 0
cases O 0
of O 0
ticlopidine B-Chemical 1
- O 0
induced O 0
cholestatic B-Disease 1
hepatitis I-Disease 1
, O 0
investigate O 0
its O 0
mechanism O 0
, O 0
and O 0
compare O 0
the O 0
observed O 0
main O 0
characteristics O 0
with O 0
those O 0
of O 0
the O 0
published O 0
cases O 0
. O 0

CASE O 0
SUMMARIES O 0
: O 0
Two O 0
patients O 0
developed O 0
prolonged O 0
cholestatic B-Disease 1
hepatitis I-Disease 1
after O 0
receiving O 0
ticlopidine B-Chemical 1
following O 0
percutaneous O 0
coronary O 0
angioplasty O 0
, O 0
with O 0
complete O 0
remission O 0
during O 0
the O 0
follow O 0
- O 0
up O 0
period O 0
. O 0

T O 0
- O 0
cell O 0
stimulation O 0
by O 0
therapeutic O 0
concentration O 0
of O 0
ticlopidine B-Chemical 1
was O 0
demonstrated O 0
in O 0
vitro O 0
in O 0
the O 0
patients O 0
, O 0
but O 0
not O 0
in O 0
healthy O 0
controls O 0
. O 0

DISCUSSION O 0
: O 0
Cholestatic B-Disease 1
hepatitis I-Disease 1
is O 0
a O 0
rare O 0
complication O 0
of O 0
the O 0
antiplatelet O 0
agent O 0
ticlopidine B-Chemical 1
; O 0
several O 0
cases O 0
have O 0
been O 0
reported O 0
but O 0
few O 0
in O 0
the O 0
English O 0
literature O 0
. O 0

Our O 0
patients O 0
developed O 0
jaundice B-Disease 1
following O 0
treatment O 0
with O 0
ticlopidine B-Chemical 1
and O 0
showed O 0
the O 0
clinical O 0
and O 0
laboratory O 0
characteristics O 0
of O 0
cholestatic B-Disease 1
hepatitis I-Disease 1
, O 0
which O 0
resolved O 0
after O 0
discontinuation O 0
of O 0
the O 0
drug O 0
. O 0

Hepatitis B-Disease 1
may O 0
develop O 0
weeks O 0
after O 0
discontinuation O 0
of O 0
the O 0
drug O 0
and O 0
may O 0
run O 0
a O 0
prolonged O 0
course O 0
, O 0
but O 0
complete O 0
remission O 0
was O 0
observed O 0
in O 0
all O 0
reported O 0
cases O 0
. O 0

An O 0
objective O 0
causality O 0
assessment O 0
revealed O 0
that O 0
the O 0
adverse O 0
drug O 0
event O 0
was O 0
probably O 0
related O 0
to O 0
the O 0
use O 0
of O 0
ticlopidine B-Chemical 1
. O 0

The O 0
mechanisms O 0
of O 0
this O 0
ticlopidine B-Chemical 1
- O 0
induced O 0
cholestasis B-Disease 1
are O 0
unclear O 0
. O 0

Immune O 0
mechanisms O 0
may O 0
be O 0
involved O 0
in O 0
the O 0
drug O 0
' O 0
s O 0
hepatotoxicity B-Disease 1
, O 0
as O 0
suggested O 0
by O 0
the O 0
T O 0
- O 0
cell O 0
stimulation O 0
study O 0
reported O 0
here O 0
. O 0

CONCLUSIONS O 0
: O 0
Cholestatic B-Disease 1
hepatitis I-Disease 1
is O 0
a O 0
rare O 0
adverse O 0
effect O 0
of O 0
ticlopidine B-Chemical 1
that O 0
may O 0
be O 0
immune O 0
mediated O 0
. O 0

Patients O 0
receiving O 0
the O 0
drug O 0
should O 0
be O 0
monitored O 0
with O 0
liver O 0
function O 0
tests O 0
along O 0
with O 0
complete O 0
blood O 0
cell O 0
counts O 0
. O 0

This O 0
complication O 0
will O 0
be O 0
observed O 0
even O 0
less O 0
often O 0
in O 0
the O 0
future O 0
as O 0
ticlopidine B-Chemical 1
is O 0
being O 0
replaced O 0
by O 0
the O 0
newer O 0
antiplatelet O 0
agent O 0
clopidogrel B-Chemical 1
. O 0

Epithelial O 0
sodium B-Chemical 1
channel O 0
( O 0
ENaC O 0
) O 0
subunit O 0
mRNA O 0
and O 0
protein O 0
expression O 0
in O 0
rats O 0
with O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
- O 0
induced O 0
nephrotic B-Disease 1
syndrome I-Disease 1
. O 0

In O 0
experimental O 0
nephrotic B-Disease 1
syndrome I-Disease 1
, O 0
urinary O 0
sodium B-Chemical 1
excretion O 0
is O 0
decreased O 0
during O 0
the O 0
early O 0
phase O 0
of O 0
the O 0
disease O 0
. O 0

The O 0
molecular O 0
mechanism O 0
( O 0
s O 0
) O 0
leading O 0
to O 0
salt O 0
retention O 0
has O 0
not O 0
been O 0
completely O 0
elucidated O 0
. O 0

The O 0
rate O 0
- O 0
limiting O 0
constituent O 0
of O 0
collecting O 0
duct O 0
sodium B-Chemical 1
transport O 0
is O 0
the O 0
epithelial O 0
sodium B-Chemical 1
channel O 0
( O 0
ENaC O 0
) O 0
. O 0

We O 0
examined O 0
the O 0
abundance O 0
of O 0
ENaC O 0
subunit O 0
mRNAs O 0
and O 0
proteins O 0
in O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
( O 0
PAN B-Chemical 1
) O 0
- O 0
induced O 0
nephrotic B-Disease 1
syndrome I-Disease 1
. O 0

The O 0
time O 0
courses O 0
of O 0
urinary O 0
sodium B-Chemical 1
excretion O 0
, O 0
plasma O 0
aldosterone B-Chemical 1
concentration O 0
and O 0
proteinuria B-Disease 1
were O 0
studied O 0
in O 0
male O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
treated O 0
with O 0
a O 0
single O 0
dose O 0
of O 0
either O 0
PAN B-Chemical 1
or O 0
vehicle O 0
. O 0

The O 0
relative O 0
amounts O 0
of O 0
alphaENaC O 0
, O 0
betaENaC O 0
and O 0
gammaENaC O 0
mRNAs O 0
were O 0
determined O 0
in O 0
kidneys O 0
from O 0
these O 0
rats O 0
by O 0
real O 0
- O 0
time O 0
quantitative O 0
TaqMan O 0
PCR O 0
, O 0
and O 0
the O 0
amounts O 0
of O 0
proteins O 0
by O 0
Western O 0
blot O 0
. O 0

The O 0
kinetics O 0
of O 0
urinary O 0
sodium B-Chemical 1
excretion O 0
and O 0
the O 0
appearance O 0
of O 0
proteinuria B-Disease 1
were O 0
comparable O 0
with O 0
those O 0
reported O 0
previously O 0
. O 0

Sodium B-Chemical 1
retention O 0
occurred O 0
on O 0
days O 0
2 O 0
, O 0
3 O 0
and O 0
6 O 0
after O 0
PAN B-Chemical 1
injection O 0
. O 0

A O 0
significant O 0
up O 0
- O 0
regulation O 0
of O 0
alphaENaC O 0
and O 0
betaENaC O 0
mRNA O 0
abundance O 0
on O 0
days O 0
1 O 0
and O 0
2 O 0
preceded O 0
sodium B-Chemical 1
retention O 0
on O 0
days O 0
2 O 0
and O 0
3 O 0
. O 0

Conversely O 0
, O 0
down O 0
- O 0
regulation O 0
of O 0
alphaENaC O 0
, O 0
betaENaC O 0
and O 0
gammaENaC O 0
mRNA O 0
expression O 0
on O 0
day O 0
3 O 0
occurred O 0
in O 0
the O 0
presence O 0
of O 0
high O 0
aldosterone B-Chemical 1
concentrations O 0
, O 0
and O 0
was O 0
followed O 0
by O 0
a O 0
return O 0
of O 0
sodium B-Chemical 1
excretion O 0
to O 0
control O 0
values O 0
. O 0

The O 0
amounts O 0
of O 0
alphaENaC O 0
, O 0
betaENaC O 0
and O 0
gammaENaC O 0
proteins O 0
were O 0
not O 0
increased O 0
during O 0
PAN B-Chemical 1
- O 0
induced O 0
sodium B-Chemical 1
retention O 0
. O 0

In O 0
conclusion O 0
, O 0
ENaC O 0
mRNA O 0
expression O 0
, O 0
especially O 0
alphaENaC O 0
, O 0
is O 0
increased O 0
in O 0
the O 0
very O 0
early O 0
phase O 0
of O 0
the O 0
experimental O 0
model O 0
of O 0
PAN B-Chemical 1
- O 0
induced O 0
nephrotic B-Disease 1
syndrome I-Disease 1
in O 0
rats O 0
, O 0
but O 0
appears O 0
to O 0
escape O 0
from O 0
the O 0
regulation O 0
by O 0
aldosterone B-Chemical 1
after O 0
day O 0
3 O 0
. O 0

Sub O 0
- O 0
chronic O 0
low O 0
dose O 0
gamma B-Chemical 1
- I-Chemical 1
vinyl I-Chemical 1
GABA I-Chemical 1
( O 0
vigabatrin B-Chemical 1
) O 0
inhibits O 0
cocaine B-Chemical 1
- O 0
induced O 0
increases O 0
in O 0
nucleus O 0
accumbens O 0
dopamine B-Chemical 1
. O 0

RATIONALE O 0
: O 0
gamma B-Chemical 1
- I-Chemical 1
Vinyl I-Chemical 1
GABA I-Chemical 1
( O 0
GVG B-Chemical 1
) O 0
irreversibly O 0
inhibits O 0
GABA B-Chemical 1
- O 0
transaminase O 0
. O 0

This O 0
non O 0
- O 0
receptor O 0
mediated O 0
inhibition O 0
requires O 0
de O 0
novo O 0
synthesis O 0
for O 0
restoration O 0
of O 0
functional O 0
GABA B-Chemical 1
catabolism O 0
. O 0

OBJECTIVES O 0
: O 0
Given O 0
its O 0
preclinical O 0
success O 0
for O 0
treating O 0
substance B-Disease 1
abuse I-Disease 1
and O 0
the O 0
increased O 0
risk O 0
of O 0
visual B-Disease 1
field I-Disease 1
defects I-Disease 1
( O 0
VFD B-Disease 1
) O 0
associated O 0
with O 0
cumulative O 0
lifetime O 0
exposure O 0
, O 0
we O 0
explored O 0
the O 0
effects O 0
of O 0
sub O 0
- O 0
chronic O 0
low O 0
dose O 0
GVG B-Chemical 1
on O 0
cocaine B-Chemical 1
- O 0
induced O 0
increases O 0
in O 0
nucleus O 0
accumbens O 0
( O 0
NAcc O 0
) O 0
dopamine B-Chemical 1
( O 0
DA B-Chemical 1
) O 0
. O 0

METHODS O 0
: O 0
Using O 0
in O 0
vivo O 0
microdialysis O 0
, O 0
we O 0
compared O 0
acute O 0
exposure O 0
( O 0
450 O 0
mg O 0
/ O 0
kg O 0
) O 0
to O 0
an O 0
identical O 0
sub O 0
- O 0
chronic O 0
exposure O 0
( O 0
150 O 0
mg O 0
/ O 0
kg O 0
per O 0
day O 0
for O 0
3 O 0
days O 0
) O 0
, O 0
followed O 0
by O 0
1 O 0
- O 0
or O 0
3 O 0
- O 0
day O 0
washout O 0
. O 0

Finally O 0
, O 0
we O 0
examined O 0
the O 0
low O 0
dose O 0
of O 0
150 O 0
mg O 0
/ O 0
kg O 0
( O 0
50 O 0
mg O 0
/ O 0
kg O 0
per O 0
day O 0
) O 0
using O 0
a O 0
similar O 0
washout O 0
period O 0
. O 0

RESULTS O 0
: O 0
Sub O 0
- O 0
chronic O 0
GVG B-Chemical 1
exposure O 0
inhibited O 0
the O 0
effect O 0
of O 0
cocaine B-Chemical 1
for O 0
3 O 0
days O 0
, O 0
which O 0
exceeded O 0
in O 0
magnitude O 0
and O 0
duration O 0
the O 0
identical O 0
acute O 0
dose O 0
. O 0

CONCLUSIONS O 0
: O 0
Sub O 0
- O 0
chronic O 0
low O 0
dose O 0
GVG B-Chemical 1
potentiates O 0
and O 0
extends O 0
the O 0
inhibition O 0
of O 0
cocaine B-Chemical 1
- O 0
induced O 0
increases O 0
in O 0
dopamine B-Chemical 1
, O 0
effectively O 0
reducing O 0
cumulative O 0
exposures O 0
and O 0
the O 0
risk O 0
for O 0
VFDS O 0
. O 0

MR O 0
imaging O 0
with O 0
quantitative O 0
diffusion O 0
mapping O 0
of O 0
tacrolimus B-Chemical 1
- O 0
induced O 0
neurotoxicity B-Disease 1
in O 0
organ O 0
transplant O 0
patients O 0
. O 0

Our O 0
objective O 0
was O 0
to O 0
investigate O 0
brain O 0
MR O 0
imaging O 0
findings O 0
and O 0
the O 0
utility O 0
of O 0
diffusion O 0
- O 0
weighted O 0
( O 0
DW O 0
) O 0
imaging O 0
in O 0
organ O 0
transplant O 0
patients O 0
who O 0
developed O 0
neurologic O 0
symptoms O 0
during O 0
tacrolimus B-Chemical 1
therapy O 0
. O 0

Brain O 0
MR O 0
studies O 0
, O 0
including O 0
DW O 0
imaging O 0
, O 0
were O 0
prospectively O 0
performed O 0
in O 0
14 O 0
organ O 0
transplant O 0
patients O 0
receiving O 0
tacrolimus B-Chemical 1
who O 0
developed O 0
neurologic B-Disease 1
complications I-Disease 1
. O 0

In O 0
each O 0
patient O 0
who O 0
had O 0
abnormalities O 0
on O 0
the O 0
initial O 0
MR O 0
study O 0
, O 0
a O 0
follow O 0
- O 0
up O 0
MR O 0
study O 0
was O 0
performed O 0
1 O 0
month O 0
later O 0
. O 0

Apparent O 0
diffusion O 0
coefficient O 0
( O 0
ADC O 0
) O 0
values O 0
on O 0
the O 0
initial O 0
MR O 0
study O 0
were O 0
correlated O 0
with O 0
reversibility O 0
of O 0
the O 0
lesions O 0
. O 0

Of O 0
the O 0
14 O 0
patients O 0
, O 0
5 O 0
( O 0
35 O 0
. O 0
7 O 0
% O 0
) O 0
had O 0
white B-Disease 1
matter I-Disease 1
abnormalities I-Disease 1
, O 0
1 O 0
( O 0
7 O 0
. O 0
1 O 0
% O 0
) O 0
had O 0
putaminal B-Disease 1
hemorrhage I-Disease 1
, O 0
and O 0
8 O 0
( O 0
57 O 0
. O 0
1 O 0
% O 0
) O 0
had O 0
normal O 0
findings O 0
on O 0
initial O 0
MR O 0
images O 0
. O 0

Among O 0
the O 0
5 O 0
patients O 0
with O 0
white B-Disease 1
matter I-Disease 1
abnormalities I-Disease 1
, O 0
4 O 0
patients O 0
( O 0
80 O 0
. O 0
0 O 0
% O 0
) O 0
showed O 0
higher O 0
than O 0
normal O 0
ADC O 0
values O 0
on O 0
initial O 0
MR O 0
images O 0
, O 0
and O 0
all O 0
showed O 0
complete O 0
resolution O 0
on O 0
follow O 0
- O 0
up O 0
images O 0
. O 0

The O 0
remaining O 0
1 O 0
patient O 0
( O 0
20 O 0
. O 0
0 O 0
% O 0
) O 0
showed O 0
lower O 0
than O 0
normal O 0
ADC O 0
value O 0
and O 0
showed O 0
incomplete O 0
resolution O 0
with O 0
cortical B-Disease 1
laminar I-Disease 1
necrosis I-Disease 1
. O 0

Diffusion O 0
- O 0
weighted O 0
imaging O 0
may O 0
be O 0
useful O 0
in O 0
predicting O 0
the O 0
outcomes O 0
of O 0
the O 0
lesions O 0
of O 0
tacrolimus B-Chemical 1
- O 0
induced O 0
neurotoxicity B-Disease 1
. O 0

L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
transport O 0
in O 0
humans O 0
with O 0
cortisol B-Chemical 1
- O 0
induced O 0
hypertension B-Disease 1
. O 0

A O 0
deficient O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
- O 0
nitric B-Chemical 1
oxide I-Chemical 1
system O 0
is O 0
implicated O 0
in O 0
cortisol B-Chemical 1
- O 0
induced O 0
hypertension B-Disease 1
. O 0

We O 0
investigate O 0
whether O 0
abnormalities O 0
in O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
uptake O 0
contribute O 0
to O 0
this O 0
deficiency O 0
. O 0

Eight O 0
healthy O 0
men O 0
were O 0
recruited O 0
. O 0

Hydrocortisone B-Chemical 1
acetate I-Chemical 1
( O 0
50 O 0
mg O 0
) O 0
was O 0
given O 0
orally O 0
every O 0
6 O 0
hours O 0
for O 0
24 O 0
hours O 0
after O 0
a O 0
5 O 0
- O 0
day O 0
fixed O 0
- O 0
salt O 0
diet O 0
( O 0
150 O 0
mmol O 0
/ O 0
d O 0
) O 0
. O 0

Crossover O 0
studies O 0
were O 0
performed O 0
2 O 0
weeks O 0
apart O 0
. O 0

Thirty O 0
milliliters O 0
of O 0
blood O 0
was O 0
obtained O 0
for O 0
isolation O 0
of O 0
peripheral O 0
blood O 0
mononuclear O 0
cells O 0
after O 0
each O 0
treatment O 0
period O 0
. O 0

L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
uptake O 0
was O 0
assessed O 0
in O 0
mononuclear O 0
cells O 0
incubated O 0
with O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
( O 0
1 O 0
to O 0
300 O 0
micromol O 0
/ O 0
L O 0
) O 0
, O 0
incorporating O 0
100 O 0
nmol O 0
/ O 0
L O 0
[ B-Chemical 1
3H I-Chemical 1
] I-Chemical 1
- I-Chemical 1
l I-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
for O 0
a O 0
period O 0
of O 0
5 O 0
minutes O 0
at O 0
37 O 0
degrees O 0
C O 0
. O 0

Forearm O 0
[ B-Chemical 1
3H I-Chemical 1
] I-Chemical 1
- I-Chemical 1
L I-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
extraction O 0
was O 0
calculated O 0
after O 0
infusion O 0
of O 0
[ B-Chemical 1
3H I-Chemical 1
] I-Chemical 1
- I-Chemical 1
L I-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
into O 0
the O 0
brachial O 0
artery O 0
at O 0
a O 0
rate O 0
of O 0
100 O 0
nCi O 0
/ O 0
min O 0
for O 0
80 O 0
minutes O 0
. O 0

Deep O 0
forearm O 0
venous O 0
samples O 0
were O 0
collected O 0
for O 0
determination O 0
of O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
extraction O 0
. O 0

Plasma O 0
cortisol B-Chemical 1
concentrations O 0
were O 0
significantly O 0
raised O 0
during O 0
the O 0
active O 0
phase O 0
( O 0
323 O 0
+ O 0
/ O 0
- O 0
43 O 0
to O 0
1082 O 0
+ O 0
/ O 0
- O 0
245 O 0
mmol O 0
/ O 0
L O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Systolic O 0
blood O 0
pressure O 0
was O 0
elevated O 0
by O 0
an O 0
average O 0
of O 0
7 O 0
mm O 0
Hg O 0
. O 0

Neither O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
transport O 0
into O 0
mononuclear O 0
cells O 0
( O 0
placebo O 0
vs O 0
active O 0
, O 0
26 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
3 O 0
. O 0
6 O 0
vs O 0
29 O 0
. O 0
0 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
1 O 0
pmol O 0
/ O 0
10 O 0
000 O 0
cells O 0
per O 0
5 O 0
minutes O 0
, O 0
respectively O 0
, O 0
at O 0
an O 0
l B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
concentration O 0
of O 0
300 O 0
micromol O 0
/ O 0
L O 0
) O 0
nor O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
extraction O 0
in O 0
the O 0
forearm O 0
( O 0
at O 0
80 O 0
minutes O 0
, O 0
placebo O 0
vs O 0
active O 0
, O 0
1 O 0
868 O 0
904 O 0
+ O 0
/ O 0
- O 0
434 O 0
962 O 0
vs O 0
2 O 0
013 O 0
910 O 0
+ O 0
/ O 0
- O 0
770 O 0
619 O 0
disintegrations O 0
per O 0
minute O 0
) O 0
was O 0
affected O 0
by O 0
cortisol B-Chemical 1
treatment O 0
; O 0
ie O 0
, O 0
that O 0
L B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
uptake O 0
is O 0
not O 0
affected O 0
by O 0
short O 0
- O 0
term O 0
cortisol B-Chemical 1
treatment O 0
. O 0

We O 0
conclude O 0
that O 0
cortisol B-Chemical 1
- O 0
induced O 0
increases B-Disease 1
in I-Disease 1
blood I-Disease 1
pressure I-Disease 1
are O 0
not O 0
associated O 0
with O 0
abnormalities O 0
in O 0
the O 0
l B-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
transport O 0
system O 0
. O 0

Amount O 0
of O 0
bleeding B-Disease 1
and O 0
hematoma B-Disease 1
size O 0
in O 0
the O 0
collagenase O 0
- O 0
induced O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
rat O 0
model O 0
. O 0

The O 0
aggravated O 0
risk O 0
on O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
( O 0
ICH B-Disease 1
) O 0
with O 0
drugs O 0
used O 0
for O 0
stroke B-Disease 1
patients O 0
should O 0
be O 0
estimated O 0
carefully O 0
. O 0

We O 0
therefore O 0
established O 0
sensitive O 0
quantification O 0
methods O 0
and O 0
provided O 0
a O 0
rat O 0
ICH B-Disease 1
model O 0
for O 0
detection O 0
of O 0
ICH B-Disease 1
deterioration O 0
. O 0

In O 0
ICH B-Disease 1
intrastriatally O 0
induced O 0
by O 0
0 O 0
. O 0
014 O 0
- O 0
unit O 0
, O 0
0 O 0
. O 0
070 O 0
- O 0
unit O 0
, O 0
and O 0
0 O 0
. O 0
350 O 0
- O 0
unit O 0
collagenase O 0
, O 0
the O 0
amount O 0
of O 0
bleeding B-Disease 1
was O 0
measured O 0
using O 0
a O 0
hemoglobin O 0
assay O 0
developed O 0
in O 0
the O 0
present O 0
study O 0
and O 0
was O 0
compared O 0
with O 0
the O 0
morphologically O 0
determined O 0
hematoma B-Disease 1
volume O 0
. O 0

The O 0
blood O 0
amounts O 0
and O 0
hematoma B-Disease 1
volumes O 0
were O 0
significantly O 0
correlated O 0
, O 0
and O 0
the O 0
hematoma B-Disease 1
induced O 0
by O 0
0 O 0
. O 0
014 O 0
- O 0
unit O 0
collagenase O 0
was O 0
adequate O 0
to O 0
detect O 0
ICH B-Disease 1
deterioration O 0
. O 0

In O 0
ICH B-Disease 1
induction O 0
using O 0
0 O 0
. O 0
014 O 0
- O 0
unit O 0
collagenase O 0
, O 0
heparin B-Chemical 1
enhanced O 0
the O 0
hematoma B-Disease 1
volume O 0
3 O 0
. O 0
4 O 0
- O 0
fold O 0
over O 0
that O 0
seen O 0
in O 0
control O 0
ICH B-Disease 1
animals O 0
and O 0
the O 0
bleeding B-Disease 1
7 O 0
. O 0
6 O 0
- O 0
fold O 0
. O 0

Data O 0
suggest O 0
that O 0
this O 0
sensitive O 0
hemoglobin O 0
assay O 0
is O 0
useful O 0
for O 0
ICH B-Disease 1
detection O 0
, O 0
and O 0
that O 0
a O 0
model O 0
with O 0
a O 0
small O 0
ICH B-Disease 1
induced O 0
with O 0
a O 0
low O 0
- O 0
dose O 0
collagenase O 0
should O 0
be O 0
used O 0
for O 0
evaluation O 0
of O 0
drugs O 0
that O 0
may O 0
affect O 0
ICH B-Disease 1
. O 0

Estradiol B-Chemical 1
reduces O 0
seizure B-Disease 1
- O 0
induced O 0
hippocampal B-Disease 1
injury I-Disease 1
in O 0
ovariectomized O 0
female O 0
but O 0
not O 0
in O 0
male O 0
rats O 0
. O 0

Estrogens O 0
protect O 0
ovariectomized O 0
rats O 0
from O 0
hippocampal B-Disease 1
injury I-Disease 1
induced O 0
by O 0
kainic B-Chemical 1
acid I-Chemical 1
- O 0
induced O 0
status B-Disease 1
epilepticus I-Disease 1
( O 0
SE B-Disease 1
) O 0
. O 0

We O 0
compared O 0
the O 0
effects O 0
of O 0
17beta B-Chemical 1
- I-Chemical 1
estradiol I-Chemical 1
in O 0
adult O 0
male O 0
and O 0
ovariectomized O 0
female O 0
rats O 0
subjected O 0
to O 0
lithium B-Chemical 1
- O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
SE B-Disease 1
. O 0

Rats O 0
received O 0
subcutaneous O 0
injections O 0
of O 0
17beta B-Chemical 1
- I-Chemical 1
estradiol I-Chemical 1
( O 0
2 O 0
microg O 0
/ O 0
rat O 0
) O 0
or O 0
oil O 0
once O 0
daily O 0
for O 0
four O 0
consecutive O 0
days O 0
. O 0

SE B-Disease 1
was O 0
induced O 0
20 O 0
h O 0
following O 0
the O 0
second O 0
injection O 0
and O 0
terminated O 0
3 O 0
h O 0
later O 0
. O 0

The O 0
extent O 0
of O 0
silver B-Chemical 1
- O 0
stained O 0
CA3 O 0
and O 0
CA1 O 0
hippocampal O 0
neurons O 0
was O 0
evaluated O 0
2 O 0
days O 0
after O 0
SE B-Disease 1
. O 0

17beta B-Chemical 1
- I-Chemical 1
Estradiol I-Chemical 1
did O 0
not O 0
alter O 0
the O 0
onset O 0
of O 0
first O 0
clonus O 0
in O 0
ovariectomized O 0
rats O 0
but O 0
accelerated O 0
it O 0
in O 0
males O 0
. O 0

17beta B-Chemical 1
- I-Chemical 1
Estradiol I-Chemical 1
reduced O 0
the O 0
argyrophilic O 0
neurons O 0
in O 0
the O 0
CA1 O 0
and O 0
CA3 O 0
- O 0
C O 0
sectors O 0
of O 0
ovariectomized O 0
rats O 0
. O 0

In O 0
males O 0
, O 0
estradiol B-Chemical 1
increased O 0
the O 0
total O 0
damage O 0
score O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
the O 0
effects O 0
of O 0
estradiol B-Chemical 1
on O 0
seizure B-Disease 1
threshold O 0
and O 0
damage O 0
may O 0
be O 0
altered O 0
by O 0
sex O 0
- O 0
related O 0
differences O 0
in O 0
the O 0
hormonal O 0
environment O 0
. O 0

Pseudoacromegaly B-Disease 1
induced O 0
by O 0
the O 0
long O 0
- O 0
term O 0
use O 0
of O 0
minoxidil B-Chemical 1
. O 0

Acromegaly B-Disease 1
is O 0
an O 0
endocrine B-Disease 1
disorder I-Disease 1
caused O 0
by O 0
chronic O 0
excessive O 0
growth O 0
hormone O 0
secretion O 0
from O 0
the O 0
anterior O 0
pituitary O 0
gland O 0
. O 0

Significant O 0
disfiguring O 0
changes O 0
occur O 0
as O 0
a O 0
result O 0
of O 0
bone O 0
, O 0
cartilage O 0
, O 0
and O 0
soft O 0
tissue O 0
hypertrophy B-Disease 1
, O 0
including O 0
the O 0
thickening O 0
of O 0
the O 0
skin O 0
, O 0
coarsening O 0
of O 0
facial O 0
features O 0
, O 0
and O 0
cutis B-Disease 1
verticis I-Disease 1
gyrata I-Disease 1
. O 0

Pseudoacromegaly B-Disease 1
, O 0
on O 0
the O 0
other O 0
hand O 0
, O 0
is O 0
the O 0
presence O 0
of O 0
similar O 0
acromegaloid O 0
features O 0
in O 0
the O 0
absence O 0
of O 0
elevated O 0
growth O 0
hormone O 0
or O 0
insulin O 0
- O 0
like O 0
growth O 0
factor O 0
levels O 0
. O 0

We O 0
present O 0
a O 0
patient O 0
with O 0
pseudoacromegaly B-Disease 1
that O 0
resulted O 0
from O 0
the O 0
long O 0
- O 0
term O 0
use O 0
of O 0
minoxidil B-Chemical 1
at O 0
an O 0
unusually O 0
high O 0
dose O 0
. O 0

This O 0
is O 0
the O 0
first O 0
case O 0
report O 0
of O 0
pseudoacromegaly B-Disease 1
as O 0
a O 0
side O 0
effect O 0
of O 0
minoxidil B-Chemical 1
use O 0
. O 0

Combined O 0
androgen O 0
blockade O 0
- O 0
induced O 0
anemia B-Disease 1
in O 0
prostate B-Disease 1
cancer I-Disease 1
patients O 0
without O 0
bone O 0
involvement O 0
. O 0

BACKGROUND O 0
: O 0
To O 0
determine O 0
the O 0
onset O 0
and O 0
extent O 0
of O 0
combined O 0
androgen O 0
blockade O 0
( O 0
CAB O 0
) O 0
- O 0
induced O 0
anemia B-Disease 1
in O 0
prostate B-Disease 1
cancer I-Disease 1
patients O 0
without O 0
bone O 0
involvement O 0
. O 0

PATIENTS O 0
AND O 0
METHODS O 0
: O 0
Forty O 0
- O 0
two O 0
patients O 0
with O 0
biopsy O 0
- O 0
proven O 0
prostatic B-Disease 1
adenocarcinoma I-Disease 1
[ O 0
26 O 0
with O 0
stage O 0
C O 0
( O 0
T3N0M0 O 0
) O 0
and O 0
16 O 0
with O 0
stage O 0
D1 O 0
( O 0
T3N1M0 O 0
) O 0
] O 0
were O 0
included O 0
in O 0
this O 0
study O 0
. O 0

All O 0
patients O 0
received O 0
CAB O 0
[ O 0
leuprolide B-Chemical 1
acetate I-Chemical 1
( O 0
LHRH B-Chemical 1
- I-Chemical 1
A I-Chemical 1
) O 0
3 O 0
. O 0
75 O 0
mg O 0
, O 0
intramuscularly O 0
, O 0
every O 0
28 O 0
days O 0
plus O 0
250 O 0
mg O 0
flutamide B-Chemical 1
, O 0
tid O 0
, O 0
per O 0
Os O 0
] O 0
and O 0
were O 0
evaluated O 0
for O 0
anemia B-Disease 1
by O 0
physical O 0
examination O 0
and O 0
laboratory O 0
tests O 0
at O 0
baseline O 0
and O 0
4 O 0
subsequent O 0
intervals O 0
( O 0
1 O 0
, O 0
2 O 0
, O 0
3 O 0
and O 0
6 O 0
months O 0
post O 0
- O 0
CAB O 0
) O 0
. O 0

Hb O 0
, O 0
PSA O 0
and O 0
Testosterone B-Chemical 1
measurements O 0
were O 0
recorded O 0
. O 0

Patients O 0
with O 0
stage O 0
D2 O 0
- O 0
3 O 0
disease O 0
, O 0
abnormal O 0
hemoglobin O 0
level O 0
or O 0
renal O 0
and O 0
liver O 0
function O 0
tests O 0
that O 0
were O 0
higher O 0
than O 0
the O 0
upper O 0
limits O 0
were O 0
excluded O 0
from O 0
the O 0
study O 0
. O 0

The O 0
duration O 0
of O 0
the O 0
study O 0
was O 0
six O 0
months O 0
. O 0

RESULTS O 0
: O 0
The O 0
mean O 0
hemoglobin O 0
( O 0
Hb O 0
) O 0
levels O 0
were O 0
significantly O 0
declined O 0
in O 0
all O 0
patients O 0
from O 0
baseline O 0
of O 0
14 O 0
. O 0
2 O 0
g O 0
/ O 0
dl O 0
to O 0
14 O 0
. O 0
0 O 0
g O 0
/ O 0
dl O 0
, O 0
13 O 0
. O 0
5 O 0
g O 0
/ O 0
dl O 0
, O 0
13 O 0
. O 0
2 O 0
g O 0
/ O 0
dl O 0
and O 0
12 O 0
. O 0
7 O 0
g O 0
/ O 0
dl O 0
at O 0
1 O 0
, O 0
2 O 0
, O 0
3 O 0
and O 0
6 O 0
months O 0
post O 0
- O 0
CAB O 0
, O 0
respectively O 0
. O 0

Severe O 0
and O 0
clinically O 0
evident O 0
anemia B-Disease 1
of O 0
Hb O 0
< O 0
11 O 0
g O 0
/ O 0
dl O 0
with O 0
clinical O 0
symptoms O 0
was O 0
detected O 0
in O 0
6 O 0
patients O 0
( O 0
14 O 0
. O 0
3 O 0
% O 0
) O 0
. O 0

This O 0
CAB O 0
- O 0
induced O 0
anemia B-Disease 1
was O 0
normochromic O 0
and O 0
normocytic O 0
. O 0

At O 0
six O 0
months O 0
post O 0
- O 0
CAB O 0
, O 0
patients O 0
with O 0
severe O 0
anemia B-Disease 1
had O 0
a O 0
Hb O 0
mean O 0
value O 0
of O 0
10 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
1 O 0
g O 0
/ O 0
dl O 0
( O 0
X O 0
+ O 0
/ O 0
- O 0
SE O 0
) O 0
, O 0
whereas O 0
the O 0
other O 0
patients O 0
had O 0
mild O 0
anemia B-Disease 1
with O 0
Hb O 0
mean O 0
value O 0
of O 0
13 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
17 O 0
( O 0
X O 0
+ O 0
/ O 0
- O 0
SE O 0
) O 0
. O 0

The O 0
development O 0
of O 0
severe O 0
anemia B-Disease 1
at O 0
6 O 0
months O 0
post O 0
- O 0
CAB O 0
was O 0
predictable O 0
by O 0
the O 0
reduction O 0
of O 0
Hb O 0
baseline O 0
value O 0
of O 0
more O 0
than O 0
2 O 0
. O 0
5 O 0
g O 0
/ O 0
dl O 0
after O 0
3 O 0
months O 0
of O 0
CAB O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

The O 0
development O 0
of O 0
severe O 0
CAB O 0
- O 0
induced O 0
anemia B-Disease 1
in O 0
prostate B-Disease 1
cancer I-Disease 1
patients O 0
did O 0
not O 0
correlate O 0
with O 0
T O 0
baseline O 0
values O 0
( O 0
T O 0
< O 0
3 O 0
ng O 0
/ O 0
ml O 0
versus O 0
T O 0
> O 0
or O 0
= O 0
3 O 0
ng O 0
/ O 0
ml O 0
) O 0
, O 0
with O 0
age O 0
( O 0
< O 0
76 O 0
yrs O 0
versus O 0
> O 0
or O 0
= O 0
76 O 0
yrs O 0
) O 0
, O 0
and O 0
clinical O 0
stage O 0
( O 0
stage O 0
C O 0
versus O 0
stage O 0
D1 O 0
) O 0
. O 0

Severe O 0
and O 0
clinically O 0
evident O 0
anemia B-Disease 1
was O 0
easily O 0
corrected O 0
by O 0
subcutaneous O 0
injections O 0
( O 0
3 O 0
times O 0
/ O 0
week O 0
for O 0
1 O 0
month O 0
) O 0
of O 0
recombinant O 0
erythropoietin O 0
( O 0
rHuEPO O 0
- O 0
beta O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
Our O 0
data O 0
suggest O 0
that O 0
rHuEPO O 0
- O 0
beta O 0
correctable O 0
CAB O 0
- O 0
induced O 0
anemia B-Disease 1
occurs O 0
in O 0
14 O 0
. O 0
3 O 0
% O 0
of O 0
prostate B-Disease 1
cancer I-Disease 1
patients O 0
after O 0
6 O 0
months O 0
of O 0
therapy O 0
. O 0

Delirium B-Disease 1
during O 0
clozapine B-Chemical 1
treatment O 0
: O 0
incidence O 0
and O 0
associated O 0
risk O 0
factors O 0
. O 0

BACKGROUND O 0
: O 0
Incidence O 0
and O 0
risk O 0
factors O 0
for O 0
delirium B-Disease 1
during O 0
clozapine B-Chemical 1
treatment O 0
require O 0
further O 0
clarification O 0
. O 0

METHODS O 0
: O 0
We O 0
used O 0
computerized O 0
pharmacy O 0
records O 0
to O 0
identify O 0
all O 0
adult O 0
psychiatric B-Disease 1
inpatients O 0
treated O 0
with O 0
clozapine B-Chemical 1
( O 0
1995 O 0
- O 0
96 O 0
) O 0
, O 0
reviewed O 0
their O 0
medical O 0
records O 0
to O 0
score O 0
incidence O 0
and O 0
severity O 0
of O 0
delirium B-Disease 1
, O 0
and O 0
tested O 0
associations O 0
with O 0
potential O 0
risk O 0
factors O 0
. O 0

RESULTS O 0
: O 0
Subjects O 0
( O 0
n O 0
= O 0
139 O 0
) O 0
were O 0
72 O 0
women O 0
and O 0
67 O 0
men O 0
, O 0
aged O 0
40 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
12 O 0
. O 0
1 O 0
years O 0
, O 0
hospitalized O 0
for O 0
24 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
23 O 0
. O 0
3 O 0
days O 0
, O 0
and O 0
given O 0
clozapine B-Chemical 1
, O 0
gradually O 0
increased O 0
to O 0
an O 0
average O 0
daily O 0
dose O 0
of O 0
282 O 0
+ O 0
/ O 0
- O 0
203 O 0
mg O 0
( O 0
3 O 0
. O 0
45 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
45 O 0
mg O 0
/ O 0
kg O 0
) O 0
for O 0
18 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
16 O 0
. O 0
4 O 0
days O 0
. O 0

Delirium B-Disease 1
was O 0
diagnosed O 0
in O 0
14 O 0
( O 0
10 O 0
. O 0
1 O 0
% O 0
incidence O 0
, O 0
or O 0
1 O 0
. O 0
48 O 0
cases O 0
/ O 0
person O 0
- O 0
years O 0
of O 0
exposure O 0
) O 0
; O 0
71 O 0
. O 0
4 O 0
% O 0
of O 0
cases O 0
were O 0
moderate O 0
or O 0
severe O 0
. O 0

Associated O 0
factors O 0
were O 0
co O 0
- O 0
treatment O 0
with O 0
other O 0
centrally O 0
antimuscarinic O 0
agents O 0
, O 0
poor O 0
clinical O 0
outcome O 0
, O 0
older O 0
age O 0
, O 0
and O 0
longer O 0
hospitalization O 0
( O 0
by O 0
17 O 0
. O 0
5 O 0
days O 0
, O 0
increasing O 0
cost O 0
) O 0
; O 0
sex O 0
, O 0
diagnosis O 0
or O 0
medical O 0
co O 0
- O 0
morbidity O 0
, O 0
and O 0
daily O 0
clozapine B-Chemical 1
dose O 0
, O 0
which O 0
fell O 0
with O 0
age O 0
, O 0
were O 0
unrelated O 0
. O 0

CONCLUSIONS O 0
: O 0
Delirium B-Disease 1
was O 0
found O 0
in O 0
10 O 0
% O 0
of O 0
clozapine B-Chemical 1
- O 0
treated O 0
inpatients O 0
, O 0
particularly O 0
in O 0
older O 0
patients O 0
exposed O 0
to O 0
other O 0
central O 0
anticholinergics O 0
. O 0

Delirium B-Disease 1
was O 0
inconsistently O 0
recognized O 0
clinically O 0
in O 0
milder O 0
cases O 0
and O 0
was O 0
associated O 0
with O 0
increased O 0
length O 0
- O 0
of O 0
- O 0
stay O 0
and O 0
higher O 0
costs O 0
, O 0
and O 0
inferior O 0
clinical O 0
outcome O 0
. O 0

Neuroprotective O 0
action O 0
of O 0
MPEP B-Chemical 1
, O 0
a O 0
selective O 0
mGluR5 O 0
antagonist O 0
, O 0
in O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
dopaminergic O 0
neurotoxicity B-Disease 1
is O 0
associated O 0
with O 0
a O 0
decrease O 0
in O 0
dopamine B-Chemical 1
outflow O 0
and O 0
inhibition O 0
of O 0
hyperthermia B-Disease 1
in O 0
rats O 0
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
examine O 0
the O 0
role O 0
of O 0
metabotropic O 0
glutamate B-Chemical 1
receptor O 0
5 O 0
( O 0
mGluR5 O 0
) O 0
in O 0
the O 0
toxic O 0
action O 0
of O 0
methamphetamine B-Chemical 1
on O 0
dopaminergic O 0
neurones O 0
in O 0
rats O 0
. O 0

Methamphetamine B-Chemical 1
( O 0
10 O 0
mg O 0
/ O 0
kg O 0
sc O 0
) O 0
, O 0
administered O 0
five O 0
times O 0
, O 0
reduced O 0
the O 0
levels O 0
of O 0
dopamine B-Chemical 1
and O 0
its O 0
metabolites O 0
in O 0
striatal O 0
tissue O 0
when O 0
measured O 0
72 O 0
h O 0
after O 0
the O 0
last O 0
injection O 0
. O 0

A O 0
selective O 0
antagonist O 0
of O 0
mGluR5 O 0
, O 0
2 B-Chemical 1
- I-Chemical 1
methyl I-Chemical 1
- I-Chemical 1
6 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
phenylethynyl I-Chemical 1
) I-Chemical 1
pyridine I-Chemical 1
( O 0
MPEP B-Chemical 1
; O 0
5 O 0
mg O 0
/ O 0
kg O 0
ip O 0
) O 0
, O 0
when O 0
administered O 0
five O 0
times O 0
immediately O 0
before O 0
each O 0
methamphetamine B-Chemical 1
injection O 0
reversed O 0
the O 0
above O 0
- O 0
mentioned O 0
methamphetamine B-Chemical 1
effects O 0
. O 0

A O 0
single O 0
MPEP B-Chemical 1
( O 0
5 O 0
mg O 0
/ O 0
kg O 0
ip O 0
) O 0
injection O 0
reduced O 0
the O 0
basal O 0
extracellular O 0
dopamine B-Chemical 1
level O 0
in O 0
the O 0
striatum O 0
, O 0
as O 0
well O 0
as O 0
dopamine B-Chemical 1
release O 0
stimulated O 0
either O 0
by O 0
methamphetamine B-Chemical 1
( O 0
10 O 0
mg O 0
/ O 0
kg O 0
sc O 0
) O 0
or O 0
by O 0
intrastriatally O 0
administered O 0
veratridine B-Chemical 1
( O 0
100 O 0
microM O 0
) O 0
. O 0

Moreover O 0
, O 0
it O 0
transiently O 0
diminished O 0
the O 0
methamphetamine B-Chemical 1
( O 0
10 O 0
mg O 0
/ O 0
kg O 0
sc O 0
) O 0
- O 0
induced O 0
hyperthermia B-Disease 1
and O 0
reduced O 0
basal O 0
body O 0
temperature O 0
. O 0

MPEP B-Chemical 1
administered O 0
into O 0
the O 0
striatum O 0
at O 0
high O 0
concentrations O 0
( O 0
500 O 0
microM O 0
) O 0
increased O 0
extracellular O 0
dopamine B-Chemical 1
levels O 0
, O 0
while O 0
lower O 0
concentrations O 0
( O 0
50 O 0
- O 0
100 O 0
microM O 0
) O 0
were O 0
devoid O 0
of O 0
any O 0
effect O 0
. O 0

The O 0
results O 0
of O 0
this O 0
study O 0
suggest O 0
that O 0
the O 0
blockade O 0
of O 0
mGluR5 O 0
by O 0
MPEP B-Chemical 1
may O 0
protect O 0
dopaminergic O 0
neurones O 0
against O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
toxicity B-Disease 1
. O 0

Neuroprotection O 0
rendered O 0
by O 0
MPEP B-Chemical 1
may O 0
be O 0
associated O 0
with O 0
the O 0
reduction O 0
of O 0
the O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
dopamine B-Chemical 1
efflux O 0
in O 0
the O 0
striatum O 0
due O 0
to O 0
the O 0
blockade O 0
of O 0
extrastriatal O 0
mGluR5 O 0
, O 0
and O 0
with O 0
a O 0
decrease O 0
in O 0
hyperthermia B-Disease 1
. O 0

Protective O 0
efficacy O 0
of O 0
neuroactive O 0
steroids B-Chemical 1
against O 0
cocaine B-Chemical 1
kindled O 0
- O 0
seizures B-Disease 1
in O 0
mice O 0
. O 0

Neuroactive O 0
steroids B-Chemical 1
demonstrate O 0
pharmacological O 0
actions O 0
that O 0
have O 0
relevance O 0
for O 0
a O 0
host O 0
of O 0
neurological B-Disease 1
and I-Disease 1
psychiatric I-Disease 1
disorders I-Disease 1
. O 0

They O 0
offer O 0
protection O 0
against O 0
seizures B-Disease 1
in O 0
a O 0
range O 0
of O 0
models O 0
and O 0
seem O 0
to O 0
inhibit O 0
certain O 0
stages O 0
of O 0
drug B-Disease 1
dependence I-Disease 1
in O 0
preclinical O 0
assessments O 0
. O 0

The O 0
present O 0
study O 0
was O 0
designed O 0
to O 0
evaluate O 0
two O 0
endogenous O 0
and O 0
one O 0
synthetic O 0
neuroactive O 0
steroid B-Chemical 1
that O 0
positively O 0
modulate O 0
the O 0
gamma B-Chemical 1
- I-Chemical 1
aminobutyric I-Chemical 1
acid I-Chemical 1
( O 0
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It O 0
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Effects O 0
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Rats O 0
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. O 0

Newborn O 0
female O 0
Wistar O 0
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19 O 0
% O 0
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Corresponding O 0
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When O 0
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) O 0
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) O 0
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lithium B-Chemical 1
clearance O 0
. O 0

Consequently O 0
, O 0
lithium B-Chemical 1
pretreatment O 0
caused O 0
a O 0
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filtration O 0
fraction O 0
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fractional O 0
Li B-Chemical 1
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. O 0

Lithium B-Chemical 1
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. O 0

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NX O 0
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Li B-Chemical 1
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The O 0
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that O 0
Li B-Chemical 1
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nephropathy B-Disease 1
, O 0
even O 0
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In O 0
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The O 0
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ABSTRACT O 0
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) O 0

Treatment O 0
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Fusidic O 0
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. O 0

Because O 0
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new O 0
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, O 0
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Eight O 0
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patients O 0
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Fusidic B-Chemical 1
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s O 0
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. O 0

The O 0
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. O 0

Five O 0
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8 O 0
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) O 0
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treatment O 0
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3 O 0
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. O 0

There O 0
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. O 0

Biochemically O 0
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5 O 0
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. O 0

All O 0
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. O 0

The O 0
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may O 0
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Crohn B-Disease 1
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patients O 0
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. O 0

Because O 0
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, O 0
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that O 0
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Changes O 0
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Depression B-Disease 1
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have O 0
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We O 0
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. O 0

Eight O 0
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0 O 0
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5 O 0
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R O 0
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. O 0

During O 0
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was O 0
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Conde O 0
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. O 0

In O 0
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, O 0
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timolol B-Chemical 1
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presented O 0
higher O 0
depression B-Disease 1
values O 0
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Conde O 0
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0 O 0
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001 O 0
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) O 0
. O 0

These O 0
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that O 0
betaxolol B-Chemical 1
could O 0
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less O 0
of O 0
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depression B-Disease 1
- O 0
inducer O 0
than O 0
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in O 0
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patients O 0
. O 0

Protection O 0
against O 0
amphetamine B-Chemical 1
- O 0
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toward O 0
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dopamine B-Chemical 1
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rodents O 0
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LY274614 B-Chemical 1
, O 0
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acid I-Chemical 1
antagonist O 0
. O 0

LY274614 B-Chemical 1
, O 0
3SR B-Chemical 1
, I-Chemical 1
4aRS I-Chemical 1
, I-Chemical 1
6SR I-Chemical 1
, I-Chemical 1
8aRS I-Chemical 1
- I-Chemical 1
6 I-Chemical 1
- I-Chemical 1
[ I-Chemical 1
phosphonomethyl I-Chemical 1
] I-Chemical 1
decahydr I-Chemical 1
oisoquinoline I-Chemical 1
- I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
carboxylic I-Chemical 1
acid I-Chemical 1
, O 0
has O 0
been O 0
described O 0
as O 0
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of O 0
the O 0
N B-Chemical 1
- I-Chemical 1
methyl I-Chemical 1
- I-Chemical 1
D I-Chemical 1
- I-Chemical 1
aspartate I-Chemical 1
( O 0
NMDA B-Chemical 1
) O 0
subtype O 0
of O 0
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receptor O 0
. O 0

Here O 0
its O 0
ability O 0
to O 0
antagonize O 0
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depletion O 0
of O 0
dopamine B-Chemical 1
in O 0
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by O 0
amphetamine B-Chemical 1
in O 0
iprindole B-Chemical 1
- O 0
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rats O 0
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reported O 0
. O 0

A O 0
single O 0
18 O 0
. O 0
4 O 0
mg O 0
/ O 0
kg O 0
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. O 0
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. O 0
) O 0
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of O 0
( O 0
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/ O 0
- O 0
) O 0
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, O 0
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to O 0
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with O 0
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, O 0
resulted O 0
in O 0
persistent O 0
depletion O 0
of O 0
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in O 0
the O 0
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1 O 0
week O 0
later O 0
. O 0

This O 0
prolonged O 0
depletion O 0
of O 0
dopamine B-Chemical 1
in O 0
the O 0
striatum O 0
was O 0
antagonized O 0
by O 0
dizocilpine B-Chemical 1
( O 0
MK B-Chemical 1
- I-Chemical 1
801 I-Chemical 1
, O 0
a O 0
non O 0
- O 0
competitive O 0
antagonist O 0
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NMDA B-Chemical 1
receptors O 0
) O 0
or O 0
by O 0
LY274614 B-Chemical 1
( O 0
a O 0
competitive O 0
antagonist O 0
of O 0
NMDA B-Chemical 1
receptors O 0
) O 0
. O 0

The O 0
protective O 0
effect O 0
of O 0
LY274614 B-Chemical 1
was O 0
dose O 0
- O 0
dependent O 0
, O 0
being O 0
maximum O 0
at O 0
10 O 0
- O 0
40 O 0
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( O 0
i O 0
. O 0
p O 0
. O 0
) O 0
. O 0

A O 0
10 O 0
mg O 0
/ O 0
kg O 0
dose O 0
of O 0
LY274614 B-Chemical 1
was O 0
effective O 0
in O 0
antagonizing O 0
the O 0
depletion O 0
of O 0
dopamine B-Chemical 1
in O 0
the O 0
striatum O 0
, O 0
when O 0
given O 0
as O 0
long O 0
as O 0
8 O 0
hr O 0
prior O 0
to O 0
amphetamine B-Chemical 1
but O 0
not O 0
when O 0
given O 0
24 O 0
hr O 0
prior O 0
to O 0
amphetamine B-Chemical 1
. O 0

Depletion O 0
of O 0
dopamine B-Chemical 1
in O 0
the O 0
striatum O 0
was O 0
also O 0
antagonized O 0
when O 0
LY274614 B-Chemical 1
was O 0
given O 0
after O 0
the O 0
injection O 0
of O 0
amphetamine B-Chemical 1
; O 0
LY274614 B-Chemical 1
protected O 0
when O 0
given O 0
up O 0
to O 0
4 O 0
hr O 0
after O 0
but O 0
not O 0
when O 0
given O 0
8 O 0
or O 0
24 O 0
hr O 0
after O 0
amphetamine B-Chemical 1
. O 0

The O 0
prolonged O 0
depletion O 0
of O 0
dopamine B-Chemical 1
in O 0
the O 0
striatum O 0
in O 0
mice O 0
, O 0
given O 0
multiple O 0
injections O 0
of O 0
methamphetamine B-Chemical 1
, O 0
was O 0
also O 0
antagonized O 0
dose O 0
- O 0
dependently O 0
and O 0
completely O 0
by O 0
LY274614 B-Chemical 1
. O 0

The O 0
data O 0
strengthen O 0
the O 0
evidence O 0
that O 0
the O 0
neurotoxic B-Disease 1
effect O 0
of O 0
amphetamine B-Chemical 1
and O 0
related O 0
compounds O 0
toward O 0
nigrostriatal O 0
dopamine B-Chemical 1
neurons O 0
involves O 0
NMDA B-Chemical 1
receptors O 0
and O 0
that O 0
LY274614 B-Chemical 1
is O 0
an O 0
NMDA B-Chemical 1
receptor O 0
antagonist O 0
with O 0
long O 0
- O 0
lasting O 0
in O 0
vivo O 0
effects O 0
in O 0
rats O 0
. O 0

Ketoconazole B-Chemical 1
- O 0
induced O 0
neurologic B-Disease 1
sequelae I-Disease 1
. O 0

A O 0
77 O 0
- O 0
y O 0
- O 0
old O 0
patient O 0
developed O 0
weakness B-Disease 1
of I-Disease 1
extremities I-Disease 1
, O 0
legs B-Disease 1
paralysis I-Disease 1
, O 0
dysarthria B-Disease 1
and O 0
tremor B-Disease 1
1 O 0
h O 0
after O 0
ingestion O 0
of O 0
200 O 0
mg O 0
ketoconazole B-Chemical 1
for O 0
the O 0
first O 0
time O 0
in O 0
his O 0
life O 0
. O 0

All O 0
complaints O 0
faded O 0
away O 0
within O 0
24 O 0
h O 0
. O 0

Few O 0
days O 0
later O 0
, O 0
the O 0
patient O 0
used O 0
another O 0
200 O 0
mg O 0
ketoconazole B-Chemical 1
tablet O 0
, O 0
and O 0
within O 0
an O 0
hour O 0
experienced O 0
a O 0
similar O 0
clinical O 0
picture O 0
, O 0
which O 0
resolved O 0
again O 0
spontaneously O 0
within O 0
hours O 0
. O 0

Laboratory O 0
evaluations O 0
, O 0
including O 0
head O 0
CT O 0
scan O 0
, O 0
were O 0
normal O 0
. O 0

This O 0
case O 0
illustrates O 0
the O 0
need O 0
for O 0
close O 0
vigilance O 0
in O 0
adverse B-Disease 1
drug I-Disease 1
reactions I-Disease 1
, O 0
particularly O 0
in O 0
the O 0
elderly O 0
. O 0

Development O 0
of O 0
levodopa B-Chemical 1
- O 0
induced O 0
dyskinesias B-Disease 1
in O 0
parkinsonian B-Disease 1
monkeys O 0
may O 0
depend O 0
upon O 0
rate O 0
of O 0
symptom O 0
onset O 0
and O 0
/ O 0
or O 0
duration O 0
of O 0
symptoms O 0
. O 0

Levodopa B-Chemical 1
- O 0
induced O 0
dyskinesias B-Disease 1
( O 0
LIDs B-Disease 1
) O 0
present O 0
a O 0
major O 0
problem O 0
for O 0
the O 0
long O 0
- O 0
term O 0
management O 0
of O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
( O 0
PD B-Disease 1
) O 0
patients O 0
. O 0

Due O 0
to O 0
the O 0
interdependence O 0
of O 0
risk O 0
factors O 0
in O 0
clinical O 0
populations O 0
, O 0
it O 0
is O 0
difficult O 0
to O 0
independently O 0
examine O 0
factors O 0
that O 0
may O 0
influence O 0
the O 0
development O 0
of O 0
LIDs B-Disease 1
. O 0

Using O 0
macaque O 0
monkeys O 0
with O 0
different O 0
types O 0
of O 0
MPTP B-Chemical 1
- O 0
induced O 0
parkinsonism B-Disease 1
, O 0
the O 0
current O 0
study O 0
evaluated O 0
the O 0
degree O 0
to O 0
which O 0
rate O 0
of O 0
symptom O 0
progression O 0
, O 0
symptom O 0
severity O 0
, O 0
and O 0
response O 0
to O 0
and O 0
duration O 0
of O 0
levodopa B-Chemical 1
therapy O 0
may O 0
be O 0
involved O 0
in O 0
the O 0
development O 0
of O 0
LIDs B-Disease 1
. O 0

Monkeys O 0
with O 0
acute O 0
( O 0
short O 0
- O 0
term O 0
) O 0
MPTP B-Chemical 1
exposure O 0
, O 0
rapid O 0
symptom O 0
onset O 0
and O 0
short O 0
symptom O 0
duration O 0
prior O 0
to O 0
initiation O 0
of O 0
levodopa B-Chemical 1
therapy O 0
developed O 0
dyskinesia B-Disease 1
between O 0
11 O 0
and O 0
24 O 0
days O 0
of O 0
daily O 0
levodopa B-Chemical 1
administration O 0
. O 0

In O 0
contrast O 0
, O 0
monkeys O 0
with O 0
long O 0
- O 0
term O 0
MPTP B-Chemical 1
exposure O 0
, O 0
slow O 0
symptom O 0
progression O 0
and O 0
/ O 0
or O 0
long O 0
symptom O 0
duration O 0
prior O 0
to O 0
initiation O 0
of O 0
levodopa B-Chemical 1
therapy O 0
were O 0
more O 0
resistant O 0
to O 0
developing O 0
LIDs B-Disease 1
( O 0
e O 0
. O 0
g O 0
. O 0
, O 0
dyskinesia B-Disease 1
developed O 0
no O 0
sooner O 0
than O 0
146 O 0
days O 0
of O 0
chronic O 0
levodopa B-Chemical 1
administration O 0
) O 0
. O 0

All O 0
animals O 0
were O 0
similarly O 0
symptomatic O 0
at O 0
the O 0
start O 0
of O 0
levodopa B-Chemical 1
treatment O 0
and O 0
had O 0
similar O 0
therapeutic O 0
responses O 0
to O 0
the O 0
drug O 0
. O 0

These O 0
data O 0
suggest O 0
distinct O 0
differences O 0
in O 0
the O 0
propensity O 0
to O 0
develop O 0
LIDs B-Disease 1
in O 0
monkeys O 0
with O 0
different O 0
rates O 0
of O 0
symptom O 0
progression O 0
or O 0
symptom O 0
durations O 0
prior O 0
to O 0
levodopa B-Chemical 1
and O 0
demonstrate O 0
the O 0
value O 0
of O 0
these O 0
models O 0
for O 0
further O 0
studying O 0
the O 0
pathophysiology O 0
of O 0
LIDs B-Disease 1
. O 0

A O 0
diet O 0
promoting O 0
sugar B-Disease 1
dependency I-Disease 1
causes O 0
behavioral B-Disease 1
cross I-Disease 1
- I-Disease 1
sensitization I-Disease 1
to O 0
a O 0
low O 0
dose O 0
of O 0
amphetamine B-Chemical 1
. O 0

Previous O 0
research O 0
in O 0
this O 0
laboratory O 0
has O 0
shown O 0
that O 0
a O 0
diet O 0
of O 0
intermittent O 0
excessive O 0
sugar O 0
consumption O 0
produces O 0
a O 0
state O 0
with O 0
neurochemical O 0
and O 0
behavioral O 0
similarities O 0
to O 0
drug B-Disease 1
dependency I-Disease 1
. O 0

The O 0
present O 0
study O 0
examined O 0
whether O 0
female O 0
rats O 0
on O 0
various O 0
regimens O 0
of O 0
sugar O 0
access O 0
would O 0
show O 0
behavioral B-Disease 1
cross I-Disease 1
- I-Disease 1
sensitization I-Disease 1
to O 0
a O 0
low O 0
dose O 0
of O 0
amphetamine B-Chemical 1
. O 0

After O 0
a O 0
30 O 0
- O 0
min O 0
baseline O 0
measure O 0
of O 0
locomotor O 0
activity O 0
( O 0
day O 0
0 O 0
) O 0
, O 0
animals O 0
were O 0
maintained O 0
on O 0
a O 0
cyclic O 0
diet O 0
of O 0
12 O 0
- O 0
h O 0
deprivation O 0
followed O 0
by O 0
12 O 0
- O 0
h O 0
access O 0
to O 0
10 O 0
% O 0
sucrose B-Chemical 1
solution O 0
and O 0
chow O 0
pellets O 0
( O 0
12 O 0
h O 0
access O 0
starting O 0
4 O 0
h O 0
after O 0
onset O 0
of O 0
the O 0
dark O 0
period O 0
) O 0
for O 0
21 O 0
days O 0
. O 0

Locomotor O 0
activity O 0
was O 0
measured O 0
again O 0
for O 0
30 O 0
min O 0
at O 0
the O 0
beginning O 0
of O 0
days O 0
1 O 0
and O 0
21 O 0
of O 0
sugar O 0
access O 0
. O 0

Beginning O 0
on O 0
day O 0
22 O 0
, O 0
all O 0
rats O 0
were O 0
maintained O 0
on O 0
ad O 0
libitum O 0
chow O 0
. O 0

Nine O 0
days O 0
later O 0
locomotor O 0
activity O 0
was O 0
measured O 0
in O 0
response O 0
to O 0
a O 0
single O 0
low O 0
dose O 0
of O 0
amphetamine B-Chemical 1
( O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
) O 0
. O 0

The O 0
animals O 0
that O 0
had O 0
experienced O 0
cyclic O 0
sucrose B-Chemical 1
and O 0
chow O 0
were O 0
hyperactive B-Disease 1
in O 0
response O 0
to O 0
amphetamine B-Chemical 1
compared O 0
with O 0
four O 0
control O 0
groups O 0
( O 0
ad O 0
libitum O 0
10 O 0
% O 0
sucrose B-Chemical 1
and O 0
chow O 0
followed O 0
by O 0
amphetamine B-Chemical 1
injection O 0
, O 0
cyclic O 0
chow O 0
followed O 0
by O 0
amphetamine B-Chemical 1
injection O 0
, O 0
ad O 0
libitum O 0
chow O 0
with O 0
amphetamine B-Chemical 1
, O 0
or O 0
cyclic O 0
10 O 0
% O 0
sucrose B-Chemical 1
and O 0
chow O 0
with O 0
a O 0
saline O 0
injection O 0
) O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
a O 0
diet O 0
comprised O 0
of O 0
alternating O 0
deprivation O 0
and O 0
access O 0
to O 0
a O 0
sugar O 0
solution O 0
and O 0
chow O 0
produces O 0
bingeing O 0
on O 0
sugar O 0
that O 0
leads O 0
to O 0
a O 0
long O 0
lasting O 0
state O 0
of O 0
increased O 0
sensitivity O 0
to O 0
amphetamine B-Chemical 1
, O 0
possibly O 0
due O 0
to O 0
a O 0
lasting O 0
alteration O 0
in O 0
the O 0
dopamine B-Chemical 1
system O 0
. O 0

Reversible O 0
dilated B-Disease 1
cardiomyopathy I-Disease 1
related O 0
to O 0
amphotericin B-Chemical 1
B I-Chemical 1
therapy O 0
. O 0

We O 0
describe O 0
a O 0
patient O 0
who O 0
developed O 0
dilated B-Disease 1
cardiomyopathy I-Disease 1
and O 0
clinical O 0
congestive O 0
heart B-Disease 1
failure I-Disease 1
after O 0
2 O 0
months O 0
of O 0
therapy O 0
with O 0
amphotericin B-Chemical 1
B I-Chemical 1
( O 0
AmB B-Chemical 1
) O 0
for O 0
disseminated O 0
coccidioidomycosis B-Disease 1
. O 0

His O 0
echocardiographic O 0
abnormalities O 0
and O 0
heart B-Disease 1
failure I-Disease 1
resolved O 0
after O 0
posaconazole B-Chemical 1
was O 0
substituted O 0
for O 0
AmB B-Chemical 1
. O 0

It O 0
is O 0
important O 0
to O 0
recognize O 0
the O 0
rare O 0
and O 0
potentially O 0
reversible O 0
toxicity B-Disease 1
of O 0
AmB B-Chemical 1
. O 0

NO B-Chemical 1
- O 0
induced O 0
migraine B-Disease 1
attack O 0
: O 0
strong O 0
increase O 0
in O 0
plasma O 0
calcitonin B-Chemical 1
gene I-Chemical 1
- I-Chemical 1
related I-Chemical 1
peptide I-Chemical 1
( O 0
CGRP B-Chemical 1
) O 0
concentration O 0
and O 0
negative O 0
correlation O 0
with O 0
platelet O 0
serotonin B-Chemical 1
release O 0
. O 0

The O 0
aim O 0
of O 0
the O 0
present O 0
study O 0
was O 0
to O 0
investigate O 0
changes O 0
in O 0
the O 0
plasma O 0
calcitonin B-Chemical 1
gene I-Chemical 1
- I-Chemical 1
related I-Chemical 1
peptide I-Chemical 1
( O 0
CGRP B-Chemical 1
) O 0
concentration O 0
and O 0
platelet O 0
serotonin B-Chemical 1
( O 0
5 B-Chemical 1
- I-Chemical 1
hydroxytriptamine I-Chemical 1
, O 0
5 B-Chemical 1
- I-Chemical 1
HT I-Chemical 1
) O 0
content O 0
during O 0
the O 0
immediate O 0
headache B-Disease 1
and O 0
the O 0
delayed O 0
genuine O 0
migraine B-Disease 1
attack O 0
provoked O 0
by O 0
nitroglycerin B-Chemical 1
. O 0

Fifteen O 0
female O 0
migraineurs B-Disease 1
( I-Disease 1
without I-Disease 1
aura I-Disease 1
) I-Disease 1
and O 0
eight O 0
controls O 0
participated O 0
in O 0
the O 0
study O 0
. O 0

Sublingual O 0
nitroglycerin B-Chemical 1
( O 0
0 O 0
. O 0
5 O 0
mg O 0
) O 0
was O 0
administered O 0
. O 0

Blood O 0
was O 0
collected O 0
from O 0
the O 0
antecubital O 0
vein O 0
four O 0
times O 0
: O 0
60 O 0
min O 0
before O 0
and O 0
after O 0
the O 0
nitroglycerin B-Chemical 1
application O 0
, O 0
and O 0
60 O 0
and O 0
120 O 0
min O 0
after O 0
the O 0
beginning O 0
of O 0
the O 0
migraine B-Disease 1
attack O 0
( O 0
mean O 0
344 O 0
and O 0
404 O 0
min O 0
; O 0
12 O 0
subjects O 0
) O 0
. O 0

In O 0
those O 0
subjects O 0
who O 0
had O 0
no O 0
migraine B-Disease 1
attack O 0
( O 0
11 O 0
subjects O 0
) O 0
a O 0
similar O 0
time O 0
schedule O 0
was O 0
used O 0
. O 0

Plasma O 0
CGRP B-Chemical 1
concentration O 0
increased O 0
significantly O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
during O 0
the O 0
migraine B-Disease 1
attack O 0
and O 0
returned O 0
to O 0
baseline O 0
after O 0
the O 0
cessation O 0
of O 0
the O 0
migraine B-Disease 1
. O 0

In O 0
addition O 0
, O 0
both O 0
change O 0
and O 0
peak O 0
, O 0
showed O 0
significant O 0
positive O 0
correlations O 0
with O 0
migraine B-Disease 1
headache B-Disease 1
intensity O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

However O 0
, O 0
plasma O 0
CGRP B-Chemical 1
concentrations O 0
failed O 0
to O 0
change O 0
during O 0
immediate O 0
headache B-Disease 1
and O 0
in O 0
the O 0
subjects O 0
with O 0
no O 0
migraine B-Disease 1
attack O 0
. O 0

Basal O 0
CGRP B-Chemical 1
concentration O 0
was O 0
significantly O 0
higher O 0
and O 0
platelet O 0
5 B-Chemical 1
- I-Chemical 1
HT I-Chemical 1
content O 0
tended O 0
to O 0
be O 0
lower O 0
in O 0
subjects O 0
who O 0
experienced O 0
a O 0
migraine B-Disease 1
attack O 0
. O 0

Platelet O 0
serotonin B-Chemical 1
content O 0
decreased O 0
significantly O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
after O 0
nitroglycerin B-Chemical 1
in O 0
subjects O 0
with O 0
no O 0
migraine B-Disease 1
attack O 0
but O 0
no O 0
consistent O 0
change O 0
was O 0
observed O 0
in O 0
patients O 0
with O 0
migraine B-Disease 1
attack O 0
. O 0

In O 0
conclusion O 0
, O 0
the O 0
fact O 0
that O 0
plasma O 0
CGRP B-Chemical 1
concentration O 0
correlates O 0
with O 0
the O 0
timing O 0
and O 0
severity O 0
of O 0
a O 0
migraine B-Disease 1
headache B-Disease 1
suggests O 0
a O 0
direct O 0
relationship O 0
between O 0
CGRP B-Chemical 1
and O 0
migraine B-Disease 1
. O 0

In O 0
contrast O 0
, O 0
serotonin B-Chemical 1
release O 0
from O 0
platelets O 0
does O 0
not O 0
provoke O 0
migraine B-Disease 1
, O 0
it O 0
may O 0
even O 0
counteract O 0
the O 0
headache B-Disease 1
and O 0
the O 0
concomitant O 0
CGRP B-Chemical 1
release O 0
in O 0
this O 0
model O 0
. O 0

Hyperbaric O 0
oxygen B-Chemical 1
therapy O 0
for O 0
control O 0
of O 0
intractable O 0
cyclophosphamide B-Chemical 1
- O 0
induced O 0
hemorrhagic B-Disease 1
cystitis I-Disease 1
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
intractable O 0
hemorrhagic B-Disease 1
cystitis I-Disease 1
due O 0
to O 0
cyclophosphamide B-Chemical 1
therapy O 0
for O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
. O 0

Conservative O 0
treatment O 0
, O 0
including O 0
bladder O 0
irrigation O 0
with O 0
physiological O 0
saline O 0
and O 0
instillation O 0
of O 0
prostaglandin B-Chemical 1
F2 I-Chemical 1
alpha I-Chemical 1
, O 0
failed O 0
to O 0
totally O 0
control O 0
hemorrhage B-Disease 1
. O 0

We O 0
then O 0
used O 0
hyperbaric O 0
oxygen B-Chemical 1
at O 0
an O 0
absolute O 0
pressure O 0
of O 0
2 O 0
atm O 0
, O 0
5 O 0
days O 0
a O 0
week O 0
for O 0
8 O 0
consecutive O 0
weeks O 0
. O 0

The O 0
bleeding B-Disease 1
ceased O 0
completely O 0
by O 0
the O 0
end O 0
of O 0
treatment O 0
and O 0
the O 0
patient O 0
remained O 0
free O 0
of O 0
hematuria B-Disease 1
thereafter O 0
. O 0

No O 0
side O 0
effect O 0
was O 0
noted O 0
during O 0
the O 0
course O 0
of O 0
therapy O 0
. O 0

In O 0
future O 0
, O 0
this O 0
form O 0
of O 0
therapy O 0
can O 0
offer O 0
a O 0
safe O 0
alternative O 0
in O 0
the O 0
treatment O 0
of O 0
cyclophosphamide B-Chemical 1
- O 0
induced O 0
hemorrhagic B-Disease 1
cystitis I-Disease 1
. O 0

Acute B-Disease 1
psychosis I-Disease 1
due O 0
to O 0
treatment O 0
with O 0
phenytoin B-Chemical 1
in O 0
a O 0
nonepileptic O 0
patient O 0
. O 0

The O 0
development O 0
of O 0
psychosis B-Disease 1
related O 0
to O 0
antiepileptic O 0
drug O 0
treatment O 0
is O 0
usually O 0
attributed O 0
to O 0
the O 0
interaction O 0
between O 0
the O 0
epileptic B-Disease 1
brain O 0
substratum O 0
and O 0
the O 0
antiepileptic O 0
drugs O 0
. O 0

The O 0
case O 0
of O 0
a O 0
nonepileptic O 0
patient O 0
who O 0
developed O 0
psychosis B-Disease 1
following O 0
phenytoin B-Chemical 1
treatment O 0
for O 0
trigeminal B-Disease 1
neuralgia I-Disease 1
is O 0
described O 0
. O 0

This O 0
case O 0
suggests O 0
that O 0
the O 0
psychotic B-Disease 1
symptoms I-Disease 1
that O 0
occur O 0
following O 0
phenytoin B-Chemical 1
treatment O 0
in O 0
some O 0
epileptic B-Disease 1
patients O 0
may O 0
be O 0
the O 0
direct O 0
result O 0
of O 0
medication O 0
, O 0
unrelated O 0
to O 0
seizures B-Disease 1
. O 0

Risks O 0
of O 0
the O 0
consumption O 0
of O 0
beverages O 0
containing O 0
quinine B-Chemical 1
. O 0

Although O 0
the O 0
United O 0
States O 0
Food O 0
and O 0
Drug O 0
Administration O 0
banned O 0
its O 0
use O 0
for O 0
nocturnal B-Disease 1
leg I-Disease 1
cramps I-Disease 1
due O 0
to O 0
lack O 0
of O 0
safety O 0
and O 0
efficacy O 0
, O 0
quinine B-Chemical 1
is O 0
widely O 0
available O 0
in O 0
beverages O 0
including O 0
tonic O 0
water O 0
and O 0
bitter O 0
lemon O 0
. O 0

Numerous O 0
anecdotal O 0
reports O 0
suggest O 0
that O 0
products O 0
containing O 0
quinine B-Chemical 1
may O 0
produce O 0
neurological B-Disease 1
complications I-Disease 1
, O 0
including O 0
confusion B-Disease 1
, O 0
altered O 0
mental O 0
status O 0
, O 0
seizures B-Disease 1
, O 0
and O 0
coma B-Disease 1
, O 0
particularly O 0
in O 0
older O 0
women O 0
. O 0

Psychologists O 0
need O 0
to O 0
inquire O 0
about O 0
consumption O 0
of O 0
quinine B-Chemical 1
- O 0
containing O 0
beverages O 0
as O 0
part O 0
of O 0
an O 0
evaluation O 0
process O 0
. O 0

Transient O 0
platypnea B-Disease 1
- I-Disease 1
orthodeoxia I-Disease 1
- I-Disease 1
like I-Disease 1
syndrome I-Disease 1
induced O 0
by O 0
propafenone B-Chemical 1
overdose B-Disease 1
in O 0
a O 0
young O 0
woman O 0
with O 0
Ebstein B-Disease 1
' I-Disease 1
s I-Disease 1
anomaly I-Disease 1
. O 0

In O 0
this O 0
report O 0
we O 0
describe O 0
the O 0
case O 0
of O 0
a O 0
37 O 0
- O 0
year O 0
- O 0
old O 0
white O 0
woman O 0
with O 0
Ebstein B-Disease 1
' I-Disease 1
s I-Disease 1
anomaly I-Disease 1
, O 0
who O 0
developed O 0
a O 0
rare O 0
syndrome O 0
called O 0
platypnea B-Disease 1
- I-Disease 1
orthodeoxia I-Disease 1
, O 0
characterized O 0
by O 0
massive O 0
right O 0
- O 0
to O 0
- O 0
left O 0
interatrial O 0
shunting O 0
with O 0
transient O 0
profound O 0
hypoxia B-Disease 1
and O 0
cyanosis B-Disease 1
. O 0

This O 0
shunt O 0
of O 0
blood O 0
via O 0
a O 0
patent B-Disease 1
foramen I-Disease 1
ovale I-Disease 1
occurred O 0
in O 0
the O 0
presence O 0
of O 0
a O 0
normal O 0
pulmonary O 0
artery O 0
pressure O 0
, O 0
and O 0
was O 0
probably O 0
precipitated O 0
by O 0
a O 0
propafenone B-Chemical 1
overdose B-Disease 1
. O 0

This O 0
drug O 0
caused O 0
biventricular B-Disease 1
dysfunction I-Disease 1
, O 0
due O 0
to O 0
its O 0
negative O 0
inotropic O 0
effect O 0
, O 0
and O 0
hypotension B-Disease 1
, O 0
due O 0
to O 0
its O 0
peripheral O 0
vasodilatory O 0
effect O 0
. O 0

These O 0
effects O 0
gave O 0
rise O 0
to O 0
an O 0
increase O 0
in O 0
the O 0
right O 0
atrial O 0
pressure O 0
and O 0
a O 0
decrease O 0
in O 0
the O 0
left O 0
one O 0
with O 0
a O 0
consequent O 0
stretching O 0
of O 0
the O 0
foramen O 0
ovale O 0
and O 0
the O 0
creation O 0
of O 0
massive O 0
right O 0
- O 0
to O 0
- O 0
left O 0
shunting O 0
. O 0

In O 0
our O 0
case O 0
this O 0
interatrial O 0
shunt O 0
was O 0
very O 0
accurately O 0
detected O 0
at O 0
bubble O 0
contrast O 0
echocardiography O 0
. O 0

Noxious O 0
chemical O 0
stimulation O 0
of O 0
rat O 0
facial O 0
mucosa O 0
increases O 0
intracranial O 0
blood O 0
flow O 0
through O 0
a O 0
trigemino O 0
- O 0
parasympathetic O 0
reflex O 0
- O 0
- O 0
an O 0
experimental O 0
model O 0
for O 0
vascular B-Disease 1
dysfunctions I-Disease 1
in O 0
cluster B-Disease 1
headache I-Disease 1
. O 0

Cluster B-Disease 1
headache I-Disease 1
is O 0
characterized O 0
by O 0
typical O 0
autonomic O 0
dysfunctions O 0
including O 0
facial O 0
and O 0
intracranial B-Disease 1
vascular I-Disease 1
disturbances I-Disease 1
. O 0

Both O 0
the O 0
trigeminal O 0
and O 0
the O 0
cranial O 0
parasympathetic O 0
systems O 0
may O 0
be O 0
involved O 0
in O 0
mediating O 0
these O 0
dysfunctions O 0
. O 0

An O 0
experimental O 0
model O 0
was O 0
developed O 0
in O 0
the O 0
rat O 0
to O 0
measure O 0
changes O 0
in O 0
lacrimation O 0
and O 0
intracranial O 0
blood O 0
flow O 0
following O 0
noxious O 0
chemical O 0
stimulation O 0
of O 0
facial O 0
mucosa O 0
. O 0

Blood O 0
flow O 0
was O 0
monitored O 0
in O 0
arteries O 0
of O 0
the O 0
exposed O 0
cranial O 0
dura O 0
mater O 0
and O 0
the O 0
parietal O 0
cortex O 0
using O 0
laser O 0
Doppler O 0
flowmetry O 0
. O 0

Capsaicin B-Chemical 1
( O 0
0 O 0
. O 0
01 O 0
- O 0
1 O 0
mm O 0
) O 0
applied O 0
to O 0
oral O 0
or O 0
nasal O 0
mucosa O 0
induced O 0
increases B-Disease 1
in I-Disease 1
dural I-Disease 1
and I-Disease 1
cortical I-Disease 1
blood I-Disease 1
flow I-Disease 1
and O 0
provoked O 0
lacrimation O 0
. O 0

These O 0
responses O 0
were O 0
blocked O 0
by O 0
systemic O 0
pre O 0
- O 0
administration O 0
of O 0
hexamethonium B-Chemical 1
chloride I-Chemical 1
( O 0
20 O 0
mg O 0
/ O 0
kg O 0
) O 0
. O 0

The O 0
evoked O 0
increases B-Disease 1
in I-Disease 1
dural I-Disease 1
blood I-Disease 1
flow I-Disease 1
were O 0
also O 0
abolished O 0
by O 0
topical O 0
pre O 0
- O 0
administration O 0
of O 0
atropine B-Chemical 1
( O 0
1 O 0
mm O 0
) O 0
and O 0
[ O 0
Lys1 O 0
, O 0
Pro2 O 0
, O 0
5 O 0
, O 0
Arg3 O 0
, O 0
4 O 0
, O 0
Tyr6 O 0
] O 0
- O 0
VIP O 0
( O 0
0 O 0
. O 0
1 O 0
mm O 0
) O 0
, O 0
a O 0
vasoactive O 0
intestinal O 0
polypeptide O 0
( O 0
VIP O 0
) O 0
antagonist O 0
, O 0
onto O 0
the O 0
exposed O 0
dura O 0
mater O 0
. O 0

We O 0
conclude O 0
that O 0
noxious O 0
stimulation O 0
of O 0
facial O 0
mucosa O 0
increases O 0
intracranial O 0
blood O 0
flow O 0
and O 0
lacrimation O 0
via O 0
a O 0
trigemino O 0
- O 0
parasympathetic O 0
reflex O 0
. O 0

The O 0
blood O 0
flow O 0
responses O 0
seem O 0
to O 0
be O 0
mediated O 0
by O 0
the O 0
release O 0
of O 0
acetylcholine B-Chemical 1
and O 0
VIP O 0
within O 0
the O 0
meninges O 0
. O 0

Similar O 0
mechanisms O 0
may O 0
be O 0
involved O 0
in O 0
the O 0
pathogenesis O 0
of O 0
cluster B-Disease 1
headache I-Disease 1
. O 0

Organophosphate B-Chemical 1
- O 0
induced O 0
convulsions B-Disease 1
and O 0
prevention O 0
of O 0
neuropathological B-Disease 1
damages I-Disease 1
. O 0

Such O 0
organophosphorus B-Chemical 1
( O 0
OP B-Chemical 1
) O 0
compounds O 0
as O 0
diisopropylfluorophosphate B-Chemical 1
( O 0
DFP B-Chemical 1
) O 0
, O 0
sarin B-Chemical 1
and O 0
soman B-Chemical 1
are O 0
potent O 0
inhibitors O 0
of O 0
acetylcholinesterases O 0
( O 0
AChEs O 0
) O 0
and O 0
butyrylcholinesterases O 0
( O 0
BChEs O 0
) O 0
. O 0

The O 0
acute O 0
toxicity B-Disease 1
of O 0
OPs B-Chemical 1
is O 0
the O 0
result O 0
of O 0
their O 0
irreversible O 0
binding O 0
with O 0
AChEs O 0
in O 0
the O 0
central O 0
nervous O 0
system O 0
( O 0
CNS O 0
) O 0
, O 0
which O 0
elevates O 0
acetylcholine B-Chemical 1
( O 0
ACh B-Chemical 1
) O 0
levels O 0
. O 0

The O 0
protective O 0
action O 0
of O 0
subcutaneously O 0
( O 0
SC O 0
) O 0
administered O 0
antidotes O 0
or O 0
their O 0
combinations O 0
in O 0
DFP B-Chemical 1
( O 0
2 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
BW O 0
) O 0
intoxication O 0
was O 0
studied O 0
in O 0
9 O 0
- O 0
10 O 0
- O 0
weeks O 0
- O 0
old O 0
Han O 0
- O 0
Wistar O 0
male O 0
rats O 0
. O 0

The O 0
rats O 0
received O 0
AChE O 0
reactivator O 0
pralidoxime B-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
chloride I-Chemical 1
( O 0
2PAM B-Chemical 1
) O 0
( O 0
30 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
BW O 0
) O 0
, O 0
anticonvulsant O 0
diazepam B-Chemical 1
( O 0
2 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
BW O 0
) O 0
, O 0
A O 0
( O 0
1 O 0
) O 0
- O 0
adenosine B-Chemical 1
receptor O 0
agonist O 0
N B-Chemical 1
( I-Chemical 1
6 I-Chemical 1
) I-Chemical 1
- I-Chemical 1
cyclopentyl I-Chemical 1
adenosine I-Chemical 1
( O 0
CPA B-Chemical 1
) O 0
( O 0
2 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
BW O 0
) O 0
, O 0
NMDA B-Chemical 1
- O 0
receptor O 0
antagonist O 0
dizocilpine B-Chemical 1
maleate I-Chemical 1
( O 0
+ O 0
- O 0
MK801 O 0
hydrogen O 0
maleate O 0
) O 0
( O 0
2 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
BW O 0
) O 0
or O 0
their O 0
combinations O 0
with O 0
cholinolytic O 0
drug O 0
atropine B-Chemical 1
sulfate I-Chemical 1
( O 0
50 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
BW O 0
) O 0
immediately O 0
or O 0
30 O 0
min O 0
after O 0
the O 0
single O 0
SC O 0
injection O 0
of O 0
DFP B-Chemical 1
. O 0

The O 0
control O 0
rats O 0
received O 0
atropine B-Chemical 1
sulfate I-Chemical 1
, O 0
but O 0
also O 0
saline O 0
and O 0
olive O 0
oil O 0
instead O 0
of O 0
other O 0
antidotes O 0
and O 0
DFP B-Chemical 1
, O 0
respectively O 0
. O 0

All O 0
rats O 0
were O 0
terminated O 0
either O 0
24 O 0
h O 0
or O 0
3 O 0
weeks O 0
after O 0
the O 0
DFP B-Chemical 1
injection O 0
. O 0

The O 0
rats O 0
treated O 0
with O 0
DFP B-Chemical 1
- O 0
atropine B-Chemical 1
showed O 0
severe O 0
typical O 0
OP B-Chemical 1
- O 0
induced O 0
toxicity B-Disease 1
signs O 0
. O 0

When O 0
CPA B-Chemical 1
, O 0
diazepam B-Chemical 1
or O 0
2PAM B-Chemical 1
was O 0
given O 0
immediately O 0
after O 0
DFP B-Chemical 1
- O 0
atropine B-Chemical 1
, O 0
these O 0
treatments O 0
prevented O 0
, O 0
delayed O 0
or O 0
shortened O 0
the O 0
occurrence O 0
of O 0
serious O 0
signs O 0
of O 0
poisoning B-Disease 1
. O 0

Atropine B-Chemical 1
- O 0
MK801 B-Chemical 1
did O 0
not O 0
offer O 0
any O 0
additional O 0
protection O 0
against O 0
DFP B-Chemical 1
toxicity B-Disease 1
. O 0

In O 0
conclusion O 0
, O 0
CPA B-Chemical 1
, O 0
diazepam B-Chemical 1
and O 0
2PAM B-Chemical 1
in O 0
combination O 0
with O 0
atropine B-Chemical 1
prevented O 0
the O 0
occurrence O 0
of O 0
serious O 0
signs O 0
of O 0
poisoning B-Disease 1
and O 0
thus O 0
reduced O 0
the O 0
toxicity B-Disease 1
of O 0
DFP B-Chemical 1
in O 0
rat O 0
. O 0

A O 0
pyridoxine B-Chemical 1
- O 0
dependent O 0
behavioral B-Disease 1
disorder I-Disease 1
unmasked O 0
by O 0
isoniazid B-Chemical 1
. O 0

A O 0
3 O 0
- O 0
year O 0
- O 0
old O 0
girl O 0
had O 0
behavioral B-Disease 1
deterioration I-Disease 1
, O 0
with O 0
hyperkinesis B-Disease 1
, O 0
irritability B-Disease 1
, O 0
and O 0
sleeping B-Disease 1
difficulties I-Disease 1
after O 0
the O 0
therapeutic O 0
administration O 0
of O 0
isoniazid B-Chemical 1
. O 0

The O 0
administration O 0
of O 0
pharmacologic O 0
doses O 0
of O 0
pyridoxine B-Chemical 1
hydrochloride I-Chemical 1
led O 0
to O 0
a O 0
disappearance O 0
of O 0
symptoms O 0
. O 0

After O 0
discontinuing O 0
isoniazid B-Chemical 1
therapy O 0
a O 0
similar O 0
pattern O 0
of O 0
behavior O 0
was O 0
noted O 0
that O 0
was O 0
controlled O 0
by O 0
pyridoxine B-Chemical 1
. O 0

A O 0
placebo O 0
had O 0
no O 0
effect O 0
, O 0
but O 0
niacinamide B-Chemical 1
was O 0
as O 0
effective O 0
as O 0
pyridoxine B-Chemical 1
. O 0

Periodic O 0
withdrawal O 0
of O 0
pyridoxine B-Chemical 1
was O 0
associated O 0
with O 0
return O 0
of O 0
the O 0
hyperkinesis B-Disease 1
. O 0

The O 0
level O 0
of O 0
pyridoxal B-Chemical 1
in O 0
the O 0
blood O 0
was O 0
normal O 0
during O 0
the O 0
periods O 0
of O 0
relapse O 0
. O 0

Metabolic O 0
studies O 0
suggested O 0
a O 0
block O 0
in O 0
the O 0
kynurenine B-Chemical 1
pathway O 0
of O 0
tryptophan B-Chemical 1
metabolism O 0
. O 0

The O 0
patient O 0
has O 0
been O 0
followed O 0
for O 0
six O 0
years O 0
and O 0
has O 0
required O 0
pharmacologic O 0
doses O 0
of O 0
pyridoxine B-Chemical 1
to O 0
control O 0
her O 0
behavior O 0
. O 0

Recurrent O 0
excitation O 0
in O 0
the O 0
dentate O 0
gyrus O 0
of O 0
a O 0
murine O 0
model O 0
of O 0
temporal B-Disease 1
lobe I-Disease 1
epilepsy I-Disease 1
. O 0

Similar O 0
to O 0
rats O 0
, O 0
systemic O 0
pilocarpine B-Chemical 1
injection O 0
causes O 0
status B-Disease 1
epilepticus I-Disease 1
( O 0
SE B-Disease 1
) O 0
and O 0
the O 0
eventual O 0
development O 0
of O 0
spontaneous O 0
seizures B-Disease 1
and O 0
mossy O 0
fiber O 0
sprouting O 0
in O 0
C57BL O 0
/ O 0
6 O 0
and O 0
CD1 O 0
mice O 0
, O 0
but O 0
the O 0
physiological O 0
correlates O 0
of O 0
these O 0
events O 0
have O 0
not O 0
been O 0
identified O 0
in O 0
mice O 0
. O 0

Population O 0
responses O 0
in O 0
granule O 0
cells O 0
of O 0
the O 0
dentate O 0
gyrus O 0
were O 0
examined O 0
in O 0
transverse O 0
slices O 0
of O 0
the O 0
ventral O 0
hippocampus O 0
from O 0
pilocarpine B-Chemical 1
- O 0
treated O 0
and O 0
untreated O 0
mice O 0
. O 0

In O 0
Mg B-Chemical 1
( O 0
2 O 0
+ O 0
) O 0
- O 0
free O 0
bathing O 0
medium O 0
containing O 0
bicuculline B-Chemical 1
, O 0
conditions O 0
designed O 0
to O 0
increase O 0
excitability O 0
in O 0
the O 0
slices O 0
, O 0
electrical O 0
stimulation O 0
of O 0
the O 0
hilus O 0
resulted O 0
in O 0
a O 0
single O 0
population O 0
spike O 0
in O 0
granule O 0
cells O 0
from O 0
control O 0
mice O 0
and O 0
pilocarpine B-Chemical 1
- O 0
treated O 0
mice O 0
that O 0
did O 0
not O 0
experience O 0
SE B-Disease 1
. O 0

In O 0
SE B-Disease 1
survivors O 0
, O 0
similar O 0
stimulation O 0
resulted O 0
in O 0
a O 0
population O 0
spike O 0
followed O 0
, O 0
at O 0
a O 0
variable O 0
latency O 0
, O 0
by O 0
negative O 0
DC O 0
shifts O 0
and O 0
repetitive O 0
afterdischarges O 0
of O 0
3 O 0
- O 0
60 O 0
s O 0
duration O 0
, O 0
which O 0
were O 0
blocked O 0
by O 0
ionotropic O 0
glutamate B-Chemical 1
receptor O 0
antagonists O 0
. O 0

Focal O 0
glutamate B-Chemical 1
photostimulation O 0
of O 0
the O 0
granule O 0
cell O 0
layer O 0
at O 0
sites O 0
distant O 0
from O 0
the O 0
recording O 0
pipette O 0
resulted O 0
in O 0
population O 0
responses O 0
of O 0
1 O 0
- O 0
30 O 0
s O 0
duration O 0
in O 0
slices O 0
from O 0
SE B-Disease 1
survivors O 0
but O 0
not O 0
other O 0
groups O 0
. O 0

These O 0
data O 0
support O 0
the O 0
hypothesis O 0
that O 0
SE B-Disease 1
- O 0
induced O 0
mossy O 0
fiber O 0
sprouting O 0
and O 0
synaptic O 0
reorganization O 0
are O 0
relevant O 0
characteristics O 0
of O 0
seizure B-Disease 1
development O 0
in O 0
these O 0
murine O 0
strains O 0
, O 0
resembling O 0
rat O 0
models O 0
of O 0
human O 0
temporal B-Disease 1
lobe I-Disease 1
epilepsy I-Disease 1
. O 0

Urinary B-Disease 1
bladder I-Disease 1
cancer I-Disease 1
in O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
: O 0
risks O 0
and O 0
relation O 0
to O 0
cyclophosphamide B-Chemical 1
. O 0

OBJECTIVE O 0
: O 0
To O 0
assess O 0
and O 0
characterise O 0
the O 0
risk O 0
of O 0
bladder B-Disease 1
cancer I-Disease 1
, O 0
and O 0
its O 0
relation O 0
to O 0
cyclophosphamide B-Chemical 1
, O 0
in O 0
patients O 0
with O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
. O 0

METHODS O 0
: O 0
In O 0
the O 0
population O 0
based O 0
, O 0
nationwide O 0
Swedish O 0
Inpatient O 0
Register O 0
a O 0
cohort O 0
of O 0
1065 O 0
patients O 0
with O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
, O 0
1969 O 0
- O 0
95 O 0
, O 0
was O 0
identified O 0
. O 0

Through O 0
linkage O 0
with O 0
the O 0
Swedish O 0
Cancer B-Disease 1
Register O 0
, O 0
all O 0
subjects O 0
in O 0
this O 0
cohort O 0
diagnosed O 0
with O 0
bladder B-Disease 1
cancer I-Disease 1
were O 0
identified O 0
. O 0

Nested O 0
within O 0
the O 0
cohort O 0
, O 0
a O 0
matched O 0
case O 0
- O 0
control O 0
study O 0
was O 0
performed O 0
to O 0
estimate O 0
the O 0
association O 0
between O 0
cyclophosphamide B-Chemical 1
and O 0
bladder B-Disease 1
cancer I-Disease 1
using O 0
odds O 0
ratios O 0
( O 0
ORs O 0
) O 0
as O 0
relative O 0
risk O 0
. O 0

In O 0
the O 0
cohort O 0
the O 0
cumulative O 0
risk O 0
of O 0
bladder B-Disease 1
cancer I-Disease 1
after O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
, O 0
and O 0
the O 0
relative O 0
prevalence O 0
of O 0
a O 0
history O 0
of O 0
bladder B-Disease 1
cancer I-Disease 1
at O 0
the O 0
time O 0
of O 0
diagnosis O 0
of O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
, O 0
were O 0
also O 0
estimated O 0
. O 0

RESULTS O 0
: O 0
The O 0
median O 0
cumulative O 0
doses O 0
of O 0
cyclophosphamide B-Chemical 1
among O 0
cases O 0
( O 0
n O 0
= O 0
11 O 0
) O 0
and O 0
controls O 0
( O 0
n O 0
= O 0
25 O 0
) O 0
were O 0
113 O 0
g O 0
and O 0
25 O 0
g O 0
, O 0
respectively O 0
. O 0

The O 0
risk O 0
of O 0
bladder B-Disease 1
cancer I-Disease 1
doubled O 0
for O 0
every O 0
10 O 0
g O 0
increment O 0
in O 0
cyclophosphamide B-Chemical 1
( O 0
OR O 0
= O 0
2 O 0
. O 0
0 O 0
, O 0
95 O 0
% O 0
confidence O 0
interval O 0
( O 0
CI O 0
) O 0
0 O 0
. O 0
8 O 0
to O 0
4 O 0
. O 0
9 O 0
) O 0
. O 0

Treatment O 0
duration O 0
longer O 0
than O 0
1 O 0
year O 0
was O 0
associated O 0
with O 0
an O 0
eightfold O 0
increased O 0
risk O 0
( O 0
OR O 0
= O 0
7 O 0
. O 0
7 O 0
, O 0
95 O 0
% O 0
CI O 0
0 O 0
. O 0
9 O 0
to O 0
69 O 0
) O 0
. O 0

The O 0
absolute O 0
risk O 0
for O 0
bladder B-Disease 1
cancer I-Disease 1
in O 0
the O 0
cohort O 0
reached O 0
10 O 0
% O 0
16 O 0
years O 0
after O 0
diagnosis O 0
of O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
, O 0
and O 0
a O 0
history O 0
of O 0
bladder B-Disease 1
cancer I-Disease 1
was O 0
( O 0
non O 0
- O 0
significantly O 0
) O 0
twice O 0
as O 0
common O 0
as O 0
expected O 0
at O 0
the O 0
time O 0
of O 0
diagnosis O 0
of O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
. O 0

CONCLUSION O 0
: O 0
The O 0
results O 0
indicate O 0
a O 0
dose O 0
- O 0
response O 0
relationship O 0
between O 0
cyclophosphamide B-Chemical 1
and O 0
the O 0
risk O 0
of O 0
bladder B-Disease 1
cancer I-Disease 1
, O 0
high O 0
cumulative O 0
risks O 0
in O 0
the O 0
entire O 0
cohort O 0
, O 0
and O 0
also O 0
the O 0
possibility O 0
of O 0
risk O 0
factors O 0
operating O 0
even O 0
before O 0
Wegener B-Disease 1
' I-Disease 1
s I-Disease 1
granulomatosis I-Disease 1
. O 0

Differential O 0
modulation O 0
by O 0
estrogen B-Chemical 1
of O 0
alpha2 O 0
- O 0
adrenergic O 0
and O 0
I1 O 0
- O 0
imidazoline B-Chemical 1
receptor O 0
- O 0
mediated O 0
hypotension B-Disease 1
in O 0
female O 0
rats O 0
. O 0

We O 0
have O 0
recently O 0
shown O 0
that O 0
estrogen B-Chemical 1
negatively O 0
modulates O 0
the O 0
hypotensive B-Disease 1
effect O 0
of O 0
clonidine B-Chemical 1
( O 0
mixed O 0
alpha2 O 0
- O 0
/ O 0
I1 O 0
- O 0
receptor O 0
agonist O 0
) O 0
in O 0
female O 0
rats O 0
and O 0
implicates O 0
the O 0
cardiovascular O 0
autonomic O 0
control O 0
in O 0
this O 0
interaction O 0
. O 0

The O 0
present O 0
study O 0
investigated O 0
whether O 0
this O 0
effect O 0
of O 0
estrogen B-Chemical 1
involves O 0
interaction O 0
with O 0
alpha2 O 0
- O 0
and O 0
/ O 0
or O 0
I1 O 0
- O 0
receptors O 0
. O 0

Changes O 0
evoked O 0
by O 0
a O 0
single O 0
intraperitoneal O 0
injection O 0
of O 0
rilmenidine B-Chemical 1
( O 0
600 O 0
microg O 0
/ O 0
kg O 0
) O 0
or O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
( O 0
100 O 0
mg O 0
/ O 0
kg O 0
) O 0
, O 0
selective O 0
I1 O 0
- O 0
and O 0
alpha2 O 0
- O 0
receptor O 0
agonists O 0
, O 0
respectively O 0
, O 0
in O 0
blood O 0
pressure O 0
, O 0
hemodynamic O 0
variability O 0
, O 0
and O 0
locomotor O 0
activity O 0
were O 0
assessed O 0
in O 0
radiotelemetered O 0
sham O 0
- O 0
operated O 0
and O 0
ovariectomized O 0
( O 0
Ovx O 0
) O 0
Sprague O 0
- O 0
Dawley O 0
female O 0
rats O 0
with O 0
or O 0
without O 0
12 O 0
- O 0
wk O 0
estrogen B-Chemical 1
replacement O 0
. O 0

Three O 0
time O 0
domain O 0
indexes O 0
of O 0
hemodynamic O 0
variability O 0
were O 0
employed O 0
: O 0
the O 0
standard O 0
deviation O 0
of O 0
mean O 0
arterial O 0
pressure O 0
as O 0
a O 0
measure O 0
of O 0
blood O 0
pressure O 0
variability O 0
and O 0
the O 0
standard O 0
deviation O 0
of O 0
beat O 0
- O 0
to O 0
- O 0
beat O 0
intervals O 0
( O 0
SDRR O 0
) O 0
and O 0
the O 0
root O 0
mean O 0
square O 0
of O 0
successive O 0
differences O 0
in O 0
R O 0
- O 0
wave O 0
- O 0
to O 0
- O 0
R O 0
- O 0
wave O 0
intervals O 0
as O 0
measures O 0
of O 0
heart O 0
rate O 0
variability O 0
. O 0

In O 0
sham O 0
- O 0
operated O 0
rats O 0
, O 0
rilmenidine B-Chemical 1
or O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
elicited O 0
similar O 0
hypotension B-Disease 1
that O 0
lasted O 0
at O 0
least O 0
5 O 0
h O 0
and O 0
was O 0
associated O 0
with O 0
reductions O 0
in O 0
standard O 0
deviation O 0
of O 0
mean O 0
arterial O 0
pressure O 0
. O 0

SDRR O 0
was O 0
reduced O 0
only O 0
by O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
. O 0

Ovx O 0
significantly O 0
enhanced O 0
the O 0
hypotensive B-Disease 1
response O 0
to O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
, O 0
in O 0
contrast O 0
to O 0
no O 0
effect O 0
on O 0
rilmenidine B-Chemical 1
hypotension B-Disease 1
. O 0

The O 0
enhanced O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
hypotension B-Disease 1
in O 0
Ovx O 0
rats O 0
was O 0
paralleled O 0
with O 0
further O 0
reduction O 0
in O 0
SDRR O 0
and O 0
a B-Disease 1
reduced I-Disease 1
locomotor I-Disease 1
activity I-Disease 1
. O 0

Estrogen O 0
replacement O 0
( O 0
17beta B-Chemical 1
- I-Chemical 1
estradiol I-Chemical 1
subcutaneous O 0
pellet O 0
, O 0
14 O 0
. O 0
2 O 0
microg O 0
/ O 0
day O 0
, O 0
12 O 0
wk O 0
) O 0
of O 0
Ovx O 0
rats O 0
restored O 0
the O 0
hemodynamic O 0
and O 0
locomotor O 0
effects O 0
of O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
to O 0
sham O 0
- O 0
operated O 0
levels O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
estrogen B-Chemical 1
downregulates O 0
alpha2 O 0
- O 0
but O 0
not O 0
I1 O 0
- O 0
receptor O 0
- O 0
mediated O 0
hypotension B-Disease 1
and O 0
highlight O 0
a O 0
role O 0
for O 0
the O 0
cardiac O 0
autonomic O 0
control O 0
in O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
- O 0
estrogen B-Chemical 1
interaction O 0
. O 0

Severe O 0
reversible O 0
left B-Disease 1
ventricular I-Disease 1
systolic I-Disease 1
and I-Disease 1
diastolic I-Disease 1
dysfunction I-Disease 1
due O 0
to O 0
accidental O 0
iatrogenic O 0
epinephrine B-Chemical 1
overdose B-Disease 1
. O 0

Catecholamine B-Chemical 1
- O 0
induced O 0
cardiomyopathy B-Disease 1
due O 0
to O 0
chronic O 0
excess O 0
of O 0
endogenous O 0
catecholamines B-Chemical 1
has O 0
been O 0
recognized O 0
for O 0
decades O 0
as O 0
a O 0
clinical O 0
phenomenon O 0
. O 0

In O 0
contrast O 0
, O 0
reports O 0
of O 0
myocardial B-Disease 1
dysfunction I-Disease 1
due O 0
to O 0
acute O 0
iatrogenic O 0
overdose B-Disease 1
are O 0
rare O 0
. O 0

A O 0
35 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
whose O 0
cervix O 0
uteri O 0
was O 0
inadvertently O 0
injected O 0
with O 0
8 O 0
mg O 0
of O 0
epinephrine B-Chemical 1
developed O 0
myocardial B-Disease 1
stunning I-Disease 1
that O 0
was O 0
characterized O 0
by O 0
severe O 0
hemodynamic O 0
compromise O 0
, O 0
profound O 0
, O 0
albeit O 0
transient O 0
, O 0
left B-Disease 1
ventricular I-Disease 1
systolic I-Disease 1
and I-Disease 1
diastolic I-Disease 1
dysfunction I-Disease 1
, O 0
and O 0
only O 0
modestly O 0
elevated O 0
biochemical O 0
markers O 0
of O 0
myocardial B-Disease 1
necrosis I-Disease 1
. O 0

Our O 0
case O 0
illustrates O 0
the O 0
serious O 0
consequences O 0
of O 0
medical O 0
errors O 0
that O 0
can O 0
be O 0
avoided O 0
through O 0
improved O 0
medication O 0
labeling O 0
and O 0
staff O 0
supervision O 0
. O 0

Cardioprotective O 0
effect O 0
of O 0
tincture B-Chemical 1
of I-Chemical 1
Crataegus I-Chemical 1
on O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

Tincture B-Chemical 1
of I-Chemical 1
Crataegus I-Chemical 1
( O 0
TCR B-Chemical 1
) O 0
, O 0
an O 0
alcoholic B-Chemical 1
extract I-Chemical 1
of I-Chemical 1
the I-Chemical 1
berries I-Chemical 1
of I-Chemical 1
hawthorn I-Chemical 1
( O 0
Crataegus B-Chemical 1
oxycantha I-Chemical 1
) O 0
, O 0
is O 0
used O 0
in O 0
herbal O 0
and O 0
homeopathic O 0
medicine O 0
. O 0

The O 0
present O 0
study O 0
was O 0
done O 0
to O 0
investigate O 0
the O 0
protective O 0
effect O 0
of O 0
TCR B-Chemical 1
on O 0
experimentally O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

Pretreatment O 0
of O 0
TCR B-Chemical 1
, O 0
at O 0
a O 0
dose O 0
of O 0
0 O 0
. O 0
5 O 0
mL O 0
/ O 0
100 O 0
g O 0
bodyweight O 0
per O 0
day O 0
, O 0
orally O 0
for O 0
30 O 0
days O 0
, O 0
prevented O 0
the O 0
increase O 0
in O 0
lipid O 0
peroxidation O 0
and O 0
activity O 0
of O 0
marker O 0
enzymes O 0
observed O 0
in O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
rats O 0
( O 0
85 O 0
mg O 0
kg O 0
( O 0
- O 0
1 O 0
) O 0
s O 0
. O 0
c O 0
. O 0
for O 0
2 O 0
days O 0
at O 0
an O 0
interval O 0
of O 0
24 O 0
h O 0
) O 0
. O 0

TCR B-Chemical 1
prevented O 0
the O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
decrease O 0
in O 0
antioxidant O 0
enzymes O 0
in O 0
the O 0
heart O 0
and O 0
increased O 0
the O 0
rate O 0
of O 0
ADP B-Chemical 1
- O 0
stimulated O 0
oxygen B-Chemical 1
uptake O 0
and O 0
respiratory O 0
coupling O 0
ratio O 0
. O 0

TCR B-Chemical 1
protected O 0
against O 0
pathological O 0
changes O 0
induced O 0
by O 0
isoproterenol B-Chemical 1
in O 0
rat O 0
heart O 0
. O 0

The O 0
results O 0
show O 0
that O 0
pretreatment O 0
with O 0
TCR B-Chemical 1
may O 0
be O 0
useful O 0
in O 0
preventing O 0
the O 0
damage O 0
induced O 0
by O 0
isoproterenol B-Chemical 1
in O 0
rat O 0
heart O 0
. O 0

Treatment O 0
of O 0
tinnitus B-Disease 1
by O 0
intratympanic O 0
instillation O 0
of O 0
lignocaine B-Chemical 1
( O 0
lidocaine B-Chemical 1
) O 0
2 O 0
per O 0
cent O 0
through O 0
ventilation O 0
tubes O 0
. O 0

Idiopathic B-Disease 1
subjective I-Disease 1
tinnitus I-Disease 1
( O 0
IST B-Disease 1
) O 0
is O 0
one O 0
of O 0
the O 0
most O 0
obscure O 0
otological O 0
pathologies O 0
. O 0

This O 0
paper O 0
presents O 0
the O 0
results O 0
of O 0
treating O 0
IST B-Disease 1
by O 0
intratympanic O 0
instillation O 0
of O 0
lignocaine B-Chemical 1
( O 0
lidocaine B-Chemical 1
) O 0
2 O 0
per O 0
cent O 0
through O 0
a O 0
grommet O 0
, O 0
for O 0
five O 0
weekly O 0
courses O 0
. O 0

Fifty O 0
- O 0
two O 0
patients O 0
suffering O 0
from O 0
intractable O 0
tinnitus B-Disease 1
entered O 0
this O 0
therapeutic O 0
trial O 0
, O 0
but O 0
only O 0
nine O 0
finished O 0
all O 0
five O 0
courses O 0
. O 0

In O 0
one O 0
patient O 0
, O 0
the O 0
tinnitus B-Disease 1
was O 0
almost O 0
completely O 0
abolished O 0
, O 0
but O 0
in O 0
all O 0
the O 0
nine O 0
patients O 0
the O 0
decompensated O 0
tinnitus B-Disease 1
changed O 0
to O 0
a O 0
compensated O 0
one O 0
. O 0

We O 0
suggest O 0
this O 0
mode O 0
of O 0
treatment O 0
for O 0
patients O 0
that O 0
were O 0
previously O 0
treated O 0
by O 0
drugs O 0
, O 0
acupuncture O 0
and O 0
biofeedback O 0
, O 0
with O 0
disappointing O 0
results O 0
. O 0

Patients O 0
should O 0
be O 0
warned O 0
about O 0
the O 0
side O 0
effects O 0
of O 0
vertigo B-Disease 1
and O 0
vomiting B-Disease 1
, O 0
which O 0
subsides O 0
gradually O 0
with O 0
every O 0
new O 0
instillation O 0
, O 0
and O 0
that O 0
the O 0
tinnitus B-Disease 1
may O 0
not O 0
disappear O 0
but O 0
will O 0
be O 0
alleviated O 0
, O 0
enabling O 0
them O 0
to O 0
cope O 0
more O 0
easily O 0
with O 0
the O 0
disease O 0
and O 0
lead O 0
a O 0
more O 0
normal O 0
life O 0
. O 0

The O 0
alpha3 O 0
and O 0
beta4 O 0
nicotinic O 0
acetylcholine B-Chemical 1
receptor O 0
subunits O 0
are O 0
necessary O 0
for O 0
nicotine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
and O 0
hypolocomotion B-Disease 1
in O 0
mice O 0
. O 0

Binding O 0
of O 0
nicotine B-Chemical 1
to O 0
nicotinic O 0
acetylcholine B-Chemical 1
receptors O 0
( O 0
nAChRs O 0
) O 0
elicits O 0
a O 0
series O 0
of O 0
dose O 0
- O 0
dependent O 0
behaviors O 0
that O 0
go O 0
from O 0
altered O 0
exploration O 0
, O 0
sedation O 0
, O 0
and O 0
tremors B-Disease 1
, O 0
to O 0
seizures B-Disease 1
and O 0
death B-Disease 1
. O 0

nAChRs O 0
are O 0
pentameric O 0
ion O 0
channels O 0
usually O 0
composed O 0
of O 0
alpha O 0
and O 0
beta O 0
subunits O 0
. O 0

A O 0
gene O 0
cluster O 0
comprises O 0
the O 0
alpha3 O 0
, O 0
alpha5 O 0
and O 0
beta4 O 0
subunits O 0
, O 0
which O 0
coassemble O 0
to O 0
form O 0
functional O 0
receptors O 0
. O 0

We O 0
examined O 0
the O 0
role O 0
of O 0
the O 0
beta4 O 0
subunits O 0
in O 0
nicotine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
and O 0
hypolocomotion B-Disease 1
in O 0
beta4 O 0
homozygous O 0
null O 0
( O 0
beta4 O 0
- O 0
/ O 0
- O 0
) O 0
and O 0
alpha3 O 0
heterozygous O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
mice O 0
. O 0

beta4 O 0
- O 0
/ O 0
- O 0
mice O 0
were O 0
less O 0
sensitive O 0
to O 0
the O 0
effects O 0
of O 0
nicotine B-Chemical 1
both O 0
at O 0
low O 0
doses O 0
, O 0
measured O 0
as O 0
decreased O 0
exploration O 0
in O 0
an O 0
open O 0
field O 0
, O 0
and O 0
at O 0
high O 0
doses O 0
, O 0
measured O 0
as O 0
sensitivity O 0
to O 0
nicotine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
. O 0

Using O 0
in O 0
situ O 0
hybridization O 0
probes O 0
for O 0
the O 0
alpha3 O 0
and O 0
alpha5 O 0
subunits O 0
, O 0
we O 0
showed O 0
that O 0
alpha5 O 0
mRNA O 0
levels O 0
are O 0
unchanged O 0
, O 0
whereas O 0
alpha3 O 0
mRNA O 0
levels O 0
are O 0
selectively O 0
decreased O 0
in O 0
the O 0
mitral O 0
cell O 0
layer O 0
of O 0
the O 0
olfactory O 0
bulb O 0
, O 0
and O 0
the O 0
inferior O 0
and O 0
the O 0
superior O 0
colliculus O 0
of O 0
beta4 O 0
- O 0
/ O 0
- O 0
brains O 0
. O 0

alpha3 O 0
+ O 0
/ O 0
- O 0
mice O 0
were O 0
partially O 0
resistant O 0
to O 0
nicotine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
when O 0
compared O 0
to O 0
wild O 0
- O 0
type O 0
littermates O 0
. O 0

mRNA O 0
levels O 0
for O 0
the O 0
alpha5 O 0
and O 0
the O 0
beta4 O 0
subunits O 0
were O 0
unchanged O 0
in O 0
alpha3 O 0
+ O 0
/ O 0
- O 0
brains O 0
. O 0

Together O 0
, O 0
these O 0
results O 0
suggest O 0
that O 0
the O 0
beta4 O 0
and O 0
the O 0
alpha3 O 0
subunits O 0
are O 0
mediators O 0
of O 0
nicotine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
and O 0
hypolocomotion B-Disease 1
. O 0

The O 0
effects O 0
of O 0
sevoflurane B-Chemical 1
on O 0
lidocaine B-Chemical 1
- O 0
induced O 0
convulsions B-Disease 1
. O 0

The O 0
influence O 0
of O 0
sevoflurane B-Chemical 1
on O 0
lidocaine B-Chemical 1
- O 0
induced O 0
convulsions B-Disease 1
was O 0
studied O 0
in O 0
cats O 0
. O 0

The O 0
convulsive B-Disease 1
threshold O 0
( O 0
mean O 0
+ O 0
/ O 0
- O 0
SD O 0
) O 0
was O 0
41 O 0
. O 0
4 O 0
+ O 0
/ O 0
- O 0
6 O 0
. O 0
5 O 0
mg O 0
. O 0

l O 0
( O 0
- O 0
1 O 0
) O 0
with O 0
lidocaine B-Chemical 1
infusion O 0
( O 0
6 O 0
mg O 0
. O 0
kg O 0
( O 0
- O 0
1 O 0
) O 0
. O 0
min O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
, O 0
increasing O 0
significantly O 0
to O 0
66 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
10 O 0
. O 0
9 O 0
mg O 0
. O 0

l O 0
( O 0
- O 0
1 O 0
) O 0
when O 0
the O 0
end O 0
- O 0
tidal O 0
concentration O 0
of O 0
sevoflurane B-Chemical 1
was O 0
0 O 0
. O 0
8 O 0
% O 0
. O 0

However O 0
, O 0
the O 0
threshold O 0
( O 0
61 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
8 O 0
. O 0
7 O 0
mg O 0
. O 0
l O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
during O 0
1 O 0
. O 0
6 O 0
% O 0
sevoflurane B-Chemical 1
was O 0
not O 0
significant O 0
from O 0
that O 0
during O 0
0 O 0
. O 0
8 O 0
% O 0
sevoflurane B-Chemical 1
, O 0
indicating O 0
a O 0
celling O 0
effect O 0
. O 0

There O 0
was O 0
no O 0
significant O 0
difference O 0
in O 0
the O 0
convulsive B-Disease 1
threshold O 0
between O 0
sevoflurane B-Chemical 1
and O 0
enflurane B-Chemical 1
. O 0

The O 0
rise O 0
in O 0
blood O 0
pressure O 0
became O 0
less O 0
marked O 0
when O 0
higher O 0
concentrations O 0
of O 0
sevoflurane B-Chemical 1
or O 0
enflurane B-Chemical 1
were O 0
administered O 0
and O 0
the O 0
blood O 0
pressure O 0
at O 0
convulsions B-Disease 1
decreased O 0
significantly O 0
in O 0
1 O 0
. O 0
6 O 0
% O 0
sevoflurane B-Chemical 1
, O 0
and O 0
in O 0
0 O 0
. O 0
8 O 0
% O 0
and O 0
1 O 0
. O 0
6 O 0
% O 0
enflurane B-Chemical 1
. O 0

However O 0
, O 0
there O 0
was O 0
no O 0
significant O 0
difference O 0
in O 0
the O 0
lidocaine B-Chemical 1
concentrations O 0
measured O 0
when O 0
the O 0
systolic O 0
blood O 0
pressure O 0
became O 0
70 O 0
mmHg O 0
. O 0

Apamin B-Chemical 1
, O 0
a O 0
selective O 0
blocker O 0
of O 0
calcium B-Chemical 1
- O 0
dependent O 0
potassium B-Chemical 1
channels O 0
, O 0
was O 0
administered O 0
intracerebroventricularly O 0
in O 0
rats O 0
anesthetized O 0
with O 0
0 O 0
. O 0
8 O 0
% O 0
sevoflurane B-Chemical 1
to O 0
investigate O 0
the O 0
mechanism O 0
of O 0
the O 0
anticonvulsive O 0
effects O 0
. O 0

Apamin B-Chemical 1
( O 0
10 O 0
ng O 0
) O 0
had O 0
a O 0
tendency O 0
to O 0
decrease O 0
the O 0
convulsive B-Disease 1
threshold O 0
( O 0
21 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
2 O 0
to O 0
19 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
5 O 0
mg O 0
. O 0
l O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
but O 0
this O 0
was O 0
not O 0
statistically O 0
significant O 0
. O 0

It O 0
is O 0
suggested O 0
that O 0
sevoflurane B-Chemical 1
reduces O 0
the O 0
convulsive B-Disease 1
effect O 0
of O 0
lidocaine B-Chemical 1
toxicity B-Disease 1
but O 0
carries O 0
some O 0
risk O 0
due O 0
to O 0
circulatory O 0
depression B-Disease 1
. O 0

Cardiac B-Disease 1
toxicity I-Disease 1
observed O 0
in O 0
association O 0
with O 0
high O 0
- O 0
dose O 0
cyclophosphamide B-Chemical 1
- O 0
based O 0
chemotherapy O 0
for O 0
metastatic O 0
breast B-Disease 1
cancer I-Disease 1
. O 0

INTRODUCTION O 0
: O 0
Cyclophosphamide B-Chemical 1
is O 0
an O 0
alkylating O 0
agent O 0
given O 0
frequently O 0
as O 0
a O 0
component O 0
of O 0
many O 0
conditioning O 0
regimens O 0
. O 0

In O 0
high O 0
doses O 0
, O 0
its O 0
nonhematological O 0
dose O 0
- O 0
limiting O 0
toxicity B-Disease 1
is O 0
cardiomyopathy B-Disease 1
. O 0

STUDY O 0
DESIGN O 0
: O 0
We O 0
combined O 0
paclitaxel B-Chemical 1
, O 0
melphalan B-Chemical 1
and O 0
high O 0
- O 0
dose O 0
cyclophosphamide B-Chemical 1
, O 0
thiotepa B-Chemical 1
, O 0
and O 0
carboplatin B-Chemical 1
in O 0
a O 0
triple O 0
sequential O 0
high O 0
- O 0
dose O 0
regimen O 0
for O 0
patients O 0
with O 0
metastatic O 0
breast B-Disease 1
cancer I-Disease 1
. O 0

Analysis O 0
was O 0
performed O 0
on O 0
61 O 0
women O 0
with O 0
chemotherapy O 0
- O 0
responsive O 0
metastatic O 0
breast B-Disease 1
cancer I-Disease 1
receiving O 0
96 O 0
- O 0
h O 0
infusional O 0
cyclophosphamide B-Chemical 1
as O 0
part O 0
of O 0
a O 0
triple O 0
sequential O 0
high O 0
- O 0
dose O 0
regimen O 0
to O 0
assess O 0
association O 0
between O 0
presence O 0
of O 0
peritransplant O 0
congestive B-Disease 1
heart I-Disease 1
failure I-Disease 1
( O 0
CHF B-Disease 1
) O 0
and O 0
the O 0
following O 0
pretreatment O 0
characteristics O 0
: O 0
presence O 0
of O 0
electrocardiogram O 0
( O 0
EKG O 0
) O 0
abnormalities O 0
, O 0
age O 0
, O 0
hypertension B-Disease 1
, O 0
prior O 0
cardiac O 0
history O 0
, O 0
smoking O 0
, O 0
diabetes B-Disease 1
mellitus I-Disease 1
, O 0
prior O 0
use O 0
of O 0
anthracyclines B-Chemical 1
, O 0
and O 0
left O 0
- O 0
sided O 0
chest O 0
irradiation O 0
. O 0

RESULTS O 0
: O 0
Six O 0
of O 0
61 O 0
women O 0
( O 0
10 O 0
% O 0
) O 0
developed O 0
clinically O 0
reversible O 0
grade O 0
3 O 0
CHF B-Disease 1
following O 0
infusional O 0
cyclophosphamide B-Chemical 1
with O 0
a O 0
median O 0
percent O 0
decline O 0
in O 0
ejection O 0
fraction O 0
of O 0
31 O 0
% O 0
. O 0

Incidence O 0
of O 0
transient O 0
cyclophosphamide B-Chemical 1
- O 0
related O 0
cardiac B-Disease 1
toxicity I-Disease 1
( O 0
10 O 0
% O 0
) O 0
is O 0
comparable O 0
to O 0
previous O 0
recorded O 0
literature O 0
. O 0

Older O 0
age O 0
was O 0
significantly O 0
correlated O 0
with O 0
the O 0
CHF B-Disease 1
development O 0
; O 0
with O 0
median O 0
ages O 0
for O 0
the O 0
entire O 0
group O 0
and O 0
for O 0
patients O 0
developing O 0
CHF B-Disease 1
of O 0
45 O 0
and O 0
59 O 0
, O 0
respectively O 0
. O 0

No O 0
association O 0
was O 0
found O 0
with O 0
other O 0
pretreatment O 0
characteristics O 0
. O 0

CONCLUSIONS O 0
: O 0
As O 0
a O 0
result O 0
of O 0
these O 0
findings O 0
, O 0
oncologists O 0
should O 0
carefully O 0
monitor O 0
fluid O 0
balance O 0
in O 0
older O 0
patients O 0
. O 0

Routine O 0
EKG O 0
monitoring O 0
during O 0
infusional O 0
cyclophosphamide B-Chemical 1
did O 0
not O 0
predict O 0
CHF B-Disease 1
development O 0
. O 0

Tremor B-Disease 1
side O 0
effects O 0
of O 0
salbutamol B-Chemical 1
, O 0
quantified O 0
by O 0
a O 0
laser O 0
pointer O 0
technique O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
study O 0
tremor B-Disease 1
side O 0
effects O 0
of O 0
salbutamol B-Chemical 1
an O 0
easily O 0
applicable O 0
, O 0
quick O 0
and O 0
low O 0
- O 0
priced O 0
method O 0
is O 0
needed O 0
. O 0

A O 0
new O 0
method O 0
using O 0
a O 0
commercially O 0
available O 0
, O 0
pen O 0
- O 0
shaped O 0
laser O 0
pointer O 0
was O 0
developed O 0
. O 0

Aim O 0
of O 0
the O 0
study O 0
was O 0
to O 0
determine O 0
sensitivity O 0
, O 0
reproducibility O 0
, O 0
reference O 0
values O 0
and O 0
the O 0
agreement O 0
with O 0
a O 0
questionnaire O 0
. O 0

METHODS O 0
: O 0
Tremor B-Disease 1
was O 0
measured O 0
using O 0
a O 0
laser O 0
pointer O 0
technique O 0
. O 0

To O 0
determine O 0
sensitivity O 0
we O 0
assessed O 0
tremor B-Disease 1
in O 0
44 O 0
patients O 0
with O 0
obstructive B-Disease 1
lung I-Disease 1
disease I-Disease 1
after O 0
administration O 0
of O 0
cumulative O 0
doses O 0
of O 0
salbutamol B-Chemical 1
. O 0

Subjects O 0
were O 0
asked O 0
to O 0
aim O 0
at O 0
the O 0
centre O 0
of O 0
a O 0
target O 0
, O 0
subdivided O 0
in O 0
concentric O 0
circles O 0
, O 0
from O 0
5 O 0
m O 0
distance O 0
. O 0

The O 0
circle O 0
in O 0
which O 0
the O 0
participant O 0
succeeded O 0
to O 0
aim O 0
was O 0
recorded O 0
in O 0
millimetres O 0
radius O 0
. O 0

In O 0
another O 0
series O 0
of O 0
measurements O 0
, O 0
reproducibility O 0
and O 0
reference O 0
values O 0
of O 0
the O 0
tremor B-Disease 1
was O 0
assessed O 0
in O 0
65 O 0
healthy O 0
subjects O 0
in O 0
three O 0
sessions O 0
, O 0
at O 0
9 O 0
a O 0
. O 0
m O 0
. O 0
, O 0
4 O 0
p O 0
. O 0
m O 0
. O 0
and O 0
9 O 0
a O 0
. O 0
m O 0
. O 0
, O 0
respectively O 0
, O 0
1 O 0
week O 0
later O 0
. O 0

Postural O 0
tremor B-Disease 1
was O 0
measured O 0
with O 0
the O 0
arm O 0
horizontally O 0
outstretched O 0
rest O 0
tremor B-Disease 1
with O 0
the O 0
arm O 0
supported O 0
by O 0
an O 0
armrest O 0
and O 0
finally O 0
tremor B-Disease 1
was O 0
measured O 0
after O 0
holding O 0
a O 0
2 O 0
- O 0
kg O 0
weight O 0
until O 0
exhaustion O 0
. O 0

Inter O 0
- O 0
observer O 0
variability O 0
was O 0
measured O 0
in O 0
a O 0
series O 0
of O 0
10 O 0
healthy O 0
subjects O 0
. O 0

Tremor B-Disease 1
was O 0
measured O 0
simultaneously O 0
by O 0
two O 0
independent O 0
observers O 0
. O 0

RESULTS O 0
: O 0
Salbutamol B-Chemical 1
significantly O 0
increased O 0
tremor B-Disease 1
severity O 0
in O 0
patients O 0
in O 0
a O 0
dose O 0
- O 0
dependent O 0
way O 0
. O 0

Within O 0
healthy O 0
adults O 0
no O 0
age O 0
- O 0
dependency O 0
could O 0
be O 0
found O 0
( O 0
b O 0
= O 0
0 O 0
. O 0
262 O 0
mm O 0
/ O 0
year O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
72 O 0
) O 0
. O 0

There O 0
was O 0
no O 0
agreement O 0
between O 0
the O 0
questionnaire O 0
and O 0
tremor B-Disease 1
severity O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
093 O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
53 O 0
) O 0
. O 0

Postural O 0
tremor B-Disease 1
showed O 0
no O 0
significant O 0
difference O 0
between O 0
the O 0
first O 0
and O 0
third O 0
session O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
07 O 0
) O 0
. O 0

Support O 0
of O 0
the O 0
arm O 0
decreased O 0
tremor B-Disease 1
severity O 0
, O 0
exhaustion O 0
increased O 0
tremor B-Disease 1
severity O 0
significantly O 0
. O 0

A O 0
good O 0
agreement O 0
was O 0
found O 0
between O 0
two O 0
independent O 0
observers O 0
( O 0
interclass O 0
correlation O 0
coefficient O 0
0 O 0
. O 0
72 O 0
) O 0
. O 0

DISCUSSION O 0
: O 0
Quantifying O 0
tremor B-Disease 1
by O 0
using O 0
an O 0
inexpensive O 0
laser O 0
pointer O 0
is O 0
, O 0
with O 0
the O 0
exception O 0
of O 0
children O 0
( O 0
< O 0
12 O 0
years O 0
) O 0
a O 0
sensitive O 0
and O 0
reproducible O 0
method O 0
. O 0

Safety O 0
and O 0
adverse O 0
effects O 0
associated O 0
with O 0
raloxifene B-Chemical 1
: O 0
multiple O 0
outcomes O 0
of O 0
raloxifene B-Chemical 1
evaluation O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
examine O 0
the O 0
effect O 0
of O 0
raloxifene B-Chemical 1
on O 0
major O 0
adverse O 0
events O 0
that O 0
occur O 0
with O 0
postmenopausal O 0
estrogen B-Chemical 1
therapy O 0
or O 0
tamoxifen B-Chemical 1
. O 0

METHODS O 0
: O 0
The O 0
Multiple O 0
Outcomes O 0
of O 0
Raloxifene B-Chemical 1
Evaluation O 0
, O 0
a O 0
multicenter O 0
, O 0
randomized O 0
, O 0
double O 0
- O 0
blind O 0
trial O 0
, O 0
enrolled O 0
7 O 0
, O 0
705 O 0
postmenopausal O 0
women O 0
with O 0
osteoporosis B-Disease 1
. O 0

Women O 0
were O 0
randomly O 0
assigned O 0
to O 0
raloxifene B-Chemical 1
60 O 0
mg O 0
/ O 0
d O 0
or O 0
120 O 0
mg O 0
/ O 0
d O 0
or O 0
placebo O 0
. O 0

Outcomes O 0
included O 0
venous B-Disease 1
thromboembolism I-Disease 1
, O 0
cataracts B-Disease 1
, O 0
gallbladder B-Disease 1
disease I-Disease 1
, O 0
and O 0
endometrial B-Disease 1
hyperplasia I-Disease 1
or I-Disease 1
cancer I-Disease 1
. O 0

RESULTS O 0
: O 0
During O 0
a O 0
mean O 0
follow O 0
- O 0
up O 0
of O 0
3 O 0
. O 0
3 O 0
years O 0
, O 0
raloxifene B-Chemical 1
was O 0
associated O 0
with O 0
an O 0
increased O 0
risk O 0
for O 0
venous B-Disease 1
thromboembolism I-Disease 1
( O 0
relative O 0
risk O 0
[ O 0
RR O 0
] O 0
2 O 0
. O 0
1 O 0
; O 0
95 O 0
% O 0
confidence O 0
interval O 0
[ O 0
CI O 0
] O 0
1 O 0
. O 0
2 O 0
- O 0
3 O 0
. O 0
8 O 0
) O 0
. O 0

The O 0
excess O 0
event O 0
rate O 0
was O 0
1 O 0
. O 0
8 O 0
per O 0
1 O 0
, O 0
000 O 0
woman O 0
- O 0
years O 0
( O 0
95 O 0
% O 0
CI O 0
- O 0
0 O 0
. O 0
5 O 0
- O 0
4 O 0
. O 0
1 O 0
) O 0
, O 0
and O 0
the O 0
number O 0
needed O 0
to O 0
treat O 0
to O 0
cause O 0
1 O 0
event O 0
was O 0
170 O 0
( O 0
95 O 0
% O 0
CI O 0
100 O 0
- O 0
582 O 0
) O 0
over O 0
3 O 0
. O 0
3 O 0
years O 0
. O 0

Risk O 0
in O 0
the O 0
raloxifene B-Chemical 1
group O 0
was O 0
higher O 0
than O 0
in O 0
the O 0
placebo O 0
group O 0
for O 0
the O 0
first O 0
2 O 0
years O 0
, O 0
but O 0
decreased O 0
to O 0
about O 0
the O 0
same O 0
rate O 0
as O 0
in O 0
the O 0
placebo O 0
group O 0
thereafter O 0
. O 0

Raloxifene B-Chemical 1
did O 0
not O 0
increase O 0
risk O 0
for O 0
cataracts B-Disease 1
( O 0
RR O 0
0 O 0
. O 0
9 O 0
; O 0
95 O 0
% O 0
CI O 0
0 O 0
. O 0
8 O 0
- O 0
1 O 0
. O 0
1 O 0
) O 0
, O 0
gallbladder B-Disease 1
disease I-Disease 1
( O 0
RR O 0
1 O 0
. O 0
0 O 0
; O 0
95 O 0
% O 0
CI O 0
0 O 0
. O 0
7 O 0
- O 0
1 O 0
. O 0
3 O 0
) O 0
, O 0
endometrial B-Disease 1
hyperplasia I-Disease 1
( O 0
RR O 0
1 O 0
. O 0
3 O 0
; O 0
95 O 0
% O 0
CI O 0
0 O 0
. O 0
4 O 0
- O 0
5 O 0
. O 0
1 O 0
) O 0
, O 0
or O 0
endometrial B-Disease 1
cancer I-Disease 1
( O 0
RR O 0
0 O 0
. O 0
9 O 0
; O 0
95 O 0
% O 0
CI O 0
0 O 0
. O 0
3 O 0
- O 0
2 O 0
. O 0
7 O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
Raloxifene B-Chemical 1
was O 0
associated O 0
with O 0
an O 0
increased O 0
risk O 0
for O 0
venous B-Disease 1
thromboembolism I-Disease 1
, O 0
but O 0
there O 0
was O 0
no O 0
increased O 0
risk O 0
for O 0
cataracts B-Disease 1
, O 0
gallbladder B-Disease 1
disease I-Disease 1
, O 0
endometrial B-Disease 1
hyperplasia I-Disease 1
, O 0
or O 0
endometrial B-Disease 1
cancer I-Disease 1
. O 0

LEVEL O 0
OF O 0
EVIDENCE O 0
: O 0
I O 0

Optimization O 0
of O 0
levodopa B-Chemical 1
therapy O 0
. O 0

While O 0
there O 0
is O 0
no O 0
single O 0
correct O 0
starting O 0
dose O 0
for O 0
levodopa B-Chemical 1
therapy O 0
, O 0
many O 0
individuals O 0
can O 0
be O 0
started O 0
on O 0
either O 0
the O 0
25 O 0
/ O 0
100 O 0
or O 0
controlled O 0
- O 0
release O 0
formula O 0
, O 0
following O 0
the O 0
general O 0
rule O 0
not O 0
to O 0
attempt O 0
to O 0
titrate O 0
carbidopa B-Chemical 1
- O 0
levodopa B-Chemical 1
to O 0
the O 0
point O 0
of O 0
" O 0
normality O 0
, O 0
" O 0
which O 0
can O 0
lead O 0
to O 0
toxicity B-Disease 1
. O 0

The O 0
physician O 0
should O 0
also O 0
determine O 0
the O 0
proper O 0
use O 0
of O 0
any O 0
adjunctive O 0
medications O 0
; O 0
such O 0
combined O 0
therapy O 0
has O 0
become O 0
the O 0
standard O 0
approach O 0
to O 0
treatment O 0
. O 0

Following O 0
the O 0
initial O 0
period O 0
of O 0
therapy O 0
, O 0
emerging O 0
difficulties O 0
require O 0
a O 0
reassessment O 0
of O 0
therapeutic O 0
approaches O 0
, O 0
such O 0
as O 0
dosage O 0
adjustment O 0
or O 0
introduction O 0
of O 0
a O 0
dopamine B-Chemical 1
agonist O 0
. O 0

Other O 0
possible O 0
adverse O 0
effects O 0
- O 0
- O 0
such O 0
as O 0
gastrointestinal B-Disease 1
disorders I-Disease 1
, O 0
orthostatic B-Disease 1
hypotension I-Disease 1
, O 0
levodopa B-Chemical 1
- O 0
induced O 0
psychosis B-Disease 1
, O 0
sleep B-Disease 1
disturbances I-Disease 1
or O 0
parasomnias B-Disease 1
, O 0
or O 0
drug O 0
interactions O 0
- O 0
- O 0
also O 0
require O 0
carefully O 0
monitored O 0
individual O 0
treatment O 0
. O 0

Nonpharmacologic O 0
concerns O 0
can O 0
help O 0
the O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
patient O 0
achieve O 0
and O 0
maintain O 0
optimal O 0
functioning O 0
, O 0
including O 0
daily O 0
exercise O 0
, O 0
physical O 0
therapy O 0
, O 0
and O 0
involvement O 0
with O 0
support O 0
groups O 0
. O 0

Long O 0
term O 0
audiological O 0
evaluation O 0
of O 0
beta B-Disease 1
- I-Disease 1
thalassemic I-Disease 1
patients O 0
. O 0

OBJECTIVE O 0
: O 0
The O 0
objective O 0
of O 0
this O 0
study O 0
was O 0
to O 0
identify O 0
the O 0
incidence O 0
and O 0
to O 0
monitor O 0
the O 0
progression O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
in O 0
children O 0
and O 0
young O 0
adults O 0
with O 0
beta B-Disease 1
- I-Disease 1
thalassemia I-Disease 1
major O 0
. O 0

METHODS O 0
: O 0
One O 0
hundred O 0
and O 0
four O 0
( O 0
104 O 0
) O 0
patients O 0
aged O 0
6 O 0
- O 0
35 O 0
years O 0
( O 0
mean O 0
17 O 0
, O 0
2 O 0
years O 0
) O 0
participated O 0
in O 0
the O 0
study O 0
. O 0

All O 0
patients O 0
were O 0
on O 0
a O 0
regular O 0
transfusion O 0
- O 0
chelation O 0
program O 0
maintaining O 0
a O 0
mean O 0
hemoglobin O 0
level O 0
of O 0
9 O 0
. O 0
5 O 0
gr O 0
/ O 0
dl O 0
. O 0

Subjects O 0
were O 0
receiving O 0
desferrioxamine B-Chemical 1
( O 0
DFO B-Chemical 1
) O 0
chelation O 0
treatment O 0
with O 0
a O 0
mean O 0
daily O 0
dose O 0
of O 0
50 O 0
- O 0
60 O 0
mg O 0
/ O 0
kg O 0
, O 0
5 O 0
- O 0
6 O 0
days O 0
a O 0
week O 0
during O 0
the O 0
first O 0
six O 0
years O 0
of O 0
the O 0
study O 0
, O 0
which O 0
was O 0
then O 0
reduced O 0
to O 0
40 O 0
- O 0
50 O 0
mg O 0
/ O 0
kg O 0
for O 0
the O 0
following O 0
eight O 0
years O 0
. O 0

Patients O 0
were O 0
followed O 0
for O 0
8 O 0
- O 0
14 O 0
years O 0
. O 0

RESULTS O 0
: O 0
Overall O 0
, O 0
21 O 0
out O 0
of O 0
104 O 0
patients O 0
( O 0
20 O 0
. O 0
2 O 0
% O 0
) O 0
presented O 0
with O 0
high O 0
frequency O 0
sensorineural B-Disease 1
hearing I-Disease 1
loss I-Disease 1
( O 0
SNHL B-Disease 1
) O 0
, O 0
either O 0
unilateral O 0
or O 0
bilateral O 0
. O 0

No O 0
ototoxic B-Disease 1
factor O 0
, O 0
other O 0
than O 0
DFO B-Chemical 1
, O 0
was O 0
present O 0
in O 0
any O 0
of O 0
the O 0
patients O 0
. O 0

Patients O 0
with O 0
SNHL B-Disease 1
presented O 0
with O 0
relatively O 0
lower O 0
serum O 0
ferritin O 0
levels O 0
than O 0
those O 0
with O 0
normal O 0
hearing O 0
, O 0
however O 0
, O 0
no O 0
statistically O 0
significant O 0
difference O 0
was O 0
observed O 0
. O 0

Subjects O 0
with O 0
SNHL B-Disease 1
were O 0
submitted O 0
to O 0
DFO B-Chemical 1
reduction O 0
or O 0
temporary O 0
withdrawal O 0
. O 0

Following O 0
intervention O 0
, O 0
7 O 0
out O 0
of O 0
21 O 0
affected O 0
patients O 0
recovered O 0
, O 0
10 O 0
remained O 0
stable O 0
and O 0
4 O 0
demonstrated O 0
aggravation O 0
. O 0

CONCLUSION O 0
: O 0
The O 0
findings O 0
are O 0
indicative O 0
of O 0
DFO B-Chemical 1
' O 0
s O 0
contributing O 0
role O 0
in O 0
the O 0
development O 0
of O 0
hearing B-Disease 1
impairment I-Disease 1
. O 0

Regular O 0
audiologic O 0
evaluation O 0
is O 0
imperative O 0
in O 0
all O 0
thalassemic B-Disease 1
patients O 0
so O 0
that O 0
early O 0
changes O 0
may O 0
be O 0
recognized O 0
and O 0
treatment O 0
may O 0
be O 0
judiciously O 0
adjusted O 0
in O 0
order O 0
to O 0
prevent O 0
or O 0
reverse O 0
hearing B-Disease 1
impairment I-Disease 1
. O 0

Individual O 0
differences O 0
in O 0
renal O 0
ACE O 0
activity O 0
in O 0
healthy O 0
rats O 0
predict O 0
susceptibility O 0
to O 0
adriamycin B-Chemical 1
- O 0
induced O 0
renal B-Disease 1
damage I-Disease 1
. O 0

BACKGROUND O 0
: O 0
In O 0
man O 0
, O 0
differences O 0
in O 0
angiotensin B-Chemical 1
- O 0
converting O 0
enzyme O 0
( O 0
ACE O 0
) O 0
levels O 0
, O 0
related O 0
to O 0
ACE O 0
( O 0
I O 0
/ O 0
D O 0
) O 0
genotype O 0
, O 0
are O 0
associated O 0
with O 0
renal O 0
prognosis O 0
. O 0

This O 0
raises O 0
the O 0
hypothesis O 0
that O 0
individual O 0
differences O 0
in O 0
renal O 0
ACE O 0
activity O 0
are O 0
involved O 0
in O 0
renal O 0
susceptibility O 0
to O 0
inflicted O 0
damage O 0
. O 0

Therefore O 0
, O 0
we O 0
studied O 0
the O 0
predictive O 0
effect O 0
of O 0
renal O 0
ACE O 0
activity O 0
for O 0
the O 0
severity O 0
of O 0
renal B-Disease 1
damage I-Disease 1
induced O 0
by O 0
a O 0
single O 0
injection O 0
of O 0
adriamycin B-Chemical 1
in O 0
rats O 0
. O 0

METHODS O 0
: O 0
Renal O 0
ACE O 0
activity O 0
( O 0
Hip B-Chemical 1
- I-Chemical 1
His I-Chemical 1
- I-Chemical 1
Leu I-Chemical 1
cleavage O 0
by O 0
cortical O 0
homogenates O 0
) O 0
was O 0
determined O 0
by O 0
renal O 0
biopsy O 0
in O 0
27 O 0
adult O 0
male O 0
Wistar O 0
rats O 0
. O 0

After O 0
1 O 0
week O 0
of O 0
recovery O 0
, O 0
proteinuria B-Disease 1
was O 0
induced O 0
by O 0
adriamycin B-Chemical 1
[ O 0
1 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
intravenously O 0
( O 0
i O 0
. O 0
v O 0
. O 0
) O 0
n O 0
= O 0
18 O 0
; O 0
controls O 0
, O 0
saline O 0
i O 0
. O 0
v O 0
. O 0
n O 0
= O 0
9 O 0
] O 0
. O 0

Proteinuria B-Disease 1
was O 0
measured O 0
every O 0
2 O 0
weeks O 0
. O 0

After O 0
12 O 0
weeks O 0
, O 0
rats O 0
were O 0
sacrificed O 0
and O 0
their O 0
kidneys O 0
harvested O 0
. O 0

RESULTS O 0
: O 0
As O 0
anticipated O 0
, O 0
adriamycin B-Chemical 1
elicited O 0
nephrotic B-Disease 1
range O 0
proteinuria B-Disease 1
, O 0
renal B-Disease 1
interstitial I-Disease 1
damage I-Disease 1
and O 0
mild O 0
focal B-Disease 1
glomerulosclerosis I-Disease 1
. O 0

Baseline O 0
renal O 0
ACE O 0
positively O 0
correlated O 0
with O 0
the O 0
relative O 0
rise O 0
in O 0
proteinuria B-Disease 1
after O 0
adriamycin B-Chemical 1
( O 0
r O 0
= O 0
0 O 0
. O 0
62 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
, O 0
renal O 0
interstitial O 0
alpha O 0
- O 0
smooth O 0
muscle O 0
actin O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
49 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
interstitial O 0
macrophage O 0
influx O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
56 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
interstitial O 0
collagen O 0
III O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
53 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
glomerular O 0
alpha O 0
- O 0
smooth O 0
muscle O 0
actin O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
74 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
and O 0
glomerular O 0
desmin O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
48 O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Baseline O 0
renal O 0
ACE O 0
did O 0
not O 0
correlate O 0
with O 0
focal B-Disease 1
glomerulosclerosis I-Disease 1
( O 0
r O 0
= O 0
0 O 0
. O 0
22 O 0
, O 0
NS O 0
) O 0
. O 0

In O 0
controls O 0
, O 0
no O 0
predictive O 0
values O 0
for O 0
renal O 0
parameters O 0
were O 0
observed O 0
. O 0

CONCLUSION O 0
: O 0
Individual O 0
differences O 0
in O 0
renal O 0
ACE O 0
activity O 0
predict O 0
the O 0
severity O 0
of O 0
adriamycin B-Chemical 1
- O 0
induced O 0
renal B-Disease 1
damage I-Disease 1
in O 0
this O 0
outbred O 0
rat O 0
strain O 0
. O 0

This O 0
supports O 0
the O 0
assumption O 0
that O 0
differences O 0
in O 0
renal O 0
ACE O 0
activity O 0
predispose O 0
to O 0
a O 0
less O 0
favourable O 0
course O 0
of O 0
renal B-Disease 1
damage I-Disease 1
. O 0

Recurrent O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
induced O 0
by O 0
azithromycin B-Chemical 1
. O 0

A O 0
14 O 0
- O 0
year O 0
- O 0
old O 0
girl O 0
is O 0
reported O 0
with O 0
recurrent O 0
, O 0
azithromycin B-Chemical 1
- O 0
induced O 0
, O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
. O 0

The O 0
second O 0
episode O 0
was O 0
more O 0
severe O 0
than O 0
the O 0
first O 0
; O 0
and O 0
although O 0
both O 0
were O 0
treated O 0
with O 0
intensive O 0
corticosteroid O 0
therapy O 0
, O 0
renal O 0
function O 0
remained O 0
impaired O 0
. O 0

Although O 0
most O 0
cases O 0
of O 0
antibiotic O 0
induced O 0
acute O 0
interstitial B-Disease 1
nephritis I-Disease 1
are O 0
benign O 0
and O 0
self O 0
- O 0
limited O 0
, O 0
some O 0
patients O 0
are O 0
at O 0
risk O 0
for O 0
permanent O 0
renal B-Disease 1
injury I-Disease 1
. O 0

Spironolactone B-Chemical 1
- O 0
induced O 0
renal B-Disease 1
insufficiency I-Disease 1
and O 0
hyperkalemia B-Disease 1
in O 0
patients O 0
with O 0
heart B-Disease 1
failure I-Disease 1
. O 0

BACKGROUND O 0
: O 0
A O 0
previous O 0
randomized O 0
controlled O 0
trial O 0
evaluating O 0
the O 0
use O 0
of O 0
spironolactone B-Chemical 1
in O 0
heart B-Disease 1
failure I-Disease 1
patients O 0
reported O 0
a O 0
low O 0
risk O 0
of O 0
hyperkalemia B-Disease 1
( O 0
2 O 0
% O 0
) O 0
and O 0
renal B-Disease 1
insufficiency I-Disease 1
( O 0
0 O 0
% O 0
) O 0
. O 0

Because O 0
treatments O 0
for O 0
heart B-Disease 1
failure I-Disease 1
have O 0
changed O 0
since O 0
the O 0
benefits O 0
of O 0
spironolactone B-Chemical 1
were O 0
reported O 0
, O 0
the O 0
prevalence O 0
of O 0
these O 0
complications O 0
may O 0
differ O 0
in O 0
current O 0
clinical O 0
practice O 0
. O 0

We O 0
therefore O 0
sought O 0
to O 0
determine O 0
the O 0
prevalence O 0
and O 0
clinical O 0
associations O 0
of O 0
hyperkalemia B-Disease 1
and O 0
renal B-Disease 1
insufficiency I-Disease 1
in O 0
heart B-Disease 1
failure I-Disease 1
patients O 0
treated O 0
with O 0
spironolactone B-Chemical 1
. O 0

METHODS O 0
: O 0
We O 0
performed O 0
a O 0
case O 0
control O 0
study O 0
of O 0
heart B-Disease 1
failure I-Disease 1
patients O 0
treated O 0
with O 0
spironolactone B-Chemical 1
in O 0
our O 0
clinical O 0
practice O 0
. O 0

Cases O 0
were O 0
patients O 0
who O 0
developed O 0
hyperkalemia B-Disease 1
( O 0
K B-Chemical 1
( O 0
+ O 0
) O 0
> O 0
5 O 0
. O 0
0 O 0
mEq O 0
/ O 0
L O 0
) O 0
or O 0
renal B-Disease 1
insufficiency I-Disease 1
( O 0
Cr B-Chemical 1
> O 0
or O 0
= O 0
2 O 0
. O 0
5 O 0
mg O 0
/ O 0
dL O 0
) O 0
, O 0
and O 0
they O 0
were O 0
compared O 0
to O 0
2 O 0
randomly O 0
selected O 0
controls O 0
per O 0
case O 0
. O 0

Clinical O 0
characteristics O 0
, O 0
medications O 0
, O 0
and O 0
serum O 0
chemistries O 0
at O 0
baseline O 0
and O 0
follow O 0
- O 0
up O 0
time O 0
periods O 0
were O 0
compared O 0
. O 0

RESULTS O 0
: O 0
Sixty O 0
- O 0
seven O 0
of O 0
926 O 0
patients O 0
( O 0
7 O 0
. O 0
2 O 0
% O 0
) O 0
required O 0
discontinuation O 0
of O 0
spironolactone B-Chemical 1
due O 0
to O 0
hyperkalemia B-Disease 1
( O 0
n O 0
= O 0
33 O 0
) O 0
or O 0
renal B-Disease 1
failure I-Disease 1
( O 0
n O 0
= O 0
34 O 0
) O 0
. O 0

Patients O 0
who O 0
developed O 0
hyperkalemia B-Disease 1
were O 0
older O 0
and O 0
more O 0
likely O 0
to O 0
have O 0
diabetes B-Disease 1
, O 0
had O 0
higher O 0
baseline O 0
serum O 0
potassium B-Chemical 1
levels O 0
and O 0
lower O 0
baseline O 0
potassium B-Chemical 1
supplement O 0
doses O 0
, O 0
and O 0
were O 0
more O 0
likely O 0
to O 0
be O 0
treated O 0
with O 0
beta O 0
- O 0
blockers O 0
than O 0
controls O 0
( O 0
n O 0
= O 0
134 O 0
) O 0
. O 0

Patients O 0
who O 0
developed O 0
renal B-Disease 1
insufficiency I-Disease 1
had O 0
lower O 0
baseline O 0
body O 0
weight O 0
and O 0
higher O 0
baseline O 0
serum O 0
creatinine B-Chemical 1
, O 0
required O 0
higher O 0
doses O 0
of O 0
loop O 0
diuretics O 0
, O 0
and O 0
were O 0
more O 0
likely O 0
to O 0
be O 0
treated O 0
with O 0
thiazide B-Chemical 1
diuretics O 0
than O 0
controls O 0
. O 0

CONCLUSIONS O 0
: O 0
Spironolactone B-Chemical 1
- O 0
induced O 0
hyperkalemia B-Disease 1
and O 0
renal B-Disease 1
insufficiency I-Disease 1
are O 0
more O 0
common O 0
in O 0
our O 0
clinical O 0
experience O 0
than O 0
reported O 0
previously O 0
. O 0

This O 0
difference O 0
is O 0
explained O 0
by O 0
patient O 0
comorbidities O 0
and O 0
more O 0
frequent O 0
use O 0
of O 0
beta O 0
- O 0
blockers O 0
. O 0

Acute O 0
reserpine B-Chemical 1
and O 0
subchronic O 0
haloperidol B-Chemical 1
treatments O 0
change O 0
synaptosomal O 0
brain O 0
glutamate B-Chemical 1
uptake O 0
and O 0
elicit O 0
orofacial B-Disease 1
dyskinesia I-Disease 1
in O 0
rats O 0
. O 0

Reserpine B-Chemical 1
- O 0
and O 0
haloperidol B-Chemical 1
- O 0
induced O 0
orofacial B-Disease 1
dyskinesia I-Disease 1
are O 0
putative O 0
animal O 0
models O 0
of O 0
tardive B-Disease 1
dyskinesia I-Disease 1
( O 0
TD B-Disease 1
) O 0
whose O 0
pathophysiology O 0
has O 0
been O 0
related O 0
to O 0
free O 0
radical O 0
generation O 0
and O 0
oxidative O 0
stress O 0
. O 0

In O 0
the O 0
present O 0
study O 0
, O 0
the O 0
authors O 0
induced O 0
orofacial B-Disease 1
dyskinesia I-Disease 1
by O 0
acute O 0
reserpine B-Chemical 1
and O 0
subchronic O 0
haloperidol B-Chemical 1
administration O 0
to O 0
rats O 0
. O 0

Reserpine B-Chemical 1
injection O 0
( O 0
one O 0
dose O 0
of O 0
1 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
) O 0
every O 0
other O 0
day O 0
for O 0
3 O 0
days O 0
caused O 0
a O 0
significant O 0
increase O 0
in O 0
vacuous O 0
chewing O 0
, O 0
tongue O 0
protrusion O 0
and O 0
duration O 0
of O 0
facial O 0
twitching O 0
, O 0
compared O 0
to O 0
the O 0
control O 0
. O 0

Haloperidol B-Chemical 1
administration O 0
( O 0
one O 0
dose O 0
of O 0
12 O 0
mg O 0
/ O 0
kg O 0
once O 0
a O 0
week O 0
s O 0
. O 0
c O 0
. O 0
) O 0
for O 0
4 O 0
weeks O 0
caused O 0
an O 0
increase O 0
in O 0
vacuous O 0
chewing O 0
, O 0
tongue O 0
protrusion O 0
and O 0
duration O 0
of O 0
facial O 0
twitching O 0
observed O 0
in O 0
four O 0
weekly O 0
evaluations O 0
. O 0

After O 0
the O 0
treatments O 0
and O 0
behavioral O 0
observation O 0
, O 0
glutamate B-Chemical 1
uptake O 0
by O 0
segments O 0
of O 0
the O 0
brain O 0
was O 0
analyzed O 0
. O 0

A O 0
decreased O 0
glutamate B-Chemical 1
uptake O 0
was O 0
observed O 0
in O 0
the O 0
subcortical O 0
parts O 0
of O 0
animals O 0
treated O 0
with O 0
reserpine B-Chemical 1
and O 0
haloperidol B-Chemical 1
, O 0
compared O 0
to O 0
the O 0
control O 0
. O 0

Importantly O 0
, O 0
a O 0
decrease O 0
in O 0
glutamate B-Chemical 1
uptake O 0
correlates O 0
negatively O 0
with O 0
an O 0
increase O 0
in O 0
the O 0
incidence O 0
of O 0
orofacial B-Disease 1
diskinesia I-Disease 1
. O 0

These O 0
results O 0
indicate O 0
that O 0
early O 0
changes O 0
in O 0
glutamate B-Chemical 1
transport O 0
may O 0
be O 0
related O 0
to O 0
the O 0
development O 0
of O 0
vacuous O 0
chewing O 0
movements O 0
in O 0
rats O 0
. O 0

Ceftriaxone B-Chemical 1
- O 0
associated O 0
biliary B-Disease 1
pseudolithiasis I-Disease 1
in O 0
paediatric O 0
surgical O 0
patients O 0
. O 0

It O 0
is O 0
well O 0
known O 0
that O 0
ceftriaxone B-Chemical 1
leads O 0
to O 0
pseudolithiasis B-Disease 1
in O 0
some O 0
patients O 0
. O 0

Clinical O 0
and O 0
experimental O 0
studies O 0
also O 0
suggest O 0
that O 0
situations O 0
causing O 0
gallbladder B-Disease 1
dysfunction I-Disease 1
, O 0
such O 0
as O 0
fasting O 0
, O 0
may O 0
have O 0
a O 0
role O 0
for O 0
the O 0
development O 0
of O 0
pseudolithiasis B-Disease 1
. O 0

In O 0
this O 0
study O 0
, O 0
we O 0
prospectively O 0
evaluated O 0
the O 0
incidence O 0
and O 0
clinical O 0
importance O 0
of O 0
pseudolithiasis B-Disease 1
in O 0
paediatric O 0
surgical O 0
patients O 0
receiving O 0
ceftriaxone B-Chemical 1
treatment O 0
, O 0
who O 0
often O 0
had O 0
to O 0
fast O 0
in O 0
the O 0
post O 0
- O 0
operative O 0
period O 0
. O 0

Fifty O 0
children O 0
who O 0
were O 0
given O 0
ceftriaxone B-Chemical 1
were O 0
evaluated O 0
by O 0
serial O 0
abdominal O 0
sonograms O 0
. O 0

Of O 0
those O 0
, O 0
13 O 0
( O 0
26 O 0
% O 0
) O 0
developed O 0
biliary O 0
pathology O 0
. O 0

Comparison O 0
of O 0
the O 0
patients O 0
with O 0
or O 0
without O 0
pseudolithiasis B-Disease 1
revealed O 0
no O 0
significant O 0
difference O 0
with O 0
respect O 0
to O 0
age O 0
, O 0
sex O 0
, O 0
duration O 0
of O 0
the O 0
treatment O 0
and O 0
starvation O 0
variables O 0
. O 0

After O 0
cessation O 0
of O 0
the O 0
treatment O 0
, O 0
pseudolithiasis B-Disease 1
resolved O 0
spontaneously O 0
within O 0
a O 0
short O 0
period O 0
. O 0

The O 0
incidence O 0
of O 0
pseudolithiasis B-Disease 1
is O 0
not O 0
affected O 0
by O 0
fasting O 0
. O 0

Coronary B-Disease 1
aneurysm I-Disease 1
after O 0
implantation O 0
of O 0
a O 0
paclitaxel B-Chemical 1
- O 0
eluting O 0
stent O 0
. O 0

Formation O 0
of O 0
coronary B-Disease 1
aneurysm I-Disease 1
is O 0
a O 0
rare O 0
complication O 0
of O 0
stenting O 0
with O 0
bare O 0
metal O 0
stents O 0
, O 0
but O 0
based O 0
on O 0
experimental O 0
studies O 0
drug O 0
- O 0
eluting O 0
stents O 0
may O 0
induce O 0
toxic O 0
effects O 0
on O 0
the O 0
vessel O 0
wall O 0
with O 0
incomplete O 0
stent O 0
apposition O 0
, O 0
aneurysm B-Disease 1
formation O 0
and O 0
with O 0
the O 0
potential O 0
of O 0
stent O 0
thrombosis B-Disease 1
or O 0
vessel B-Disease 1
rupture I-Disease 1
. O 0

We O 0
present O 0
a O 0
43 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
who O 0
developed O 0
a O 0
coronary B-Disease 1
aneurysm I-Disease 1
in O 0
the O 0
right O 0
coronary O 0
artery O 0
6 O 0
months O 0
after O 0
receiving O 0
a O 0
paclitaxel B-Chemical 1
- O 0
eluting O 0
stent O 0
. O 0

The O 0
patient O 0
was O 0
asymptomatic O 0
and O 0
the O 0
aneurysm B-Disease 1
was O 0
detected O 0
in O 0
a O 0
routine O 0
control O 0
. O 0

Angiography O 0
and O 0
intracoronary O 0
ultrasound O 0
demonstrated O 0
lack O 0
of O 0
contact O 0
between O 0
stent O 0
and O 0
vessel O 0
wall O 0
in O 0
a O 0
15 O 0
- O 0
mm O 0
long O 0
segment O 0
with O 0
maximal O 0
aneurysm B-Disease 1
diameter O 0
of O 0
6 O 0
. O 0
0 O 0
mm O 0
. O 0

The O 0
patient O 0
was O 0
successfully O 0
treated O 0
with O 0
a O 0
graft O 0
stent O 0
. O 0

Causes O 0
of O 0
acute O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
in O 0
patients O 0
receiving O 0
kidney O 0
transplantation O 0
. O 0

OBJECTIVES O 0
: O 0
Thrombotic B-Disease 1
microangiopathy I-Disease 1
is O 0
a O 0
well O 0
- O 0
known O 0
problem O 0
in O 0
patients O 0
following O 0
renal O 0
transplantation O 0
. O 0

In O 0
postrenal O 0
transplantation O 0
, O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
is O 0
often O 0
a O 0
reflection O 0
of O 0
hemolytic B-Disease 1
uremic I-Disease 1
syndrome I-Disease 1
. O 0

We O 0
aimed O 0
to O 0
determine O 0
the O 0
causes O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
in O 0
a O 0
population O 0
of O 0
renal O 0
transplantation O 0
recipients O 0
and O 0
discuss O 0
the O 0
literature O 0
. O 0

MATERIALS O 0
AND O 0
METHODS O 0
: O 0
We O 0
investigated O 0
the O 0
causes O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
during O 0
a O 0
1 O 0
- O 0
year O 0
period O 0
, O 0
from O 0
June O 0
2003 O 0
to O 0
June O 0
2004 O 0
, O 0
at O 0
the O 0
King O 0
Fahad O 0
National O 0
Guard O 0
Hospital O 0
in O 0
Riyadh O 0
, O 0
Saudi O 0
Arabia O 0
, O 0
by O 0
reviewing O 0
the O 0
slides O 0
of O 0
all O 0
transplant O 0
biopsies O 0
( O 0
n O 0
= O 0
25 O 0
) O 0
performed O 0
during O 0
this O 0
interval O 0
. O 0

Pre O 0
- O 0
and O 0
posttransplant O 0
crossmatching O 0
was O 0
done O 0
when O 0
possible O 0
. O 0

RESULTS O 0
: O 0
Five O 0
cases O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
were O 0
found O 0
. O 0

Three O 0
of O 0
these O 0
cases O 0
were O 0
from O 0
the O 0
25 O 0
transplantations O 0
performed O 0
at O 0
King O 0
Fahad O 0
National O 0
Guard O 0
Hospital O 0
, O 0
while O 0
the O 0
other O 0
2 O 0
transplantations O 0
had O 0
been O 0
performed O 0
abroad O 0
and O 0
were O 0
referred O 0
to O 0
us O 0
for O 0
follow O 0
- O 0
up O 0
. O 0

Three O 0
cases O 0
were O 0
related O 0
to O 0
cyclosporine B-Chemical 1
, O 0
and O 0
1 O 0
case O 0
was O 0
secondary O 0
to O 0
both O 0
cyclosporine B-Chemical 1
and O 0
tacrolimus B-Chemical 1
. O 0

The O 0
fifth O 0
case O 0
had O 0
features O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
related O 0
to O 0
an O 0
antiphospholipid B-Disease 1
syndrome I-Disease 1
in O 0
a O 0
patient O 0
with O 0
systemic B-Disease 1
lupus I-Disease 1
erythematosus I-Disease 1
. O 0

CONCLUSIONS O 0
: O 0
In O 0
the O 0
literature O 0
, O 0
the O 0
most O 0
- O 0
frequent O 0
cause O 0
of O 0
hemolytic B-Disease 1
uremic I-Disease 1
syndrome I-Disease 1
in O 0
patients O 0
following O 0
renal O 0
transplantation O 0
is O 0
recurrence O 0
of O 0
the O 0
hemolytic B-Disease 1
uremic I-Disease 1
syndrome I-Disease 1
. O 0

Other O 0
causes O 0
include O 0
drug O 0
- O 0
related O 0
( O 0
cyclosporine B-Chemical 1
, O 0
tacrolimus B-Chemical 1
) O 0
toxicity B-Disease 1
, O 0
procoagulant O 0
status O 0
, O 0
and O 0
antibody O 0
- O 0
mediated O 0
rejection O 0
. O 0

We O 0
found O 0
that O 0
the O 0
most O 0
- O 0
frequent O 0
cause O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
was O 0
drug O 0
related O 0
, O 0
secondary O 0
mainly O 0
to O 0
cyclosporine B-Chemical 1
. O 0

In O 0
the O 0
current O 0
study O 0
, O 0
the O 0
frequency O 0
of O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
was O 0
similar O 0
to O 0
the O 0
percentage O 0
reported O 0
in O 0
the O 0
literature O 0
( O 0
20 O 0
% O 0
) O 0
. O 0

Comparison O 0
of O 0
developmental O 0
toxicity B-Disease 1
of O 0
selective O 0
and O 0
non O 0
- O 0
selective O 0
cyclooxygenase O 0
- O 0
2 O 0
inhibitors O 0
in O 0
CRL O 0
: O 0
( O 0
WI O 0
) O 0
WUBR O 0
Wistar O 0
rats O 0
- O 0
- O 0
DFU B-Chemical 1
and O 0
piroxicam B-Chemical 1
study O 0
. O 0

BACKGROUND O 0
: O 0
Cyclooxygenase O 0
( O 0
COX O 0
) O 0
inhibitors O 0
are O 0
one O 0
of O 0
the O 0
most O 0
often O 0
ingested O 0
drugs O 0
during O 0
pregnancy O 0
. O 0

Unlike O 0
general O 0
toxicity B-Disease 1
data O 0
, O 0
their O 0
prenatal O 0
toxic O 0
effects O 0
were O 0
not O 0
extensively O 0
studied O 0
before O 0
. O 0

The O 0
aim O 0
of O 0
the O 0
experiment O 0
was O 0
to O 0
evaluate O 0
the O 0
developmental O 0
toxicity B-Disease 1
of O 0
the O 0
non O 0
- O 0
selective O 0
( O 0
piroxicam B-Chemical 1
) O 0
and O 0
selective O 0
( O 0
DFU B-Chemical 1
; O 0
5 B-Chemical 1
, I-Chemical 1
5 I-Chemical 1
- I-Chemical 1
dimethyl I-Chemical 1
- I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
fluorophenyl I-Chemical 1
) I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
methylsulphonyl I-Chemical 1
) I-Chemical 1
phenyl I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
( I-Chemical 1
5H I-Chemical 1
) I-Chemical 1
- I-Chemical 1
furanon I-Chemical 1
) O 0
COX O 0
- O 0
2 O 0
inhibitors O 0
. O 0

METHODS O 0
: O 0
Drugs O 0
were O 0
separately O 0
, O 0
orally O 0
once O 0
daily O 0
dosed O 0
to O 0
pregnant O 0
rats O 0
from O 0
day O 0
8 O 0
to O 0
21 O 0
( O 0
GD1 O 0
= O 0
plug O 0
day O 0
) O 0
. O 0

Doses O 0
were O 0
set O 0
at O 0
0 O 0
. O 0
3 O 0
, O 0
3 O 0
. O 0
0 O 0
and O 0
30 O 0
. O 0
0mg O 0
/ O 0
kg O 0
for O 0
piroxicam B-Chemical 1
and O 0
0 O 0
. O 0
2 O 0
, O 0
2 O 0
. O 0
0 O 0
and O 0
20 O 0
. O 0
0mg O 0
/ O 0
kg O 0
for O 0
DFU B-Chemical 1
. O 0

Fetuses O 0
were O 0
delivered O 0
on O 0
GD O 0
21 O 0
and O 0
routinely O 0
examined O 0
. O 0

Comprehensive O 0
clinical O 0
and O 0
developmental O 0
measurements O 0
were O 0
done O 0
. O 0

The O 0
pooled O 0
statistical O 0
analysis O 0
for O 0
ventricular B-Disease 1
septal I-Disease 1
( I-Disease 1
VSD I-Disease 1
) I-Disease 1
and I-Disease 1
midline I-Disease 1
( I-Disease 1
MD I-Disease 1
) I-Disease 1
defects I-Disease 1
was O 0
performed O 0
for O 0
rat O 0
fetuses O 0
exposed O 0
to O 0
piroxicam B-Chemical 1
, O 0
selective O 0
and O 0
non O 0
- O 0
selective O 0
COX O 0
- O 0
2 O 0
inhibitor O 0
based O 0
on O 0
present O 0
and O 0
historic O 0
data O 0
. O 0

RESULTS O 0
: O 0
Maternal O 0
toxicity B-Disease 1
, O 0
intrauterine B-Disease 1
growth I-Disease 1
retardation I-Disease 1
, O 0
and O 0
increase B-Disease 1
of I-Disease 1
external I-Disease 1
and I-Disease 1
skeletal I-Disease 1
variations I-Disease 1
were O 0
found O 0
in O 0
rats O 0
treated O 0
with O 0
the O 0
highest O 0
dose O 0
of O 0
piroxicam B-Chemical 1
. O 0

Decrease O 0
of O 0
fetal O 0
length O 0
was O 0
the O 0
only O 0
signs O 0
of O 0
the O 0
DFU B-Chemical 1
developmental O 0
toxicity B-Disease 1
observed O 0
in O 0
pups O 0
exposed O 0
to O 0
the O 0
highest O 0
compound O 0
dose O 0
. O 0

Lack O 0
of O 0
teratogenicity O 0
was O 0
found O 0
in O 0
piroxicam B-Chemical 1
and O 0
DFU B-Chemical 1
- O 0
exposed O 0
groups O 0
. O 0

Prenatal O 0
exposure O 0
to O 0
non O 0
- O 0
selective O 0
COX O 0
inhibitors O 0
increases O 0
the O 0
risk O 0
of O 0
VSD O 0
and O 0
MD O 0
when O 0
compared O 0
to O 0
historic O 0
control O 0
but O 0
not O 0
with O 0
selective O 0
COX O 0
- O 0
2 O 0
inhibitors O 0
. O 0

CONCLUSION O 0
: O 0
Both O 0
selective O 0
and O 0
non O 0
- O 0
selective O 0
COX O 0
- O 0
2 O 0
inhibitors O 0
were O 0
toxic O 0
for O 0
rats O 0
fetuses O 0
when O 0
administered O 0
in O 0
the O 0
highest O 0
dose O 0
. O 0

Unlike O 0
DFU B-Chemical 1
, O 0
piroxicam B-Chemical 1
was O 0
also O 0
highly O 0
toxic O 0
to O 0
the O 0
dams O 0
. O 0

Prenatal O 0
exposure O 0
to O 0
selective O 0
COX O 0
- O 0
2 O 0
inhibitors O 0
does O 0
not O 0
increase O 0
the O 0
risk O 0
of O 0
ventricular B-Disease 1
septal I-Disease 1
and I-Disease 1
midline I-Disease 1
defects I-Disease 1
in O 0
rat O 0
when O 0
compared O 0
to O 0
non O 0
- O 0
selective O 0
drugs O 0
and O 0
historic O 0
control O 0
. O 0

Lone O 0
atrial B-Disease 1
fibrillation I-Disease 1
associated O 0
with O 0
creatine B-Chemical 1
monohydrate O 0
supplementation O 0
. O 0

Atrial B-Disease 1
fibrillation I-Disease 1
in O 0
young O 0
patients O 0
without O 0
structural O 0
heart B-Disease 1
disease I-Disease 1
is O 0
rare O 0
. O 0

Therefore O 0
, O 0
when O 0
the O 0
arrhythmia B-Disease 1
is O 0
present O 0
in O 0
this O 0
population O 0
, O 0
reversible O 0
causes O 0
must O 0
be O 0
identified O 0
and O 0
resolved O 0
. O 0

Thyroid B-Disease 1
disorders I-Disease 1
, O 0
illicit O 0
drug O 0
or O 0
stimulant O 0
use O 0
, O 0
and O 0
acute B-Disease 1
alcohol I-Disease 1
intoxication I-Disease 1
are O 0
among O 0
these O 0
causes O 0
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
30 O 0
- O 0
year O 0
- O 0
old O 0
Caucasian O 0
man O 0
who O 0
came O 0
to O 0
the O 0
emergency O 0
department O 0
in O 0
atrial B-Disease 1
fibrillation I-Disease 1
with O 0
rapid O 0
ventricular O 0
response O 0
. O 0

His O 0
medical O 0
history O 0
was O 0
unremarkable O 0
, O 0
except O 0
for O 0
minor O 0
fractures B-Disease 1
of O 0
the O 0
fingers O 0
and O 0
foot O 0
. O 0

Thyroid O 0
- O 0
stimulating O 0
hormone O 0
, O 0
magnesium B-Chemical 1
, O 0
and O 0
potassium B-Chemical 1
levels O 0
were O 0
within O 0
normal O 0
limits O 0
, O 0
urine O 0
drug O 0
screen O 0
was O 0
negative O 0
, O 0
and O 0
alcohol B-Chemical 1
use O 0
was O 0
denied O 0
. O 0

However O 0
, O 0
when O 0
the O 0
patient O 0
was O 0
questioned O 0
about O 0
use O 0
of O 0
herbal O 0
products O 0
and O 0
supplements O 0
, O 0
the O 0
use O 0
of O 0
creatine B-Chemical 1
monohydrate O 0
was O 0
revealed O 0
. O 0

The O 0
patient O 0
was O 0
admitted O 0
to O 0
the O 0
hospital O 0
, O 0
anticoagulated O 0
with O 0
unfractionated O 0
heparin B-Chemical 1
, O 0
and O 0
given O 0
intravenous O 0
diltiazem B-Chemical 1
for O 0
rate O 0
control O 0
and O 0
intravenous O 0
amiodarone B-Chemical 1
for O 0
rate O 0
and O 0
rhythm O 0
control O 0
. O 0

When O 0
discharged O 0
less O 0
than O 0
24 O 0
hours O 0
later O 0
, O 0
he O 0
was O 0
receiving O 0
metoprolol B-Chemical 1
and O 0
aspirin B-Chemical 1
, O 0
with O 0
follow O 0
- O 0
up O 0
plans O 0
for O 0
echocardiography O 0
and O 0
nuclear O 0
imaging O 0
to O 0
assess O 0
perfusion O 0
. O 0

Exogenous O 0
creatine B-Chemical 1
is O 0
used O 0
by O 0
athletes O 0
to O 0
theoretically O 0
improve O 0
exercise O 0
performance O 0
. O 0

Vegetarians O 0
may O 0
also O 0
take O 0
creatine B-Chemical 1
to O 0
replace O 0
what O 0
they O 0
are O 0
not O 0
consuming O 0
from O 0
meat O 0
, O 0
fish O 0
, O 0
and O 0
other O 0
animal O 0
products O 0
. O 0

Previous O 0
anecdotal O 0
reports O 0
have O 0
linked O 0
creatine B-Chemical 1
to O 0
the O 0
development O 0
of O 0
arrhythmia B-Disease 1
. O 0

Clinicians O 0
must O 0
be O 0
diligent O 0
when O 0
interviewing O 0
patients O 0
about O 0
their O 0
drug O 0
therapy O 0
histories O 0
and O 0
include O 0
questions O 0
about O 0
their O 0
use O 0
of O 0
herbal O 0
products O 0
and O 0
dietary O 0
supplements O 0
. O 0

In O 0
addition O 0
, O 0
it O 0
is O 0
important O 0
to O 0
report O 0
adverse O 0
effects O 0
associated O 0
with O 0
frequently O 0
consumed O 0
supplements O 0
and O 0
herbal O 0
products O 0
to O 0
the O 0
Food O 0
and O 0
Drug O 0
Administration O 0
and O 0
in O 0
the O 0
literature O 0
. O 0

Seizures B-Disease 1
induced O 0
by O 0
the O 0
cocaine B-Chemical 1
metabolite O 0
benzoylecgonine B-Chemical 1
in O 0
rats O 0
. O 0

The O 0
half O 0
- O 0
life O 0
( O 0
t1 O 0
/ O 0
2 O 0
) O 0
of O 0
cocaine B-Chemical 1
is O 0
relatively O 0
short O 0
, O 0
but O 0
some O 0
of O 0
the O 0
consequences O 0
of O 0
its O 0
use O 0
, O 0
such O 0
as O 0
seizures B-Disease 1
and O 0
strokes B-Disease 1
, O 0
can O 0
occur O 0
hours O 0
after O 0
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We O 0
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Two O 0
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BE B-Chemical 1
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Evaluation O 0
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The O 0
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Current O 0
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Significant O 0
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Importantly O 0
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. O 0

The O 0
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. O 0

Electrocardiographic O 0
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in O 0
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The O 0
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. O 0

Behavioral O 0
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centrally O 0
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Urotensin B-Chemical 1
- I-Chemical 1
II I-Chemical 1
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Intracerebroventricular O 0
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U B-Chemical 1
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causes O 0
hypertension B-Disease 1
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However O 0
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In O 0
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U B-Chemical 1
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Administration O 0
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. O 0

Intracerebroventricular O 0
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U B-Chemical 1
- I-Chemical 1
II I-Chemical 1
also O 0
caused O 0
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food O 0
intake O 0
at O 0
doses O 0
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10 O 0
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mouse O 0
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horizontal O 0
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Whatever O 0
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administration O 0
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U B-Chemical 1
- I-Chemical 1
II I-Chemical 1
had O 0
no O 0
effect O 0
on O 0
body O 0
temperature O 0
, O 0
nociception O 0
, O 0
apomorphine B-Chemical 1
- O 0
induced O 0
penile B-Disease 1
erection I-Disease 1
and O 0
climbing O 0
behavior O 0
, O 0
and O 0
stress O 0
- O 0
induced O 0
plasma O 0
corticosterone B-Chemical 1
level O 0
. O 0

Taken O 0
together O 0
, O 0
the O 0
present O 0
study O 0
demonstrates O 0
that O 0
the O 0
central O 0
injection O 0
of O 0
U B-Chemical 1
- I-Chemical 1
II I-Chemical 1
at O 0
doses O 0
of O 0
1 O 0
- O 0
10 O 0
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and O 0
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like O 0
effects O 0
in O 0
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. O 0

These O 0
data O 0
suggest O 0
that O 0
U B-Chemical 1
- I-Chemical 1
II I-Chemical 1
may O 0
be O 0
involved O 0
in O 0
some O 0
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of O 0
psychiatric B-Disease 1
disorders I-Disease 1
. O 0

Learning O 0
of O 0
rats O 0
under O 0
amnesia B-Disease 1
caused O 0
by O 0
pentobarbital B-Chemical 1
. O 0

Dissociated O 0
learning O 0
of O 0
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in O 0
the O 0
normal O 0
state O 0
and O 0
the O 0
state O 0
of O 0
amnesia B-Disease 1
produced O 0
by O 0
pentobarbital B-Chemical 1
( O 0
15 O 0
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ip O 0
) O 0
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carried O 0
out O 0
. O 0

Rats O 0
were O 0
trained O 0
to O 0
approach O 0
a O 0
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where O 0
they O 0
received O 0
food O 0
reinforcement O 0
. O 0

In O 0
Group O 0
1 O 0
the O 0
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were O 0
trained O 0
under O 0
the O 0
influence O 0
of O 0
pentobarbital B-Chemical 1
to O 0
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to O 0
the O 0
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as O 0
in O 0
the O 0
normal O 0
state O 0
. O 0

In O 0
Group O 0
2 O 0
the O 0
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were O 0
trained O 0
to O 0
approach O 0
different O 0
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in O 0
different O 0
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states O 0
. O 0

It O 0
was O 0
shown O 0
that O 0
memory B-Disease 1
dissociation I-Disease 1
occurred O 0
in O 0
both O 0
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. O 0

Differences O 0
in O 0
the O 0
parameters O 0
of O 0
training O 0
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the O 0
influence O 0
of O 0
pentobarbital B-Chemical 1
between O 0
Groups O 0
1 O 0
and O 0
2 O 0
were O 0
revealed O 0
. O 0

These O 0
findings O 0
show O 0
that O 0
the O 0
brain O 0
- O 0
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induced O 0
by O 0
pentobarbital B-Chemical 1
is O 0
formed O 0
with O 0
the O 0
participation O 0
of O 0
the O 0
mechanisms O 0
of O 0
information O 0
perception O 0
. O 0

The O 0
effects O 0
of O 0
short O 0
- O 0
term O 0
raloxifene B-Chemical 1
therapy O 0
on O 0
fibrinolysis O 0
markers O 0
: O 0
TAFI O 0
, O 0
tPA O 0
, O 0
and O 0
PAI O 0
- O 0
1 O 0
. O 0

BACKGROUND O 0
: O 0
Markers O 0
of O 0
fibrinolysis O 0
, O 0
thrombin O 0
- O 0
activatable O 0
fibrinolysis O 0
inhibitor O 0
( O 0
TAFI O 0
) O 0
, O 0
tissue O 0
- O 0
type O 0
plasminogen O 0
activator O 0
( O 0
tPA O 0
) O 0
, O 0
and O 0
plasminogen O 0
activator O 0
inhibitor O 0
- O 0
1 O 0
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PAI O 0
- O 0
1 O 0
) O 0
levels O 0
were O 0
studied O 0
for O 0
the O 0
evaluation O 0
of O 0
short O 0
- O 0
term O 0
effects O 0
of O 0
raloxifene B-Chemical 1
administration O 0
in O 0
postmenopausal O 0
women O 0
. O 0

METHODS O 0
: O 0
Thirty O 0
- O 0
nine O 0
postmenopausal O 0
women O 0
with O 0
osteopenia B-Disease 1
or O 0
osteoporosis B-Disease 1
were O 0
included O 0
in O 0
this O 0
prospective O 0
, O 0
controlled O 0
clinical O 0
study O 0
. O 0

Twenty O 0
- O 0
five O 0
women O 0
were O 0
given O 0
raloxifene B-Chemical 1
hydrochloride I-Chemical 1
( O 0
60 O 0
mg O 0
/ O 0
day O 0
) O 0
plus O 0
calcium B-Chemical 1
( O 0
500 O 0
mg O 0
/ O 0
day O 0
) O 0
. O 0

Age O 0
- O 0
matched O 0
controls O 0
( O 0
n O 0
= O 0
14 O 0
) O 0
were O 0
given O 0
only O 0
calcium B-Chemical 1
. O 0

Plasma O 0
TAFI O 0
, O 0
tPA O 0
, O 0
and O 0
PAI O 0
- O 0
1 O 0
antigen O 0
levels O 0
were O 0
measured O 0
at O 0
baseline O 0
and O 0
after O 0
3 O 0
months O 0
of O 0
treatment O 0
by O 0
commercially O 0
available O 0
ELISA O 0
kits O 0
. O 0

Variations O 0
of O 0
individuals O 0
were O 0
assessed O 0
by O 0
Wilcoxon O 0
' O 0
s O 0
test O 0
. O 0

Relationship O 0
between O 0
those O 0
markers O 0
and O 0
demographic O 0
characteristics O 0
were O 0
investigated O 0
. O 0

RESULTS O 0
: O 0
Three O 0
months O 0
of O 0
raloxifene B-Chemical 1
treatment O 0
was O 0
associated O 0
with O 0
a O 0
significant O 0
decrease O 0
in O 0
the O 0
plasma O 0
TAFI O 0
antigen O 0
concentrations O 0
( O 0
16 O 0
% O 0
change O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
, O 0
and O 0
a O 0
significant O 0
increase O 0
in O 0
tPA O 0
antigen O 0
concentrations O 0
( O 0
25 O 0
% O 0
change O 0
, O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

A O 0
significant O 0
correlation O 0
was O 0
found O 0
between O 0
baseline O 0
TAFI O 0
antigen O 0
concentrations O 0
and O 0
the O 0
duration O 0
of O 0
amenorrhea B-Disease 1
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
; O 0
r O 0
= O 0
0 O 0
. O 0
33 O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
We O 0
suggest O 0
that O 0
the O 0
increased O 0
risk O 0
of O 0
venous B-Disease 1
thromboembolism I-Disease 1
due O 0
to O 0
raloxifene B-Chemical 1
treatment O 0
may O 0
be O 0
related O 0
to O 0
increased O 0
tPA O 0
levels O 0
, O 0
but O 0
not O 0
TAFI O 0
levels O 0
. O 0

Valproate B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
. O 0

Valproate B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
is O 0
a O 0
rare O 0
syndrome O 0
that O 0
may O 0
manifest O 0
in O 0
otherwise O 0
normal O 0
epileptic B-Disease 1
individuals O 0
. O 0

It O 0
may O 0
even O 0
present O 0
in O 0
patients O 0
who O 0
have O 0
tolerated O 0
this O 0
medicine O 0
well O 0
in O 0
the O 0
past O 0
. O 0

It O 0
is O 0
usually O 0
but O 0
not O 0
necessarily O 0
associated O 0
with O 0
hyperammonemia B-Disease 1
. O 0

The O 0
EEG O 0
shows O 0
characteristic O 0
triphasic O 0
waves O 0
in O 0
most O 0
patients O 0
with O 0
this O 0
complication O 0
. O 0

A O 0
case O 0
of O 0
valproate B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
is O 0
presented O 0
. O 0

The O 0
problems O 0
in O 0
diagnosing O 0
this O 0
condition O 0
are O 0
subsequently O 0
discussed O 0
. O 0

Recurrent O 0
dysphonia B-Disease 1
and O 0
acitretin B-Chemical 1
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
woman O 0
complaining O 0
of O 0
dysphonia B-Disease 1
while O 0
she O 0
was O 0
treated O 0
by O 0
acitretin B-Chemical 1
. O 0

Her O 0
symptoms O 0
totally O 0
regressed O 0
after O 0
drug O 0
withdrawal O 0
and O 0
reappeared O 0
when O 0
acitretin B-Chemical 1
was O 0
reintroduced O 0
. O 0

To O 0
our O 0
knowledge O 0
, O 0
this O 0
is O 0
the O 0
first O 0
case O 0
of O 0
acitretin B-Chemical 1
- O 0
induced O 0
dysphonia B-Disease 1
. O 0

This O 0
effect O 0
may O 0
be O 0
related O 0
to O 0
the O 0
pharmacological O 0
effect O 0
of O 0
this O 0
drug O 0
on O 0
mucous O 0
membranes O 0
. O 0

Nitro B-Chemical 1
- I-Chemical 1
L I-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
methyl I-Chemical 1
ester I-Chemical 1
: O 0
a O 0
potential O 0
protector O 0
against O 0
gentamicin B-Chemical 1
ototoxicity B-Disease 1
. O 0

The O 0
nitric B-Chemical 1
oxide I-Chemical 1
( O 0
NO B-Chemical 1
) O 0
inhibitor O 0
nitro B-Chemical 1
- I-Chemical 1
L I-Chemical 1
- I-Chemical 1
arginine I-Chemical 1
methyl I-Chemical 1
ester I-Chemical 1
( O 0
L B-Chemical 1
- I-Chemical 1
NAME I-Chemical 1
) O 0
may O 0
act O 0
as O 0
an O 0
otoprotectant O 0
against O 0
high B-Disease 1
- I-Disease 1
frequency I-Disease 1
hearing I-Disease 1
loss I-Disease 1
caused O 0
by O 0
gentamicin B-Chemical 1
, O 0
but O 0
further O 0
studies O 0
are O 0
needed O 0
to O 0
confirm O 0
this O 0
. O 0
Aminoglycoside B-Chemical 1
antibiotics O 0
are O 0
still O 0
widely O 0
used O 0
by O 0
virtue O 0
of O 0
their O 0
efficacy O 0
and O 0
low O 0
cost O 0
. O 0

Their O 0
ototoxicity B-Disease 1
is O 0
a O 0
serious O 0
health O 0
problem O 0
and O 0
, O 0
as O 0
their O 0
ototoxic B-Disease 1
mechanism O 0
involves O 0
the O 0
production O 0
of O 0
NO B-Chemical 1
, O 0
we O 0
need O 0
to O 0
assess O 0
the O 0
use O 0
of O 0
NO B-Chemical 1
inhibitors O 0
for O 0
the O 0
prevention O 0
of O 0
aminoglycoside B-Chemical 1
- O 0
induced O 0
sensorineural B-Disease 1
hearing I-Disease 1
loss I-Disease 1
. O 0

In O 0
this O 0
experimental O 0
study O 0
we O 0
used O 0
30 O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
, O 0
27 O 0
of O 0
which O 0
had O 0
gentamicin B-Chemical 1
instilled O 0
into O 0
the O 0
middle O 0
ear O 0
. O 0

The O 0
otoprotectant O 0
L B-Chemical 1
- I-Chemical 1
NAME I-Chemical 1
was O 0
administered O 0
topically O 0
to O 0
12 O 0
/ O 0
27 O 0
animals O 0
. O 0

Its O 0
effect O 0
was O 0
determined O 0
in O 0
terms O 0
of O 0
attenuation O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
, O 0
measured O 0
by O 0
shifts O 0
in O 0
the O 0
auditory O 0
brainstem O 0
response O 0
threshold O 0
. O 0

L B-Chemical 1
- I-Chemical 1
NAME I-Chemical 1
reduced O 0
gentamicin B-Chemical 1
- O 0
induced O 0
hearing B-Disease 1
loss I-Disease 1
in O 0
the O 0
high O 0
- O 0
frequency O 0
range O 0
, O 0
but O 0
gave O 0
no O 0
protection O 0
in O 0
the O 0
middle O 0
or O 0
low O 0
frequencies O 0
. O 0

Safety O 0
profile O 0
of O 0
a O 0
nicotine B-Chemical 1
lozenge O 0
compared O 0
with O 0
that O 0
of O 0
nicotine B-Chemical 1
gum O 0
in O 0
adult O 0
smokers O 0
with O 0
underlying O 0
medical O 0
conditions O 0
: O 0
a O 0
12 O 0
- O 0
week O 0
, O 0
randomized O 0
, O 0
open O 0
- O 0
label O 0
study O 0
. O 0

BACKGROUND O 0
: O 0
Nicotine B-Chemical 1
polacrilex O 0
lozenges O 0
deliver O 0
25 O 0
% O 0
to O 0
27 O 0
% O 0
more O 0
nicotine B-Chemical 1
compared O 0
with O 0
equivalent O 0
doses O 0
of O 0
nicotine B-Chemical 1
polacrilex O 0
gum O 0
. O 0

The O 0
increased O 0
nicotine B-Chemical 1
exposure O 0
from O 0
the O 0
lozenge O 0
has O 0
raised O 0
questions O 0
about O 0
the O 0
relative O 0
safety O 0
of O 0
the O 0
lozenge O 0
and O 0
gum O 0
. O 0

OBJECTIVE O 0
: O 0
The O 0
objective O 0
of O 0
this O 0
study O 0
was O 0
to O 0
compare O 0
the O 0
safety O 0
profiles O 0
of O 0
the O 0
4 O 0
- O 0
mg O 0
nicotine B-Chemical 1
lozenge O 0
and O 0
4 O 0
- O 0
mg O 0
nicotine B-Chemical 1
gum O 0
in O 0
smokers O 0
with O 0
selected O 0
label O 0
- O 0
restricted O 0
diseases O 0
. O 0

METHODS O 0
: O 0
This O 0
was O 0
a O 0
multicenter O 0
, O 0
randomized O 0
, O 0
open O 0
- O 0
label O 0
study O 0
in O 0
adult O 0
smokers O 0
with O 0
heart B-Disease 1
disease I-Disease 1
, O 0
hypertension B-Disease 1
not O 0
controlled O 0
by O 0
medication O 0
, O 0
and O 0
/ O 0
or O 0
diabetes B-Disease 1
mellitus I-Disease 1
. O 0

Patients O 0
were O 0
randomized O 0
in O 0
a O 0
1 O 0
: O 0
1 O 0
ratio O 0
to O 0
receive O 0
the O 0
4 O 0
- O 0
mg O 0
nicotine B-Chemical 1
lozenge O 0
or O 0
4 O 0
- O 0
mg O 0
nicotine B-Chemical 1
gum O 0
. O 0

Safety O 0
assessments O 0
were O 0
made O 0
at O 0
baseline O 0
and O 0
at O 0
2 O 0
, O 0
4 O 0
, O 0
6 O 0
, O 0
and O 0
12 O 0
weeks O 0
after O 0
the O 0
start O 0
of O 0
product O 0
use O 0
. O 0

RESULTS O 0
: O 0
Nine O 0
hundred O 0
one O 0
patients O 0
were O 0
randomized O 0
to O 0
treatment O 0
, O 0
447 O 0
who O 0
received O 0
the O 0
lozenge O 0
and O 0
454 O 0
who O 0
received O 0
the O 0
gum O 0
( O 0
safety O 0
population O 0
) O 0
. O 0

The O 0
majority O 0
were O 0
women O 0
( O 0
52 O 0
. O 0
7 O 0
% O 0
) O 0
. O 0

Patients O 0
' O 0
mean O 0
age O 0
was O 0
53 O 0
. O 0
9 O 0
years O 0
, O 0
their O 0
mean O 0
weight O 0
was O 0
193 O 0
. O 0
9 O 0
pounds O 0
, O 0
and O 0
they O 0
smoked O 0
a O 0
mean O 0
of O 0
25 O 0
. O 0
2 O 0
cigarettes O 0
per O 0
day O 0
at O 0
baseline O 0
. O 0

Five O 0
hundred O 0
fifty O 0
- O 0
three O 0
patients O 0
, O 0
264 O 0
taking O 0
the O 0
lozenge O 0
and O 0
289 O 0
taking O 0
the O 0
gum O 0
, O 0
used O 0
the O 0
study O 0
product O 0
for O 0
> O 0
or O 0
= O 0
4 O 0
days O 0
per O 0
week O 0
during O 0
the O 0
first O 0
2 O 0
weeks O 0
( O 0
evaluable O 0
population O 0
) O 0
. O 0

The O 0
nicotine B-Chemical 1
lozenge O 0
and O 0
nicotine B-Chemical 1
gum O 0
were O 0
equally O 0
well O 0
tolerated O 0
, O 0
despite O 0
increased O 0
nicotine B-Chemical 1
exposure O 0
from O 0
the O 0
lozenge O 0
. O 0

The O 0
incidence O 0
of O 0
adverse O 0
events O 0
in O 0
the O 0
2 O 0
groups O 0
was O 0
similar O 0
during O 0
the O 0
first O 0
2 O 0
weeks O 0
of O 0
product O 0
use O 0
( O 0
evaluation O 0
population O 0
: O 0
55 O 0
. O 0
3 O 0
% O 0
lozenge O 0
, O 0
54 O 0
. O 0
7 O 0
% O 0
gum O 0
) O 0
, O 0
as O 0
well O 0
as O 0
during O 0
the O 0
entire O 0
study O 0
( O 0
safety O 0
population O 0
: O 0
63 O 0
. O 0
8 O 0
% O 0
and O 0
58 O 0
. O 0
6 O 0
% O 0
, O 0
respectively O 0
) O 0
. O 0

Stratification O 0
of O 0
patients O 0
by O 0
sex O 0
, O 0
age O 0
, O 0
extent O 0
of O 0
concurrent O 0
smoking O 0
, O 0
extent O 0
of O 0
product O 0
use O 0
, O 0
and O 0
severity O 0
of O 0
adverse O 0
events O 0
revealed O 0
no O 0
clinically O 0
significant O 0
differences O 0
between O 0
the O 0
lozenge O 0
and O 0
gum O 0
. O 0

The O 0
most O 0
common O 0
adverse O 0
events O 0
were O 0
nausea B-Disease 1
( O 0
17 O 0
. O 0
2 O 0
% O 0
and O 0
16 O 0
. O 0
1 O 0
% O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
- O 0
3 O 0
. O 0
7 O 0
to O 0
6 O 0
. O 0
0 O 0
) O 0
, O 0
hiccups B-Disease 1
( O 0
10 O 0
. O 0
7 O 0
% O 0
and O 0
6 O 0
. O 0
6 O 0
% O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
0 O 0
. O 0
5 O 0
to O 0
7 O 0
. O 0
8 O 0
) O 0
, O 0
and O 0
headache B-Disease 1
( O 0
8 O 0
. O 0
7 O 0
% O 0
and O 0
9 O 0
. O 0
9 O 0
% O 0
; O 0
95 O 0
% O 0
Cl O 0
, O 0
- O 0
5 O 0
. O 0
0 O 0
to O 0
2 O 0
. O 0
6 O 0
) O 0
. O 0

Serious O 0
adverse O 0
events O 0
were O 0
reported O 0
in O 0
11 O 0
and O 0
13 O 0
patients O 0
in O 0
the O 0
respective O 0
groups O 0
. O 0

Fewer O 0
than O 0
6 O 0
% O 0
of O 0
patients O 0
in O 0
either O 0
group O 0
were O 0
considered O 0
by O 0
the O 0
investigator O 0
to O 0
have O 0
a O 0
worsening O 0
of O 0
their O 0
overall O 0
disease O 0
condition O 0
during O 0
the O 0
study O 0
. O 0

The O 0
majority O 0
of O 0
patients O 0
( O 0
> O 0
60 O 0
% O 0
) O 0
experienced O 0
no O 0
change O 0
in O 0
their O 0
disease O 0
status O 0
from O 0
baseline O 0
. O 0

CONCLUSION O 0
: O 0
The O 0
4 O 0
- O 0
mg O 0
nicotine B-Chemical 1
lozenge O 0
and O 0
4 O 0
- O 0
mg O 0
nicotine B-Chemical 1
gum O 0
had O 0
comparable O 0
safety O 0
profiles O 0
in O 0
these O 0
patients O 0
with O 0
label O 0
- O 0
restricted O 0
medical O 0
conditions O 0
. O 0

Pharmacological O 0
modulation O 0
of O 0
pain B-Disease 1
- O 0
related O 0
brain O 0
activity O 0
during O 0
normal O 0
and O 0
central O 0
sensitization O 0
states O 0
in O 0
humans O 0
. O 0

Abnormal O 0
processing O 0
of O 0
somatosensory O 0
inputs O 0
in O 0
the O 0
central O 0
nervous O 0
system O 0
( O 0
central O 0
sensitization O 0
) O 0
is O 0
the O 0
mechanism O 0
accounting O 0
for O 0
the O 0
enhanced O 0
pain B-Disease 1
sensitivity O 0
in O 0
the O 0
skin O 0
surrounding O 0
tissue B-Disease 1
injury I-Disease 1
( O 0
secondary B-Disease 1
hyperalgesia I-Disease 1
) O 0
. O 0

Secondary B-Disease 1
hyperalgesia I-Disease 1
shares O 0
clinical O 0
characteristics O 0
with O 0
neurogenic B-Disease 1
hyperalgesia I-Disease 1
in O 0
patients O 0
with O 0
neuropathic B-Disease 1
pain I-Disease 1
. O 0

Abnormal O 0
brain O 0
responses O 0
to O 0
somatosensory O 0
stimuli O 0
have O 0
been O 0
found O 0
in O 0
patients O 0
with O 0
hyperalgesia B-Disease 1
as O 0
well O 0
as O 0
in O 0
normal O 0
subjects O 0
during O 0
experimental O 0
central O 0
sensitization O 0
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
assess O 0
the O 0
effects O 0
of O 0
gabapentin B-Chemical 1
, O 0
a O 0
drug O 0
effective O 0
in O 0
neuropathic B-Disease 1
pain I-Disease 1
patients O 0
, O 0
on O 0
brain O 0
processing O 0
of O 0
nociceptive O 0
information O 0
in O 0
normal O 0
and O 0
central O 0
sensitization O 0
states O 0
. O 0

Using O 0
functional O 0
magnetic O 0
resonance O 0
imaging O 0
( O 0
fMRI O 0
) O 0
in O 0
normal O 0
volunteers O 0
, O 0
we O 0
studied O 0
the O 0
gabapentin B-Chemical 1
- O 0
induced O 0
modulation O 0
of O 0
brain O 0
activity O 0
in O 0
response O 0
to O 0
nociceptive O 0
mechanical O 0
stimulation O 0
of O 0
normal O 0
skin O 0
and O 0
capsaicin B-Chemical 1
- O 0
induced O 0
secondary B-Disease 1
hyperalgesia I-Disease 1
. O 0

The O 0
dose O 0
of O 0
gabapentin B-Chemical 1
was O 0
1 O 0
, O 0
800 O 0
mg O 0
per O 0
os O 0
, O 0
in O 0
a O 0
single O 0
administration O 0
. O 0

We O 0
found O 0
that O 0
( O 0
i O 0
) O 0
gabapentin B-Chemical 1
reduced O 0
the O 0
activations O 0
in O 0
the O 0
bilateral O 0
operculoinsular O 0
cortex O 0
, O 0
independently O 0
of O 0
the O 0
presence O 0
of O 0
central O 0
sensitization O 0
; O 0
( O 0
ii O 0
) O 0
gabapentin B-Chemical 1
reduced O 0
the O 0
activation O 0
in O 0
the O 0
brainstem O 0
, O 0
only O 0
during O 0
central O 0
sensitization O 0
; O 0
( O 0
iii O 0
) O 0
gabapentin B-Chemical 1
suppressed O 0
stimulus O 0
- O 0
induced O 0
deactivations O 0
, O 0
only O 0
during O 0
central O 0
sensitization O 0
; O 0
this O 0
effect O 0
was O 0
more O 0
robust O 0
than O 0
the O 0
effect O 0
on O 0
brain O 0
activation O 0
. O 0

The O 0
observed O 0
drug O 0
- O 0
induced O 0
effects O 0
were O 0
not O 0
due O 0
to O 0
changes O 0
in O 0
the O 0
baseline O 0
fMRI O 0
signal O 0
. O 0

These O 0
findings O 0
indicate O 0
that O 0
gabapentin B-Chemical 1
has O 0
a O 0
measurable O 0
antinociceptive O 0
effect O 0
and O 0
a O 0
stronger O 0
antihyperalgesic O 0
effect O 0
most O 0
evident O 0
in O 0
the O 0
brain O 0
areas O 0
undergoing O 0
deactivation O 0
, O 0
thus O 0
supporting O 0
the O 0
concept O 0
that O 0
gabapentin B-Chemical 1
is O 0
more O 0
effective O 0
in O 0
modulating O 0
nociceptive O 0
transmission O 0
when O 0
central O 0
sensitization O 0
is O 0
present O 0
. O 0

Investigation O 0
of O 0
mitochondrial O 0
involvement O 0
in O 0
the O 0
experimental O 0
model O 0
of O 0
epilepsy B-Disease 1
induced O 0
by O 0
pilocarpine B-Chemical 1
. O 0

Mitochondrial B-Disease 1
abnormalities I-Disease 1
have O 0
been O 0
associated O 0
with O 0
several O 0
aspects O 0
of O 0
epileptogenesis O 0
, O 0
such O 0
as O 0
energy O 0
generation O 0
, O 0
control O 0
of O 0
cell O 0
death B-Disease 1
, O 0
neurotransmitter O 0
synthesis O 0
, O 0
and O 0
free O 0
radical O 0
( O 0
FR O 0
) O 0
production O 0
. O 0

Increased O 0
production O 0
of O 0
FRs O 0
may O 0
cause O 0
mtDNA O 0
damage O 0
leading O 0
to O 0
decreased O 0
activities O 0
of O 0
oxidative O 0
phosphorylation O 0
complexes O 0
containing O 0
mtDNA O 0
- O 0
encoded O 0
subunits O 0
. O 0

In O 0
this O 0
study O 0
, O 0
we O 0
investigated O 0
whether O 0
increased O 0
generation O 0
of O 0
FR O 0
during O 0
status B-Disease 1
epilepticus I-Disease 1
would O 0
be O 0
sufficient O 0
to O 0
provoke O 0
abnormalities O 0
in O 0
mtDNA O 0
and O 0
in O 0
the O 0
expression O 0
and O 0
activity O 0
of O 0
cytochrome O 0
c O 0
oxidase O 0
( O 0
CCO O 0
) O 0
, O 0
complex O 0
IV O 0
of O 0
the O 0
respiratory O 0
chain O 0
, O 0
in O 0
the O 0
chronic O 0
phase O 0
of O 0
the O 0
pilocarpine B-Chemical 1
model O 0
of O 0
temporal B-Disease 1
lobe I-Disease 1
epilepsy I-Disease 1
. O 0

DNA O 0
analysis O 0
revealed O 0
low O 0
amounts O 0
of O 0
a O 0
4 O 0
. O 0
8 O 0
kb O 0
mtDNA O 0
deletion O 0
but O 0
with O 0
no O 0
differences O 0
in O 0
frequency O 0
or O 0
quantity O 0
in O 0
the O 0
control O 0
and O 0
experimental O 0
groups O 0
. O 0

We O 0
did O 0
not O 0
find O 0
abnormalities O 0
in O 0
the O 0
expression O 0
and O 0
distribution O 0
of O 0
an O 0
mtDNA O 0
- O 0
encoded O 0
subunit O 0
of O 0
CCO O 0
( O 0
CCO O 0
- O 0
I O 0
) O 0
or O 0
a O 0
relative O 0
decrease O 0
in O 0
CCO O 0
- O 0
I O 0
when O 0
compared O 0
with O 0
nuclear O 0
- O 0
encoded O 0
subunits O 0
( O 0
CCO O 0
- O 0
IV O 0
and O 0
SDH O 0
- O 0
fp O 0
) O 0
. O 0

No O 0
abnormality O 0
in O 0
CCO O 0
activity O 0
was O 0
observed O 0
through O 0
histochemistry O 0
. O 0

Although O 0
evidences O 0
of O 0
mitochondrial B-Disease 1
abnormalities I-Disease 1
were O 0
found O 0
in O 0
previously O 0
published O 0
studies O 0
, O 0
our O 0
results O 0
do O 0
not O 0
suggest O 0
that O 0
the O 0
FRs O 0
, O 0
generated O 0
during O 0
the O 0
acute O 0
phase O 0
, O 0
determined O 0
important O 0
abnormalities O 0
in O 0
mtDNA O 0
, O 0
in O 0
expression O 0
of O 0
CCO O 0
- O 0
I O 0
, O 0
and O 0
in O 0
CCO O 0
activity O 0
. O 0

Adverse O 0
effect O 0
of O 0
the O 0
calcium B-Chemical 1
channel O 0
blocker O 0
nitrendipine B-Chemical 1
on O 0
nephrosclerosis B-Disease 1
in O 0
rats O 0
with O 0
renovascular B-Disease 1
hypertension I-Disease 1
. O 0

The O 0
effect O 0
of O 0
a O 0
6 O 0
- O 0
week O 0
treatment O 0
with O 0
the O 0
calcium B-Chemical 1
channel O 0
blocker O 0
nitrendipine B-Chemical 1
or O 0
the O 0
angiotensin B-Chemical 1
converting O 0
enzyme O 0
inhibitor O 0
enalapril B-Chemical 1
on O 0
blood O 0
pressure O 0
, O 0
albuminuria B-Disease 1
, O 0
renal O 0
hemodynamics O 0
, O 0
and O 0
morphology O 0
of O 0
the O 0
nonclipped O 0
kidney O 0
was O 0
studied O 0
in O 0
rats O 0
with O 0
two O 0
- O 0
kidney O 0
, O 0
one O 0
clip O 0
renovascular B-Disease 1
hypertension I-Disease 1
. O 0

Six O 0
weeks O 0
after O 0
clipping O 0
of O 0
one O 0
renal O 0
artery O 0
, O 0
hypertensive B-Disease 1
rats O 0
( O 0
178 O 0
+ O 0
/ O 0
- O 0
4 O 0
mm O 0
Hg O 0
) O 0
were O 0
randomly O 0
assigned O 0
to O 0
three O 0
groups O 0
: O 0
untreated O 0
hypertensive B-Disease 1
controls O 0
( O 0
n O 0
= O 0
8 O 0
) O 0
, O 0
enalapril B-Chemical 1
- O 0
treated O 0
( O 0
n O 0
= O 0
8 O 0
) O 0
, O 0
or O 0
nitrendipine B-Chemical 1
- O 0
treated O 0
( O 0
n O 0
= O 0
10 O 0
) O 0
. O 0

Sham O 0
- O 0
operated O 0
rats O 0
served O 0
as O 0
normotensive O 0
controls O 0
( O 0
128 O 0
+ O 0
/ O 0
- O 0
3 O 0
mm O 0
Hg O 0
, O 0
n O 0
= O 0
8 O 0
) O 0
. O 0

After O 0
6 O 0
weeks O 0
of O 0
treatment O 0
, O 0
renal O 0
hemodynamics O 0
( O 0
glomerular O 0
filtration O 0
rate O 0
and O 0
renal O 0
plasma O 0
flow O 0
) O 0
were O 0
measured O 0
in O 0
the O 0
anesthetized O 0
rats O 0
. O 0

Renal O 0
tissue O 0
was O 0
obtained O 0
for O 0
determination O 0
of O 0
glomerular O 0
size O 0
and O 0
sclerosis O 0
. O 0

Enalapril B-Chemical 1
but O 0
not O 0
nitrendipine B-Chemical 1
reduced O 0
blood O 0
pressure O 0
significantly O 0
. O 0

After O 0
6 O 0
weeks O 0
of O 0
therapy O 0
, O 0
glomerular O 0
filtration O 0
rate O 0
was O 0
not O 0
different O 0
among O 0
the O 0
studied O 0
groups O 0
. O 0

Renal O 0
plasma O 0
flow O 0
increased O 0
, O 0
but O 0
albumin O 0
excretion O 0
and O 0
glomerulosclerosis B-Disease 1
did O 0
not O 0
change O 0
after O 0
enalapril B-Chemical 1
treatment O 0
. O 0

In O 0
contrast O 0
, O 0
in O 0
the O 0
nitrendipine B-Chemical 1
- O 0
treated O 0
group O 0
albuminuria B-Disease 1
increased O 0
from O 0
12 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
2 O 0
progressively O 0
to O 0
163 O 0
+ O 0
/ O 0
- O 0
55 O 0
compared O 0
with O 0
19 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
9 O 0
mg O 0
/ O 0
24 O 0
hr O 0
in O 0
the O 0
hypertensive B-Disease 1
controls O 0
. O 0

Furthermore O 0
, O 0
glomerulosclerosis B-Disease 1
index O 0
was O 0
significantly O 0
increased O 0
in O 0
the O 0
nitrendipine B-Chemical 1
- O 0
treated O 0
group O 0
compared O 0
with O 0
the O 0
hypertensive B-Disease 1
controls O 0
( O 0
0 O 0
. O 0
38 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
1 O 0
versus O 0
0 O 0
. O 0
13 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
04 O 0
) O 0
. O 0

In O 0
addition O 0
, O 0
glomerular O 0
size O 0
was O 0
higher O 0
in O 0
the O 0
nitrendipine B-Chemical 1
- O 0
treated O 0
group O 0
( O 0
14 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
17 O 0
10 O 0
( O 0
- O 0
3 O 0
) O 0
mm2 O 0
) O 0
but O 0
lower O 0
in O 0
the O 0
enalapril B-Chemical 1
- O 0
treated O 0
group O 0
( O 0
11 O 0
. O 0
5 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
15 O 0
10 O 0
( O 0
- O 0
3 O 0
) O 0
mm2 O 0
) O 0
compared O 0
with O 0
the O 0
hypertensive B-Disease 1
controls O 0
( O 0
12 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
17 O 0
10 O 0
( O 0
- O 0
3 O 0
) O 0
mm2 O 0
) O 0
. O 0
( O 0
ABSTRACT O 0
TRUNCATED O 0
AT O 0
250 O 0
WORDS O 0
) O 0

Ketoconazole B-Chemical 1
induced O 0
torsades B-Disease 1
de I-Disease 1
pointes I-Disease 1
without O 0
concomitant O 0
use O 0
of O 0
QT O 0
interval O 0
- O 0
prolonging O 0
drug O 0
. O 0

Ketoconazole B-Chemical 1
is O 0
not O 0
known O 0
to O 0
be O 0
proarrhythmic O 0
without O 0
concomitant O 0
use O 0
of O 0
QT O 0
interval O 0
- O 0
prolonging O 0
drugs O 0
. O 0

We O 0
report O 0
a O 0
woman O 0
with O 0
coronary B-Disease 1
artery I-Disease 1
disease I-Disease 1
who O 0
developed O 0
a O 0
markedly O 0
prolonged B-Disease 1
QT I-Disease 1
interval I-Disease 1
and O 0
torsades B-Disease 1
de I-Disease 1
pointes I-Disease 1
( O 0
TdP B-Disease 1
) O 0
after O 0
taking O 0
ketoconazole B-Chemical 1
for O 0
treatment O 0
of O 0
fungal B-Disease 1
infection I-Disease 1
. O 0

Her O 0
QT O 0
interval O 0
returned O 0
to O 0
normal O 0
upon O 0
withdrawal O 0
of O 0
ketoconazole B-Chemical 1
. O 0

Genetic O 0
study O 0
did O 0
not O 0
find O 0
any O 0
mutation O 0
in O 0
her O 0
genes O 0
that O 0
encode O 0
cardiac O 0
IKr O 0
channel O 0
proteins O 0
. O 0

We O 0
postulate O 0
that O 0
by O 0
virtue O 0
of O 0
its O 0
direct O 0
blocking O 0
action O 0
on O 0
IKr O 0
, O 0
ketoconazole B-Chemical 1
alone O 0
may O 0
prolong O 0
QT O 0
interval O 0
and O 0
induce O 0
TdP B-Disease 1
. O 0

This O 0
calls O 0
for O 0
attention O 0
when O 0
ketoconazole B-Chemical 1
is O 0
administered O 0
to O 0
patients O 0
with O 0
risk O 0
factors O 0
for O 0
acquired O 0
long B-Disease 1
QT I-Disease 1
syndrome I-Disease 1
. O 0

Cerebral B-Disease 1
vasculitis I-Disease 1
following O 0
oral O 0
methylphenidate B-Chemical 1
intake O 0
in O 0
an O 0
adult O 0
: O 0
a O 0
case O 0
report O 0
. O 0

Methylphenidate B-Chemical 1
is O 0
structurally O 0
and O 0
functionally O 0
similar O 0
to O 0
amphetamine B-Chemical 1
. O 0

Cerebral B-Disease 1
vasculitis I-Disease 1
associated O 0
with O 0
amphetamine B-Disease 1
abuse I-Disease 1
is O 0
well O 0
documented O 0
, O 0
and O 0
in O 0
rare O 0
cases O 0
ischaemic B-Disease 1
stroke I-Disease 1
has O 0
been O 0
reported O 0
after O 0
methylphenidate B-Chemical 1
intake O 0
in O 0
children O 0
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
63 O 0
- O 0
year O 0
- O 0
old O 0
female O 0
who O 0
was O 0
treated O 0
with O 0
methylphenidate B-Chemical 1
due O 0
to O 0
hyperactivity B-Disease 1
and O 0
suffered O 0
from O 0
multiple O 0
ischaemic B-Disease 1
strokes I-Disease 1
. O 0

We O 0
consider O 0
drug O 0
- O 0
induced O 0
cerebral B-Disease 1
vasculitis I-Disease 1
as O 0
the O 0
most O 0
likely O 0
cause O 0
of O 0
recurrent O 0
ischaemic B-Disease 1
strokes I-Disease 1
in O 0
the O 0
absence O 0
of O 0
any O 0
pathological O 0
findings O 0
during O 0
the O 0
diagnostic O 0
work O 0
- O 0
up O 0
. O 0

We O 0
conclude O 0
that O 0
methylphenidate B-Chemical 1
mediated O 0
vasculitis B-Disease 1
should O 0
be O 0
considered O 0
in O 0
patients O 0
with O 0
neurological O 0
symptoms O 0
and O 0
a O 0
history O 0
of O 0
methylphenidate B-Chemical 1
therapy O 0
. O 0

This O 0
potential O 0
side O 0
- O 0
effect O 0
, O 0
though O 0
very O 0
rare O 0
, O 0
represents O 0
one O 0
more O 0
reason O 0
to O 0
be O 0
very O 0
restrictive O 0
in O 0
the O 0
use O 0
of O 0
methylphenidate B-Chemical 1
. O 0

MDMA B-Chemical 1
polydrug O 0
users O 0
show O 0
process O 0
- O 0
specific O 0
central O 0
executive O 0
impairments O 0
coupled O 0
with O 0
impaired B-Disease 1
social I-Disease 1
and I-Disease 1
emotional I-Disease 1
judgement I-Disease 1
processes I-Disease 1
. O 0

In O 0
recent O 0
years O 0
working O 0
memory B-Disease 1
deficits I-Disease 1
have O 0
been O 0
reported O 0
in O 0
users O 0
of O 0
MDMA B-Chemical 1
( O 0
3 B-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
methylenedioxymethamphetamine I-Chemical 1
, O 0
ecstasy B-Chemical 1
) O 0
. O 0

The O 0
current O 0
study O 0
aimed O 0
to O 0
assess O 0
the O 0
impact O 0
of O 0
MDMA B-Chemical 1
use O 0
on O 0
three O 0
separate O 0
central O 0
executive O 0
processes O 0
( O 0
set O 0
shifting O 0
, O 0
inhibition O 0
and O 0
memory O 0
updating O 0
) O 0
and O 0
also O 0
on O 0
" O 0
prefrontal O 0
" O 0
mediated O 0
social O 0
and O 0
emotional O 0
judgement O 0
processes O 0
. O 0

Fifteen O 0
polydrug O 0
ecstasy B-Chemical 1
users O 0
and O 0
15 O 0
polydrug O 0
non O 0
- O 0
ecstasy B-Chemical 1
user O 0
controls O 0
completed O 0
a O 0
general O 0
drug O 0
use O 0
questionnaire O 0
, O 0
the O 0
Brixton O 0
Spatial O 0
Anticipation O 0
task O 0
( O 0
set O 0
shifting O 0
) O 0
, O 0
Backward O 0
Digit O 0
Span O 0
procedure O 0
( O 0
memory O 0
updating O 0
) O 0
, O 0
Inhibition O 0
of O 0
Return O 0
( O 0
inhibition O 0
) O 0
, O 0
an O 0
emotional O 0
intelligence O 0
scale O 0
, O 0
the O 0
Tromso O 0
Social O 0
Intelligence O 0
Scale O 0
and O 0
the O 0
Dysexecutive O 0
Questionnaire O 0
( O 0
DEX O 0
) O 0
. O 0

Compared O 0
with O 0
MDMA B-Chemical 1
- O 0
free O 0
polydrug O 0
controls O 0
, O 0
MDMA B-Chemical 1
polydrug O 0
users O 0
showed O 0
impairments O 0
in O 0
set O 0
shifting O 0
and O 0
memory O 0
updating O 0
, O 0
and O 0
also O 0
in O 0
social O 0
and O 0
emotional O 0
judgement O 0
processes O 0
. O 0

The O 0
latter O 0
two O 0
deficits O 0
remained O 0
significant O 0
after O 0
controlling O 0
for O 0
other O 0
drug O 0
use O 0
. O 0

These O 0
data O 0
lend O 0
further O 0
support O 0
to O 0
the O 0
proposal O 0
that O 0
cognitive O 0
processes O 0
mediated O 0
by O 0
the O 0
prefrontal O 0
cortex O 0
may O 0
be O 0
impaired O 0
by O 0
recreational O 0
ecstasy B-Chemical 1
use O 0
. O 0

Phase O 0
II O 0
study O 0
of O 0
the O 0
amsacrine B-Chemical 1
analogue O 0
CI B-Chemical 1
- I-Chemical 1
921 I-Chemical 1
( O 0
NSC B-Chemical 1
343499 I-Chemical 1
) O 0
in O 0
non B-Disease 1
- I-Disease 1
small I-Disease 1
cell I-Disease 1
lung I-Disease 1
cancer I-Disease 1
. O 0

CI B-Chemical 1
- I-Chemical 1
921 I-Chemical 1
( O 0
NSC B-Chemical 1
343499 I-Chemical 1
; O 0
9 B-Chemical 1
- I-Chemical 1
[ I-Chemical 1
[ I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
methoxy I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
[ I-Chemical 1
( I-Chemical 1
methylsulphonyl I-Chemical 1
) I-Chemical 1
amino I-Chemical 1
] I-Chemical 1
phenyl I-Chemical 1
] I-Chemical 1
amino I-Chemical 1
] I-Chemical 1
- I-Chemical 1
N I-Chemical 1
, I-Chemical 1
5 I-Chemical 1
- I-Chemical 1
dimethyl I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
acridinecarboxamide I-Chemical 1
) O 0
is O 0
a O 0
topoisomerase O 0
II O 0
poison O 0
with O 0
high O 0
experimental O 0
antitumour O 0
activity O 0
. O 0

It O 0
was O 0
administered O 0
by O 0
15 O 0
min O 0
infusion O 0
to O 0
16 O 0
evaluable O 0
patients O 0
with O 0
non B-Disease 1
- I-Disease 1
small I-Disease 1
cell I-Disease 1
lung I-Disease 1
cancer I-Disease 1
( O 0
NSCLC B-Disease 1
) O 0
( O 0
7 O 0
with O 0
no O 0
prior O 0
treatment O 0
, O 0
9 O 0
patients O 0
in O 0
relapse O 0
following O 0
surgery O 0
/ O 0
radiotherapy O 0
) O 0
at O 0
a O 0
dose O 0
( O 0
648 O 0
mg O 0
/ O 0
m2 O 0
divided O 0
over O 0
3 O 0
days O 0
, O 0
repeated O 0
every O 0
3 O 0
weeks O 0
) O 0
determined O 0
by O 0
phase O 0
I O 0
trial O 0
. O 0

Patients O 0
had O 0
a O 0
median O 0
performance O 0
status O 0
of O 0
1 O 0
( O 0
WHO O 0
) O 0
, O 0
and O 0
median O 0
age O 0
of O 0
61 O 0
years O 0
. O 0

The O 0
histology O 0
comprised O 0
squamous B-Disease 1
carcinoma I-Disease 1
( O 0
11 O 0
) O 0
, O 0
adenocarcinoma B-Disease 1
( O 0
1 O 0
) O 0
, O 0
mixed O 0
histology O 0
( O 0
2 O 0
) O 0
, O 0
bronchio B-Disease 1
- I-Disease 1
alveolar I-Disease 1
carcinoma I-Disease 1
( O 0
1 O 0
) O 0
and O 0
large O 0
cell O 0
undifferentiated B-Disease 1
carcinoma I-Disease 1
( O 0
1 O 0
) O 0
. O 0

Neutropenia B-Disease 1
grade O 0
greater O 0
than O 0
or O 0
equal O 0
to O 0
3 O 0
was O 0
seen O 0
in O 0
15 O 0
patients O 0
, O 0
infections B-Disease 1
with O 0
recovery O 0
in O 0
3 O 0
, O 0
and O 0
grand O 0
mal O 0
seizures B-Disease 1
in O 0
1 O 0
patient O 0
. O 0

Grade O 0
less O 0
than O 0
or O 0
equal O 0
to O 0
2 O 0
nausea B-Disease 1
and O 0
vomiting B-Disease 1
occurred O 0
in O 0
66 O 0
% O 0
courses O 0
and O 0
phlebitis B-Disease 1
in O 0
the O 0
infusion O 0
arm O 0
in O 0
37 O 0
% O 0
. O 0

1 O 0
patient O 0
with O 0
squamous B-Disease 1
cell I-Disease 1
carcinoma I-Disease 1
achieved O 0
a O 0
partial O 0
response O 0
lasting O 0
5 O 0
months O 0
. O 0

Further O 0
testing O 0
in O 0
this O 0
and O 0
other O 0
tumour B-Disease 1
types O 0
using O 0
multiple O 0
daily O 0
schedules O 0
is O 0
warranted O 0
. O 0

Pharmacokinetics O 0
of O 0
desipramine B-Chemical 1
HCl I-Chemical 1
when O 0
administered O 0
with O 0
cinacalcet B-Chemical 1
HCl I-Chemical 1
. O 0

OBJECTIVE O 0
: O 0
In O 0
vitro O 0
work O 0
has O 0
demonstrated O 0
that O 0
cinacalcet B-Chemical 1
is O 0
a O 0
strong O 0
inhibitor O 0
of O 0
cytochrome O 0
P450 O 0
isoenzyme O 0
( O 0
CYP O 0
) O 0
2D6 O 0
. O 0

The O 0
purpose O 0
of O 0
this O 0
study O 0
was O 0
to O 0
evaluate O 0
the O 0
effect O 0
of O 0
cinacalcet B-Chemical 1
on O 0
CYP2D6 O 0
activity O 0
, O 0
using O 0
desipramine B-Chemical 1
as O 0
a O 0
probe O 0
substrate O 0
, O 0
in O 0
healthy O 0
subjects O 0
. O 0

METHODS O 0
: O 0
Seventeen O 0
subjects O 0
who O 0
were O 0
genotyped O 0
as O 0
CYP2D6 O 0
extensive O 0
metabolizers O 0
were O 0
enrolled O 0
in O 0
this O 0
randomized O 0
, O 0
open O 0
- O 0
label O 0
, O 0
crossover O 0
study O 0
to O 0
receive O 0
a O 0
single O 0
oral O 0
dose O 0
of O 0
desipramine B-Chemical 1
( O 0
50 O 0
mg O 0
) O 0
on O 0
two O 0
separate O 0
occasions O 0
, O 0
once O 0
alone O 0
and O 0
once O 0
after O 0
multiple O 0
doses O 0
of O 0
cinacalcet B-Chemical 1
( O 0
90 O 0
mg O 0
for O 0
7 O 0
days O 0
) O 0
. O 0

Blood O 0
samples O 0
were O 0
obtained O 0
predose O 0
and O 0
up O 0
to O 0
72 O 0
h O 0
postdose O 0
. O 0

RESULTS O 0
: O 0
Fourteen O 0
subjects O 0
completed O 0
both O 0
treatment O 0
arms O 0
. O 0

Relative O 0
to O 0
desipramine B-Chemical 1
alone O 0
, O 0
mean O 0
AUC O 0
and O 0
C O 0
( O 0
max O 0
) O 0
of O 0
desipramine B-Chemical 1
increased O 0
3 O 0
. O 0
6 O 0
- O 0
and O 0
1 O 0
. O 0
8 O 0
- O 0
fold O 0
when O 0
coadministered O 0
with O 0
cinacalcet B-Chemical 1
. O 0

The O 0
t O 0
( O 0
1 O 0
/ O 0
2 O 0
, O 0
z O 0
) O 0
of O 0
desipramine B-Chemical 1
was O 0
longer O 0
when O 0
desipramine B-Chemical 1
was O 0
coadministered O 0
with O 0
cinacalcet B-Chemical 1
( O 0
21 O 0
. O 0
0 O 0
versus O 0
43 O 0
. O 0
3 O 0
hs O 0
) O 0
. O 0

The O 0
t O 0
( O 0
max O 0
) O 0
was O 0
similar O 0
between O 0
the O 0
regimens O 0
. O 0

Fewer O 0
subjects O 0
reported O 0
adverse O 0
events O 0
following O 0
treatment O 0
with O 0
desipramine B-Chemical 1
alone O 0
than O 0
when O 0
receiving O 0
desipramine B-Chemical 1
with O 0
cinacalcet B-Chemical 1
( O 0
33 O 0
versus O 0
86 O 0
% O 0
) O 0
, O 0
the O 0
most O 0
frequent O 0
of O 0
which O 0
( O 0
nausea B-Disease 1
and O 0
headache B-Disease 1
) O 0
have O 0
been O 0
reported O 0
for O 0
patients O 0
treated O 0
with O 0
either O 0
desipramine B-Chemical 1
or O 0
cinacalcet B-Chemical 1
. O 0

CONCLUSION O 0
: O 0
This O 0
study O 0
demonstrates O 0
that O 0
cinacalcet B-Chemical 1
is O 0
a O 0
strong O 0
inhibitor O 0
of O 0
CYP2D6 O 0
. O 0

These O 0
data O 0
suggest O 0
that O 0
during O 0
concomitant O 0
treatment O 0
with O 0
cinacalcet B-Chemical 1
, O 0
dose O 0
adjustment O 0
may O 0
be O 0
necessary O 0
for O 0
drugs O 0
that O 0
demonstrate O 0
a O 0
narrow O 0
therapeutic O 0
index O 0
and O 0
are O 0
metabolized O 0
by O 0
CYP2D6 O 0
. O 0

Case O 0
report O 0
: O 0
acute O 0
unintentional O 0
carbachol B-Chemical 1
intoxication O 0
. O 0

INTRODUCTION O 0
: O 0
Intoxications O 0
with O 0
carbachol B-Chemical 1
, O 0
a O 0
muscarinic O 0
cholinergic O 0
receptor O 0
agonist O 0
are O 0
rare O 0
. O 0

We O 0
report O 0
an O 0
interesting O 0
case O 0
investigating O 0
a O 0
( O 0
near O 0
) O 0
fatal O 0
poisoning B-Disease 1
. O 0

METHODS O 0
: O 0
The O 0
son O 0
of O 0
an O 0
84 O 0
- O 0
year O 0
- O 0
old O 0
male O 0
discovered O 0
a O 0
newspaper O 0
report O 0
stating O 0
clinical O 0
success O 0
with O 0
plant O 0
extracts O 0
in O 0
Alzheimer B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

The O 0
mode O 0
of O 0
action O 0
was O 0
said O 0
to O 0
be O 0
comparable O 0
to O 0
that O 0
of O 0
the O 0
synthetic O 0
compound O 0
' O 0
carbamylcholin B-Chemical 1
' O 0
; O 0
that O 0
is O 0
, O 0
carbachol B-Chemical 1
. O 0

He O 0
bought O 0
25 O 0
g O 0
of O 0
carbachol B-Chemical 1
as O 0
pure O 0
substance O 0
in O 0
a O 0
pharmacy O 0
, O 0
and O 0
the O 0
father O 0
was O 0
administered O 0
400 O 0
to O 0
500 O 0
mg O 0
. O 0

Carbachol B-Chemical 1
concentrations O 0
in O 0
serum O 0
and O 0
urine O 0
on O 0
day O 0
1 O 0
and O 0
2 O 0
of O 0
hospital O 0
admission O 0
were O 0
analysed O 0
by O 0
HPLC O 0
- O 0
mass O 0
spectrometry O 0
. O 0

RESULTS O 0
: O 0
Minutes O 0
after O 0
oral O 0
administration O 0
, O 0
the O 0
patient O 0
developed O 0
nausea B-Disease 1
, O 0
sweating O 0
and O 0
hypotension B-Disease 1
, O 0
and O 0
finally O 0
collapsed O 0
. O 0

Bradycardia B-Disease 1
, O 0
cholinergic O 0
symptoms O 0
and O 0
asystole B-Disease 1
occurred O 0
. O 0

Initial O 0
cardiopulmonary O 0
resuscitation O 0
and O 0
immediate O 0
treatment O 0
with O 0
adrenaline B-Chemical 1
( O 0
epinephrine B-Chemical 1
) O 0
, O 0
atropine B-Chemical 1
and O 0
furosemide B-Chemical 1
was O 0
successful O 0
. O 0

On O 0
hospital O 0
admission O 0
, O 0
blood O 0
pressure O 0
of O 0
the O 0
intubated O 0
, O 0
bradyarrhythmic O 0
patient O 0
was O 0
100 O 0
/ O 0
65 O 0
mmHg O 0
. O 0

Further O 0
signs O 0
were O 0
hyperhidrosis B-Disease 1
, O 0
hypersalivation B-Disease 1
, O 0
bronchorrhoea B-Disease 1
, O 0
and O 0
severe O 0
miosis B-Disease 1
; O 0
the O 0
electrocardiographic O 0
finding O 0
was O 0
atrio B-Disease 1
- I-Disease 1
ventricular I-Disease 1
dissociation I-Disease 1
. O 0

High O 0
doses O 0
of O 0
atropine B-Chemical 1
( O 0
up O 0
to O 0
50 O 0
mg O 0
per O 0
24 O 0
hours O 0
) O 0
, O 0
adrenaline B-Chemical 1
and O 0
dopamine B-Chemical 1
were O 0
necessary O 0
. O 0

The O 0
patient O 0
was O 0
extubated O 0
1 O 0
week O 0
later O 0
. O 0

However O 0
, O 0
increased O 0
dyspnoea B-Disease 1
and O 0
bronchospasm B-Disease 1
necessitated O 0
reintubation O 0
. O 0

Respiratory B-Disease 1
insufficiency I-Disease 1
was O 0
further O 0
worsened O 0
by O 0
Proteus B-Disease 1
mirabilis I-Disease 1
infection I-Disease 1
and O 0
severe O 0
bronchoconstriction O 0
. O 0

One O 0
week O 0
later O 0
, O 0
the O 0
patient O 0
was O 0
again O 0
extubated O 0
and O 0
3 O 0
days O 0
later O 0
was O 0
transferred O 0
to O 0
a O 0
peripheral O 0
ward O 0
. O 0

On O 0
the O 0
next O 0
day O 0
he O 0
died O 0
, O 0
probably O 0
as O 0
a O 0
result O 0
of O 0
heart B-Disease 1
failure I-Disease 1
. O 0

Serum O 0
samples O 0
from O 0
the O 0
first O 0
and O 0
second O 0
days O 0
contained O 0
3 O 0
. O 0
6 O 0
and O 0
1 O 0
. O 0
9 O 0
mg O 0
/ O 0
l O 0
carbachol B-Chemical 1
, O 0
respectively O 0
. O 0

The O 0
corresponding O 0
urine O 0
concentrations O 0
amounted O 0
to O 0
374 O 0
and O 0
554 O 0
mg O 0
/ O 0
l O 0
. O 0

CONCLUSION O 0
: O 0
This O 0
case O 0
started O 0
with O 0
a O 0
media O 0
report O 0
in O 0
a O 0
popular O 0
newspaper O 0
, O 0
initiated O 0
by O 0
published O 0
, O 0
peer O 0
- O 0
reviewed O 0
research O 0
on O 0
herbals O 0
, O 0
and O 0
involved O 0
human O 0
failure O 0
in O 0
a O 0
case O 0
history O 0
, O 0
medical O 0
examination O 0
and O 0
clinical O 0
treatment O 0
. O 0

For O 0
the O 0
first O 0
time O 0
, O 0
an O 0
analytical O 0
method O 0
for O 0
the O 0
determination O 0
of O 0
carbachol B-Chemical 1
in O 0
plasma O 0
and O 0
urine O 0
has O 0
been O 0
developed O 0
. O 0

The O 0
analysed O 0
carbachol B-Chemical 1
concentration O 0
exceeded O 0
the O 0
supposed O 0
serum O 0
level O 0
resulting O 0
from O 0
a O 0
therapeutic O 0
dose O 0
by O 0
a O 0
factor O 0
of O 0
130 O 0
to O 0
260 O 0
. O 0

Especially O 0
in O 0
old O 0
patients O 0
, O 0
intensivists O 0
should O 0
consider O 0
intoxications O 0
( O 0
with O 0
cholinergics O 0
) O 0
as O 0
a O 0
cause O 0
of O 0
acute B-Disease 1
cardiovascular I-Disease 1
failure I-Disease 1
. O 0

Pharmacological O 0
evidence O 0
for O 0
the O 0
potential O 0
of O 0
Daucus O 0
carota O 0
in O 0
the O 0
management O 0
of O 0
cognitive B-Disease 1
dysfunctions I-Disease 1
. O 0

The O 0
present O 0
study O 0
was O 0
aimed O 0
at O 0
investigating O 0
the O 0
effects O 0
of O 0
Daucus O 0
carota O 0
seeds O 0
on O 0
cognitive O 0
functions O 0
, O 0
total O 0
serum O 0
cholesterol B-Chemical 1
levels O 0
and O 0
brain O 0
cholinesterase O 0
activity O 0
in O 0
mice O 0
. O 0

The O 0
ethanolic O 0
extract B-Chemical 1
of I-Chemical 1
Daucus I-Chemical 1
carota I-Chemical 1
seeds I-Chemical 1
( O 0
DCE B-Chemical 1
) O 0
was O 0
administered O 0
orally O 0
in O 0
three O 0
doses O 0
( O 0
100 O 0
, O 0
200 O 0
, O 0
400 O 0
mg O 0
/ O 0
kg O 0
) O 0
for O 0
seven O 0
successive O 0
days O 0
to O 0
different O 0
groups O 0
of O 0
young O 0
and O 0
aged O 0
mice O 0
. O 0

Elevated O 0
plus O 0
maze O 0
and O 0
passive O 0
avoidance O 0
apparatus O 0
served O 0
as O 0
the O 0
exteroceptive O 0
behavioral O 0
models O 0
for O 0
testing O 0
memory O 0
. O 0

Diazepam B-Chemical 1
- O 0
, O 0
scopolamine B-Chemical 1
- O 0
and O 0
ageing O 0
- O 0
induced O 0
amnesia B-Disease 1
served O 0
as O 0
the O 0
interoceptive O 0
behavioral O 0
models O 0
. O 0

DCE B-Chemical 1
( O 0
200 O 0
, O 0
400 O 0
mg O 0
/ O 0
kg O 0
, O 0
p O 0
. O 0
o O 0
. O 0
) O 0
showed O 0
significant O 0
improvement O 0
in O 0
memory O 0
scores O 0
of O 0
young O 0
and O 0
aged O 0
mice O 0
. O 0

The O 0
extent O 0
of O 0
memory O 0
improvement O 0
evoked O 0
by O 0
DCE B-Chemical 1
was O 0
23 O 0
% O 0
at O 0
the O 0
dose O 0
of O 0
200 O 0
mg O 0
/ O 0
kg O 0
and O 0
35 O 0
% O 0
at O 0
the O 0
dose O 0
of O 0
400 O 0
mg O 0
/ O 0
kg O 0
in O 0
young O 0
mice O 0
using O 0
elevated O 0
plus O 0
maze O 0
. O 0

Similarly O 0
, O 0
significant O 0
improvements O 0
in O 0
memory O 0
scores O 0
were O 0
observed O 0
using O 0
passive O 0
avoidance O 0
apparatus O 0
and O 0
aged O 0
mice O 0
. O 0

Furthermore O 0
, O 0
DCE B-Chemical 1
reversed O 0
the O 0
amnesia B-Disease 1
induced O 0
by O 0
scopolamine B-Chemical 1
( O 0
0 O 0
. O 0
4 O 0
mg O 0
/ O 0
kg O 0
, O 0
i O 0
. O 0
p O 0
. O 0
) O 0
and O 0
diazepam B-Chemical 1
( O 0
1 O 0
mg O 0
/ O 0
kg O 0
, O 0
i O 0
. O 0
p O 0
. O 0
) O 0
. O 0

Daucus B-Chemical 1
carota I-Chemical 1
extract I-Chemical 1
( O 0
200 O 0
, O 0
400 O 0
mg O 0
/ O 0
kg O 0
, O 0
p O 0
. O 0
o O 0
. O 0
) O 0
reduced O 0
significantly O 0
the O 0
brain O 0
acetylcholinesterase O 0
activity O 0
and O 0
cholesterol B-Chemical 1
levels O 0
in O 0
young O 0
and O 0
aged O 0
mice O 0
. O 0

The O 0
extent O 0
of O 0
inhibition O 0
of O 0
brain O 0
cholinesterase O 0
activity O 0
evoked O 0
by O 0
DCE B-Chemical 1
at O 0
the O 0
dose O 0
of O 0
400 O 0
mg O 0
/ O 0
kg O 0
was O 0
22 O 0
% O 0
in O 0
young O 0
and O 0
19 O 0
% O 0
in O 0
aged O 0
mice O 0
. O 0

There O 0
was O 0
a O 0
remarkable O 0
reduction O 0
in O 0
total O 0
cholesterol B-Chemical 1
level O 0
as O 0
well O 0
, O 0
to O 0
the O 0
extent O 0
of O 0
23 O 0
% O 0
in O 0
young O 0
and O 0
21 O 0
% O 0
in O 0
aged O 0
animals O 0
with O 0
this O 0
dose O 0
of O 0
DCE B-Chemical 1
. O 0

Therefore O 0
, O 0
DCE B-Chemical 1
may O 0
prove O 0
to O 0
be O 0
a O 0
useful O 0
remedy O 0
for O 0
the O 0
management O 0
of O 0
cognitive B-Disease 1
dysfunctions I-Disease 1
on O 0
account O 0
of O 0
its O 0
multifarious O 0
beneficial O 0
effects O 0
such O 0
as O 0
, O 0
memory O 0
improving O 0
property O 0
, O 0
cholesterol B-Chemical 1
lowering O 0
property O 0
and O 0
anticholinesterase O 0
activity O 0
. O 0

Valproic B-Chemical 1
acid I-Chemical 1
induced O 0
encephalopathy B-Disease 1
- O 0
- O 0
19 O 0
new O 0
cases O 0
in O 0
Germany O 0
from O 0
1994 O 0
to O 0
2003 O 0
- O 0
- O 0
a O 0
side O 0
effect O 0
associated O 0
to O 0
VPA B-Chemical 1
- O 0
therapy O 0
not O 0
only O 0
in O 0
young O 0
children O 0
. O 0

Valproic B-Chemical 1
acid I-Chemical 1
( O 0
VPA B-Chemical 1
) O 0
is O 0
a O 0
broad O 0
- O 0
spectrum O 0
antiepileptic O 0
drug O 0
and O 0
is O 0
usually O 0
well O 0
- O 0
tolerated O 0
. O 0

Rare O 0
serious O 0
complications O 0
may O 0
occur O 0
in O 0
some O 0
patients O 0
, O 0
including O 0
haemorrhagic O 0
pancreatitis B-Disease 1
, O 0
bone B-Disease 1
marrow I-Disease 1
suppression I-Disease 1
, O 0
VPA B-Chemical 1
- O 0
induced O 0
hepatotoxicity B-Disease 1
and O 0
VPA B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
. O 0

The O 0
typical O 0
signs O 0
of O 0
VPA B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
are O 0
impaired B-Disease 1
consciousness I-Disease 1
, O 0
sometimes O 0
marked O 0
EEG O 0
background O 0
slowing O 0
, O 0
increased O 0
seizure B-Disease 1
frequency O 0
, O 0
with O 0
or O 0
without O 0
hyperammonemia B-Disease 1
. O 0

There O 0
is O 0
still O 0
no O 0
proof O 0
of O 0
causative O 0
effect O 0
of O 0
VPA B-Chemical 1
in O 0
patients O 0
with O 0
encephalopathy B-Disease 1
, O 0
but O 0
only O 0
of O 0
an O 0
association O 0
with O 0
an O 0
assumed O 0
causal O 0
relation O 0
. O 0

We O 0
report O 0
19 O 0
patients O 0
with O 0
VPA B-Chemical 1
- O 0
associated O 0
encephalopathy B-Disease 1
in O 0
Germany O 0
from O 0
the O 0
years O 0
1994 O 0
to O 0
2003 O 0
, O 0
none O 0
of O 0
whom O 0
had O 0
been O 0
published O 0
previously O 0
. O 0

Cerebral B-Disease 1
haemorrhage I-Disease 1
induced O 0
by O 0
warfarin B-Chemical 1
- O 0
the O 0
influence O 0
of O 0
drug O 0
- O 0
drug O 0
interactions O 0
. O 0

PURPOSE O 0
: O 0
To O 0
evaluate O 0
the O 0
frequency O 0
, O 0
severity O 0
and O 0
preventability O 0
of O 0
warfarin B-Chemical 1
- O 0
induced O 0
cerebral B-Disease 1
haemorrhages I-Disease 1
due O 0
to O 0
warfarin B-Chemical 1
and O 0
warfarin B-Chemical 1
- O 0
drug O 0
interactions O 0
in O 0
patients O 0
living O 0
in O 0
the O 0
county O 0
of O 0
Osterg O 0
tland O 0
, O 0
Sweden O 0
. O 0

METHODS O 0
: O 0
All O 0
patients O 0
with O 0
a O 0
diagnosed O 0
cerebral B-Disease 1
haemorrhage I-Disease 1
at O 0
three O 0
hospitals O 0
during O 0
the O 0
period O 0
2000 O 0
- O 0
2002 O 0
were O 0
identified O 0
. O 0

Medical O 0
records O 0
were O 0
studied O 0
retrospectively O 0
to O 0
evaluate O 0
whether O 0
warfarin B-Chemical 1
and O 0
warfarin B-Chemical 1
- O 0
drug O 0
interactions O 0
could O 0
have O 0
caused O 0
the O 0
cerebral B-Disease 1
haemorrhage I-Disease 1
. O 0

The O 0
proportion O 0
of O 0
possibly O 0
avoidable O 0
cases O 0
due O 0
to O 0
drug O 0
interactions O 0
was O 0
estimated O 0
. O 0

RESULTS O 0
: O 0
Among O 0
593 O 0
patients O 0
with O 0
cerebral B-Disease 1
haemorrhage I-Disease 1
, O 0
59 O 0
( O 0
10 O 0
% O 0
) O 0
were O 0
assessed O 0
as O 0
related O 0
to O 0
warfarin B-Chemical 1
treatment O 0
. O 0

This O 0
imply O 0
an O 0
incidence O 0
of O 0
1 O 0
. O 0
7 O 0
/ O 0
100 O 0
, O 0
000 O 0
treatment O 0
years O 0
. O 0

Of O 0
the O 0
59 O 0
cases O 0
, O 0
26 O 0
( O 0
44 O 0
% O 0
) O 0
had O 0
a O 0
fatal O 0
outcome O 0
, O 0
compared O 0
to O 0
136 O 0
( O 0
25 O 0
% O 0
) O 0
among O 0
the O 0
non O 0
- O 0
warfarin B-Chemical 1
patients O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

A O 0
warfarin B-Chemical 1
- O 0
drug O 0
interaction O 0
could O 0
have O 0
contributed O 0
to O 0
the O 0
haemorrhage B-Disease 1
in O 0
24 O 0
( O 0
41 O 0
% O 0
) O 0
of O 0
the O 0
warfarin B-Chemical 1
patients O 0
and O 0
in O 0
7 O 0
of O 0
these O 0
( O 0
12 O 0
% O 0
) O 0
the O 0
bleeding B-Disease 1
complication O 0
was O 0
considered O 0
being O 0
possible O 0
to O 0
avoid O 0
. O 0

CONCLUSIONS O 0
: O 0
Warfarin B-Chemical 1
- O 0
induced O 0
cerebral B-Disease 1
haemorrhages I-Disease 1
are O 0
a O 0
major O 0
clinical O 0
problem O 0
with O 0
a O 0
high O 0
fatality O 0
rate O 0
. O 0

Almost O 0
half O 0
of O 0
the O 0
cases O 0
was O 0
related O 0
to O 0
a O 0
warfarin B-Chemical 1
- O 0
drug O 0
interaction O 0
. O 0

A O 0
significant O 0
proportion O 0
of O 0
warfarin B-Chemical 1
- O 0
related O 0
cerebral B-Disease 1
haemorrhages I-Disease 1
might O 0
have O 0
been O 0
prevented O 0
if O 0
greater O 0
caution O 0
had O 0
been O 0
taken O 0
when O 0
prescribing O 0
drugs O 0
known O 0
to O 0
interact O 0
with O 0
warfarin B-Chemical 1
. O 0

Antipsychotic O 0
- O 0
like O 0
profile O 0
of O 0
thioperamide B-Chemical 1
, O 0
a O 0
selective O 0
H3 O 0
- O 0
receptor O 0
antagonist O 0
in O 0
mice O 0
. O 0

Experimental O 0
and O 0
clinical O 0
evidence O 0
points O 0
to O 0
a O 0
role O 0
of O 0
central O 0
histaminergic O 0
system O 0
in O 0
the O 0
pathogenesis O 0
of O 0
schizophrenia B-Disease 1
. O 0

The O 0
present O 0
study O 0
was O 0
designed O 0
to O 0
study O 0
the O 0
effect O 0
of O 0
histamine B-Chemical 1
H O 0
( O 0
3 O 0
) O 0
- O 0
receptor O 0
ligands O 0
on O 0
neuroleptic O 0
- O 0
induced O 0
catalepsy B-Disease 1
, O 0
apomorphine B-Chemical 1
- O 0
induced O 0
climbing O 0
behavior O 0
and O 0
amphetamine B-Chemical 1
- O 0
induced O 0
locomotor O 0
activities O 0
in O 0
mice O 0
. O 0

Catalepsy B-Disease 1
was O 0
induced O 0
by O 0
haloperidol B-Chemical 1
( O 0
2 O 0
mg O 0
/ O 0
kg O 0
p O 0
. O 0
o O 0
. O 0
) O 0
, O 0
while O 0
apomorphine B-Chemical 1
( O 0
1 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
) O 0
and O 0
amphetamine B-Chemical 1
( O 0
2 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
) O 0
were O 0
used O 0
for O 0
studying O 0
climbing O 0
behavior O 0
and O 0
locomotor O 0
activities O 0
, O 0
respectively O 0
. O 0

( B-Chemical 1
R I-Chemical 1
) I-Chemical 1
- I-Chemical 1
alpha I-Chemical 1
- I-Chemical 1
methylhistamine I-Chemical 1
( O 0
RAMH B-Chemical 1
) O 0
( O 0
5 O 0
microg O 0
i O 0
. O 0
c O 0
. O 0
v O 0
. O 0
) O 0
and O 0
thioperamide B-Chemical 1
( O 0
THP B-Chemical 1
) O 0
( O 0
15 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
, O 0
per O 0
se O 0
did O 0
not O 0
cause O 0
catalepsy B-Disease 1
. O 0

Administration O 0
of O 0
THP B-Chemical 1
( O 0
3 O 0
. O 0
75 O 0
, O 0
7 O 0
. O 0
5 O 0
and O 0
15 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
1 O 0
h O 0
prior O 0
to O 0
haloperidol B-Chemical 1
resulted O 0
in O 0
a O 0
dose O 0
- O 0
dependent O 0
increase O 0
in O 0
the O 0
catalepsy B-Disease 1
times O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

However O 0
, O 0
pretreatment O 0
with O 0
RAMH B-Chemical 1
significantly O 0
reversed O 0
such O 0
an O 0
effect O 0
of O 0
THP B-Chemical 1
( O 0
15 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
. O 0

RAMH B-Chemical 1
per O 0
se O 0
showed O 0
significant O 0
reduction O 0
in O 0
locomotor O 0
time O 0
, O 0
distance O 0
traveled O 0
and O 0
average O 0
speed O 0
but O 0
THP B-Chemical 1
( O 0
15 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
per O 0
se O 0
had O 0
no O 0
effect O 0
on O 0
these O 0
parameters O 0
. O 0

On O 0
amphetamine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
, O 0
THP B-Chemical 1
( O 0
3 O 0
. O 0
75 O 0
and O 0
7 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
reduced O 0
locomotor O 0
time O 0
, O 0
distance O 0
traveled O 0
and O 0
average O 0
speed O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Pretreatment O 0
with O 0
RAMH B-Chemical 1
( O 0
5 O 0
microg O 0
i O 0
. O 0
c O 0
. O 0
v O 0
. O 0
) O 0
could O 0
partially O 0
reverse O 0
such O 0
effects O 0
of O 0
THP B-Chemical 1
( O 0
3 O 0
. O 0
75 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
. O 0

Climbing O 0
behavior O 0
induced O 0
by O 0
apomorphine B-Chemical 1
was O 0
reduced O 0
in O 0
animals O 0
treated O 0
with O 0
THP B-Chemical 1
. O 0

Such O 0
an O 0
effect O 0
was O 0
, O 0
however O 0
, O 0
reversed O 0
in O 0
presence O 0
of O 0
RAMH B-Chemical 1
. O 0

THP B-Chemical 1
exhibited O 0
an O 0
antipsychotic O 0
- O 0
like O 0
profile O 0
by O 0
potentiating O 0
haloperidol B-Chemical 1
- O 0
induced O 0
catalepsy B-Disease 1
, O 0
reducing O 0
amphetamine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
and O 0
reducing O 0
apomorphine B-Chemical 1
- O 0
induced O 0
climbing O 0
in O 0
mice O 0
. O 0

Such O 0
effects O 0
of O 0
THP B-Chemical 1
were O 0
reversed O 0
by O 0
RAMH B-Chemical 1
indicating O 0
the O 0
involvement O 0
of O 0
histamine B-Chemical 1
H O 0
( O 0
3 O 0
) O 0
- O 0
receptors O 0
. O 0

Findings O 0
suggest O 0
a O 0
potential O 0
for O 0
H O 0
( O 0
3 O 0
) O 0
- O 0
receptor O 0
antagonists O 0
in O 0
improving O 0
the O 0
refractory O 0
cases O 0
of O 0
schizophrenia B-Disease 1
. O 0

Cauda B-Disease 1
equina I-Disease 1
syndrome I-Disease 1
after O 0
epidural O 0
steroid B-Chemical 1
injection O 0
: O 0
a O 0
case O 0
report O 0
. O 0

OBJECTIVE O 0
: O 0
Conventional O 0
treatment O 0
methods O 0
of O 0
lumbusacral O 0
radiculopathy B-Disease 1
are O 0
physical O 0
therapy O 0
, O 0
epidural O 0
steroid B-Chemical 1
injections O 0
, O 0
oral O 0
medications O 0
, O 0
and O 0
spinal O 0
manipulative O 0
therapy O 0
. O 0

Cauda B-Disease 1
equina I-Disease 1
syndrome I-Disease 1
is O 0
a O 0
rare O 0
complication O 0
of O 0
epidural O 0
anesthesia O 0
. O 0

The O 0
following O 0
case O 0
is O 0
a O 0
report O 0
of O 0
cauda B-Disease 1
equina I-Disease 1
syndrome I-Disease 1
possibly O 0
caused O 0
by O 0
epidural O 0
injection O 0
of O 0
triamcinolone B-Chemical 1
and O 0
bupivacaine B-Chemical 1
. O 0

CLINICAL O 0
FEATURES O 0
: O 0
A O 0
50 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
with O 0
low B-Disease 1
back I-Disease 1
and I-Disease 1
right I-Disease 1
leg I-Disease 1
pain I-Disease 1
was O 0
scheduled O 0
for O 0
epidural O 0
steroid B-Chemical 1
injection O 0
. O 0

INTERVENTION O 0
AND O 0
OUTCOME O 0
: O 0
An O 0
18 O 0
- O 0
gauge O 0
Touhy O 0
needle O 0
was O 0
inserted O 0
until O 0
loss O 0
of O 0
resistance O 0
occurred O 0
at O 0
the O 0
L4 O 0
- O 0
5 O 0
level O 0
. O 0

Spread O 0
of O 0
the O 0
contrast O 0
medium O 0
within O 0
the O 0
epidural O 0
space O 0
was O 0
determined O 0
by O 0
radiographic O 0
imaging O 0
. O 0

After O 0
verifying O 0
the O 0
epidural O 0
space O 0
, O 0
bupivacaine B-Chemical 1
and O 0
triamcinolone B-Chemical 1
diacetate I-Chemical 1
were O 0
injected O 0
. O 0

After O 0
the O 0
injection O 0
, O 0
there O 0
was O 0
a O 0
reduction O 0
in O 0
radicular O 0
symptoms O 0
. O 0

Three O 0
hours O 0
later O 0
, O 0
she O 0
complained O 0
of O 0
perineal O 0
numbness B-Disease 1
and O 0
lower B-Disease 1
extremity I-Disease 1
weakness I-Disease 1
. O 0

The O 0
neurologic O 0
evaluation O 0
revealed O 0
loss B-Disease 1
of I-Disease 1
sensation I-Disease 1
in O 0
the O 0
saddle O 0
area O 0
and O 0
medial O 0
aspect O 0
of O 0
her O 0
right O 0
leg O 0
. O 0

There O 0
was O 0
a O 0
decrease O 0
in O 0
the O 0
perception O 0
of O 0
pinprick O 0
test O 0
. O 0

Deep O 0
- O 0
tendon O 0
reflexes O 0
were O 0
decreased O 0
especially O 0
in O 0
the O 0
right O 0
leg O 0
. O 0

She O 0
was O 0
unable O 0
to O 0
urinate O 0
. O 0

The O 0
patient O 0
' O 0
s O 0
symptoms O 0
improved O 0
slightly O 0
over O 0
the O 0
next O 0
few O 0
hours O 0
. O 0

She O 0
had O 0
a O 0
gradual O 0
return O 0
of O 0
motor O 0
function O 0
and O 0
ability O 0
of O 0
feeling O 0
Foley O 0
catheter O 0
. O 0

All O 0
of O 0
the O 0
symptoms O 0
were O 0
completely O 0
resolved O 0
over O 0
the O 0
next O 0
8 O 0
hours O 0
. O 0

CONCLUSION O 0
: O 0
Complications O 0
associated O 0
with O 0
epidural O 0
steroid B-Chemical 1
injections O 0
are O 0
rare O 0
. O 0

Clinical O 0
examination O 0
and O 0
continued O 0
vigilance O 0
for O 0
neurologic B-Disease 1
deterioration I-Disease 1
after O 0
epidural O 0
steroid B-Chemical 1
injections O 0
is O 0
important O 0
. O 0

High O 0
- O 0
dose O 0
testosterone B-Chemical 1
is O 0
associated O 0
with O 0
atherosclerosis B-Disease 1
in O 0
postmenopausal O 0
women O 0
. O 0

OBJECTIVES O 0
: O 0
To O 0
study O 0
the O 0
long O 0
- O 0
term O 0
effects O 0
of O 0
androgen O 0
treatment O 0
on O 0
atherosclerosis B-Disease 1
in O 0
postmenopausal O 0
women O 0
. O 0

METHODS O 0
: O 0
In O 0
a O 0
population O 0
- O 0
based O 0
study O 0
in O 0
513 O 0
naturally O 0
postmenopausal O 0
women O 0
aged O 0
54 O 0
- O 0
67 O 0
years O 0
, O 0
we O 0
studied O 0
the O 0
association O 0
between O 0
self O 0
- O 0
reported O 0
intramuscularly O 0
administered O 0
high O 0
- O 0
dose O 0
estrogen B-Chemical 1
- O 0
testosterone B-Chemical 1
therapy O 0
( O 0
estradiol B-Chemical 1
- I-Chemical 1
and I-Chemical 1
testosterone I-Chemical 1
esters I-Chemical 1
) O 0
and O 0
aortic O 0
atherosclerosis B-Disease 1
. O 0

Aortic O 0
atherosclerosis B-Disease 1
was O 0
diagnosed O 0
by O 0
radiographic O 0
detection O 0
of O 0
calcified O 0
deposits O 0
in O 0
the O 0
abdominal O 0
aorta O 0
, O 0
which O 0
have O 0
been O 0
shown O 0
to O 0
reflect O 0
intima O 0
atherosclerosis B-Disease 1
. O 0

Hormone O 0
therapy O 0
users O 0
were O 0
compared O 0
with O 0
never O 0
users O 0
. O 0

RESULTS O 0
: O 0
Intramuscular O 0
hormone O 0
therapy O 0
use O 0
for O 0
1 O 0
year O 0
or O 0
longer O 0
was O 0
reported O 0
by O 0
25 O 0
women O 0
. O 0

In O 0
almost O 0
half O 0
of O 0
these O 0
women O 0
severe O 0
atherosclerosis B-Disease 1
of O 0
the O 0
aorta O 0
was O 0
present O 0
( O 0
n O 0
= O 0
11 O 0
) O 0
, O 0
while O 0
in O 0
women O 0
without O 0
hormone O 0
use O 0
severe O 0
atherosclerosis B-Disease 1
of O 0
the O 0
aorta O 0
was O 0
present O 0
in O 0
less O 0
than O 0
20 O 0
% O 0
( O 0
OR O 0
3 O 0
. O 0
1 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
1 O 0
- O 0
8 O 0
. O 0
5 O 0
, O 0
adjusted O 0
for O 0
age O 0
, O 0
years O 0
since O 0
menopause O 0
, O 0
smoking O 0
, O 0
and O 0
body O 0
mass O 0
index O 0
) O 0
. O 0

The O 0
association O 0
remained O 0
after O 0
additional O 0
adjustment O 0
for O 0
diabetes B-Disease 1
, O 0
cholesterol B-Chemical 1
level O 0
, O 0
systolic O 0
blood O 0
pressure O 0
, O 0
or O 0
alcohol B-Chemical 1
use O 0
. O 0

No O 0
association O 0
was O 0
found O 0
for O 0
hormone O 0
use O 0
less O 0
than O 0
1 O 0
year O 0
. O 0

CONCLUSION O 0
: O 0
Our O 0
results O 0
suggest O 0
that O 0
high O 0
- O 0
dose O 0
testosterone B-Chemical 1
therapy O 0
may O 0
adversely O 0
affect O 0
atherosclerosis B-Disease 1
in O 0
postmenopausal O 0
women O 0
and O 0
indicate O 0
that O 0
androgen O 0
replacement O 0
in O 0
these O 0
women O 0
may O 0
not O 0
be O 0
harmless O 0
. O 0

Optimising O 0
stroke B-Disease 1
prevention O 0
in O 0
non O 0
- O 0
valvular O 0
atrial B-Disease 1
fibrillation I-Disease 1
. O 0

Atrial B-Disease 1
fibrillation I-Disease 1
is O 0
associated O 0
with O 0
substantial O 0
morbidity O 0
and O 0
mortality O 0
. O 0

Pooled O 0
data O 0
from O 0
trials O 0
comparing O 0
antithrombotic O 0
treatment O 0
with O 0
placebo O 0
have O 0
shown O 0
that O 0
warfarin B-Chemical 1
reduces O 0
the O 0
risk O 0
of O 0
stroke B-Disease 1
by O 0
62 O 0
% O 0
, O 0
and O 0
that O 0
aspirin B-Chemical 1
alone O 0
reduces O 0
the O 0
risk O 0
by O 0
22 O 0
% O 0
. O 0

Overall O 0
, O 0
in O 0
high O 0
- O 0
risk O 0
patients O 0
, O 0
warfarin B-Chemical 1
is O 0
superior O 0
to O 0
aspirin B-Chemical 1
in O 0
preventing O 0
strokes B-Disease 1
, O 0
with O 0
a O 0
relative O 0
risk O 0
reduction O 0
of O 0
36 O 0
% O 0
. O 0

Ximelagatran B-Chemical 1
, O 0
an O 0
oral O 0
direct O 0
thrombin O 0
inhibitor O 0
, O 0
was O 0
found O 0
to O 0
be O 0
as O 0
efficient O 0
as O 0
vitamin B-Chemical 1
K I-Chemical 1
antagonist O 0
drugs O 0
in O 0
the O 0
prevention O 0
of O 0
embolic B-Disease 1
events I-Disease 1
, O 0
but O 0
has O 0
been O 0
recently O 0
withdrawn O 0
because O 0
of O 0
abnormal B-Disease 1
liver I-Disease 1
function I-Disease 1
tests O 0
. O 0

The O 0
ACTIVE O 0
- O 0
W O 0
( O 0
Atrial B-Disease 1
Fibrillation I-Disease 1
Clopidogrel B-Chemical 1
Trial O 0
with O 0
Irbesartan B-Chemical 1
for O 0
Prevention O 0
of O 0
Vascular O 0
Events O 0
) O 0
study O 0
has O 0
demonstrated O 0
that O 0
warfarin B-Chemical 1
is O 0
superior O 0
to O 0
platelet O 0
therapy O 0
( O 0
clopidogrel B-Chemical 1
plus O 0
aspirin B-Chemical 1
) O 0
in O 0
the O 0
prevention O 0
af O 0
embolic B-Disease 1
events I-Disease 1
. O 0

Idraparinux B-Chemical 1
, O 0
a O 0
Factor O 0
Xa O 0
inhibitor O 0
, O 0
is O 0
being O 0
evaluated O 0
in O 0
patients O 0
with O 0
atrial B-Disease 1
fibrillation I-Disease 1
. O 0

Angiotensin B-Chemical 1
- O 0
converting O 0
enzyme O 0
inhibitors O 0
and O 0
angiotensin B-Chemical 1
II I-Chemical 1
receptor O 0
- O 0
blocking O 0
drugs O 0
hold O 0
promise O 0
in O 0
atrial B-Disease 1
fibrillation I-Disease 1
through O 0
cardiac B-Disease 1
remodelling I-Disease 1
. O 0

Preliminary O 0
studies O 0
suggest O 0
that O 0
statins B-Chemical 1
could O 0
interfere O 0
with O 0
the O 0
risk O 0
of O 0
recurrence O 0
after O 0
electrical O 0
cardioversion O 0
. O 0

Finally O 0
, O 0
percutaneous O 0
methods O 0
for O 0
the O 0
exclusion O 0
of O 0
left O 0
atrial O 0
appendage O 0
are O 0
under O 0
investigation O 0
in O 0
high O 0
- O 0
risk O 0
patients O 0
. O 0

Anti O 0
- O 0
oxidant O 0
effects O 0
of O 0
atorvastatin B-Chemical 1
in O 0
dexamethasone B-Chemical 1
- O 0
induced O 0
hypertension B-Disease 1
in O 0
the O 0
rat O 0
. O 0

1 O 0
. O 0

Dexamethasone B-Chemical 1
( O 0
Dex B-Chemical 1
) O 0
- O 0
induced O 0
hypertension B-Disease 1
is O 0
characterized O 0
by O 0
endothelial O 0
dysfunction O 0
associated O 0
with O 0
nitric B-Chemical 1
oxide I-Chemical 1
( O 0
NO B-Chemical 1
) O 0
deficiency O 0
and O 0
increased O 0
superoxide B-Chemical 1
( O 0
O2 B-Chemical 1
- I-Chemical 1
) O 0
production O 0
. O 0

Atorvastatin B-Chemical 1
( O 0
Ato B-Chemical 1
) O 0
possesses O 0
pleiotropic O 0
properties O 0
that O 0
have O 0
been O 0
reported O 0
to O 0
improve O 0
endothelial O 0
function O 0
through O 0
increased O 0
availability O 0
of O 0
NO B-Chemical 1
and O 0
reduced O 0
O2 B-Chemical 1
- I-Chemical 1
production O 0
in O 0
various O 0
forms O 0
of O 0
hypertension B-Disease 1
. O 0

In O 0
the O 0
present O 0
study O 0
, O 0
we O 0
investigated O 0
whether O 0
50 O 0
mg O 0
/ O 0
kg O 0
per O 0
day O 0
, O 0
p O 0
. O 0
o O 0
. O 0
, O 0
Ato B-Chemical 1
could O 0
prevent O 0
endothelial O 0
NO B-Chemical 1
synthase O 0
( O 0
eNOS O 0
) O 0
downregulation O 0
and O 0
the O 0
increase O 0
in O 0
O2 B-Chemical 1
- I-Chemical 1
in O 0
Sprague O 0
- O 0
Dawley O 0
( O 0
SD O 0
) O 0
rats O 0
, O 0
thereby O 0
reducing O 0
blood O 0
pressure O 0
. O 0

2 O 0
. O 0

Male O 0
SD O 0
rats O 0
( O 0
n O 0
= O 0
30 O 0
) O 0
were O 0
treated O 0
with O 0
Ato B-Chemical 1
( O 0
50 O 0
mg O 0
/ O 0
kg O 0
per O 0
day O 0
in O 0
drinking O 0
water O 0
) O 0
or O 0
tap O 0
water O 0
for O 0
15 O 0
days O 0
. O 0

Dexamethasone B-Chemical 1
( O 0
10 O 0
microg O 0
/ O 0
kg O 0
per O 0
day O 0
, O 0
s O 0
. O 0
c O 0
. O 0
) O 0
or O 0
saline O 0
was O 0
started O 0
after O 0
4 O 0
days O 0
in O 0
Ato B-Chemical 1
- O 0
treated O 0
and O 0
non O 0
- O 0
treated O 0
rats O 0
and O 0
continued O 0
for O 0
11 O 0
- O 0
13 O 0
days O 0
. O 0

Systolic O 0
blood O 0
pressure O 0
( O 0
SBP O 0
) O 0
was O 0
measured O 0
on O 0
alternate O 0
days O 0
using O 0
the O 0
tail O 0
- O 0
cuff O 0
method O 0
. O 0

Endothelial O 0
function O 0
was O 0
assessed O 0
by O 0
acetylcholine B-Chemical 1
- O 0
induced O 0
vasorelaxation O 0
and O 0
phenylephrine B-Chemical 1
- O 0
induced O 0
vasoconstriction O 0
in O 0
aortic O 0
segments O 0
. O 0

Vascular O 0
eNOS O 0
mRNA O 0
was O 0
assessed O 0
by O 0
semi O 0
- O 0
quantitative O 0
reverse O 0
transcription O 0
- O 0
polymerase O 0
chain O 0
reaction O 0
. O 0

3 O 0
. O 0

In O 0
rats O 0
treated O 0
with O 0
Dex B-Chemical 1
alone O 0
, O 0
SBP O 0
was O 0
increased O 0
from O 0
109 O 0
+ O 0
/ O 0
- O 0
2 O 0
to O 0
133 O 0
+ O 0
/ O 0
- O 0
2 O 0
mmHg O 0
on O 0
Days O 0
4 O 0
and O 0
Day O 0
14 O 0
, O 0
respectively O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

In O 0
the O 0
Ato B-Chemical 1
+ O 0
Dex B-Chemical 1
group O 0
, O 0
SBP O 0
was O 0
increased O 0
from O 0
113 O 0
+ O 0
/ O 0
- O 0
2 O 0
to O 0
119 O 0
+ O 0
/ O 0
- O 0
2 O 0
mmHg O 0
on O 0
Days O 0
4 O 0
to O 0
14 O 0
, O 0
respectively O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
but O 0
was O 0
significantly O 0
lower O 0
than O 0
SBP O 0
in O 0
the O 0
group O 0
treated O 0
with O 0
Dex B-Chemical 1
alone O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Endothelial O 0
- O 0
dependent O 0
relaxation O 0
and O 0
eNOS O 0
mRNA O 0
expression O 0
were O 0
greater O 0
in O 0
the O 0
Dex B-Chemical 1
+ O 0
Ato B-Chemical 1
group O 0
than O 0
in O 0
the O 0
Dex B-Chemical 1
only O 0
group O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
and O 0
P O 0
< O 0
0 O 0
. O 0
0001 O 0
, O 0
respectively O 0
) O 0
. O 0

Aortic O 0
superoxide B-Chemical 1
production O 0
was O 0
lower O 0
in O 0
the O 0
Dex B-Chemical 1
+ O 0
Ato B-Chemical 1
group O 0
compared O 0
with O 0
the O 0
group O 0
treated O 0
with O 0
Dex B-Chemical 1
alone O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
0001 O 0
) O 0
. O 0

4 O 0
. O 0

Treatment O 0
with O 0
Ato B-Chemical 1
improved O 0
endothelial O 0
function O 0
, O 0
reduced O 0
superoxide B-Chemical 1
production O 0
and O 0
reduced O 0
SBP O 0
in O 0
Dex B-Chemical 1
- O 0
treated O 0
SD O 0
rats O 0
. O 0

Severe O 0
citrate B-Chemical 1
toxicity B-Disease 1
complicating O 0
volunteer O 0
apheresis O 0
platelet O 0
donation O 0
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
severe O 0
citrate B-Chemical 1
toxicity B-Disease 1
during O 0
volunteer O 0
donor O 0
apheresis O 0
platelet O 0
collection O 0
. O 0

The O 0
donor O 0
was O 0
a O 0
40 O 0
- O 0
year O 0
- O 0
old O 0
female O 0
, O 0
first O 0
- O 0
time O 0
apheresis O 0
platelet O 0
donor O 0
. O 0

Past O 0
medical O 0
history O 0
was O 0
remarkable O 0
for O 0
hypertension B-Disease 1
, O 0
hyperlipidemia B-Disease 1
, O 0
and O 0
depression B-Disease 1
. O 0

Reported O 0
medications O 0
included O 0
bumetanide B-Chemical 1
, O 0
pravastatin B-Chemical 1
, O 0
and O 0
paroxetine B-Chemical 1
. O 0

Thirty O 0
minutes O 0
from O 0
the O 0
start O 0
of O 0
the O 0
procedure O 0
, O 0
the O 0
donor O 0
noted O 0
tingling O 0
around O 0
the O 0
mouth O 0
, O 0
hands O 0
, O 0
and O 0
feet O 0
. O 0

She O 0
then O 0
very O 0
rapidly O 0
developed O 0
acute O 0
onset O 0
of O 0
severe O 0
facial O 0
and O 0
extremity O 0
tetany B-Disease 1
. O 0

Empirical O 0
treatment O 0
with O 0
intravenous O 0
calcium B-Chemical 1
gluconate I-Chemical 1
was O 0
initiated O 0
, O 0
and O 0
muscle B-Disease 1
contractions I-Disease 1
slowly O 0
subsided O 0
over O 0
approximately O 0
10 O 0
to O 0
15 O 0
minutes O 0
. O 0

The O 0
events O 0
are O 0
consistent O 0
with O 0
a O 0
severe O 0
reaction O 0
to O 0
calcium B-Chemical 1
chelation O 0
by O 0
sodium B-Chemical 1
citrate I-Chemical 1
anticoagulant O 0
resulting O 0
in O 0
symptomatic O 0
systemic O 0
hypocalcemia B-Disease 1
. O 0

Upon O 0
additional O 0
retrospective O 0
analysis O 0
, O 0
it O 0
was O 0
noted O 0
that O 0
bumetanide B-Chemical 1
is O 0
a O 0
loop B-Chemical 1
diuretic I-Chemical 1
that O 0
may O 0
cause O 0
significant O 0
hypocalcemia B-Disease 1
. O 0

We O 0
conclude O 0
that O 0
careful O 0
screening O 0
for O 0
medications O 0
and O 0
underlying O 0
conditions O 0
predisposing O 0
to O 0
hypocalcemia B-Disease 1
is O 0
recommended O 0
to O 0
help O 0
prevent O 0
severe O 0
reactions O 0
due O 0
to O 0
citrate B-Chemical 1
toxicity B-Disease 1
. O 0

Laboratory O 0
measurement O 0
of O 0
pre O 0
- O 0
procedure O 0
serum O 0
calcium B-Chemical 1
levels O 0
in O 0
selected O 0
donors O 0
may O 0
identify O 0
cases O 0
requiring O 0
heightened O 0
vigilance O 0
. O 0

The O 0
case O 0
also O 0
illustrates O 0
the O 0
importance O 0
of O 0
maintaining O 0
preparedness O 0
for O 0
managing O 0
rare O 0
but O 0
serious O 0
reactions O 0
in O 0
volunteer O 0
apheresis O 0
blood O 0
donors O 0
. O 0

Sirolimus B-Chemical 1
- O 0
associated O 0
proteinuria B-Disease 1
and O 0
renal B-Disease 1
dysfunction I-Disease 1
. O 0

Sirolimus B-Chemical 1
is O 0
a O 0
novel O 0
immunosuppressant O 0
with O 0
potent O 0
antiproliferative O 0
actions O 0
through O 0
its O 0
ability O 0
to O 0
inhibit O 0
the O 0
raptor O 0
- O 0
containing O 0
mammalian O 0
target O 0
of O 0
rapamycin B-Chemical 1
protein O 0
kinase O 0
. O 0

Sirolimus B-Chemical 1
represents O 0
a O 0
major O 0
therapeutic O 0
advance O 0
in O 0
the O 0
prevention O 0
of O 0
acute O 0
renal O 0
allograft O 0
rejection O 0
and O 0
chronic O 0
allograft O 0
nephropathy B-Disease 1
. O 0

Its O 0
role O 0
in O 0
the O 0
therapy O 0
of O 0
glomerulonephritis B-Disease 1
, O 0
autoimmunity B-Disease 1
, O 0
cystic B-Disease 1
renal I-Disease 1
diseases I-Disease 1
and O 0
renal B-Disease 1
cancer I-Disease 1
is O 0
under O 0
investigation O 0
. O 0

Because O 0
sirolimus B-Chemical 1
does O 0
not O 0
share O 0
the O 0
vasomotor O 0
renal O 0
adverse O 0
effects O 0
exhibited O 0
by O 0
calcineurin O 0
inhibitors O 0
, O 0
it O 0
has O 0
been O 0
designated O 0
a O 0
' O 0
non O 0
- O 0
nephrotoxic B-Disease 1
drug O 0
' O 0
. O 0

However O 0
, O 0
clinical O 0
reports O 0
suggest O 0
that O 0
, O 0
under O 0
some O 0
circumstances O 0
, O 0
sirolimus B-Chemical 1
is O 0
associated O 0
with O 0
proteinuria B-Disease 1
and O 0
acute B-Disease 1
renal I-Disease 1
dysfunction I-Disease 1
. O 0

A O 0
common O 0
risk O 0
factor O 0
appears O 0
to O 0
be O 0
presence O 0
of O 0
pre O 0
- O 0
existing O 0
chronic B-Disease 1
renal I-Disease 1
damage I-Disease 1
. O 0

The O 0
mechanisms O 0
of O 0
sirolimus B-Chemical 1
- O 0
associated O 0
proteinuria B-Disease 1
are O 0
multifactorial O 0
and O 0
may O 0
be O 0
due O 0
to O 0
an O 0
increase O 0
in O 0
glomerular O 0
capillary O 0
pressure O 0
following O 0
calcineurin O 0
inhibitor O 0
withdrawal O 0
. O 0

It O 0
has O 0
also O 0
been O 0
suggested O 0
that O 0
sirolimus B-Chemical 1
directly O 0
causes O 0
increased O 0
glomerular O 0
permeability O 0
/ O 0
injury O 0
, O 0
but O 0
evidence O 0
for O 0
this O 0
mechanism O 0
is O 0
currently O 0
inconclusive O 0
. O 0

The O 0
acute B-Disease 1
renal I-Disease 1
dysfunction I-Disease 1
associated O 0
with O 0
sirolimus B-Chemical 1
( O 0
such O 0
as O 0
in O 0
delayed O 0
graft O 0
function O 0
) O 0
may O 0
be O 0
due O 0
to O 0
suppression O 0
of O 0
compensatory O 0
renal O 0
cell O 0
proliferation O 0
and O 0
survival O 0
/ O 0
repair O 0
processes O 0
. O 0

Although O 0
these O 0
adverse O 0
effects O 0
occur O 0
in O 0
some O 0
patients O 0
, O 0
their O 0
occurrence O 0
could O 0
be O 0
minimised O 0
by O 0
knowledge O 0
of O 0
the O 0
molecular O 0
effects O 0
of O 0
sirolimus B-Chemical 1
on O 0
the O 0
kidney O 0
, O 0
the O 0
use O 0
of O 0
sirolimus B-Chemical 1
in O 0
appropriate O 0
patient O 0
populations O 0
, O 0
close O 0
monitoring O 0
of O 0
proteinuria B-Disease 1
and O 0
renal O 0
function O 0
, O 0
use O 0
of O 0
angiotensin B-Chemical 1
- O 0
converting O 0
enzyme O 0
inhibitors O 0
or O 0
angiotensin B-Chemical 1
II I-Chemical 1
receptor O 0
blockers O 0
if O 0
proteinuria B-Disease 1
occurs O 0
and O 0
withdrawal O 0
if O 0
needed O 0
. O 0

Further O 0
long O 0
- O 0
term O 0
analysis O 0
of O 0
renal O 0
allograft O 0
studies O 0
using O 0
sirolimus B-Chemical 1
as O 0
de O 0
novo O 0
immunosuppression O 0
along O 0
with O 0
clinical O 0
and O 0
laboratory O 0
studies O 0
will O 0
refine O 0
these O 0
issues O 0
in O 0
the O 0
future O 0
. O 0

Proteinuria B-Disease 1
after O 0
conversion O 0
to O 0
sirolimus B-Chemical 1
in O 0
renal O 0
transplant O 0
recipients O 0
. O 0

Sirolimus B-Chemical 1
( O 0
SRL B-Chemical 1
) O 0
is O 0
a O 0
new O 0
, O 0
potent O 0
immunosuppressive O 0
agent O 0
. O 0

More O 0
recently O 0
, O 0
proteinuria B-Disease 1
has O 0
been O 0
reported O 0
as O 0
a O 0
consequence O 0
of O 0
sirolimus B-Chemical 1
therapy O 0
, O 0
although O 0
the O 0
mechanism O 0
has O 0
remained O 0
unclear O 0
. O 0

We O 0
retrospectively O 0
examined O 0
the O 0
records O 0
of O 0
25 O 0
renal O 0
transplant O 0
patients O 0
, O 0
who O 0
developed O 0
or O 0
displayed O 0
increased O 0
proteinuria B-Disease 1
after O 0
SRL B-Chemical 1
conversion O 0
. O 0

The O 0
patient O 0
cohort O 0
( O 0
14 O 0
men O 0
, O 0
11 O 0
women O 0
) O 0
was O 0
treated O 0
with O 0
SRL B-Chemical 1
as O 0
conversion O 0
therapy O 0
, O 0
due O 0
to O 0
chronic B-Disease 1
allograft I-Disease 1
nephropathy I-Disease 1
( O 0
CAN B-Disease 1
) O 0
( O 0
n O 0
= O 0
15 O 0
) O 0
neoplasia B-Disease 1
( O 0
n O 0
= O 0
8 O 0
) O 0
; O 0
Kaposi B-Disease 1
' I-Disease 1
s I-Disease 1
sarcoma I-Disease 1
, O 0
Four O 0
skin B-Disease 1
cancers I-Disease 1
, O 0
One O 0
intestinal B-Disease 1
tumors I-Disease 1
, O 0
One O 0
renal B-Disease 1
cell I-Disease 1
carsinom I-Disease 1
) O 0
or O 0
BK O 0
virus O 0
nephropathy B-Disease 1
( O 0
n O 0
= O 0
2 O 0
) O 0
. O 0

SRL B-Chemical 1
was O 0
started O 0
at O 0
a O 0
mean O 0
of O 0
78 O 0
+ O 0
/ O 0
- O 0
42 O 0
( O 0
15 O 0
to O 0
163 O 0
) O 0
months O 0
after O 0
transplantation O 0
. O 0

Mean O 0
follow O 0
- O 0
up O 0
on O 0
SRL B-Chemical 1
therapy O 0
was O 0
20 O 0
+ O 0
/ O 0
- O 0
12 O 0
( O 0
6 O 0
to O 0
43 O 0
) O 0
months O 0
. O 0

Proteinuria B-Disease 1
increased O 0
from O 0
0 O 0
. O 0
445 O 0
( O 0
0 O 0
to O 0
1 O 0
. O 0
5 O 0
) O 0
g O 0
/ O 0
d O 0
before O 0
conversion O 0
to O 0
3 O 0
. O 0
2 O 0
g O 0
/ O 0
dL O 0
( O 0
0 O 0
. O 0
2 O 0
to O 0
12 O 0
) O 0
after O 0
conversion O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

Before O 0
conversion O 0
8 O 0
( O 0
32 O 0
% O 0
) O 0
patients O 0
had O 0
no O 0
proteinuria B-Disease 1
, O 0
whereas O 0
afterwards O 0
all O 0
patients O 0
had O 0
proteinuria B-Disease 1
. O 0

In O 0
28 O 0
% O 0
of O 0
patients O 0
proteinuria B-Disease 1
remained O 0
unchanged O 0
, O 0
whereas O 0
it O 0
increased O 0
in O 0
68 O 0
% O 0
of O 0
patients O 0
. O 0

In O 0
40 O 0
% O 0
it O 0
increased O 0
by O 0
more O 0
than O 0
100 O 0
% O 0
. O 0

Twenty O 0
- O 0
eight O 0
percent O 0
of O 0
patients O 0
showed O 0
increased O 0
proteinuria B-Disease 1
to O 0
the O 0
nephrotic B-Disease 1
range O 0
. O 0

Biopsies O 0
performed O 0
in O 0
five O 0
patients O 0
revealed O 0
new O 0
pathological O 0
changes O 0
: O 0
One O 0
membranoproliferative B-Disease 1
glomerulopathy I-Disease 1
and O 0
interstitial B-Disease 1
nephritis I-Disease 1
. O 0

These O 0
patients O 0
showed O 0
persistently O 0
good O 0
graft O 0
function O 0
. O 0

Serum O 0
creatinine B-Chemical 1
values O 0
did O 0
not O 0
change O 0
significantly O 0
: O 0
1 O 0
. O 0
98 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
8 O 0
mg O 0
/ O 0
dL O 0
before O 0
SRL B-Chemical 1
therapy O 0
and O 0
2 O 0
. O 0
53 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
9 O 0
mg O 0
/ O 0
dL O 0
at O 0
last O 0
follow O 0
- O 0
up O 0
( O 0
P O 0
= O 0
. O 0
14 O 0
) O 0
. O 0

Five O 0
grafts O 0
were O 0
lost O 0
and O 0
the O 0
patients O 0
returned O 0
to O 0
dialysis O 0
. O 0

Five O 0
patients O 0
displayed O 0
CAN B-Disease 1
and O 0
Kaposi B-Disease 1
' I-Disease 1
s I-Disease 1
sarcoma I-Disease 1
. O 0

Mean O 0
urinary O 0
protein O 0
of O 0
patients O 0
who O 0
returned O 0
to O 0
dialysis O 0
was O 0
1 O 0
. O 0
26 O 0
( O 0
0 O 0
. O 0
5 O 0
to O 0
3 O 0
. O 0
5 O 0
) O 0
g O 0
/ O 0
d O 0
before O 0
and O 0
4 O 0
. O 0
7 O 0
( O 0
3 O 0
to O 0
12 O 0
) O 0
g O 0
/ O 0
d O 0
after O 0
conversion O 0
( O 0
P O 0
= O 0
. O 0
01 O 0
) O 0
. O 0

Mean O 0
serum O 0
creatinine B-Chemical 1
level O 0
before O 0
conversion O 0
was O 0
2 O 0
. O 0
21 O 0
mg O 0
/ O 0
dL O 0
and O 0
thereafter O 0
, O 0
4 O 0
. O 0
93 O 0
mg O 0
/ O 0
dL O 0
( O 0
P O 0
= O 0
. O 0
02 O 0
) O 0
. O 0

Heavy O 0
proteinuria B-Disease 1
was O 0
common O 0
after O 0
the O 0
use O 0
of O 0
SRL B-Chemical 1
as O 0
rescue O 0
therapy O 0
for O 0
renal O 0
transplantation O 0
. O 0

Therefore O 0
, O 0
conversion O 0
should O 0
be O 0
considered O 0
for O 0
patients O 0
who O 0
have O 0
not O 0
developed O 0
advanced O 0
CAN B-Disease 1
and O 0
proteinuria B-Disease 1
. O 0

The O 0
possibility O 0
of O 0
de O 0
novo O 0
glomerular O 0
pathology O 0
under O 0
SRL B-Chemical 1
treatment O 0
requires O 0
further O 0
investigation O 0
by O 0
renal O 0
biopsy O 0
. O 0

Long O 0
- O 0
term O 0
follow O 0
- O 0
up O 0
of O 0
ifosfamide B-Chemical 1
renal B-Disease 1
toxicity I-Disease 1
in O 0
children O 0
treated O 0
for O 0
malignant B-Disease 1
mesenchymal I-Disease 1
tumors I-Disease 1
: O 0
an O 0
International O 0
Society O 0
of O 0
Pediatric O 0
Oncology O 0
report O 0
. O 0

The O 0
renal O 0
function O 0
of O 0
74 O 0
children O 0
with O 0
malignant B-Disease 1
mesenchymal I-Disease 1
tumors I-Disease 1
in O 0
complete O 0
remission O 0
and O 0
who O 0
have O 0
received O 0
the O 0
same O 0
ifosfamide B-Chemical 1
chemotherapy O 0
protocol O 0
( O 0
International O 0
Society O 0
of O 0
Pediatric O 0
Oncology O 0
Malignant B-Disease 1
Mesenchymal I-Disease 1
Tumor I-Disease 1
Study O 0
84 O 0
[ O 0
SIOP O 0
MMT O 0
84 O 0
] O 0
) O 0
were O 0
studied O 0
1 O 0
year O 0
after O 0
the O 0
completion O 0
of O 0
treatment O 0
. O 0

Total O 0
cumulative O 0
doses O 0
were O 0
36 O 0
or O 0
60 O 0
g O 0
/ O 0
m2 O 0
of O 0
ifosfamide B-Chemical 1
( O 0
six O 0
or O 0
10 O 0
cycles O 0
of O 0
ifosfamide B-Chemical 1
, I-Chemical 1
vincristine I-Chemical 1
, I-Chemical 1
and I-Chemical 1
dactinomycin I-Chemical 1
[ O 0
IVA B-Chemical 1
] O 0
) O 0
. O 0

None O 0
of O 0
them O 0
had O 0
received O 0
cisplatin B-Chemical 1
chemotherapy O 0
. O 0

Ages O 0
ranged O 0
from O 0
4 O 0
months O 0
to O 0
17 O 0
years O 0
; O 0
58 O 0
patients O 0
were O 0
males O 0
and O 0
42 O 0
females O 0
. O 0

The O 0
most O 0
common O 0
primary O 0
tumor B-Disease 1
site O 0
was O 0
the O 0
head O 0
and O 0
neck O 0
. O 0

Renal O 0
function O 0
was O 0
investigated O 0
by O 0
measuring O 0
plasma O 0
and O 0
urinary O 0
electrolytes O 0
, O 0
glucosuria B-Disease 1
, O 0
proteinuria B-Disease 1
, O 0
aminoaciduria B-Disease 1
, O 0
urinary O 0
pH O 0
, O 0
osmolarity O 0
, O 0
creatinine B-Chemical 1
clearance O 0
, O 0
phosphate B-Chemical 1
tubular O 0
reabsorption O 0
, O 0
beta O 0
2 O 0
microglobulinuria O 0
, O 0
and O 0
lysozymuria O 0
. O 0

Fifty O 0
- O 0
eight O 0
patients O 0
( O 0
78 O 0
% O 0
) O 0
had O 0
normal O 0
renal O 0
tests O 0
, O 0
whereas O 0
16 O 0
patients O 0
( O 0
22 O 0
% O 0
) O 0
had O 0
renal B-Disease 1
abnormalities I-Disease 1
. O 0

Two O 0
subsets O 0
of O 0
patients O 0
were O 0
identified O 0
from O 0
this O 0
latter O 0
group O 0
: O 0
the O 0
first O 0
included O 0
four O 0
patients O 0
( O 0
5 O 0
% O 0
of O 0
the O 0
total O 0
population O 0
) O 0
who O 0
developed O 0
major O 0
toxicity B-Disease 1
resulting O 0
in O 0
Fanconi B-Disease 1
' I-Disease 1
s I-Disease 1
syndrome I-Disease 1
( O 0
TDFS B-Disease 1
) O 0
; O 0
and O 0
the O 0
second O 0
group O 0
included O 0
five O 0
patients O 0
with O 0
elevated O 0
beta O 0
2 O 0
microglobulinuria O 0
and O 0
low O 0
phosphate B-Chemical 1
reabsorption O 0
. O 0

The O 0
remaining O 0
seven O 0
patients O 0
had O 0
isolated O 0
beta O 0
2 O 0
microglobulinuria O 0
. O 0

Severe O 0
toxicity B-Disease 1
was O 0
correlated O 0
with O 0
the O 0
higher O 0
cumulative O 0
dose O 0
of O 0
60 O 0
g O 0
/ O 0
m2 O 0
of O 0
ifosfamide B-Chemical 1
, O 0
a O 0
younger O 0
age O 0
( O 0
less O 0
than O 0
2 O 0
1 O 0
/ O 0
2 O 0
years O 0
old O 0
) O 0
, O 0
and O 0
a O 0
predominance O 0
of O 0
vesicoprostatic O 0
tumor B-Disease 1
involvement O 0
. O 0

This O 0
low O 0
percentage O 0
( O 0
5 O 0
% O 0
) O 0
of O 0
TDFS O 0
must O 0
be O 0
evaluated O 0
with O 0
respect O 0
to O 0
the O 0
efficacy O 0
of O 0
ifosfamide B-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
mesenchymal B-Disease 1
tumors I-Disease 1
in O 0
children O 0
. O 0

Progressive O 0
myopathy B-Disease 1
with O 0
up O 0
- O 0
regulation O 0
of O 0
MHC O 0
- O 0
I O 0
associated O 0
with O 0
statin B-Chemical 1
therapy O 0
. O 0

Statins B-Chemical 1
can O 0
cause O 0
a O 0
necrotizing O 0
myopathy B-Disease 1
and O 0
hyperCKaemia B-Disease 1
which O 0
is O 0
reversible O 0
on O 0
cessation O 0
of O 0
the O 0
drug O 0
. O 0

What O 0
is O 0
less O 0
well O 0
known O 0
is O 0
a O 0
phenomenon O 0
whereby O 0
statins B-Chemical 1
may O 0
induce O 0
a O 0
myopathy B-Disease 1
, O 0
which O 0
persists O 0
or O 0
may O 0
progress O 0
after O 0
stopping O 0
the O 0
drug O 0
. O 0

We O 0
investigated O 0
the O 0
muscle O 0
pathology O 0
in O 0
8 O 0
such O 0
cases O 0
. O 0

All O 0
had O 0
myofibre O 0
necrosis B-Disease 1
but O 0
only O 0
3 O 0
had O 0
an O 0
inflammatory O 0
infiltrate O 0
. O 0

In O 0
all O 0
cases O 0
there O 0
was O 0
diffuse O 0
or O 0
multifocal O 0
up O 0
- O 0
regulation O 0
of O 0
MHC O 0
- O 0
I O 0
expression O 0
even O 0
in O 0
non O 0
- O 0
necrotic B-Disease 1
fibres O 0
. O 0

Progressive O 0
improvement O 0
occurred O 0
in O 0
7 O 0
cases O 0
after O 0
commencement O 0
of O 0
prednisolone B-Chemical 1
and O 0
methotrexate B-Chemical 1
, O 0
and O 0
in O 0
one O 0
case O 0
spontaneously O 0
. O 0

These O 0
observations O 0
suggest O 0
that O 0
statins B-Chemical 1
may O 0
initiate O 0
an O 0
immune O 0
- O 0
mediated O 0
myopathy B-Disease 1
that O 0
persists O 0
after O 0
withdrawal O 0
of O 0
the O 0
drug O 0
and O 0
responds O 0
to O 0
immunosuppressive O 0
therapy O 0
. O 0

The O 0
mechanism O 0
of O 0
this O 0
myopathy B-Disease 1
is O 0
uncertain O 0
but O 0
may O 0
involve O 0
the O 0
induction O 0
by O 0
statins B-Chemical 1
of O 0
an O 0
endoplasmic O 0
reticulum O 0
stress O 0
response O 0
with O 0
associated O 0
up O 0
- O 0
regulation O 0
of O 0
MHC O 0
- O 0
I O 0
expression O 0
and O 0
antigen O 0
presentation O 0
by O 0
muscle O 0
fibres O 0
. O 0

Use O 0
of O 0
chromosome O 0
substitution O 0
strains O 0
to O 0
identify O 0
seizure B-Disease 1
susceptibility O 0
loci O 0
in O 0
mice O 0
. O 0

Seizure B-Disease 1
susceptibility O 0
varies O 0
among O 0
inbred O 0
mouse O 0
strains O 0
. O 0

Chromosome O 0
substitution O 0
strains O 0
( O 0
CSS O 0
) O 0
, O 0
in O 0
which O 0
a O 0
single O 0
chromosome O 0
from O 0
one O 0
inbred O 0
strain O 0
( O 0
donor O 0
) O 0
has O 0
been O 0
transferred O 0
onto O 0
a O 0
second O 0
strain O 0
( O 0
host O 0
) O 0
by O 0
repeated O 0
backcrossing O 0
, O 0
may O 0
be O 0
used O 0
to O 0
identify O 0
quantitative O 0
trait O 0
loci O 0
( O 0
QTLs O 0
) O 0
that O 0
contribute O 0
to O 0
seizure B-Disease 1
susceptibility O 0
. O 0

QTLs O 0
for O 0
susceptibility O 0
to O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
, O 0
a O 0
model O 0
of O 0
temporal B-Disease 1
lobe I-Disease 1
epilepsy I-Disease 1
, O 0
have O 0
not O 0
been O 0
reported O 0
, O 0
and O 0
CSS O 0
have O 0
not O 0
previously O 0
been O 0
used O 0
to O 0
localize O 0
seizure B-Disease 1
susceptibility O 0
genes O 0
. O 0

We O 0
report O 0
QTLs O 0
identified O 0
using O 0
a O 0
B6 O 0
( O 0
host O 0
) O 0
x O 0
A O 0
/ O 0
J O 0
( O 0
donor O 0
) O 0
CSS O 0
panel O 0
to O 0
localize O 0
genes O 0
involved O 0
in O 0
susceptibility O 0
to O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
. O 0

Three O 0
hundred O 0
fifty O 0
- O 0
five O 0
adult O 0
male O 0
CSS O 0
mice O 0
, O 0
58 O 0
B6 O 0
, O 0
and O 0
39 O 0
A O 0
/ O 0
J O 0
were O 0
tested O 0
for O 0
susceptibility O 0
to O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
. O 0

Highest O 0
stage O 0
reached O 0
and O 0
latency O 0
to O 0
each O 0
stage O 0
were O 0
recorded O 0
for O 0
all O 0
mice O 0
. O 0

B6 O 0
mice O 0
were O 0
resistant O 0
to O 0
seizures B-Disease 1
and O 0
slower O 0
to O 0
reach O 0
stages O 0
compared O 0
to O 0
A O 0
/ O 0
J O 0
mice O 0
. O 0

The O 0
CSS O 0
for O 0
Chromosomes O 0
10 O 0
and O 0
18 O 0
progressed O 0
to O 0
the O 0
most O 0
severe O 0
stages O 0
, O 0
diverging O 0
dramatically O 0
from O 0
the O 0
B6 O 0
phenotype O 0
. O 0

Latencies O 0
to O 0
stages O 0
were O 0
also O 0
significantly O 0
shorter O 0
for O 0
CSS10 O 0
and O 0
CSS18 O 0
mice O 0
. O 0

CSS O 0
mapping O 0
suggests O 0
seizure B-Disease 1
susceptibility O 0
loci O 0
on O 0
mouse O 0
Chromosomes O 0
10 O 0
and O 0
18 O 0
. O 0

This O 0
approach O 0
provides O 0
a O 0
framework O 0
for O 0
identifying O 0
potentially O 0
novel O 0
homologous O 0
candidate O 0
genes O 0
for O 0
human O 0
temporal B-Disease 1
lobe I-Disease 1
epilepsy I-Disease 1
. O 0

In O 0
vitro O 0
characterization O 0
of O 0
parasympathetic O 0
and O 0
sympathetic O 0
responses O 0
in O 0
cyclophosphamide B-Chemical 1
- O 0
induced O 0
cystitis B-Disease 1
in O 0
the O 0
rat O 0
. O 0

In O 0
cyclophosphamide B-Chemical 1
- O 0
induced O 0
cystitis B-Disease 1
in O 0
the O 0
rat O 0
, O 0
detrusor O 0
function O 0
is O 0
impaired O 0
and O 0
the O 0
expression O 0
and O 0
effects O 0
of O 0
muscarinic O 0
receptors O 0
altered O 0
. O 0

Whether O 0
or O 0
not O 0
the O 0
neuronal O 0
transmission O 0
may O 0
be O 0
affected O 0
by O 0
cystitis B-Disease 1
was O 0
presently O 0
investigated O 0
. O 0

Responses O 0
of O 0
urinary O 0
strip O 0
preparations O 0
from O 0
control O 0
and O 0
cyclophosphamide B-Chemical 1
- O 0
pretreated O 0
rats O 0
to O 0
electrical O 0
field O 0
stimulation O 0
and O 0
to O 0
agonists O 0
were O 0
assessed O 0
in O 0
the O 0
absence O 0
and O 0
presence O 0
of O 0
muscarinic O 0
, O 0
adrenergic O 0
and O 0
purinergic O 0
receptor O 0
antagonists O 0
. O 0

Generally O 0
, O 0
atropine B-Chemical 1
reduced O 0
contractions O 0
, O 0
but O 0
in O 0
contrast O 0
to O 0
controls O 0
, O 0
it O 0
also O 0
reduced O 0
responses O 0
to O 0
low O 0
electrical O 0
field O 0
stimulation O 0
intensity O 0
( O 0
1 O 0
- O 0
5 O 0
Hz O 0
) O 0
in O 0
inflamed O 0
preparations O 0
. O 0

In O 0
both O 0
types O 0
, O 0
purinoceptor O 0
desensitization O 0
with O 0
alpha B-Chemical 1
, I-Chemical 1
beta I-Chemical 1
- I-Chemical 1
methylene I-Chemical 1
adenosine I-Chemical 1
- I-Chemical 1
5 I-Chemical 1
' I-Chemical 1
- I-Chemical 1
triphosphate I-Chemical 1
( O 0
alpha B-Chemical 1
, I-Chemical 1
beta I-Chemical 1
- I-Chemical 1
meATP I-Chemical 1
) O 0
caused O 0
further O 0
reductions O 0
at O 0
low O 0
frequencies O 0
( O 0
< O 0
10 O 0
Hz O 0
) O 0
. O 0

The O 0
muscarinic O 0
receptor O 0
antagonists O 0
atropine B-Chemical 1
, O 0
4 B-Chemical 1
- I-Chemical 1
diphenylacetoxy I-Chemical 1
- I-Chemical 1
N I-Chemical 1
- I-Chemical 1
methylpiperidine I-Chemical 1
( O 0
4 B-Chemical 1
- I-Chemical 1
DAMP I-Chemical 1
) O 0
( O 0
' O 0
M O 0
( O 0
1 O 0
) O 0
/ O 0
M O 0
( O 0
3 O 0
) O 0
/ O 0
M O 0
( O 0
5 O 0
) O 0
- O 0
selective O 0
' O 0
) O 0
, O 0
methoctramine B-Chemical 1
( O 0
' O 0
M O 0
( O 0
2 O 0
) O 0
- O 0
selective O 0
' O 0
) O 0
and O 0
pirenzepine B-Chemical 1
( O 0
' O 0
M O 0
( O 0
1 O 0
) O 0
- O 0
selective O 0
' O 0
) O 0
antagonized O 0
the O 0
tonic O 0
component O 0
of O 0
the O 0
electrical O 0
field O 0
stimulation O 0
- O 0
evoked O 0
contractile O 0
response O 0
more O 0
potently O 0
than O 0
the O 0
phasic O 0
component O 0
. O 0

4 B-Chemical 1
- I-Chemical 1
DAMP I-Chemical 1
inhibited O 0
the O 0
tonic O 0
contractions O 0
in O 0
controls O 0
more O 0
potently O 0
than O 0
methoctramine B-Chemical 1
and O 0
pirenzepine B-Chemical 1
. O 0

In O 0
inflamed O 0
preparations O 0
, O 0
the O 0
muscarinic O 0
receptor O 0
antagonism O 0
on O 0
the O 0
phasic O 0
component O 0
of O 0
the O 0
electrical O 0
field O 0
stimulation O 0
- O 0
evoked O 0
contraction O 0
was O 0
decreased O 0
and O 0
the O 0
pirenzepine B-Chemical 1
and O 0
4 B-Chemical 1
- I-Chemical 1
DAMP I-Chemical 1
antagonism O 0
on O 0
the O 0
tonic O 0
component O 0
was O 0
much O 0
less O 0
efficient O 0
than O 0
in O 0
controls O 0
. O 0

In O 0
contrast O 0
to O 0
controls O 0
, O 0
methoctramine B-Chemical 1
increased O 0
- O 0
- O 0
instead O 0
of O 0
decreased O 0
- O 0
- O 0
the O 0
tonic O 0
responses O 0
at O 0
high O 0
frequencies O 0
. O 0

While O 0
contractions O 0
to O 0
carbachol B-Chemical 1
and O 0
ATP B-Chemical 1
were O 0
the O 0
same O 0
in O 0
inflamed O 0
and O 0
in O 0
control O 0
strips O 0
when O 0
related O 0
to O 0
a O 0
reference O 0
potassium B-Chemical 1
response O 0
, O 0
isoprenaline B-Chemical 1
- O 0
induced O 0
relaxations O 0
were O 0
smaller O 0
in O 0
inflamed O 0
strips O 0
. O 0

Thus O 0
, O 0
in O 0
cystitis B-Disease 1
substantial O 0
changes O 0
of O 0
the O 0
efferent O 0
functional O 0
responses O 0
occur O 0
. O 0

While O 0
postjunctional O 0
beta O 0
- O 0
adrenoceptor O 0
- O 0
mediated O 0
relaxations O 0
are O 0
reduced O 0
, O 0
effects O 0
by O 0
prejunctional O 0
inhibitory O 0
muscarinic O 0
receptors O 0
may O 0
be O 0
increased O 0
. O 0

Direct O 0
inhibition O 0
of O 0
cardiac O 0
hyperpolarization O 0
- O 0
activated O 0
cyclic B-Chemical 1
nucleotide I-Chemical 1
- O 0
gated O 0
pacemaker O 0
channels O 0
by O 0
clonidine B-Chemical 1
. O 0

BACKGROUND O 0
: O 0
Inhibition O 0
of O 0
cardiac O 0
sympathetic O 0
tone O 0
represents O 0
an O 0
important O 0
strategy O 0
for O 0
treatment O 0
of O 0
cardiovascular B-Disease 1
disease I-Disease 1
, O 0
including O 0
arrhythmia B-Disease 1
, O 0
coronary B-Disease 1
heart I-Disease 1
disease I-Disease 1
, O 0
and O 0
chronic O 0
heart B-Disease 1
failure I-Disease 1
. O 0

Activation O 0
of O 0
presynaptic O 0
alpha2 O 0
- O 0
adrenoceptors O 0
is O 0
the O 0
most O 0
widely O 0
accepted O 0
mechanism O 0
of O 0
action O 0
of O 0
the O 0
antisympathetic O 0
drug O 0
clonidine B-Chemical 1
; O 0
however O 0
, O 0
other O 0
target O 0
proteins O 0
have O 0
been O 0
postulated O 0
to O 0
contribute O 0
to O 0
the O 0
in O 0
vivo O 0
actions O 0
of O 0
clonidine B-Chemical 1
. O 0

METHODS O 0
AND O 0
RESULTS O 0
: O 0
To O 0
test O 0
whether O 0
clonidine B-Chemical 1
elicits O 0
pharmacological O 0
effects O 0
independent O 0
of O 0
alpha2 O 0
- O 0
adrenoceptors O 0
, O 0
we O 0
have O 0
generated O 0
mice O 0
with O 0
a O 0
targeted O 0
deletion O 0
of O 0
all O 0
3 O 0
alpha2 O 0
- O 0
adrenoceptor O 0
subtypes O 0
( O 0
alpha2ABC O 0
- O 0
/ O 0
- O 0
) O 0
. O 0

Alpha2ABC O 0
- O 0
/ O 0
- O 0
mice O 0
were O 0
completely O 0
unresponsive O 0
to O 0
the O 0
analgesic O 0
and O 0
hypnotic O 0
effects O 0
of O 0
clonidine B-Chemical 1
; O 0
however O 0
, O 0
clonidine B-Chemical 1
significantly O 0
lowered O 0
heart O 0
rate O 0
in O 0
alpha2ABC O 0
- O 0
/ O 0
- O 0
mice O 0
by O 0
up O 0
to O 0
150 O 0
bpm O 0
. O 0

Clonidine B-Chemical 1
- O 0
induced O 0
bradycardia B-Disease 1
in O 0
conscious O 0
alpha2ABC O 0
- O 0
/ O 0
- O 0
mice O 0
was O 0
32 O 0
. O 0
3 O 0
% O 0
( O 0
10 O 0
microg O 0
/ O 0
kg O 0
) O 0
and O 0
26 O 0
. O 0
6 O 0
% O 0
( O 0
100 O 0
microg O 0
/ O 0
kg O 0
) O 0
of O 0
the O 0
effect O 0
in O 0
wild O 0
- O 0
type O 0
mice O 0
. O 0

A O 0
similar O 0
bradycardic O 0
effect O 0
of O 0
clonidine B-Chemical 1
was O 0
observed O 0
in O 0
isolated O 0
spontaneously O 0
beating O 0
right O 0
atria O 0
from O 0
alpha2ABC O 0
- O 0
knockout O 0
and O 0
wild O 0
- O 0
type O 0
mice O 0
. O 0

Clonidine B-Chemical 1
inhibited O 0
the O 0
native O 0
pacemaker O 0
current O 0
( O 0
I O 0
( O 0
f O 0
) O 0
) O 0
in O 0
isolated O 0
sinoatrial O 0
node O 0
pacemaker O 0
cells O 0
and O 0
the O 0
I O 0
( O 0
f O 0
) O 0
- O 0
generating O 0
hyperpolarization O 0
- O 0
activated O 0
cyclic B-Chemical 1
nucleotide I-Chemical 1
- O 0
gated O 0
( O 0
HCN O 0
) O 0
2 O 0
and O 0
HCN4 O 0
channels O 0
in O 0
transfected O 0
HEK293 O 0
cells O 0
. O 0

As O 0
a O 0
consequence O 0
of O 0
blocking O 0
I O 0
( O 0
f O 0
) O 0
, O 0
clonidine B-Chemical 1
reduced O 0
the O 0
slope O 0
of O 0
the O 0
diastolic O 0
depolarization O 0
and O 0
the O 0
frequency O 0
of O 0
pacemaker O 0
potentials O 0
in O 0
sinoatrial O 0
node O 0
cells O 0
from O 0
wild O 0
- O 0
type O 0
and O 0
alpha2ABC O 0
- O 0
knockout O 0
mice O 0
. O 0

CONCLUSIONS O 0
: O 0
Direct O 0
inhibition O 0
of O 0
cardiac O 0
HCN O 0
pacemaker O 0
channels O 0
contributes O 0
to O 0
the O 0
bradycardic O 0
effects O 0
of O 0
clonidine B-Chemical 1
gene O 0
- O 0
targeted O 0
mice O 0
in O 0
vivo O 0
, O 0
and O 0
thus O 0
, O 0
clonidine B-Chemical 1
- O 0
like O 0
drugs O 0
represent O 0
novel O 0
structures O 0
for O 0
future O 0
HCN O 0
channel O 0
inhibitors O 0
. O 0

Granulomatous B-Disease 1
hepatitis I-Disease 1
due O 0
to O 0
combination B-Chemical 1
of I-Chemical 1
amoxicillin I-Chemical 1
and I-Chemical 1
clavulanic I-Chemical 1
acid I-Chemical 1
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
patient O 0
with O 0
amoxicillin B-Chemical 1
- I-Chemical 1
clavulanic I-Chemical 1
acid I-Chemical 1
- O 0
induced O 0
hepatitis B-Disease 1
with O 0
histologic O 0
multiple O 0
granulomas B-Disease 1
. O 0

This O 0
type O 0
of O 0
lesion O 0
broadens O 0
the O 0
spectrum O 0
of O 0
liver B-Disease 1
injury I-Disease 1
due O 0
to O 0
this O 0
drug O 0
combination O 0
, O 0
mainly O 0
represented O 0
by O 0
a O 0
benign O 0
cholestatic B-Disease 1
syndrome I-Disease 1
. O 0

The O 0
association O 0
of O 0
granulomas B-Disease 1
and O 0
eosinophilia B-Disease 1
favor O 0
an O 0
immunoallergic O 0
mechanism O 0
. O 0

As O 0
penicillin B-Chemical 1
derivatives O 0
and O 0
amoxicillin B-Chemical 1
alone O 0
are O 0
known O 0
to O 0
induce O 0
such O 0
types O 0
of O 0
lesions O 0
, O 0
the O 0
amoxicillin B-Chemical 1
component O 0
, O 0
with O 0
or O 0
without O 0
a O 0
potentiating O 0
effect O 0
of O 0
clavulanic B-Chemical 1
acid I-Chemical 1
, O 0
might O 0
have O 0
a O 0
major O 0
role O 0
. O 0

Dobutamine B-Chemical 1
stress O 0
echocardiography O 0
: O 0
a O 0
sensitive O 0
indicator O 0
of O 0
diminished O 0
myocardial O 0
function O 0
in O 0
asymptomatic O 0
doxorubicin B-Chemical 1
- O 0
treated O 0
long O 0
- O 0
term O 0
survivors O 0
of O 0
childhood O 0
cancer B-Disease 1
. O 0

Doxorubicin B-Chemical 1
is O 0
an O 0
effective O 0
anticancer O 0
chemotherapeutic O 0
agent O 0
known O 0
to O 0
cause O 0
acute O 0
and O 0
chronic O 0
cardiomyopathy B-Disease 1
. O 0

To O 0
develop O 0
a O 0
more O 0
sensitive O 0
echocardiographic O 0
screening O 0
test O 0
for O 0
cardiac B-Disease 1
damage I-Disease 1
due O 0
to O 0
doxorubicin B-Chemical 1
, O 0
a O 0
cohort O 0
study O 0
was O 0
performed O 0
using O 0
dobutamine B-Chemical 1
infusion O 0
to O 0
differentiate O 0
asymptomatic O 0
long O 0
- O 0
term O 0
survivors O 0
of O 0
childhood O 0
cancer B-Disease 1
treated O 0
with O 0
doxorubicin B-Chemical 1
from O 0
healthy O 0
control O 0
subjects O 0
. O 0

Echocardiographic O 0
data O 0
from O 0
the O 0
experimental O 0
group O 0
of O 0
21 O 0
patients O 0
( O 0
mean O 0
age O 0
16 O 0
+ O 0
/ O 0
- O 0
5 O 0
years O 0
) O 0
treated O 0
from O 0
1 O 0
. O 0
6 O 0
to O 0
14 O 0
. O 0
3 O 0
years O 0
( O 0
median O 0
5 O 0
. O 0
3 O 0
) O 0
before O 0
this O 0
study O 0
with O 0
27 O 0
to O 0
532 O 0
mg O 0
/ O 0
m2 O 0
of O 0
doxorubicin B-Chemical 1
( O 0
mean O 0
196 O 0
) O 0
were O 0
compared O 0
with O 0
echocardiographic O 0
data O 0
from O 0
12 O 0
normal O 0
age O 0
- O 0
matched O 0
control O 0
subjects O 0
. O 0

Graded O 0
dobutamine B-Chemical 1
infusions O 0
of O 0
0 O 0
. O 0
5 O 0
, O 0
2 O 0
. O 0
5 O 0
, O 0
5 O 0
and O 0
10 O 0
micrograms O 0
/ O 0
kg O 0
per O 0
min O 0
were O 0
administered O 0
. O 0

Echocardiographic O 0
Doppler O 0
studies O 0
were O 0
performed O 0
before O 0
infusion O 0
and O 0
after O 0
15 O 0
min O 0
of O 0
infusion O 0
at O 0
each O 0
rate O 0
. O 0

Dobutamine B-Chemical 1
infusion O 0
at O 0
10 O 0
micrograms O 0
/ O 0
kg O 0
per O 0
min O 0
was O 0
discontinued O 0
after O 0
six O 0
studies O 0
secondary O 0
to O 0
a O 0
50 O 0
% O 0
incidence O 0
rate O 0
of O 0
adverse O 0
symptoms O 0
. O 0

The O 0
most O 0
important O 0
findings O 0
were O 0
that O 0
compared O 0
with O 0
values O 0
in O 0
control O 0
subjects O 0
, O 0
end O 0
- O 0
systolic O 0
left O 0
ventricular O 0
posterior O 0
wall O 0
dimension O 0
and O 0
percent O 0
of O 0
left O 0
ventricular O 0
posterior O 0
wall O 0
thickening O 0
in O 0
doxorubicin B-Chemical 1
- O 0
treated O 0
patients O 0
were O 0
decreased O 0
at O 0
baseline O 0
study O 0
and O 0
these O 0
findings O 0
were O 0
more O 0
clearly O 0
delineated O 0
with O 0
dobutamine B-Chemical 1
stimulation O 0
. O 0

End O 0
- O 0
systolic O 0
left O 0
ventricular O 0
posterior O 0
wall O 0
dimension O 0
at O 0
baseline O 0
for O 0
the O 0
doxorubicin B-Chemical 1
- O 0
treated O 0
group O 0
was O 0
11 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
9 O 0
mm O 0
versus O 0
13 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
5 O 0
mm O 0
for O 0
control O 0
subjects O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

End O 0
- O 0
systolic O 0
left O 0
ventricular O 0
posterior O 0
wall O 0
dimension O 0
at O 0
the O 0
5 O 0
- O 0
micrograms O 0
/ O 0
kg O 0
per O 0
min O 0
dobutamine B-Chemical 1
infusion O 0
for O 0
the O 0
doxorubicin B-Chemical 1
- O 0
treated O 0
group O 0
was O 0
14 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
4 O 0
mm O 0
versus O 0
19 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
6 O 0
mm O 0
for O 0
control O 0
subjects O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0
( O 0
ABSTRACT O 0
TRUNCATED O 0
AT O 0
250 O 0
WORDS O 0
) O 0

Influence O 0
of O 0
smoking B-Chemical 1
on O 0
developing O 0
cochlea O 0
. O 0

Does O 0
smoking B-Chemical 1
during O 0
pregnancy O 0
affect O 0
the O 0
amplitudes O 0
of O 0
transient O 0
evoked O 0
otoacoustic O 0
emissions O 0
in O 0
newborns O 0
? O 0

OBJECTIVE O 0
: O 0
Maternal O 0
tobacco O 0
smoking B-Chemical 1
has O 0
negative O 0
effects O 0
on O 0
fetal O 0
growth O 0
. O 0

The O 0
influence O 0
of O 0
smoking B-Chemical 1
during O 0
pregnancy O 0
on O 0
the O 0
developing O 0
cochlea O 0
has O 0
not O 0
been O 0
estimated O 0
, O 0
although O 0
smoking B-Chemical 1
has O 0
been O 0
positively O 0
associated O 0
with O 0
hearing B-Disease 1
loss I-Disease 1
in O 0
adults O 0
. O 0

The O 0
objective O 0
of O 0
this O 0
study O 0
was O 0
to O 0
determine O 0
the O 0
effects O 0
of O 0
maternal O 0
smoking B-Chemical 1
on O 0
transient O 0
evoked O 0
otoacoustic O 0
emissions O 0
( O 0
TEOAEs O 0
) O 0
of O 0
healthy O 0
neonates O 0
. O 0

METHODS O 0
: O 0
This O 0
study O 0
was O 0
undertaken O 0
as O 0
part O 0
of O 0
neonatal O 0
screening O 0
for O 0
hearing B-Disease 1
impairment I-Disease 1
and O 0
involved O 0
both O 0
ears O 0
of O 0
200 O 0
newborns O 0
. O 0

Newborns O 0
whose O 0
mothers O 0
reported O 0
smoking B-Chemical 1
during O 0
pregnancy O 0
( O 0
n O 0
= O 0
200 O 0
ears O 0
) O 0
were O 0
compared O 0
to O 0
a O 0
control O 0
group O 0
of O 0
newborns O 0
( O 0
n O 0
= O 0
200 O 0
ears O 0
) O 0
, O 0
whose O 0
mothers O 0
were O 0
non O 0
- O 0
smokers O 0
. O 0

Exposure O 0
to O 0
tobacco O 0
was O 0
characterized O 0
as O 0
low O 0
( O 0
< O 0
5 O 0
cigarettes O 0
per O 0
day O 0
, O 0
n O 0
= O 0
88 O 0
ears O 0
) O 0
, O 0
moderate O 0
( O 0
5 O 0
< O 0
or O 0
= O 0
cigarettes O 0
per O 0
day O 0
< O 0
10 O 0
, O 0
n O 0
= O 0
76 O 0
) O 0
or O 0
high O 0
( O 0
> O 0
or O 0
= O 0
10 O 0
cigarettes O 0
per O 0
day O 0
, O 0
n O 0
= O 0
36 O 0
) O 0
. O 0

RESULTS O 0
: O 0
In O 0
exposed O 0
neonates O 0
, O 0
TEOAEs O 0
mean O 0
response O 0
( O 0
across O 0
frequency O 0
) O 0
and O 0
mean O 0
amplitude O 0
at O 0
4000Hz O 0
was O 0
significantly O 0
lower O 0
than O 0
in O 0
non O 0
- O 0
exposed O 0
neonates O 0
. O 0

Comparisons O 0
between O 0
exposed O 0
newborns O 0
' O 0
subgroups O 0
revealed O 0
no O 0
significant O 0
differences O 0
. O 0

However O 0
, O 0
by O 0
comparing O 0
each O 0
subgroup O 0
to O 0
control O 0
group O 0
, O 0
we O 0
found O 0
statistically O 0
significant O 0
decreases B-Disease 1
of I-Disease 1
TEOAEs I-Disease 1
amplitudes I-Disease 1
at O 0
4000Hz O 0
for O 0
all O 0
three O 0
groups O 0
. O 0

Mean O 0
TEOAEs O 0
responses O 0
of O 0
highly O 0
exposed O 0
newborns O 0
were O 0
also O 0
significantly O 0
lower O 0
in O 0
comparison O 0
to O 0
our O 0
control O 0
group O 0
. O 0

CONCLUSION O 0
: O 0
In O 0
utero O 0
, O 0
exposure O 0
to O 0
tobacco O 0
smoking B-Chemical 1
seems O 0
to O 0
have O 0
a O 0
small O 0
impact O 0
on O 0
outer O 0
hair O 0
cells O 0
. O 0

These O 0
effects O 0
seem O 0
to O 0
be O 0
equally O 0
true O 0
for O 0
all O 0
exposed O 0
newborns O 0
, O 0
regardless O 0
of O 0
the O 0
degree O 0
of O 0
exposure O 0
. O 0

Further O 0
studies O 0
are O 0
needed O 0
in O 0
order O 0
to O 0
establish O 0
a O 0
potential O 0
negative O 0
effect O 0
of O 0
maternal O 0
smoking B-Chemical 1
on O 0
the O 0
neonate O 0
' O 0
s O 0
hearing O 0
acuity O 0
. O 0

Simvastatin B-Chemical 1
- O 0
induced O 0
bilateral O 0
leg O 0
compartment B-Disease 1
syndrome I-Disease 1
and O 0
myonecrosis B-Disease 1
associated O 0
with O 0
hypothyroidism B-Disease 1
. O 0

A O 0
54 O 0
- O 0
year O 0
- O 0
old O 0
hypothyroid B-Disease 1
male O 0
taking O 0
thyroxine B-Chemical 1
and O 0
simvastatin B-Chemical 1
presented O 0
with O 0
bilateral O 0
leg O 0
compartment B-Disease 1
syndrome I-Disease 1
and O 0
myonecrosis B-Disease 1
. O 0

Urgent O 0
fasciotomies O 0
were O 0
performed O 0
and O 0
the O 0
patient O 0
made O 0
an O 0
uneventful O 0
recovery O 0
with O 0
the O 0
withdrawal O 0
of O 0
simvastatin B-Chemical 1
. O 0

It O 0
is O 0
likely O 0
that O 0
this O 0
complication O 0
will O 0
be O 0
seen O 0
more O 0
often O 0
with O 0
the O 0
increased O 0
worldwide O 0
use O 0
of O 0
this O 0
drug O 0
and O 0
its O 0
approval O 0
for O 0
all O 0
arteriopathic B-Disease 1
patients O 0
. O 0

Neuroinflammation B-Disease 1
and O 0
behavioral B-Disease 1
abnormalities I-Disease 1
after O 0
neonatal O 0
terbutaline B-Chemical 1
treatment O 0
in O 0
rats O 0
: O 0
implications O 0
for O 0
autism B-Disease 1
. O 0

Autism B-Disease 1
is O 0
a O 0
neurodevelopmental B-Disease 1
disorder I-Disease 1
presenting O 0
before O 0
3 O 0
years O 0
of O 0
age O 0
with O 0
deficits B-Disease 1
in I-Disease 1
communication I-Disease 1
and I-Disease 1
social I-Disease 1
skills I-Disease 1
and O 0
repetitive B-Disease 1
behaviors I-Disease 1
. O 0

In O 0
addition O 0
to O 0
genetic O 0
influences O 0
, O 0
recent O 0
studies O 0
suggest O 0
that O 0
prenatal O 0
drug O 0
or O 0
chemical O 0
exposures O 0
are O 0
risk O 0
factors O 0
for O 0
autism B-Disease 1
. O 0

Terbutaline B-Chemical 1
, O 0
a O 0
beta2 O 0
- O 0
adrenoceptor O 0
agonist O 0
used O 0
to O 0
arrest O 0
preterm B-Disease 1
labor I-Disease 1
, O 0
has O 0
been O 0
associated O 0
with O 0
increased O 0
concordance O 0
for O 0
autism B-Disease 1
in O 0
dizygotic O 0
twins O 0
. O 0

We O 0
studied O 0
the O 0
effects O 0
of O 0
terbutaline B-Chemical 1
on O 0
microglial O 0
activation O 0
in O 0
different O 0
brain O 0
regions O 0
and O 0
behavioral O 0
outcomes O 0
in O 0
developing O 0
rats O 0
. O 0

Newborn O 0
rats O 0
were O 0
given O 0
terbutaline B-Chemical 1
( O 0
10 O 0
mg O 0
/ O 0
kg O 0
) O 0
daily O 0
on O 0
postnatal O 0
days O 0
( O 0
PN O 0
) O 0
2 O 0
to O 0
5 O 0
or O 0
PN O 0
11 O 0
to O 0
14 O 0
and O 0
examined O 0
24 O 0
h O 0
after O 0
the O 0
last O 0
dose O 0
and O 0
at O 0
PN O 0
30 O 0
. O 0

Immunohistochemical O 0
studies O 0
showed O 0
that O 0
administration O 0
of O 0
terbutaline B-Chemical 1
on O 0
PN O 0
2 O 0
to O 0
5 O 0
produced O 0
a O 0
robust O 0
increase O 0
in O 0
microglial O 0
activation O 0
on O 0
PN O 0
30 O 0
in O 0
the O 0
cerebral O 0
cortex O 0
, O 0
as O 0
well O 0
as O 0
in O 0
cerebellar O 0
and O 0
cerebrocortical O 0
white O 0
matter O 0
. O 0

None O 0
of O 0
these O 0
effects O 0
occurred O 0
in O 0
animals O 0
given O 0
terbutaline B-Chemical 1
on O 0
PN O 0
11 O 0
to O 0
14 O 0
. O 0

In O 0
behavioral O 0
tests O 0
, O 0
animals O 0
treated O 0
with O 0
terbutaline B-Chemical 1
on O 0
PN O 0
2 O 0
to O 0
5 O 0
showed O 0
consistent O 0
patterns O 0
of O 0
hyper O 0
- O 0
reactivity O 0
to O 0
novelty O 0
and O 0
aversive O 0
stimuli O 0
when O 0
assessed O 0
in O 0
a O 0
novel O 0
open O 0
field O 0
, O 0
as O 0
well O 0
as O 0
in O 0
the O 0
acoustic O 0
startle O 0
response O 0
test O 0
. O 0

Our O 0
findings O 0
indicate O 0
that O 0
beta2 O 0
- O 0
adrenoceptor O 0
overstimulation O 0
during O 0
an O 0
early O 0
critical O 0
period O 0
results O 0
in O 0
microglial O 0
activation O 0
associated O 0
with O 0
innate O 0
neuroinflammatory O 0
pathways O 0
and O 0
behavioral B-Disease 1
abnormalities I-Disease 1
, O 0
similar O 0
to O 0
those O 0
described O 0
in O 0
autism B-Disease 1
. O 0

This O 0
study O 0
provides O 0
a O 0
useful O 0
animal O 0
model O 0
for O 0
understanding O 0
the O 0
neuropathological O 0
processes O 0
underlying O 0
autism B-Disease 1
spectrum I-Disease 1
disorders I-Disease 1
. O 0

Upregulation O 0
of O 0
brain O 0
expression O 0
of O 0
P O 0
- O 0
glycoprotein O 0
in O 0
MRP2 O 0
- O 0
deficient O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
resembles O 0
seizure B-Disease 1
- O 0
induced O 0
up O 0
- O 0
regulation O 0
of O 0
this O 0
drug O 0
efflux O 0
transporter O 0
in O 0
normal O 0
rats O 0
. O 0

PURPOSE O 0
: O 0
The O 0
multidrug O 0
resistance O 0
protein O 0
2 O 0
( O 0
MRP2 O 0
) O 0
is O 0
a O 0
drug O 0
efflux O 0
transporter O 0
that O 0
is O 0
expressed O 0
predominantly O 0
at O 0
the O 0
apical O 0
domain O 0
of O 0
hepatocytes O 0
but O 0
seems O 0
also O 0
to O 0
be O 0
expressed O 0
at O 0
the O 0
apical O 0
membrane O 0
of O 0
brain O 0
capillary O 0
endothelial O 0
cells O 0
that O 0
form O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
( O 0
BBB O 0
) O 0
. O 0

MRP2 O 0
is O 0
absent O 0
in O 0
the O 0
transport O 0
- O 0
deficient O 0
( O 0
TR O 0
( O 0
- O 0
) O 0
) O 0
Wistar O 0
rat O 0
mutant O 0
, O 0
so O 0
that O 0
this O 0
rat O 0
strain O 0
was O 0
very O 0
helpful O 0
in O 0
defining O 0
substrates O 0
of O 0
MRP2 O 0
by O 0
comparing O 0
tissue O 0
concentrations O 0
or O 0
functional O 0
activities O 0
of O 0
compounds O 0
in O 0
MRP2 O 0
- O 0
deficient O 0
rats O 0
with O 0
those O 0
in O 0
transport O 0
- O 0
competent O 0
Wistar O 0
rats O 0
. O 0

By O 0
using O 0
this O 0
strategy O 0
to O 0
study O 0
the O 0
involvement O 0
of O 0
MRP2 O 0
in O 0
brain O 0
access O 0
of O 0
antiepileptic O 0
drugs O 0
( O 0
AEDs O 0
) O 0
, O 0
we O 0
recently O 0
reported O 0
that O 0
phenytoin B-Chemical 1
is O 0
a O 0
substrate O 0
for O 0
MRP2 O 0
in O 0
the O 0
BBB O 0
. O 0

However O 0
, O 0
one O 0
drawback O 0
of O 0
such O 0
studies O 0
in O 0
genetically O 0
deficient O 0
rats O 0
is O 0
the O 0
fact O 0
that O 0
compensatory O 0
changes O 0
with O 0
upregulation O 0
of O 0
other O 0
transporters O 0
can O 0
occur O 0
. O 0

This O 0
prompted O 0
us O 0
to O 0
study O 0
the O 0
brain O 0
expression O 0
of O 0
P O 0
- O 0
glycoprotein O 0
( O 0
Pgp O 0
) O 0
, O 0
a O 0
major O 0
drug O 0
efflux O 0
transporter O 0
in O 0
many O 0
tissues O 0
, O 0
including O 0
the O 0
BBB O 0
, O 0
in O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
compared O 0
with O 0
nonmutant O 0
( O 0
wild O 0
- O 0
type O 0
) O 0
Wistar O 0
rats O 0
. O 0

METHODS O 0
: O 0
The O 0
expression O 0
of O 0
MRP2 O 0
and O 0
Pgp O 0
in O 0
brain O 0
and O 0
liver O 0
sections O 0
of O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
and O 0
normal O 0
Wistar O 0
rats O 0
was O 0
determined O 0
with O 0
immunohistochemistry O 0
, O 0
by O 0
using O 0
a O 0
novel O 0
, O 0
highly O 0
selective O 0
monoclonal O 0
MRP2 O 0
antibody O 0
and O 0
the O 0
monoclonal O 0
Pgp O 0
antibody O 0
C219 O 0
, O 0
respectively O 0
. O 0

RESULTS O 0
: O 0
Immunofluorescence O 0
staining O 0
with O 0
the O 0
MRP2 O 0
antibody O 0
was O 0
found O 0
to O 0
label O 0
a O 0
high O 0
number O 0
of O 0
microvessels O 0
throughout O 0
the O 0
brain O 0
in O 0
normal O 0
Wistar O 0
rats O 0
, O 0
whereas O 0
such O 0
labeling O 0
was O 0
absent O 0
in O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
. O 0

TR O 0
( O 0
- O 0
) O 0
rats O 0
exhibited O 0
a O 0
significant O 0
up O 0
- O 0
regulation O 0
of O 0
Pgp O 0
in O 0
brain O 0
capillary O 0
endothelial O 0
cells O 0
compared O 0
with O 0
wild O 0
- O 0
type O 0
controls O 0
. O 0

No O 0
such O 0
obvious O 0
upregulation O 0
of O 0
Pgp O 0
was O 0
observed O 0
in O 0
liver O 0
sections O 0
. O 0

A O 0
comparable O 0
overexpression O 0
of O 0
Pgp O 0
in O 0
the O 0
BBB O 0
was O 0
obtained O 0
after O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
in O 0
wild O 0
- O 0
type O 0
Wistar O 0
rats O 0
. O 0

Experiments O 0
with O 0
systemic O 0
administration O 0
of O 0
the O 0
Pgp O 0
substrate O 0
phenobarbital B-Chemical 1
and O 0
the O 0
selective O 0
Pgp O 0
inhibitor O 0
tariquidar B-Chemical 1
in O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
substantiated O 0
that O 0
Pgp O 0
is O 0
functional O 0
and O 0
compensates O 0
for O 0
the O 0
lack O 0
of O 0
MRP2 O 0
in O 0
the O 0
BBB O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
data O 0
on O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
indicate O 0
that O 0
Pgp O 0
plays O 0
an O 0
important O 0
role O 0
in O 0
the O 0
compensation O 0
of O 0
MRP2 O 0
deficiency O 0
in O 0
the O 0
BBB O 0
. O 0

Because O 0
such O 0
a O 0
compensatory O 0
mechanism O 0
most O 0
likely O 0
occurs O 0
to O 0
reduce O 0
injury B-Disease 1
to I-Disease 1
the I-Disease 1
brain I-Disease 1
from O 0
cytotoxic O 0
compounds O 0
, O 0
the O 0
present O 0
data O 0
substantiate O 0
the O 0
concept O 0
that O 0
MRP2 O 0
performs O 0
a O 0
protective O 0
role O 0
in O 0
the O 0
BBB O 0
. O 0

Furthermore O 0
, O 0
our O 0
data O 0
suggest O 0
that O 0
TR O 0
( O 0
- O 0
) O 0
rats O 0
are O 0
an O 0
interesting O 0
tool O 0
to O 0
study O 0
consequences O 0
of O 0
overexpression O 0
of O 0
Pgp O 0
in O 0
the O 0
BBB O 0
on O 0
access O 0
of O 0
drugs O 0
in O 0
the O 0
brain O 0
, O 0
without O 0
the O 0
need O 0
of O 0
inducing O 0
seizures B-Disease 1
or O 0
other O 0
Pgp O 0
- O 0
enhancing O 0
events O 0
for O 0
this O 0
purpose O 0
. O 0

Role O 0
of O 0
xanthine B-Chemical 1
oxidase O 0
in O 0
dexamethasone B-Chemical 1
- O 0
induced O 0
hypertension B-Disease 1
in O 0
rats O 0
. O 0

1 O 0
. O 0

Glucocorticoid O 0
- O 0
induced O 0
hypertension B-Disease 1
( O 0
GC O 0
- O 0
HT B-Disease 1
) O 0
in O 0
the O 0
rat O 0
is O 0
associated O 0
with O 0
nitric B-Chemical 1
oxide I-Chemical 1
- O 0
redox O 0
imbalance O 0
. O 0

2 O 0
. O 0

We O 0
studied O 0
the O 0
role O 0
of O 0
xanthine B-Chemical 1
oxidase O 0
( O 0
XO O 0
) O 0
, O 0
which O 0
is O 0
implicated O 0
in O 0
the O 0
production O 0
of O 0
reactive O 0
oxygen O 0
species O 0
, O 0
in O 0
dexamethasone B-Chemical 1
- O 0
induced O 0
hypertension B-Disease 1
( O 0
dex B-Chemical 1
- O 0
HT B-Disease 1
) O 0
. O 0

3 O 0
. O 0

Thirty O 0
male O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
were O 0
divided O 0
randomly O 0
into O 0
four O 0
treatment O 0
groups O 0
: O 0
saline O 0
, O 0
dexamethasone B-Chemical 1
( O 0
dex B-Chemical 1
) O 0
, O 0
allopurinol B-Chemical 1
plus O 0
saline O 0
, O 0
and O 0
allopurinol B-Chemical 1
plus O 0
dex B-Chemical 1
. O 0

4 O 0
. O 0

Systolic O 0
blood O 0
pressures O 0
( O 0
SBP O 0
) O 0
and O 0
bodyweights O 0
were O 0
recorded O 0
each O 0
alternate O 0
day O 0
. O 0

Thymus O 0
weight O 0
was O 0
used O 0
as O 0
a O 0
marker O 0
of O 0
glucocorticoid O 0
activity O 0
, O 0
and O 0
serum O 0
urate B-Chemical 1
to O 0
assess O 0
XO O 0
inhibition O 0
. O 0

5 O 0
. O 0

Dex B-Chemical 1
increased B-Disease 1
SBP I-Disease 1
( O 0
110 O 0
+ O 0
/ O 0
- O 0
2 O 0
- O 0
126 O 0
+ O 0
/ O 0
- O 0
3 O 0
mmHg O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
and O 0
decreased B-Disease 1
thymus I-Disease 1
( I-Disease 1
P I-Disease 1
< I-Disease 1
0 I-Disease 1
. I-Disease 1
001 I-Disease 1
) I-Disease 1
and I-Disease 1
bodyweights I-Disease 1
( O 0
P O 0
" O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

Allopurinol B-Chemical 1
decreased O 0
serum O 0
urate B-Chemical 1
from O 0
76 O 0
+ O 0
/ O 0
- O 0
5 O 0
to O 0
30 O 0
+ O 0
/ O 0
- O 0
3 O 0
micromol O 0
/ O 0
L O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
in O 0
saline O 0
and O 0
from O 0
84 O 0
+ O 0
/ O 0
- O 0
13 O 0
to O 0
28 O 0
+ O 0
/ O 0
- O 0
2 O 0
micromol O 0
/ O 0
L O 0
in O 0
dex B-Chemical 1
- O 0
treated O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
groups O 0
. O 0

6 O 0
. O 0

Allopurinol B-Chemical 1
did O 0
not O 0
prevent O 0
dex B-Chemical 1
- O 0
HT B-Disease 1
. O 0

This O 0
, O 0
together O 0
with O 0
our O 0
previous O 0
findings O 0
that O 0
allopurinol B-Chemical 1
failed O 0
to O 0
prevent O 0
adrenocorticotrophic O 0
hormone O 0
induced O 0
hypertension B-Disease 1
, O 0
suggests O 0
that O 0
XO O 0
activity O 0
is O 0
not O 0
a O 0
major O 0
determinant O 0
of O 0
GC O 0
- O 0
HT B-Disease 1
in O 0
the O 0
rat O 0
. O 0

Side O 0
effects O 0
of O 0
postoperative O 0
administration O 0
of O 0
methylprednisolone B-Chemical 1
and O 0
gentamicin B-Chemical 1
into O 0
the O 0
posterior O 0
sub O 0
- O 0
Tenon O 0
' O 0
s O 0
space O 0
. O 0

PURPOSE O 0
: O 0
To O 0
assess O 0
the O 0
incidence O 0
of O 0
postoperative O 0
emetic O 0
side O 0
effects O 0
after O 0
the O 0
administration O 0
of O 0
methylprednisolone B-Chemical 1
and O 0
gentamicin B-Chemical 1
into O 0
the O 0
posterior O 0
sub O 0
- O 0
Tenon O 0
' O 0
s O 0
space O 0
at O 0
the O 0
end O 0
of O 0
routine O 0
cataract B-Disease 1
surgery O 0
. O 0

SETTING O 0
: O 0
St O 0
. O 0

Luke O 0
' O 0
s O 0
Hospital O 0
, O 0
Gwardamangia O 0
, O 0
Malta O 0
. O 0

METHODS O 0
: O 0
A O 0
double O 0
- O 0
blind O 0
double O 0
- O 0
armed O 0
prospective O 0
study O 0
comprised O 0
40 O 0
patients O 0
who O 0
had O 0
uneventful O 0
sutureless O 0
phacoemulsification O 0
under O 0
sub O 0
- O 0
Tenon O 0
' O 0
s O 0
local O 0
infiltration O 0
of O 0
3 O 0
mL O 0
of O 0
plain O 0
lignocaine B-Chemical 1
. O 0

At O 0
the O 0
end O 0
of O 0
the O 0
procedure O 0
, O 0
Group O 0
A O 0
( O 0
n O 0
= O 0
20 O 0
) O 0
had O 0
20 O 0
mg O 0
/ O 0
0 O 0
. O 0
5 O 0
mL O 0
of O 0
methylprednisolone B-Chemical 1
and O 0
10 O 0
mg O 0
/ O 0
0 O 0
. O 0
5 O 0
mL O 0
of O 0
gentamicin B-Chemical 1
injected O 0
into O 0
the O 0
posterior O 0
sub O 0
- O 0
Tenon O 0
' O 0
s O 0
space O 0
and O 0
Group O 0
B O 0
( O 0
n O 0
= O 0
20 O 0
) O 0
had O 0
the O 0
same O 0
combination O 0
injected O 0
into O 0
the O 0
anterior O 0
sub O 0
- O 0
Tenon O 0
' O 0
s O 0
space O 0
. O 0

Postoperatively O 0
, O 0
all O 0
patients O 0
were O 0
assessed O 0
for O 0
symptoms O 0
of O 0
nausea B-Disease 1
, I-Disease 1
vomiting I-Disease 1
, O 0
and O 0
headache B-Disease 1
. O 0

A O 0
chi O 0
- O 0
square O 0
test O 0
was O 0
used O 0
to O 0
assess O 0
the O 0
statistical O 0
significance O 0
of O 0
results O 0
. O 0

RESULTS O 0
: O 0
Sixty O 0
percent O 0
in O 0
Group O 0
A O 0
developed O 0
postoperative B-Disease 1
emetic I-Disease 1
symptoms I-Disease 1
, O 0
headache B-Disease 1
, O 0
or O 0
both O 0
; O 0
1 O 0
patient O 0
in O 0
Group O 0
B O 0
developed O 0
symptoms O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
administration O 0
of O 0
methylprednisolone B-Chemical 1
and O 0
gentamicin B-Chemical 1
in O 0
the O 0
posterior O 0
sub O 0
- O 0
Tenon O 0
' O 0
s O 0
space O 0
was O 0
related O 0
to O 0
a O 0
high O 0
incidence O 0
of O 0
side O 0
effects O 0
including O 0
nausea B-Disease 1
, I-Disease 1
vomiting I-Disease 1
, O 0
and O 0
headache B-Disease 1
. O 0

All O 0
adverse O 0
effects O 0
were O 0
self O 0
- O 0
limiting O 0
. O 0

Assessment O 0
of O 0
a O 0
new O 0
non O 0
- O 0
invasive O 0
index O 0
of O 0
cardiac O 0
performance O 0
for O 0
detection O 0
of O 0
dobutamine B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
ischemia I-Disease 1
. O 0

BACKGROUND O 0
: O 0
Electrocardiography O 0
has O 0
a O 0
very O 0
low O 0
sensitivity O 0
in O 0
detecting O 0
dobutamine B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
ischemia I-Disease 1
. O 0

OBJECTIVES O 0
: O 0
To O 0
assess O 0
the O 0
added O 0
diagnostic O 0
value O 0
of O 0
a O 0
new O 0
cardiac O 0
performance O 0
index O 0
( O 0
dP O 0
/ O 0
dtejc O 0
) O 0
measurement O 0
, O 0
based O 0
on O 0
brachial O 0
artery O 0
flow O 0
changes O 0
, O 0
as O 0
compared O 0
to O 0
standard O 0
12 O 0
- O 0
lead O 0
ECG O 0
, O 0
for O 0
detecting O 0
dobutamine B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
ischemia I-Disease 1
, O 0
using O 0
Tc99m B-Chemical 1
- I-Chemical 1
Sestamibi I-Chemical 1
single O 0
- O 0
photon O 0
emission O 0
computed O 0
tomography O 0
as O 0
the O 0
gold O 0
standard O 0
of O 0
comparison O 0
to O 0
assess O 0
the O 0
presence O 0
or O 0
absence O 0
of O 0
ischemia B-Disease 1
. O 0

METHODS O 0
: O 0
The O 0
study O 0
group O 0
comprised O 0
40 O 0
patients O 0
undergoing O 0
Sestamibi B-Chemical 1
- O 0
SPECT O 0
/ O 0
dobutamine B-Chemical 1
stress O 0
test O 0
. O 0

Simultaneous O 0
measurements O 0
of O 0
ECG O 0
and O 0
brachial O 0
artery O 0
dP O 0
/ O 0
dtejc O 0
were O 0
performed O 0
at O 0
each O 0
dobutamine B-Chemical 1
level O 0
. O 0

In O 0
19 O 0
of O 0
the O 0
40 O 0
patients O 0
perfusion O 0
defects O 0
compatible O 0
with O 0
ischemia B-Disease 1
were O 0
detected O 0
on O 0
SPECT O 0
. O 0

The O 0
increase O 0
in O 0
dP O 0
/ O 0
dtejc O 0
during O 0
infusion O 0
of O 0
dobutamine B-Chemical 1
in O 0
this O 0
group O 0
was O 0
severely O 0
impaired O 0
as O 0
compared O 0
to O 0
the O 0
non O 0
- O 0
ischemic O 0
group O 0
. O 0

dP O 0
/ O 0
dtejc O 0
outcome O 0
was O 0
combined O 0
with O 0
the O 0
ECG O 0
results O 0
, O 0
giving O 0
an O 0
ECG O 0
- O 0
enhanced O 0
value O 0
, O 0
and O 0
compared O 0
to O 0
ECG O 0
alone O 0
. O 0

RESULTS O 0
: O 0
The O 0
sensitivity O 0
improved O 0
dramatically O 0
from O 0
16 O 0
% O 0
to O 0
79 O 0
% O 0
, O 0
positive O 0
predictive O 0
value O 0
increased O 0
from O 0
60 O 0
% O 0
to O 0
68 O 0
% O 0
and O 0
negative O 0
predictive O 0
value O 0
from O 0
54 O 0
% O 0
to O 0
78 O 0
% O 0
, O 0
and O 0
specificity O 0
decreased O 0
from O 0
90 O 0
% O 0
to O 0
67 O 0
% O 0
. O 0

CONCLUSIONS O 0
: O 0
If O 0
ECG O 0
alone O 0
is O 0
used O 0
for O 0
specificity O 0
, O 0
the O 0
combination O 0
with O 0
dP O 0
/ O 0
dtejc O 0
improved O 0
the O 0
sensitivity O 0
of O 0
the O 0
test O 0
and O 0
could O 0
be O 0
a O 0
cost O 0
- O 0
savings O 0
alternative O 0
to O 0
cardiac O 0
imaging O 0
or O 0
perfusion O 0
studies O 0
to O 0
detect O 0
myocardial B-Disease 1
ischemia I-Disease 1
, O 0
especially O 0
in O 0
patients O 0
unable O 0
to O 0
exercise O 0
. O 0

Cocaine B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
: O 0
clinical O 0
observations O 0
and O 0
pathogenetic O 0
considerations O 0
. O 0

Clinical O 0
and O 0
experimental O 0
data O 0
published O 0
to O 0
date O 0
suggest O 0
several O 0
possible O 0
mechanisms O 0
by O 0
which O 0
cocaine B-Chemical 1
may O 0
result O 0
in O 0
acute B-Disease 1
myocardial I-Disease 1
infarction I-Disease 1
. O 0

In O 0
individuals O 0
with O 0
preexisting O 0
, O 0
high O 0
- O 0
grade O 0
coronary O 0
arterial O 0
narrowing O 0
, O 0
acute B-Disease 1
myocardial I-Disease 1
infarction I-Disease 1
may O 0
result O 0
from O 0
an O 0
increase O 0
in O 0
myocardial O 0
oxygen B-Chemical 1
demand O 0
associated O 0
with O 0
cocaine B-Chemical 1
- O 0
induced O 0
increase O 0
in O 0
rate O 0
- O 0
pressure O 0
product O 0
. O 0

In O 0
other O 0
individuals O 0
with O 0
no O 0
underlying O 0
atherosclerotic B-Disease 1
obstruction I-Disease 1
, O 0
coronary B-Disease 1
occlusion I-Disease 1
may O 0
be O 0
due O 0
to O 0
spasm B-Disease 1
, O 0
thrombus B-Disease 1
, O 0
or O 0
both O 0
. O 0

With O 0
regard O 0
to O 0
spasm B-Disease 1
, O 0
the O 0
clinical O 0
findings O 0
are O 0
largely O 0
circumstantial O 0
, O 0
and O 0
the O 0
locus O 0
of O 0
cocaine B-Chemical 1
- O 0
induced O 0
vasoconstriction O 0
remains O 0
speculative O 0
. O 0

Although O 0
certain O 0
clinical O 0
and O 0
experimental O 0
findings O 0
support O 0
the O 0
hypothesis O 0
that O 0
spasm B-Disease 1
involves O 0
the O 0
epicardial O 0
, O 0
medium O 0
- O 0
size O 0
vessels O 0
, O 0
other O 0
data O 0
suggest O 0
intramural O 0
vasoconstriction O 0
. O 0

Diffuse O 0
intramural O 0
vasoconstriction O 0
is O 0
not O 0
consistent O 0
with O 0
reports O 0
of O 0
segmental O 0
, O 0
discrete O 0
infarction B-Disease 1
. O 0

Whereas O 0
certain O 0
in O 0
vivo O 0
data O 0
suggest O 0
that O 0
these O 0
effects O 0
are O 0
alpha O 0
- O 0
mediated O 0
, O 0
other O 0
in O 0
vitro O 0
data O 0
suggest O 0
the O 0
opposite O 0
. O 0

The O 0
finding O 0
of O 0
cocaine B-Chemical 1
- O 0
induced O 0
vasoconstriction O 0
in O 0
segments O 0
of O 0
( O 0
noninnervated O 0
) O 0
human O 0
umbilical O 0
artery O 0
suggests O 0
that O 0
the O 0
presence O 0
or O 0
absence O 0
of O 0
intact O 0
innervation O 0
is O 0
not O 0
sufficient O 0
to O 0
explain O 0
the O 0
discrepant O 0
data O 0
involving O 0
the O 0
possibility O 0
of O 0
alpha O 0
- O 0
mediated O 0
effects O 0
. O 0

Finally O 0
, O 0
the O 0
contribution O 0
of O 0
a O 0
primary O 0
, O 0
thrombotic B-Disease 1
effect O 0
of O 0
cocaine B-Chemical 1
has O 0
not O 0
been O 0
excluded O 0
. O 0

Proteomic O 0
analysis O 0
of O 0
striatal O 0
proteins O 0
in O 0
the O 0
rat O 0
model O 0
of O 0
L B-Chemical 1
- I-Chemical 1
DOPA I-Chemical 1
- O 0
induced O 0
dyskinesia B-Disease 1
. O 0

L B-Chemical 1
- I-Chemical 1
DOPA I-Chemical 1
- O 0
induced O 0
dyskinesia B-Disease 1
( O 0
LID B-Disease 1
) O 0
is O 0
among O 0
the O 0
motor O 0
complications O 0
that O 0
arise O 0
in O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
( O 0
PD B-Disease 1
) O 0
patients O 0
after O 0
a O 0
prolonged O 0
treatment O 0
with O 0
L B-Chemical 1
- I-Chemical 1
DOPA I-Chemical 1
. O 0

To O 0
this O 0
day O 0
, O 0
transcriptome O 0
analysis O 0
has O 0
been O 0
performed O 0
in O 0
a O 0
rat O 0
model O 0
of O 0
LID B-Disease 1
[ O 0
Neurobiol O 0
. O 0
Dis O 0
. O 0
, O 0
17 O 0
( O 0
2004 O 0
) O 0
, O 0
219 O 0
] O 0
but O 0
information O 0
regarding O 0
the O 0
proteome O 0
is O 0
still O 0
lacking O 0
. O 0

In O 0
the O 0
present O 0
study O 0
, O 0
we O 0
investigated O 0
the O 0
changes O 0
occurring O 0
at O 0
the O 0
protein O 0
level O 0
in O 0
striatal O 0
samples O 0
obtained O 0
from O 0
the O 0
unilaterally O 0
6 B-Chemical 1
- I-Chemical 1
hydroxydopamine I-Chemical 1
- O 0
lesion O 0
rat O 0
model O 0
of O 0
PD B-Disease 1
treated O 0
with O 0
saline O 0
, O 0
L B-Chemical 1
- I-Chemical 1
DOPA I-Chemical 1
or O 0
bromocriptine B-Chemical 1
using O 0
two O 0
- O 0
dimensional O 0
difference O 0
gel O 0
electrophoresis O 0
and O 0
mass O 0
spectrometry O 0
( O 0
MS O 0
) O 0
. O 0

Rats O 0
treated O 0
with O 0
L B-Chemical 1
- I-Chemical 1
DOPA I-Chemical 1
were O 0
allocated O 0
to O 0
two O 0
groups O 0
based O 0
on O 0
the O 0
presence O 0
or O 0
absence O 0
of O 0
LID B-Disease 1
. O 0

Among O 0
the O 0
2000 O 0
spots O 0
compared O 0
for O 0
statistical O 0
difference O 0
, O 0
67 O 0
spots O 0
were O 0
significantly O 0
changed O 0
in O 0
abundance O 0
and O 0
identified O 0
using O 0
matrix O 0
- O 0
assisted O 0
laser O 0
desorption O 0
/ O 0
ionization O 0
time O 0
- O 0
of O 0
- O 0
flight O 0
MS O 0
, O 0
atmospheric O 0
pressure O 0
matrix O 0
- O 0
assisted O 0
laser O 0
desorption O 0
/ O 0
ionization O 0
and O 0
HPLC O 0
coupled O 0
tandem O 0
MS O 0
( O 0
LC O 0
/ O 0
MS O 0
/ O 0
MS O 0
) O 0
. O 0

Out O 0
of O 0
these O 0
67 O 0
proteins O 0
, O 0
LID B-Disease 1
significantly O 0
changed O 0
the O 0
expression O 0
level O 0
of O 0
five O 0
proteins O 0
: O 0
alphabeta O 0
- O 0
crystalin O 0
, O 0
gamma O 0
- O 0
enolase O 0
, O 0
guanidoacetate O 0
methyltransferase O 0
, O 0
vinculin O 0
, O 0
and O 0
proteasome O 0
alpha O 0
- O 0
2 O 0
subunit O 0
. O 0

Complementary O 0
techniques O 0
such O 0
as O 0
western O 0
immunoblotting O 0
and O 0
immunohistochemistry O 0
were O 0
performed O 0
to O 0
investigate O 0
the O 0
validity O 0
of O 0
the O 0
data O 0
obtained O 0
using O 0
the O 0
proteomic O 0
approach O 0
. O 0

In O 0
conclusion O 0
, O 0
this O 0
study O 0
provides O 0
new O 0
insights O 0
into O 0
the O 0
protein O 0
changes O 0
occurring O 0
in O 0
LID B-Disease 1
. O 0

Cardiac O 0
Angiography O 0
in O 0
Renally O 0
Impaired O 0
Patients O 0
( O 0
CARE O 0
) O 0
study O 0
: O 0
a O 0
randomized O 0
double O 0
- O 0
blind O 0
trial O 0
of O 0
contrast O 0
- O 0
induced O 0
nephropathy B-Disease 1
in O 0
patients O 0
with O 0
chronic B-Disease 1
kidney I-Disease 1
disease I-Disease 1
. O 0

BACKGROUND O 0
: O 0
No O 0
direct O 0
comparisons O 0
exist O 0
of O 0
the O 0
renal O 0
tolerability O 0
of O 0
the O 0
low O 0
- O 0
osmolality O 0
contrast B-Chemical 1
medium I-Chemical 1
iopamidol B-Chemical 1
with O 0
that O 0
of O 0
the O 0
iso O 0
- O 0
osmolality O 0
contrast B-Chemical 1
medium I-Chemical 1
iodixanol B-Chemical 1
in O 0
high O 0
- O 0
risk O 0
patients O 0
. O 0

METHODS O 0
AND O 0
RESULTS O 0
: O 0
The O 0
present O 0
study O 0
is O 0
a O 0
multicenter O 0
, O 0
randomized O 0
, O 0
double O 0
- O 0
blind O 0
comparison O 0
of O 0
iopamidol B-Chemical 1
and O 0
iodixanol B-Chemical 1
in O 0
patients O 0
with O 0
chronic B-Disease 1
kidney I-Disease 1
disease I-Disease 1
( O 0
estimated O 0
glomerular O 0
filtration O 0
rate O 0
, O 0
20 O 0
to O 0
59 O 0
mL O 0
/ O 0
min O 0
) O 0
who O 0
underwent O 0
cardiac O 0
angiography O 0
or O 0
percutaneous O 0
coronary O 0
interventions O 0
. O 0

Serum O 0
creatinine B-Chemical 1
( O 0
SCr O 0
) O 0
levels O 0
and O 0
estimated O 0
glomerular O 0
filtration O 0
rate O 0
were O 0
assessed O 0
at O 0
baseline O 0
and O 0
2 O 0
to O 0
5 O 0
days O 0
after O 0
receiving O 0
medications O 0
. O 0

The O 0
primary O 0
outcome O 0
was O 0
a O 0
postdose O 0
SCr O 0
increase O 0
> O 0
or O 0
= O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
dL O 0
( O 0
44 O 0
. O 0
2 O 0
micromol O 0
/ O 0
L O 0
) O 0
over O 0
baseline O 0
. O 0

Secondary O 0
outcomes O 0
were O 0
a O 0
postdose O 0
SCr O 0
increase O 0
> O 0
or O 0
= O 0
25 O 0
% O 0
, O 0
a O 0
postdose O 0
estimated O 0
glomerular O 0
filtration O 0
rate O 0
decrease O 0
of O 0
> O 0
or O 0
= O 0
25 O 0
% O 0
, O 0
and O 0
the O 0
mean O 0
peak O 0
change O 0
in O 0
SCr O 0
. O 0

In O 0
414 O 0
patients O 0
, O 0
contrast O 0
volume O 0
, O 0
presence O 0
of O 0
diabetes B-Disease 1
mellitus I-Disease 1
, O 0
use O 0
of O 0
N B-Chemical 1
- I-Chemical 1
acetylcysteine I-Chemical 1
, O 0
mean O 0
baseline O 0
SCr O 0
, O 0
and O 0
estimated O 0
glomerular O 0
filtration O 0
rate O 0
were O 0
comparable O 0
in O 0
the O 0
2 O 0
groups O 0
. O 0

SCr O 0
increases O 0
> O 0
or O 0
= O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
dL O 0
occurred O 0
in O 0
4 O 0
. O 0
4 O 0
% O 0
( O 0
9 O 0
of O 0
204 O 0
patients O 0
) O 0
after O 0
iopamidol B-Chemical 1
and O 0
6 O 0
. O 0
7 O 0
% O 0
( O 0
14 O 0
of O 0
210 O 0
patients O 0
) O 0
after O 0
iodixanol B-Chemical 1
( O 0
P O 0
= O 0
0 O 0
. O 0
39 O 0
) O 0
, O 0
whereas O 0
rates O 0
of O 0
SCr O 0
increases O 0
> O 0
or O 0
= O 0
25 O 0
% O 0
were O 0
9 O 0
. O 0
8 O 0
% O 0
and O 0
12 O 0
. O 0
4 O 0
% O 0
, O 0
respectively O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
44 O 0
) O 0
. O 0

In O 0
patients O 0
with O 0
diabetes B-Disease 1
, O 0
SCr O 0
increases O 0
> O 0
or O 0
= O 0
0 O 0
. O 0
5 O 0
mg O 0
/ O 0
dL O 0
were O 0
5 O 0
. O 0
1 O 0
% O 0
( O 0
4 O 0
of O 0
78 O 0
patients O 0
) O 0
with O 0
iopamidol B-Chemical 1
and O 0
13 O 0
. O 0
0 O 0
% O 0
( O 0
12 O 0
of O 0
92 O 0
patients O 0
) O 0
with O 0
iodixanol B-Chemical 1
( O 0
P O 0
= O 0
0 O 0
. O 0
11 O 0
) O 0
, O 0
whereas O 0
SCr O 0
increases O 0
> O 0
or O 0
= O 0
25 O 0
% O 0
were O 0
10 O 0
. O 0
3 O 0
% O 0
and O 0
15 O 0
. O 0
2 O 0
% O 0
, O 0
respectively O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
37 O 0
) O 0
. O 0

Mean O 0
post O 0
- O 0
SCr O 0
increases O 0
were O 0
significantly O 0
less O 0
with O 0
iopamidol B-Chemical 1
( O 0
all O 0
patients O 0
: O 0
0 O 0
. O 0
07 O 0
versus O 0
0 O 0
. O 0
12 O 0
mg O 0
/ O 0
dL O 0
, O 0
6 O 0
. O 0
2 O 0
versus O 0
10 O 0
. O 0
6 O 0
micromol O 0
/ O 0
L O 0
, O 0
P O 0
= O 0
0 O 0
. O 0
03 O 0
; O 0
patients O 0
with O 0
diabetes B-Disease 1
: O 0
0 O 0
. O 0
07 O 0
versus O 0
0 O 0
. O 0
16 O 0
mg O 0
/ O 0
dL O 0
, O 0
6 O 0
. O 0
2 O 0
versus O 0
14 O 0
. O 0
1 O 0
micromol O 0
/ O 0
L O 0
, O 0
P O 0
= O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
rate O 0
of O 0
contrast O 0
- O 0
induced O 0
nephropathy B-Disease 1
, O 0
defined O 0
by O 0
multiple O 0
end O 0
points O 0
, O 0
is O 0
not O 0
statistically O 0
different O 0
after O 0
the O 0
intraarterial O 0
administration O 0
of O 0
iopamidol B-Chemical 1
or O 0
iodixanol B-Chemical 1
to O 0
high O 0
- O 0
risk O 0
patients O 0
, O 0
with O 0
or O 0
without O 0
diabetes B-Disease 1
mellitus I-Disease 1
. O 0

Any O 0
true O 0
difference O 0
between O 0
the O 0
agents O 0
is O 0
small O 0
and O 0
not O 0
likely O 0
to O 0
be O 0
clinically O 0
significant O 0
. O 0

A O 0
novel O 0
compound O 0
, O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
, O 0
attenuates O 0
cognitive B-Disease 1
deficits I-Disease 1
and O 0
shows O 0
neuroprotective O 0
effects O 0
in O 0
vitro O 0
and O 0
in O 0
vivo O 0
dementia B-Disease 1
models O 0
. O 0

To O 0
develop O 0
a O 0
novel O 0
and O 0
effective O 0
drug O 0
that O 0
could O 0
enhance O 0
cognitive O 0
function O 0
and O 0
neuroprotection O 0
, O 0
we O 0
newly O 0
synthesized O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
by O 0
the O 0
esterification O 0
of O 0
maltol B-Chemical 1
and O 0
p B-Chemical 1
- I-Chemical 1
coumaric I-Chemical 1
acid I-Chemical 1
. O 0

In O 0
the O 0
present O 0
study O 0
, O 0
we O 0
investigated O 0
whether O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
could O 0
improve O 0
cognitive B-Disease 1
decline I-Disease 1
in O 0
scopolamine B-Chemical 1
- O 0
injected O 0
rats O 0
and O 0
in O 0
amyloid B-Chemical 1
beta I-Chemical 1
peptide I-Chemical 1
( I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
42 I-Chemical 1
) I-Chemical 1
- O 0
infused O 0
rats O 0
. O 0

Maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
was O 0
found O 0
to O 0
attenuate O 0
cognitive B-Disease 1
deficits I-Disease 1
in O 0
both O 0
rat O 0
models O 0
using O 0
passive O 0
avoidance O 0
test O 0
and O 0
to O 0
reduce O 0
apoptotic O 0
cell O 0
death O 0
observed O 0
in O 0
the O 0
hippocampus O 0
of O 0
the O 0
amyloid B-Chemical 1
beta I-Chemical 1
peptide I-Chemical 1
( I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
42 I-Chemical 1
) I-Chemical 1
- O 0
infused O 0
rats O 0
. O 0

We O 0
also O 0
examined O 0
the O 0
neuroprotective O 0
effects O 0
of O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
in O 0
vitro O 0
using O 0
SH O 0
- O 0
SY5Y O 0
cells O 0
. O 0

Cells O 0
were O 0
pretreated O 0
with O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
, O 0
before O 0
exposed O 0
to O 0
amyloid B-Chemical 1
beta I-Chemical 1
peptide I-Chemical 1
( I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
42 I-Chemical 1
) I-Chemical 1
, O 0
glutamate B-Chemical 1
or O 0
H2O2 B-Chemical 1
. O 0

We O 0
found O 0
that O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
significantly O 0
decreased O 0
apoptotic O 0
cell O 0
death O 0
and O 0
reduced O 0
reactive O 0
oxygen O 0
species O 0
, O 0
cytochrome O 0
c O 0
release O 0
, O 0
and O 0
caspase O 0
3 O 0
activation O 0
. O 0

Taking O 0
these O 0
in O 0
vitro O 0
and O 0
in O 0
vivo O 0
results O 0
together O 0
, O 0
our O 0
study O 0
suggests O 0
that O 0
maltolyl B-Chemical 1
p I-Chemical 1
- I-Chemical 1
coumarate I-Chemical 1
is O 0
a O 0
potentially O 0
effective O 0
candidate O 0
against O 0
Alzheimer B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
that O 0
is O 0
characterized O 0
by O 0
wide O 0
spread O 0
neuronal B-Disease 1
death I-Disease 1
and O 0
progressive O 0
decline B-Disease 1
of I-Disease 1
cognitive I-Disease 1
function I-Disease 1
. O 0

Attenuation O 0
of O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
nigrostriatal O 0
dopaminergic O 0
neurotoxicity B-Disease 1
in O 0
mice O 0
by O 0
lipopolysaccharide B-Chemical 1
pretreatment O 0
. O 0

Immunological O 0
activation O 0
has O 0
been O 0
proposed O 0
to O 0
play O 0
a O 0
role O 0
in O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
dopaminergic B-Disease 1
terminal I-Disease 1
damage I-Disease 1
. O 0

In O 0
this O 0
study O 0
, O 0
we O 0
examined O 0
the O 0
roles O 0
of O 0
lipopolysaccharide B-Chemical 1
, O 0
a O 0
pro O 0
- O 0
inflammatory O 0
and O 0
inflammatory O 0
factor O 0
, O 0
treatment O 0
in O 0
modulating O 0
the O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
nigrostriatal O 0
dopamine B-Chemical 1
neurotoxicity B-Disease 1
. O 0

Lipopolysaccharide B-Chemical 1
pretreatment O 0
did O 0
not O 0
affect O 0
the O 0
basal O 0
body O 0
temperature O 0
or O 0
methamphetamine B-Chemical 1
- O 0
elicited O 0
hyperthermia B-Disease 1
three O 0
days O 0
later O 0
. O 0

Such O 0
systemic O 0
lipopolysaccharide B-Chemical 1
treatment O 0
mitigated O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
striatal O 0
dopamine B-Chemical 1
and O 0
3 B-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dihydroxyphenylacetic I-Chemical 1
acid I-Chemical 1
depletions O 0
in O 0
a O 0
dose O 0
- O 0
dependent O 0
manner O 0
. O 0

As O 0
the O 0
most O 0
potent O 0
dose O 0
( O 0
1 O 0
mg O 0
/ O 0
kg O 0
) O 0
of O 0
lipopolysaccharide B-Chemical 1
was O 0
administered O 0
two O 0
weeks O 0
, O 0
one O 0
day O 0
before O 0
or O 0
after O 0
the O 0
methamphetamine B-Chemical 1
dosing O 0
regimen O 0
, O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
striatal O 0
dopamine B-Chemical 1
and O 0
3 B-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dihydroxyphenylacetic I-Chemical 1
acid I-Chemical 1
depletions O 0
remained O 0
unaltered O 0
. O 0

Moreover O 0
, O 0
systemic O 0
lipopolysaccharide B-Chemical 1
pretreatment O 0
( O 0
1 O 0
mg O 0
/ O 0
kg O 0
) O 0
attenuated O 0
local O 0
methamphetamine B-Chemical 1
infusion O 0
- O 0
produced O 0
dopamine B-Chemical 1
and O 0
3 B-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dihydroxyphenylacetic I-Chemical 1
acid I-Chemical 1
depletions O 0
in O 0
the O 0
striatum O 0
, O 0
indicating O 0
that O 0
the O 0
protective O 0
effect O 0
of O 0
lipopolysaccharide B-Chemical 1
is O 0
less O 0
likely O 0
due O 0
to O 0
interrupted O 0
peripheral O 0
distribution O 0
or O 0
metabolism O 0
of O 0
methamphetamine B-Chemical 1
. O 0

We O 0
concluded O 0
a O 0
critical O 0
time O 0
window O 0
for O 0
systemic O 0
lipopolysaccharide B-Chemical 1
pretreatment O 0
in O 0
exerting O 0
effective O 0
protection O 0
against O 0
methamphetamine B-Chemical 1
- O 0
induced O 0
nigrostriatal O 0
dopamine B-Chemical 1
neurotoxicity B-Disease 1
. O 0

Acute O 0
myocarditis B-Disease 1
associated O 0
with O 0
clozapine B-Chemical 1
. O 0

OBJECTIVE O 0
: O 0
A O 0
case O 0
of O 0
acute O 0
myocarditis B-Disease 1
associated O 0
with O 0
the O 0
commencement O 0
of O 0
clozapine B-Chemical 1
is O 0
described O 0
, O 0
highlighting O 0
the O 0
onset O 0
, O 0
course O 0
and O 0
possible O 0
contributing O 0
factors O 0
. O 0

There O 0
is O 0
an O 0
urgent O 0
need O 0
to O 0
raise O 0
awareness O 0
about O 0
this O 0
potentially O 0
fatal O 0
complication O 0
of O 0
clozapine B-Chemical 1
use O 0
. O 0

RESULTS O 0
: O 0
A O 0
20 O 0
- O 0
year O 0
- O 0
old O 0
male O 0
with O 0
schizophrenia B-Disease 1
developed O 0
a O 0
sudden O 0
onset O 0
of O 0
myocarditis B-Disease 1
after O 0
commencement O 0
of O 0
clozapine B-Chemical 1
. O 0

The O 0
patient O 0
recovered O 0
with O 0
intensive O 0
medical O 0
support O 0
. O 0

The O 0
symptoms O 0
occurred O 0
around O 0
2 O 0
weeks O 0
after O 0
starting O 0
clozapine B-Chemical 1
in O 0
an O 0
inpatient O 0
setting O 0
. O 0

Possible O 0
contributing O 0
factors O 0
may O 0
have O 0
been O 0
concomitant O 0
antidepressant B-Chemical 1
use O 0
and O 0
unaccustomed O 0
physical O 0
activity O 0
. O 0

CONCLUSIONS O 0
: O 0
Myocarditis B-Disease 1
is O 0
an O 0
increasingly O 0
recognized O 0
complication O 0
associated O 0
with O 0
the O 0
use O 0
of O 0
clozapine B-Chemical 1
. O 0

It O 0
can O 0
be O 0
fatal O 0
if O 0
not O 0
recognized O 0
and O 0
treated O 0
early O 0
. O 0

Considering O 0
that O 0
clozapine B-Chemical 1
remains O 0
the O 0
gold O 0
standard O 0
in O 0
treatment O 0
of O 0
resistant O 0
psychosis B-Disease 1
, O 0
there O 0
is O 0
an O 0
urgent O 0
need O 0
to O 0
raise O 0
awareness O 0
among O 0
medical O 0
and O 0
paramedical O 0
staff O 0
involved O 0
in O 0
the O 0
care O 0
of O 0
these O 0
patients O 0
. O 0

There O 0
are O 0
also O 0
implications O 0
for O 0
recommendations O 0
and O 0
regulations O 0
regarding O 0
the O 0
use O 0
of O 0
clozapine B-Chemical 1
. O 0

Severe O 0
rhabdomyolysis B-Disease 1
and O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
secondary O 0
to O 0
concomitant O 0
use O 0
of O 0
simvastatin B-Chemical 1
, O 0
amiodarone B-Chemical 1
, O 0
and O 0
atazanavir B-Chemical 1
. O 0

OBJECTIVE O 0
: O 0
To O 0
report O 0
a O 0
case O 0
of O 0
a O 0
severe O 0
interaction O 0
between O 0
simvastatin B-Chemical 1
, O 0
amiodarone B-Chemical 1
, O 0
and O 0
atazanavir B-Chemical 1
resulting O 0
in O 0
rhabdomyolysis B-Disease 1
and O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
. O 0

BACKGROUND O 0
: O 0
A O 0
72 O 0
- O 0
year O 0
- O 0
old O 0
white O 0
man O 0
with O 0
underlying O 0
human B-Disease 1
immunodeficiency I-Disease 1
virus I-Disease 1
, O 0
atrial B-Disease 1
fibrillation I-Disease 1
, O 0
coronary B-Disease 1
artery I-Disease 1
disease I-Disease 1
, O 0
and O 0
hyperlipidemia B-Disease 1
presented O 0
with O 0
generalized O 0
pain B-Disease 1
, O 0
fatigue B-Disease 1
, O 0
and O 0
dark O 0
orange O 0
urine O 0
for O 0
3 O 0
days O 0
. O 0

The O 0
patient O 0
was O 0
taking O 0
80 O 0
mg O 0
simvastatin B-Chemical 1
at O 0
bedtime O 0
( O 0
initiated O 0
27 O 0
days O 0
earlier O 0
) O 0
; O 0
amiodarone B-Chemical 1
at O 0
a O 0
dose O 0
of O 0
400 O 0
mg O 0
daily O 0
for O 0
7 O 0
days O 0
, O 0
then O 0
200 O 0
mg O 0
daily O 0
( O 0
initiated O 0
19 O 0
days O 0
earlier O 0
) O 0
; O 0
and O 0
400 O 0
mg O 0
atazanavir B-Chemical 1
daily O 0
( O 0
initiated O 0
at O 0
least O 0
2 O 0
years O 0
previously O 0
) O 0
. O 0

Laboratory O 0
evaluation O 0
revealed O 0
66 O 0
, O 0
680 O 0
U O 0
/ O 0
L O 0
creatine B-Chemical 1
kinase O 0
, O 0
93 O 0
mg O 0
/ O 0
dL O 0
blood B-Chemical 1
urea I-Chemical 1
nitrogen I-Chemical 1
, O 0
4 O 0
. O 0
6 O 0
mg O 0
/ O 0
dL O 0
creatinine B-Chemical 1
, O 0
1579 O 0
U O 0
/ O 0
L O 0
aspartate B-Chemical 1
aminotransferase O 0
, O 0
and O 0
738 O 0
U O 0
/ O 0
L O 0
alanine B-Chemical 1
aminotransferase O 0
. O 0

Simvastatin B-Chemical 1
, O 0
amiodarone B-Chemical 1
, O 0
and O 0
the O 0
patient O 0
' O 0
s O 0
human B-Disease 1
immunodeficiency I-Disease 1
virus I-Disease 1
medications O 0
were O 0
all O 0
temporarily O 0
discontinued O 0
and O 0
the O 0
patient O 0
was O 0
given O 0
forced O 0
alkaline O 0
diuresis O 0
and O 0
started O 0
on O 0
dialysis O 0
. O 0

Nine O 0
days O 0
later O 0
the O 0
patient O 0
' O 0
s O 0
creatine B-Chemical 1
kinase O 0
had O 0
dropped O 0
to O 0
1695 O 0
U O 0
/ O 0
L O 0
and O 0
creatinine B-Chemical 1
was O 0
3 O 0
. O 0
3 O 0
mg O 0
/ O 0
dL O 0
. O 0

The O 0
patient O 0
was O 0
discharged O 0
and O 0
continued O 0
outpatient O 0
dialysis O 0
for O 0
1 O 0
month O 0
until O 0
his O 0
renal O 0
function O 0
recovered O 0
. O 0

DISCUSSION O 0
: O 0
The O 0
risk O 0
of O 0
rhabdomyolysis B-Disease 1
is O 0
increased O 0
in O 0
the O 0
presence O 0
of O 0
concomitant O 0
drugs O 0
that O 0
inhibit O 0
simvastatin B-Chemical 1
metabolism O 0
. O 0

Simvastatin B-Chemical 1
is O 0
metabolized O 0
by O 0
CYP3A4 O 0
. O 0

Amiodarone B-Chemical 1
and O 0
atazanavir B-Chemical 1
are O 0
recognized O 0
CYP3A4 O 0
inhibitors O 0
. O 0

CONCLUSIONS O 0
: O 0
Pharmacokinetic O 0
differences O 0
in O 0
statins B-Chemical 1
are O 0
an O 0
important O 0
consideration O 0
for O 0
assessing O 0
the O 0
risk O 0
of O 0
potential O 0
drug O 0
interactions O 0
. O 0

In O 0
patients O 0
requiring O 0
the O 0
concurrent O 0
use O 0
of O 0
statins B-Chemical 1
and O 0
CYP3A4 O 0
inhibitors O 0
, O 0
pravastatin B-Chemical 1
, O 0
fluvastatin B-Chemical 1
, O 0
and O 0
rosuvastatin B-Chemical 1
carry O 0
the O 0
lowest O 0
risk O 0
of O 0
drug O 0
interactions O 0
; O 0
atorvastatin B-Chemical 1
carries O 0
moderate O 0
risk O 0
, O 0
whereas O 0
simvastatin B-Chemical 1
and O 0
lovastatin B-Chemical 1
have O 0
the O 0
highest O 0
risk O 0
and O 0
should O 0
be O 0
avoided O 0
in O 0
patients O 0
taking O 0
concomitant O 0
CYP3A4 O 0
inhibitors O 0
. O 0

Interaction O 0
between O 0
warfarin B-Chemical 1
and O 0
levofloxacin B-Chemical 1
: O 0
case O 0
series O 0
. O 0

Warfarin B-Chemical 1
is O 0
the O 0
most O 0
widely O 0
used O 0
oral O 0
anticoagulant O 0
and O 0
is O 0
indicated O 0
for O 0
many O 0
clinical O 0
conditions O 0
. O 0

Levofloxacin B-Chemical 1
, O 0
a O 0
fluoroquinolone B-Chemical 1
, O 0
is O 0
one O 0
of O 0
the O 0
most O 0
commonly O 0
prescribed O 0
antibiotics O 0
in O 0
clinical O 0
practice O 0
and O 0
is O 0
effective O 0
against O 0
Gram O 0
- O 0
positive O 0
, O 0
Gram O 0
- O 0
negative O 0
, O 0
and O 0
atypical O 0
bacteria O 0
. O 0

While O 0
small O 0
prospective O 0
studies O 0
have O 0
not O 0
revealed O 0
any O 0
significant O 0
drug O 0
- O 0
drug O 0
interaction O 0
between O 0
warfarin B-Chemical 1
and O 0
levofloxacin B-Chemical 1
, O 0
several O 0
case O 0
reports O 0
have O 0
indicated O 0
that O 0
levofloxacin B-Chemical 1
may O 0
significantly O 0
potentiate O 0
the O 0
anticoagulation O 0
effect O 0
of O 0
warfarin B-Chemical 1
. O 0

We O 0
report O 0
3 O 0
cases O 0
of O 0
serious O 0
bleeding B-Disease 1
complications O 0
that O 0
appear O 0
to O 0
be O 0
the O 0
result O 0
of O 0
the O 0
interaction O 0
between O 0
warfarin B-Chemical 1
and O 0
levofloxacin B-Chemical 1
. O 0

Physicians O 0
should O 0
be O 0
aware O 0
of O 0
this O 0
potential O 0
interaction O 0
and O 0
use O 0
caution O 0
when O 0
prescribing O 0
levofloxacin B-Chemical 1
to O 0
patients O 0
taking O 0
warfarin B-Chemical 1
. O 0

Mutations O 0
associated O 0
with O 0
lamivudine B-Chemical 1
- O 0
resistance O 0
in O 0
therapy O 0
- O 0
na B-Chemical 1
ve O 0
hepatitis B-Disease 1
B I-Disease 1
virus I-Disease 1
( I-Disease 1
HBV I-Disease 1
) I-Disease 1
infected I-Disease 1
patients O 0
with O 0
and O 0
without O 0
HIV B-Disease 1
co I-Disease 1
- I-Disease 1
infection I-Disease 1
: O 0
implications O 0
for O 0
antiretroviral O 0
therapy O 0
in O 0
HBV B-Disease 1
and I-Disease 1
HIV I-Disease 1
co I-Disease 1
- I-Disease 1
infected I-Disease 1
South O 0
African O 0
patients O 0
. O 0

This O 0
was O 0
an O 0
exploratory O 0
study O 0
to O 0
investigate O 0
lamivudine B-Chemical 1
- O 0
resistant O 0
hepatitis B-Disease 1
B I-Disease 1
virus O 0
( O 0
HBV O 0
) O 0
strains O 0
in O 0
selected O 0
lamivudine B-Chemical 1
- O 0
na B-Chemical 1
ve O 0
HBV O 0
carriers O 0
with O 0
and O 0
without O 0
human B-Disease 1
immunodeficiency I-Disease 1
virus I-Disease 1
( I-Disease 1
HIV I-Disease 1
) I-Disease 1
co I-Disease 1
- I-Disease 1
infection I-Disease 1
in O 0
South O 0
African O 0
patients O 0
. O 0

Thirty O 0
- O 0
five O 0
lamivudine B-Chemical 1
- O 0
na B-Chemical 1
ve O 0
HBV B-Disease 1
infected I-Disease 1
patients O 0
with O 0
or O 0
without O 0
HIV B-Disease 1
co I-Disease 1
- I-Disease 1
infection I-Disease 1
were O 0
studied O 0
: O 0
15 O 0
chronic O 0
HBV B-Disease 1
mono I-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
and O 0
20 O 0
HBV B-Disease 1
- I-Disease 1
HIV I-Disease 1
co I-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
. O 0

The O 0
latter O 0
group O 0
was O 0
further O 0
sub O 0
- O 0
divided O 0
into O 0
13 O 0
occult O 0
HBV O 0
( O 0
HBsAg B-Chemical 1
- O 0
negative O 0
) O 0
and O 0
7 O 0
overt O 0
HBV O 0
( O 0
HBsAg B-Chemical 1
- O 0
positive O 0
) O 0
patients O 0
. O 0

HBsAg B-Chemical 1
, O 0
anti O 0
- O 0
HBs O 0
, O 0
anti O 0
- O 0
HBc O 0
, O 0
and O 0
anti O 0
- O 0
HIV O 0
1 O 0
/ O 0
2 O 0
were O 0
determined O 0
as O 0
part O 0
of O 0
routine O 0
diagnosis O 0
using O 0
Axsym O 0
assays O 0
( O 0
Abbott O 0
Laboratories O 0
, O 0
North O 0
Chicago O 0
, O 0
IL O 0
) O 0
. O 0

Serum O 0
samples O 0
were O 0
PCR O 0
amplified O 0
with O 0
HBV O 0
reverse O 0
transcriptase O 0
( O 0
RT O 0
) O 0
primers O 0
, O 0
followed O 0
by O 0
direct O 0
sequencing O 0
across O 0
the O 0
tyrosine B-Chemical 1
- O 0
methionine B-Chemical 1
- O 0
aspartate B-Chemical 1
- O 0
aspartate B-Chemical 1
( O 0
YMDD O 0
) O 0
motif O 0
of O 0
the O 0
major O 0
catalytic O 0
region O 0
in O 0
the O 0
C O 0
domain O 0
of O 0
the O 0
HBV O 0
RT O 0
enzyme O 0
. O 0

HBV O 0
viral O 0
load O 0
was O 0
performed O 0
with O 0
Amplicor O 0
HBV O 0
Monitor O 0
test O 0
v2 O 0
. O 0
0 O 0
( O 0
Roche O 0
Diagnostics O 0
, O 0
Penzberg O 0
, O 0
Germany O 0
) O 0
. O 0

HBV O 0
lamivudine B-Chemical 1
- O 0
resistant O 0
strains O 0
were O 0
detected O 0
in O 0
3 O 0
of O 0
15 O 0
mono O 0
- O 0
infected O 0
chronic O 0
hepatitis B-Disease 1
B I-Disease 1
patients O 0
and O 0
10 O 0
of O 0
20 O 0
HBV B-Disease 1
- I-Disease 1
HIV I-Disease 1
co I-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
. O 0

To O 0
the O 0
best O 0
of O 0
our O 0
knowledge O 0
, O 0
this O 0
constitutes O 0
the O 0
first O 0
report O 0
of O 0
HBV O 0
lamivudine B-Chemical 1
- O 0
resistant O 0
strains O 0
in O 0
therapy O 0
- O 0
na B-Chemical 1
ve O 0
HBV B-Disease 1
- I-Disease 1
HIV I-Disease 1
co I-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
. O 0

The O 0
HBV O 0
viral O 0
loads O 0
for O 0
mono O 0
- O 0
infected O 0
and O 0
co O 0
- O 0
infected O 0
patients O 0
ranged O 0
from O 0
3 O 0
. O 0
32 O 0
x O 0
10 O 0
( O 0
2 O 0
) O 0
to O 0
3 O 0
. O 0
82 O 0
x O 0
10 O 0
( O 0
7 O 0
) O 0
and O 0
< O 0
200 O 0
to O 0
4 O 0
. O 0
40 O 0
x O 0
10 O 0
( O 0
3 O 0
) O 0
copies O 0
/ O 0
ml O 0
, O 0
respectively O 0
. O 0

It O 0
remains O 0
to O 0
be O 0
seen O 0
whether O 0
such O 0
pre O 0
- O 0
existing O 0
antiviral O 0
mutations O 0
could O 0
result O 0
in O 0
widespread O 0
emergence O 0
of O 0
HBV O 0
resistant O 0
strains O 0
when O 0
lamivudine B-Chemical 1
- O 0
containing O 0
highly O 0
active O 0
antiretroviral O 0
( O 0
ARV O 0
) O 0
treatment O 0
( O 0
HAART O 0
) O 0
regimens O 0
become O 0
widely O 0
applied O 0
in O 0
South O 0
Africa O 0
, O 0
as O 0
this O 0
is O 0
likely O 0
to O 0
have O 0
potential O 0
implications O 0
in O 0
the O 0
management O 0
of O 0
HBV B-Disease 1
- I-Disease 1
HIV I-Disease 1
co I-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
. O 0

Rabbit B-Disease 1
syndrome I-Disease 1
, O 0
antidepressant B-Chemical 1
use O 0
, O 0
and O 0
cerebral O 0
perfusion O 0
SPECT O 0
scan O 0
findings O 0
. O 0

The O 0
rabbit B-Disease 1
syndrome I-Disease 1
is O 0
an O 0
extrapyramidal O 0
side O 0
effect O 0
associated O 0
with O 0
chronic O 0
neuroleptic O 0
therapy O 0
. O 0

Its O 0
occurrence O 0
in O 0
a O 0
patient O 0
being O 0
treated O 0
with O 0
imipramine B-Chemical 1
is O 0
described O 0
, O 0
representing O 0
the O 0
first O 0
reported O 0
case O 0
of O 0
this O 0
syndrome O 0
in O 0
conjunction O 0
with O 0
antidepressants B-Chemical 1
. O 0

Repeated O 0
cerebral O 0
perfusion O 0
SPECT O 0
scans O 0
revealed O 0
decreased B-Disease 1
basal I-Disease 1
ganglia I-Disease 1
perfusion I-Disease 1
while O 0
the O 0
movement B-Disease 1
disorder I-Disease 1
was O 0
present O 0
, O 0
and O 0
a O 0
return O 0
to O 0
normal O 0
perfusion O 0
when O 0
the O 0
rabbit B-Disease 1
syndrome I-Disease 1
resolved O 0
. O 0

Estrogen O 0
prevents O 0
cholesteryl B-Chemical 1
ester I-Chemical 1
accumulation O 0
in O 0
macrophages O 0
induced O 0
by O 0
the O 0
HIV O 0
protease O 0
inhibitor O 0
ritonavir B-Chemical 1
. O 0

Individuals O 0
with O 0
HIV O 0
can O 0
now O 0
live O 0
long O 0
lives O 0
with O 0
drug O 0
therapy O 0
that O 0
often O 0
includes O 0
protease O 0
inhibitors O 0
such O 0
as O 0
ritonavir B-Chemical 1
. O 0

Many O 0
patients O 0
, O 0
however O 0
, O 0
develop O 0
negative O 0
long O 0
- O 0
term O 0
side O 0
effects O 0
such O 0
as O 0
premature B-Disease 1
atherosclerosis I-Disease 1
. O 0

We O 0
have O 0
previously O 0
demonstrated O 0
that O 0
ritonavir B-Chemical 1
treatment O 0
increases O 0
atherosclerotic B-Disease 1
lesion I-Disease 1
formation O 0
in O 0
male O 0
mice O 0
to O 0
a O 0
greater O 0
extent O 0
than O 0
in O 0
female O 0
mice O 0
. O 0

Furthermore O 0
, O 0
peripheral O 0
blood O 0
monocytes O 0
isolated O 0
from O 0
ritonavir B-Chemical 1
- O 0
treated O 0
females O 0
had O 0
less O 0
cholesteryl B-Chemical 1
ester I-Chemical 1
accumulation O 0
. O 0

In O 0
the O 0
present O 0
study O 0
, O 0
we O 0
have O 0
investigated O 0
the O 0
molecular O 0
mechanisms O 0
by O 0
which O 0
female O 0
hormones O 0
influence O 0
cholesterol B-Chemical 1
metabolism O 0
in O 0
macrophages O 0
in O 0
response O 0
to O 0
the O 0
HIV O 0
protease O 0
inhibitor O 0
ritonavir B-Chemical 1
. O 0

We O 0
have O 0
utilized O 0
the O 0
human O 0
monocyte O 0
cell O 0
line O 0
, O 0
THP O 0
- O 0
1 O 0
as O 0
a O 0
model O 0
to O 0
address O 0
this O 0
question O 0
. O 0

Briefly O 0
, O 0
cells O 0
were O 0
differentiated O 0
for O 0
72 O 0
h O 0
with O 0
100 O 0
nM O 0
PMA O 0
to O 0
obtain O 0
a O 0
macrophage O 0
- O 0
like O 0
phenotype O 0
in O 0
the O 0
presence O 0
or O 0
absence O 0
of O 0
1 O 0
nM O 0
17beta B-Chemical 1
- I-Chemical 1
estradiol I-Chemical 1
( O 0
E2 B-Chemical 1
) O 0
, O 0
100 O 0
nM O 0
progesterone B-Chemical 1
or O 0
vehicle O 0
( O 0
0 O 0
. O 0
01 O 0
% O 0
ethanol B-Chemical 1
) O 0
. O 0

Cells O 0
were O 0
then O 0
treated O 0
with O 0
30 O 0
ng O 0
/ O 0
ml O 0
ritonavir B-Chemical 1
or O 0
vehicle O 0
in O 0
the O 0
presence O 0
of O 0
aggregated O 0
LDL O 0
for O 0
24 O 0
h O 0
. O 0

Cell O 0
extracts O 0
were O 0
harvested O 0
, O 0
and O 0
lipid O 0
or O 0
total O 0
RNA O 0
was O 0
isolated O 0
. O 0

E2 B-Chemical 1
decreased O 0
the O 0
accumulation O 0
of O 0
cholesteryl B-Chemical 1
esters I-Chemical 1
in O 0
macrophages O 0
following O 0
ritonavir B-Chemical 1
treatment O 0
. O 0

Ritonavir B-Chemical 1
increased O 0
the O 0
expression O 0
of O 0
the O 0
scavenger O 0
receptor O 0
, O 0
CD36 O 0
mRNA O 0
, O 0
responsible O 0
for O 0
the O 0
uptake O 0
of O 0
LDL O 0
. O 0

Additionally O 0
, O 0
ritonavir B-Chemical 1
treatment O 0
selectively O 0
increased O 0
the O 0
relative O 0
levels O 0
of O 0
PPARgamma O 0
mRNA O 0
, O 0
a O 0
transcription O 0
factor O 0
responsible O 0
for O 0
the O 0
regulation O 0
of O 0
CD36 O 0
mRNA O 0
expression O 0
. O 0

Treatment O 0
with O 0
E2 B-Chemical 1
, O 0
however O 0
, O 0
failed O 0
to O 0
prevent O 0
these O 0
increases O 0
at O 0
the O 0
mRNA O 0
level O 0
. O 0

E2 B-Chemical 1
did O 0
, O 0
however O 0
, O 0
significantly O 0
suppress O 0
CD36 O 0
protein O 0
levels O 0
as O 0
measured O 0
by O 0
fluorescent O 0
immunocytochemistry O 0
. O 0

This O 0
data O 0
suggests O 0
that O 0
E2 B-Chemical 1
modifies O 0
the O 0
expression O 0
of O 0
CD36 O 0
at O 0
the O 0
level O 0
of O 0
protein O 0
expression O 0
in O 0
monocyte O 0
- O 0
derived O 0
macrophages O 0
resulting O 0
in O 0
reduced O 0
cholesteryl B-Chemical 1
ester I-Chemical 1
accumulation O 0
following O 0
ritonavir B-Chemical 1
treatment O 0
. O 0

Acute O 0
hepatitis B-Disease 1
attack O 0
after O 0
exposure O 0
to O 0
telithromycin B-Chemical 1
. O 0

INTRODUCTION O 0
: O 0
Antibiotic O 0
- O 0
associated O 0
hepatotoxicity B-Disease 1
is O 0
rare O 0
. O 0

With O 0
widespread O 0
use O 0
of O 0
antimicrobial O 0
agents O 0
, O 0
however O 0
, O 0
hepatic B-Disease 1
injury I-Disease 1
occurs O 0
frequently O 0
, O 0
and O 0
among O 0
adverse B-Disease 1
drug I-Disease 1
reactions I-Disease 1
, O 0
idiosyncratic O 0
reactions O 0
are O 0
the O 0
most O 0
serious O 0
. O 0

CASE O 0
SUMMARY O 0
: O 0
A O 0
25 O 0
- O 0
year O 0
- O 0
old O 0
male O 0
patient O 0
, O 0
with O 0
a O 0
height O 0
of O 0
175 O 0
cm O 0
and O 0
weight O 0
of O 0
72 O 0
kg O 0
presented O 0
to O 0
Marmara O 0
University O 0
Hospital O 0
Emergency O 0
Department O 0
, O 0
Istanbul O 0
, O 0
Turkey O 0
, O 0
with O 0
5 O 0
days O 0
' O 0
history O 0
of O 0
jaundice B-Disease 1
, O 0
malaise O 0
, O 0
nausea B-Disease 1
, O 0
and O 0
vomiting B-Disease 1
. O 0

He O 0
had O 0
been O 0
prescribed O 0
telithromycin B-Chemical 1
400 O 0
mg O 0
/ O 0
d O 0
PO O 0
to O 0
treat O 0
an O 0
upper B-Disease 1
respiratory I-Disease 1
tract I-Disease 1
infection I-Disease 1
7 O 0
days O 0
prior O 0
. O 0

Admission O 0
laboratory O 0
tests O 0
were O 0
as O 0
follows O 0
: O 0
alanine B-Chemical 1
aminotransferase O 0
, O 0
67 O 0
U O 0
/ O 0
L O 0
( O 0
reference O 0
range O 0
, O 0
10 O 0
- O 0
37 O 0
U O 0
/ O 0
L O 0
) O 0
; O 0
aspartate B-Chemical 1
aminotransferase O 0
, O 0
98 O 0
U O 0
/ O 0
L O 0
( O 0
10 O 0
- O 0
40 O 0
U O 0
/ O 0
L O 0
) O 0
; O 0
alkaline O 0
phosphatase O 0
, O 0
513 O 0
U O 0
/ O 0
L O 0
( O 0
0 O 0
- O 0
270 O 0
U O 0
/ O 0
L O 0
) O 0
; O 0
gamma O 0
- O 0
glutamyltransferase O 0
, O 0
32 O 0
U O 0
/ O 0
L O 0
( O 0
7 O 0
- O 0
49 O 0
U O 0
/ O 0
L O 0
) O 0
; O 0
amylase O 0
, O 0
46 O 0
U O 0
/ O 0
L O 0
( O 0
0 O 0
- O 0
220 O 0
U O 0
/ O 0
L O 0
) O 0
; O 0
total O 0
bilirubin B-Chemical 1
, O 0
20 O 0
. O 0
1 O 0
mg O 0
/ O 0
dL O 0
( O 0
0 O 0
. O 0
2 O 0
- O 0
1 O 0
. O 0
0 O 0
mg O 0
/ O 0
dL O 0
) O 0
; O 0
direct O 0
bilirubin B-Chemical 1
, O 0
14 O 0
. O 0
8 O 0
mg O 0
/ O 0
dL O 0
( O 0
0 O 0
- O 0
0 O 0
. O 0
3 O 0
mg O 0
/ O 0
dL O 0
) O 0
; O 0
and O 0
albumin O 0
, O 0
4 O 0
. O 0
7 O 0
mg O 0
/ O 0
dL O 0
( O 0
3 O 0
. O 0
5 O 0
- O 0
5 O 0
. O 0
4 O 0
mg O 0
/ O 0
dL O 0
) O 0
. O 0

No O 0
toxin O 0
, O 0
alcohol B-Chemical 1
, O 0
or O 0
other O 0
drugs O 0
were O 0
reported O 0
. O 0

The O 0
patient O 0
had O 0
suffered O 0
a O 0
previous O 0
episode O 0
of O 0
" O 0
acute O 0
hepatitis B-Disease 1
of O 0
unknown O 0
origin O 0
, O 0
" O 0
that O 0
occurred O 0
after O 0
telithromycin B-Chemical 1
usage O 0
. O 0

Both O 0
incidents O 0
occurred O 0
within O 0
a O 0
year O 0
. O 0

DISCUSSION O 0
: O 0
Telithromycin B-Chemical 1
is O 0
the O 0
first O 0
of O 0
the O 0
ketolide O 0
antibacterials O 0
to O 0
receive O 0
US O 0
Food O 0
and O 0
Drug O 0
Administration O 0
approval O 0
for O 0
clinical O 0
use O 0
. O 0

It O 0
has O 0
been O 0
associated O 0
with O 0
infrequent O 0
and O 0
usually O 0
reversible O 0
severe O 0
hepatic B-Disease 1
dysfunction I-Disease 1
. O 0

Based O 0
on O 0
a O 0
score O 0
of O 0
8 O 0
on O 0
the O 0
Naranjo O 0
adverse B-Disease 1
drug I-Disease 1
reaction I-Disease 1
probability O 0
scale O 0
, O 0
telithromycin B-Chemical 1
was O 0
the O 0
probable O 0
cause O 0
of O 0
acute O 0
hepatitis B-Disease 1
in O 0
this O 0
patient O 0
, O 0
and O 0
pathological O 0
findings O 0
suggested O 0
drug O 0
- O 0
induced O 0
toxic B-Disease 1
hepatitis I-Disease 1
. O 0

Recurrence O 0
of O 0
hepatitis B-Disease 1
attack O 0
might O 0
have O 0
been O 0
avoided O 0
if O 0
the O 0
initial O 0
incident O 0
had O 0
been O 0
communicated O 0
to O 0
the O 0
attending O 0
physician O 0
who O 0
prescribed O 0
telithromycin B-Chemical 1
the O 0
second O 0
time O 0
. O 0

CONCLUSION O 0
: O 0
Here O 0
we O 0
report O 0
a O 0
case O 0
of O 0
acute O 0
hepatitis B-Disease 1
probably O 0
associated O 0
with O 0
the O 0
administration O 0
of O 0
telithromycin B-Chemical 1
. O 0

A O 0
study O 0
on O 0
the O 0
effect O 0
of O 0
the O 0
duration O 0
of O 0
subcutaneous O 0
heparin B-Chemical 1
injection O 0
on O 0
bruising B-Disease 1
and O 0
pain B-Disease 1
. O 0

AIM O 0
: O 0
This O 0
study O 0
was O 0
carried O 0
out O 0
to O 0
determine O 0
the O 0
effect O 0
of O 0
injection O 0
duration O 0
on O 0
bruising B-Disease 1
and O 0
pain B-Disease 1
following O 0
the O 0
administration O 0
of O 0
the O 0
subcutaneous O 0
injection O 0
of O 0
heparin B-Chemical 1
. O 0

BACKGROUND O 0
: O 0
Although O 0
different O 0
methods O 0
to O 0
prevent O 0
bruising B-Disease 1
and O 0
pain B-Disease 1
following O 0
the O 0
subcutaneous O 0
injection O 0
of O 0
heparin B-Chemical 1
have O 0
been O 0
widely O 0
studied O 0
and O 0
described O 0
, O 0
the O 0
effect O 0
of O 0
injection O 0
duration O 0
on O 0
the O 0
occurrence O 0
of O 0
bruising B-Disease 1
and O 0
pain B-Disease 1
is O 0
little O 0
documented O 0
. O 0

DESIGN O 0
: O 0
This O 0
study O 0
was O 0
designed O 0
as O 0
within O 0
- O 0
subject O 0
, O 0
quasi O 0
- O 0
experimental O 0
research O 0
. O 0

METHOD O 0
: O 0
The O 0
sample O 0
for O 0
the O 0
study O 0
consisted O 0
of O 0
50 O 0
patients O 0
to O 0
whom O 0
subcutaneous O 0
heparin B-Chemical 1
was O 0
administered O 0
. O 0

Heparin B-Chemical 1
was O 0
injected O 0
over O 0
10 O 0
seconds O 0
on O 0
the O 0
right O 0
abdominal O 0
site O 0
and O 0
30 O 0
seconds O 0
on O 0
the O 0
left O 0
abdominal O 0
site O 0
. O 0

Injections O 0
areas O 0
were O 0
assessed O 0
for O 0
the O 0
presence O 0
of O 0
bruising B-Disease 1
at O 0
48 O 0
and O 0
72 O 0
hours O 0
after O 0
each O 0
injection O 0
. O 0

Dimensions O 0
of O 0
the O 0
bruising B-Disease 1
on O 0
the O 0
heparin B-Chemical 1
applied O 0
areas O 0
were O 0
measured O 0
using O 0
transparent O 0
millimetric O 0
measuring O 0
paper O 0
. O 0

The O 0
visual O 0
analog O 0
scale O 0
( O 0
VAS O 0
) O 0
was O 0
used O 0
to O 0
measure O 0
pain B-Disease 1
intensity O 0
and O 0
a O 0
stop O 0
- O 0
watch O 0
was O 0
used O 0
to O 0
time O 0
the O 0
pain B-Disease 1
period O 0
. O 0

Data O 0
were O 0
analysed O 0
using O 0
chi O 0
- O 0
square O 0
test O 0
, O 0
Mann O 0
- O 0
Whitney O 0
U O 0
, O 0
Wilcoxon O 0
signed O 0
ranks O 0
tests O 0
and O 0
correlation O 0
. O 0

RESULTS O 0
: O 0
The O 0
percentage O 0
of O 0
bruising B-Disease 1
occurrence O 0
was O 0
64 O 0
% O 0
with O 0
the O 0
injection O 0
of O 0
10 O 0
seconds O 0
duration O 0
and O 0
42 O 0
% O 0
in O 0
the O 0
30 O 0
- O 0
second O 0
injection O 0
. O 0

It O 0
was O 0
determined O 0
that O 0
the O 0
size O 0
of O 0
the O 0
bruising B-Disease 1
was O 0
smaller O 0
in O 0
the O 0
30 O 0
- O 0
second O 0
injection O 0
. O 0

Pain B-Disease 1
intensity O 0
and O 0
pain B-Disease 1
period O 0
were O 0
statistically O 0
significantly O 0
lower O 0
for O 0
the O 0
30 O 0
- O 0
second O 0
injection O 0
than O 0
for O 0
the O 0
10 O 0
- O 0
second O 0
injection O 0
. O 0

CONCLUSIONS O 0
: O 0
It O 0
was O 0
determined O 0
that O 0
injection O 0
duration O 0
had O 0
an O 0
effect O 0
on O 0
bruising B-Disease 1
and O 0
pain B-Disease 1
following O 0
the O 0
subcutaneous O 0
administration O 0
of O 0
heparin B-Chemical 1
. O 0

This O 0
study O 0
should O 0
be O 0
repeated O 0
on O 0
a O 0
larger O 0
sample O 0
. O 0

RELEVANCE O 0
TO O 0
CLINICAL O 0
PRACTICE O 0
: O 0
When O 0
administering O 0
subcutaneous O 0
heparin B-Chemical 1
injections O 0
, O 0
it O 0
is O 0
important O 0
to O 0
extend O 0
the O 0
duration O 0
of O 0
the O 0
injection O 0
. O 0

Acute B-Disease 1
liver I-Disease 1
failure I-Disease 1
in O 0
two O 0
patients O 0
with O 0
regular O 0
alcohol B-Chemical 1
consumption O 0
ingesting O 0
paracetamol B-Chemical 1
at O 0
therapeutic O 0
dosage O 0
. O 0

BACKGROUND O 0
: O 0
The O 0
possible O 0
role O 0
of O 0
alcohol B-Chemical 1
in O 0
the O 0
development O 0
of O 0
hepatotoxicity B-Disease 1
associated O 0
with O 0
therapeutic O 0
doses O 0
of O 0
paracetamol B-Chemical 1
( O 0
acetaminophen B-Chemical 1
) O 0
is O 0
currently O 0
debated O 0
. O 0

CASE O 0
REPORT O 0
: O 0
We O 0
describe O 0
2 O 0
patients O 0
who O 0
were O 0
regular O 0
consumers O 0
of O 0
alcohol B-Chemical 1
and O 0
who O 0
developed O 0
liver B-Disease 1
failure I-Disease 1
within O 0
3 O 0
- O 0
5 O 0
days O 0
after O 0
hospitalization O 0
and O 0
stopping O 0
alcohol B-Chemical 1
consumption O 0
while O 0
being O 0
treated O 0
with O 0
4 O 0
g O 0
paracetamol B-Chemical 1
/ O 0
day O 0
. O 0

A O 0
paracetamol B-Chemical 1
serum O 0
level O 0
obtained O 0
in O 0
one O 0
of O 0
these O 0
patients O 0
was O 0
not O 0
in O 0
the O 0
toxic O 0
range O 0
. O 0

Possible O 0
risk O 0
factors O 0
for O 0
the O 0
development O 0
of O 0
hepatotoxicity B-Disease 1
in O 0
patients O 0
treated O 0
with O 0
therapeutic O 0
doses O 0
of O 0
paracetamol B-Chemical 1
are O 0
discussed O 0
. O 0

CONCLUSION O 0
: O 0
In O 0
patients O 0
with O 0
risk O 0
factors O 0
, O 0
e O 0
. O 0
g O 0
. O 0
regular O 0
consumption O 0
of O 0
alcohol B-Chemical 1
, O 0
liver B-Disease 1
failure I-Disease 1
is O 0
possible O 0
when O 0
therapeutic O 0
doses O 0
are O 0
ingested O 0
. O 0

We O 0
propose O 0
that O 0
the O 0
paracetamol B-Chemical 1
dose O 0
should O 0
not O 0
exceed O 0
2 O 0
g O 0
/ O 0
day O 0
in O 0
such O 0
patients O 0
and O 0
that O 0
their O 0
liver O 0
function O 0
should O 0
be O 0
monitored O 0
closely O 0
while O 0
being O 0
treated O 0
with O 0
paracetamol B-Chemical 1
. O 0

Associations O 0
between O 0
use O 0
of O 0
benzodiazepines B-Chemical 1
or O 0
related O 0
drugs O 0
and O 0
health O 0
, O 0
physical O 0
abilities O 0
and O 0
cognitive O 0
function O 0
: O 0
a O 0
non O 0
- O 0
randomised O 0
clinical O 0
study O 0
in O 0
the O 0
elderly O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
describe O 0
associations O 0
between O 0
the O 0
use O 0
of O 0
benzodiazepines B-Chemical 1
or O 0
related O 0
drugs O 0
( O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
) O 0
and O 0
health O 0
, O 0
functional O 0
abilities O 0
and O 0
cognitive O 0
function O 0
in O 0
the O 0
elderly O 0
. O 0

METHODS O 0
: O 0
A O 0
non O 0
- O 0
randomised O 0
clinical O 0
study O 0
of O 0
patients O 0
aged O 0
> O 0
or O 0
= O 0
65 O 0
years O 0
admitted O 0
to O 0
acute O 0
hospital O 0
wards O 0
during O 0
1 O 0
month O 0
. O 0

164 O 0
patients O 0
( O 0
mean O 0
age O 0
+ O 0
/ O 0
- O 0
standard O 0
deviation O 0
[ O 0
SD O 0
] O 0
81 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
6 O 0
. O 0
8 O 0
years O 0
) O 0
were O 0
admitted O 0
. O 0

Of O 0
these O 0
, O 0
nearly O 0
half O 0
( O 0
n O 0
= O 0
78 O 0
) O 0
had O 0
used O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
before O 0
admission O 0
, O 0
and O 0
the O 0
remainder O 0
( O 0
n O 0
= O 0
86 O 0
) O 0
were O 0
non O 0
- O 0
users O 0
. O 0

Cognitive O 0
ability O 0
was O 0
assessed O 0
by O 0
the O 0
Mini O 0
- O 0
Mental O 0
State O 0
Examination O 0
( O 0
MMSE O 0
) O 0
. O 0

Patients O 0
scoring O 0
> O 0
or O 0
= O 0
20 O 0
MMSE O 0
sum O 0
points O 0
were O 0
interviewed O 0
( O 0
n O 0
= O 0
79 O 0
) O 0
and O 0
questioned O 0
regarding O 0
symptoms O 0
and O 0
functional O 0
abilities O 0
during O 0
the O 0
week O 0
prior O 0
to O 0
admission O 0
. O 0

Data O 0
on O 0
use O 0
of O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
before O 0
admission O 0
, O 0
current O 0
medications O 0
and O 0
discharge O 0
diagnoses O 0
were O 0
collected O 0
from O 0
medical O 0
records O 0
. O 0

Health O 0
, O 0
physical O 0
abilities O 0
and O 0
cognitive O 0
function O 0
were O 0
compared O 0
between O 0
BZD O 0
/ O 0
RD O 0
users O 0
and O 0
non O 0
- O 0
users O 0
, O 0
and O 0
adjustments O 0
were O 0
made O 0
for O 0
confounding O 0
variables O 0
. O 0

The O 0
residual O 0
serum O 0
concentrations O 0
of O 0
oxazepam B-Chemical 1
, O 0
temazepam B-Chemical 1
and O 0
zopiclone B-Chemical 1
were O 0
analysed O 0
. O 0

RESULTS O 0
: O 0
The O 0
mean O 0
+ O 0
/ O 0
- O 0
SD O 0
duration O 0
of O 0
BZD O 0
/ O 0
RD O 0
use O 0
was O 0
7 O 0
+ O 0
/ O 0
- O 0
7 O 0
years O 0
( O 0
range O 0
1 O 0
- O 0
31 O 0
) O 0
. O 0

Two O 0
or O 0
three O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
were O 0
concomitantly O 0
taken O 0
by O 0
26 O 0
% O 0
of O 0
users O 0
( O 0
n O 0
= O 0
20 O 0
) O 0
. O 0

Long O 0
- O 0
term O 0
use O 0
of O 0
these O 0
drugs O 0
was O 0
associated O 0
with O 0
female O 0
sex O 0
and O 0
use O 0
of O 0
a O 0
higher O 0
number O 0
of O 0
drugs O 0
with O 0
effects O 0
on O 0
the O 0
CNS O 0
, O 0
which O 0
tended O 0
to O 0
be O 0
related O 0
to O 0
diagnosed O 0
dementia B-Disease 1
. O 0

After O 0
adjustment O 0
for O 0
these O 0
variables O 0
as O 0
confounders O 0
, O 0
use O 0
of O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
was O 0
not O 0
associated O 0
with O 0
cognitive O 0
function O 0
as O 0
measured O 0
by O 0
the O 0
MMSE O 0
. O 0

However O 0
, O 0
use O 0
of O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
was O 0
associated O 0
with O 0
dizziness B-Disease 1
, O 0
inability B-Disease 1
to I-Disease 1
sleep I-Disease 1
after O 0
awaking O 0
at O 0
night O 0
and O 0
tiredness B-Disease 1
in O 0
the O 0
mornings O 0
during O 0
the O 0
week O 0
prior O 0
to O 0
admission O 0
and O 0
with O 0
stronger O 0
depressive B-Disease 1
symptoms I-Disease 1
measured O 0
at O 0
the O 0
beginning O 0
of O 0
the O 0
hospital O 0
stay O 0
. O 0

Use O 0
of O 0
BZDs B-Chemical 1
/ O 0
RDs O 0
tended O 0
to O 0
be O 0
associated O 0
with O 0
a O 0
reduced O 0
ability O 0
to O 0
walk O 0
and O 0
shorter O 0
night O 0
- O 0
time O 0
sleep O 0
during O 0
the O 0
week O 0
prior O 0
to O 0
admission O 0
. O 0

A O 0
higher O 0
residual O 0
serum O 0
concentration O 0
of O 0
temazepam B-Chemical 1
correlated O 0
with O 0
a O 0
lower O 0
MMSE O 0
sum O 0
score O 0
after O 0
adjustment O 0
for O 0
confounding O 0
variables O 0
. O 0

CONCLUSIONS O 0
: O 0
Long O 0
- O 0
term O 0
use O 0
and O 0
concomitant O 0
use O 0
of O 0
more O 0
than O 0
one O 0
BZD O 0
/ O 0
RD O 0
were O 0
common O 0
in O 0
elderly O 0
patients O 0
hospitalised O 0
because O 0
of O 0
acute O 0
illnesses O 0
. O 0

Long O 0
- O 0
term O 0
use O 0
was O 0
associated O 0
with O 0
daytime O 0
and O 0
night O 0
- O 0
time O 0
symptoms O 0
indicative O 0
of O 0
poorer O 0
health O 0
and O 0
potentially O 0
caused O 0
by O 0
the O 0
adverse O 0
effects O 0
of O 0
these O 0
drugs O 0
. O 0

Acute O 0
vocal B-Disease 1
fold I-Disease 1
palsy I-Disease 1
after O 0
acute O 0
disulfiram B-Chemical 1
intoxication O 0
. O 0

Acute O 0
peripheral B-Disease 1
neuropathy I-Disease 1
caused O 0
by O 0
a O 0
disulfiram B-Chemical 1
overdose B-Disease 1
is O 0
very O 0
rare O 0
and O 0
there O 0
is O 0
no O 0
report O 0
of O 0
it O 0
leading O 0
to O 0
vocal B-Disease 1
fold I-Disease 1
palsy I-Disease 1
. O 0

A O 0
49 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
was O 0
transferred O 0
to O 0
our O 0
department O 0
because O 0
of O 0
quadriparesis B-Disease 1
, O 0
lancinating O 0
pain B-Disease 1
, O 0
sensory B-Disease 1
loss I-Disease 1
, O 0
and O 0
paresthesia B-Disease 1
of O 0
the O 0
distal O 0
limbs O 0
. O 0

One O 0
month O 0
previously O 0
, O 0
she O 0
had O 0
taken O 0
a O 0
single O 0
high O 0
dose O 0
of O 0
disulfiram B-Chemical 1
( O 0
130 O 0
tablets O 0
of O 0
ALCOHOL B-Chemical 1
STOP O 0
TAB O 0
, O 0
Shin O 0
- O 0
Poong O 0
Pharm O 0
. O 0
Co O 0
. O 0
, O 0
Ansan O 0
, O 0
Korea O 0
) O 0
in O 0
a O 0
suicide O 0
attempt O 0
. O 0

She O 0
was O 0
not O 0
an O 0
alcoholic O 0
. O 0

For O 0
the O 0
first O 0
few O 0
days O 0
after O 0
ingestion O 0
, O 0
she O 0
was O 0
in O 0
a O 0
confused O 0
state O 0
and O 0
had O 0
mild O 0
to O 0
moderate O 0
ataxia B-Disease 1
and O 0
giddiness B-Disease 1
. O 0

She O 0
noticed O 0
hoarseness B-Disease 1
and O 0
distally O 0
accentuated O 0
motor O 0
and O 0
sensory O 0
dysfunction O 0
after O 0
she O 0
had O 0
recovered O 0
from O 0
this O 0
state O 0
. O 0

A O 0
nerve O 0
conduction O 0
study O 0
was O 0
consistent O 0
with O 0
severe O 0
sensorimotor O 0
axonal O 0
polyneuropathy B-Disease 1
. O 0

Laryngeal O 0
electromyography O 0
( O 0
thyroarytenoid O 0
muscle O 0
) O 0
showed O 0
ample O 0
denervation O 0
potentials O 0
. O 0

Laryngoscopy O 0
revealed O 0
asymmetric O 0
vocal O 0
fold O 0
movements O 0
during O 0
phonation O 0
. O 0

Her O 0
vocal O 0
change O 0
and O 0
weakness O 0
began O 0
to O 0
improve O 0
spontaneously O 0
about O 0
3 O 0
weeks O 0
after O 0
transfer O 0
. O 0

This O 0
was O 0
a O 0
case O 0
of O 0
acute O 0
palsy B-Disease 1
of O 0
the O 0
recurrent O 0
laryngeal O 0
nerve O 0
and O 0
superimposed O 0
severe O 0
acute O 0
sensorimotor O 0
axonal O 0
polyneuropathy B-Disease 1
caused O 0
by O 0
high O 0
- O 0
dose O 0
disulfiram B-Chemical 1
intoxication O 0
. O 0

Encephalopathy B-Disease 1
induced O 0
by O 0
levetiracetam B-Chemical 1
added O 0
to O 0
valproate B-Chemical 1
. O 0

BACKGROUND O 0
: O 0
We O 0
report O 0
on O 0
the O 0
manifestation O 0
of O 0
a O 0
levetiracetam B-Chemical 1
( O 0
LEV B-Chemical 1
) O 0
- O 0
induced O 0
encephalopathy B-Disease 1
. O 0

FINDINGS O 0
: O 0
A O 0
28 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
suffering O 0
from O 0
idiopathic B-Disease 1
epilepsy I-Disease 1
with O 0
generalized O 0
seizures B-Disease 1
was O 0
treated O 0
with O 0
LEV B-Chemical 1
( O 0
3000 O 0
mg O 0
) O 0
added O 0
to O 0
valproate B-Chemical 1
( O 0
VPA B-Chemical 1
) O 0
( O 0
2000 O 0
mg O 0
) O 0
. O 0

Frequency O 0
of O 0
generalized O 0
tonic B-Disease 1
- I-Disease 1
clonic I-Disease 1
seizures I-Disease 1
increased O 0
from O 0
one O 0
per O 0
6 O 0
months O 0
to O 0
two O 0
per O 0
month O 0
. O 0

Neuropsychological O 0
testing O 0
showed O 0
impaired B-Disease 1
word I-Disease 1
fluency I-Disease 1
, I-Disease 1
psychomotor I-Disease 1
speed I-Disease 1
and I-Disease 1
working I-Disease 1
memory I-Disease 1
. O 0

The O 0
interictal O 0
electroencephalogram O 0
( O 0
EEG O 0
) O 0
showed O 0
a O 0
generalized O 0
slowing O 0
to O 0
5 O 0
per O 0
second O 0
theta O 0
rhythms O 0
with O 0
bilateral O 0
generalized O 0
high O 0
- O 0
amplitude O 0
discharges O 0
. O 0

OUTCOME O 0
: O 0
Following O 0
discontinuation O 0
of O 0
LEV B-Chemical 1
, O 0
EEG O 0
and O 0
neuropsychological O 0
findings O 0
improved O 0
and O 0
seizure B-Disease 1
frequency O 0
decreased O 0
. O 0

Norepinephrine B-Chemical 1
signaling O 0
through O 0
beta O 0
- O 0
adrenergic O 0
receptors O 0
is O 0
critical O 0
for O 0
expression O 0
of O 0
cocaine B-Chemical 1
- O 0
induced O 0
anxiety B-Disease 1
. O 0

BACKGROUND O 0
: O 0
Cocaine B-Chemical 1
is O 0
a O 0
widely O 0
abused O 0
psychostimulant O 0
that O 0
has O 0
both O 0
rewarding O 0
and O 0
aversive O 0
properties O 0
. O 0

While O 0
the O 0
mechanisms O 0
underlying O 0
cocaine B-Chemical 1
' O 0
s O 0
rewarding O 0
effects O 0
have O 0
been O 0
studied O 0
extensively O 0
, O 0
less O 0
attention O 0
has O 0
been O 0
paid O 0
to O 0
the O 0
unpleasant O 0
behavioral O 0
states O 0
induced O 0
by O 0
cocaine B-Chemical 1
, O 0
such O 0
as O 0
anxiety B-Disease 1
. O 0

METHODS O 0
: O 0
In O 0
this O 0
study O 0
, O 0
we O 0
evaluated O 0
the O 0
performance O 0
of O 0
dopamine B-Chemical 1
beta O 0
- O 0
hydroxylase O 0
knockout O 0
( O 0
Dbh O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
, O 0
which O 0
lack O 0
norepinephrine B-Chemical 1
( O 0
NE B-Chemical 1
) O 0
, O 0
in O 0
the O 0
elevated O 0
plus O 0
maze O 0
( O 0
EPM O 0
) O 0
to O 0
examine O 0
the O 0
contribution O 0
of O 0
noradrenergic O 0
signaling O 0
to O 0
cocaine B-Chemical 1
- O 0
induced O 0
anxiety B-Disease 1
. O 0

RESULTS O 0
: O 0
We O 0
found O 0
that O 0
cocaine B-Chemical 1
dose O 0
- O 0
dependently O 0
increased O 0
anxiety B-Disease 1
- O 0
like O 0
behavior O 0
in O 0
control O 0
( O 0
Dbh O 0
+ O 0
/ O 0
- O 0
) O 0
mice O 0
, O 0
as O 0
measured O 0
by O 0
a O 0
decrease O 0
in O 0
open O 0
arm O 0
exploration O 0
. O 0

The O 0
Dbh O 0
- O 0
/ O 0
- O 0
mice O 0
had O 0
normal O 0
baseline O 0
performance O 0
in O 0
the O 0
EPM O 0
but O 0
were O 0
completely O 0
resistant O 0
to O 0
the O 0
anxiogenic O 0
effects O 0
of O 0
cocaine B-Chemical 1
. O 0

Cocaine B-Chemical 1
- O 0
induced O 0
anxiety B-Disease 1
was O 0
also O 0
attenuated O 0
in O 0
Dbh O 0
+ O 0
/ O 0
- O 0
mice O 0
following O 0
administration O 0
of O 0
disulfiram B-Chemical 1
, O 0
a O 0
dopamine B-Chemical 1
beta O 0
- O 0
hydroxylase O 0
( O 0
DBH O 0
) O 0
inhibitor O 0
. O 0

In O 0
experiments O 0
using O 0
specific O 0
adrenergic O 0
antagonists O 0
, O 0
we O 0
found O 0
that O 0
pretreatment O 0
with O 0
the O 0
beta O 0
- O 0
adrenergic O 0
receptor O 0
antagonist O 0
propranolol B-Chemical 1
blocked O 0
cocaine B-Chemical 1
- O 0
induced O 0
anxiety B-Disease 1
- O 0
like O 0
behavior O 0
in O 0
Dbh O 0
+ O 0
/ O 0
- O 0
and O 0
wild O 0
- O 0
type O 0
C57BL6 O 0
/ O 0
J O 0
mice O 0
, O 0
while O 0
the O 0
alpha O 0
( O 0
1 O 0
) O 0
antagonist O 0
prazosin B-Chemical 1
and O 0
the O 0
alpha O 0
( O 0
2 O 0
) O 0
antagonist O 0
yohimbine B-Chemical 1
had O 0
no O 0
effect O 0
. O 0

CONCLUSIONS O 0
: O 0
These O 0
results O 0
indicate O 0
that O 0
noradrenergic O 0
signaling O 0
via O 0
beta O 0
- O 0
adrenergic O 0
receptors O 0
is O 0
required O 0
for O 0
cocaine B-Chemical 1
- O 0
induced O 0
anxiety B-Disease 1
in O 0
mice O 0
. O 0

Hypothalamic O 0
prolactin O 0
receptor O 0
messenger O 0
ribonucleic B-Chemical 1
acid I-Chemical 1
levels O 0
, O 0
prolactin O 0
signaling O 0
, O 0
and O 0
hyperprolactinemic B-Disease 1
inhibition O 0
of O 0
pulsatile O 0
luteinizing O 0
hormone O 0
secretion O 0
are O 0
dependent O 0
on O 0
estradiol B-Chemical 1
. O 0

Hyperprolactinemia B-Disease 1
can O 0
reduce O 0
fertility O 0
and O 0
libido O 0
. O 0

Although O 0
central O 0
prolactin O 0
actions O 0
are O 0
thought O 0
to O 0
contribute O 0
to O 0
this O 0
, O 0
the O 0
mechanisms O 0
are O 0
poorly O 0
understood O 0
. O 0

We O 0
first O 0
tested O 0
whether O 0
chronic O 0
hyperprolactinemia B-Disease 1
inhibited O 0
two O 0
neuroendocrine O 0
parameters O 0
necessary O 0
for O 0
female O 0
fertility O 0
: O 0
pulsatile O 0
LH O 0
secretion O 0
and O 0
the O 0
estrogen B-Chemical 1
- O 0
induced O 0
LH O 0
surge O 0
. O 0

Chronic O 0
hyperprolactinemia B-Disease 1
induced O 0
by O 0
the O 0
dopamine B-Chemical 1
antagonist O 0
sulpiride B-Chemical 1
caused O 0
a O 0
40 O 0
% O 0
reduction O 0
LH O 0
pulse O 0
frequency O 0
in O 0
ovariectomized O 0
rats O 0
, O 0
but O 0
only O 0
in O 0
the O 0
presence O 0
of O 0
chronic O 0
low O 0
levels O 0
of O 0
estradiol B-Chemical 1
. O 0

Sulpiride B-Chemical 1
did O 0
not O 0
affect O 0
the O 0
magnitude O 0
of O 0
a O 0
steroid B-Chemical 1
- O 0
induced O 0
LH O 0
surge O 0
or O 0
the O 0
percentage O 0
of O 0
GnRH O 0
neurons O 0
activated O 0
during O 0
the O 0
surge O 0
. O 0

Estradiol B-Chemical 1
is O 0
known O 0
to O 0
influence O 0
expression O 0
of O 0
the O 0
long O 0
form O 0
of O 0
prolactin O 0
receptors O 0
( O 0
PRL O 0
- O 0
R O 0
) O 0
and O 0
components O 0
of O 0
prolactin O 0
' O 0
s O 0
signaling O 0
pathway O 0
. O 0

To O 0
test O 0
the O 0
hypothesis O 0
that O 0
estrogen B-Chemical 1
increases O 0
PRL O 0
- O 0
R O 0
expression O 0
and O 0
sensitivity O 0
to O 0
prolactin O 0
, O 0
we O 0
next O 0
demonstrated O 0
that O 0
estradiol B-Chemical 1
greatly O 0
augments O 0
prolactin O 0
- O 0
induced O 0
STAT5 O 0
activation O 0
. O 0

Lastly O 0
, O 0
we O 0
measured O 0
PRL O 0
- O 0
R O 0
and O 0
suppressor O 0
of O 0
cytokine O 0
signaling O 0
( O 0
SOCS O 0
- O 0
1 O 0
and O 0
- O 0
3 O 0
and O 0
CIS O 0
, O 0
which O 0
reflect O 0
the O 0
level O 0
of O 0
prolactin O 0
signaling O 0
) O 0
mRNAs O 0
in O 0
response O 0
to O 0
sulpiride B-Chemical 1
and O 0
estradiol B-Chemical 1
. O 0

Sulpiride B-Chemical 1
induced O 0
only O 0
SOCS O 0
- O 0
1 O 0
in O 0
the O 0
medial O 0
preoptic O 0
area O 0
, O 0
where O 0
GnRH O 0
neurons O 0
are O 0
regulated O 0
, O 0
but O 0
in O 0
the O 0
arcuate O 0
nucleus O 0
and O 0
choroid O 0
plexus O 0
, O 0
PRL O 0
- O 0
R O 0
, O 0
SOCS O 0
- O 0
3 O 0
, O 0
and O 0
CIS O 0
mRNA O 0
levels O 0
were O 0
also O 0
induced O 0
. O 0

Estradiol B-Chemical 1
enhanced O 0
these O 0
effects O 0
on O 0
SOCS O 0
- O 0
3 O 0
and O 0
CIS O 0
. O 0

Interestingly O 0
, O 0
estradiol B-Chemical 1
also O 0
induced O 0
PRL O 0
- O 0
R O 0
, O 0
SOCS O 0
- O 0
3 O 0
, O 0
and O 0
CIS O 0
mRNA O 0
levels O 0
independently O 0
. O 0

These O 0
data O 0
show O 0
that O 0
GnRH O 0
pulse O 0
frequency O 0
is O 0
inhibited O 0
by O 0
chronic O 0
hyperprolactinemia B-Disease 1
in O 0
a O 0
steroid B-Chemical 1
- O 0
dependent O 0
manner O 0
. O 0

They O 0
also O 0
provide O 0
evidence O 0
for O 0
estradiol B-Chemical 1
- O 0
dependent O 0
and O 0
brain O 0
region O 0
- O 0
specific O 0
regulation O 0
of O 0
PRL O 0
- O 0
R O 0
expression O 0
and O 0
signaling O 0
responses O 0
by O 0
prolactin O 0
. O 0

Clonidine B-Chemical 1
for O 0
attention B-Disease 1
- I-Disease 1
deficit I-Disease 1
/ I-Disease 1
hyperactivity I-Disease 1
disorder I-Disease 1
: O 0
II O 0
. O 0

ECG O 0
changes O 0
and O 0
adverse O 0
events O 0
analysis O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
examine O 0
the O 0
safety O 0
and O 0
tolerability O 0
of O 0
clonidine B-Chemical 1
used O 0
alone O 0
or O 0
with O 0
methylphenidate B-Chemical 1
in O 0
children O 0
with O 0
attention B-Disease 1
- I-Disease 1
deficit I-Disease 1
/ I-Disease 1
hyperactivity I-Disease 1
disorder I-Disease 1
( O 0
ADHD B-Disease 1
) O 0
. O 0

METHOD O 0
: O 0
In O 0
a O 0
16 O 0
- O 0
week O 0
multicenter O 0
, O 0
double O 0
- O 0
blind O 0
trial O 0
, O 0
122 O 0
children O 0
with O 0
ADHD B-Disease 1
were O 0
randomly O 0
assigned O 0
to O 0
clonidine B-Chemical 1
( O 0
n O 0
= O 0
31 O 0
) O 0
, O 0
methylphenidate B-Chemical 1
( O 0
n O 0
= O 0
29 O 0
) O 0
, O 0
clonidine B-Chemical 1
and O 0
methylphenidate B-Chemical 1
( O 0
n O 0
= O 0
32 O 0
) O 0
, O 0
or O 0
placebo O 0
( O 0
n O 0
= O 0
30 O 0
) O 0
. O 0

Doses O 0
were O 0
flexibly O 0
titrated O 0
up O 0
to O 0
0 O 0
. O 0
6 O 0
mg O 0
/ O 0
day O 0
for O 0
clonidine B-Chemical 1
and O 0
60 O 0
mg O 0
/ O 0
day O 0
for O 0
methylphenidate B-Chemical 1
( O 0
both O 0
with O 0
divided O 0
dosing O 0
) O 0
. O 0

Groups O 0
were O 0
compared O 0
regarding O 0
adverse O 0
events O 0
and O 0
changes O 0
from O 0
baseline O 0
to O 0
week O 0
16 O 0
in O 0
electrocardiograms O 0
and O 0
vital O 0
signs O 0
. O 0

RESULTS O 0
: O 0
There O 0
were O 0
more O 0
incidents O 0
of O 0
bradycardia B-Disease 1
in O 0
subjects O 0
treated O 0
with O 0
clonidine B-Chemical 1
compared O 0
with O 0
those O 0
not O 0
treated O 0
with O 0
clonidine B-Chemical 1
( O 0
17 O 0
. O 0
5 O 0
% O 0
versus O 0
3 O 0
. O 0
4 O 0
% O 0
; O 0
p O 0
= O 0
. O 0
02 O 0
) O 0
, O 0
but O 0
no O 0
other O 0
significant O 0
group O 0
differences O 0
regarding O 0
electrocardiogram O 0
and O 0
other O 0
cardiovascular O 0
outcomes O 0
. O 0

There O 0
were O 0
no O 0
suggestions O 0
of O 0
interactions O 0
between O 0
clonidine B-Chemical 1
and O 0
methylphenidate B-Chemical 1
regarding O 0
cardiovascular O 0
outcomes O 0
. O 0

Moderate O 0
or O 0
severe O 0
adverse O 0
events O 0
were O 0
more O 0
common O 0
in O 0
subjects O 0
on O 0
clonidine B-Chemical 1
( O 0
79 O 0
. O 0
4 O 0
% O 0
versus O 0
49 O 0
. O 0
2 O 0
% O 0
; O 0
p O 0
= O 0
. O 0
0006 O 0
) O 0
but O 0
not O 0
associated O 0
with O 0
higher O 0
rates O 0
of O 0
early O 0
study O 0
withdrawal O 0
. O 0

Drowsiness B-Disease 1
was O 0
common O 0
on O 0
clonidine B-Chemical 1
, O 0
but O 0
generally O 0
resolved O 0
by O 0
6 O 0
to O 0
8 O 0
weeks O 0
. O 0

CONCLUSIONS O 0
: O 0
Clonidine B-Chemical 1
, O 0
used O 0
alone O 0
or O 0
with O 0
methylphenidate B-Chemical 1
, O 0
appears O 0
safe O 0
and O 0
well O 0
tolerated O 0
in O 0
childhood O 0
ADHD B-Disease 1
. O 0

Physicians O 0
prescribing O 0
clonidine B-Chemical 1
should O 0
monitor O 0
for O 0
bradycardia B-Disease 1
and O 0
advise O 0
patients O 0
about O 0
the O 0
high O 0
likelihood O 0
of O 0
initial O 0
drowsiness B-Disease 1
. O 0

Renal B-Disease 1
Fanconi I-Disease 1
syndrome I-Disease 1
and O 0
myopathy B-Disease 1
after O 0
liver O 0
transplantation O 0
: O 0
drug O 0
- O 0
related O 0
mitochondrial B-Disease 1
cytopathy I-Disease 1
? O 0

Advances O 0
in O 0
the O 0
field O 0
of O 0
transplantation O 0
provide O 0
a O 0
better O 0
quality O 0
of O 0
life O 0
and O 0
allow O 0
more O 0
favorable O 0
conditions O 0
for O 0
growth O 0
and O 0
development O 0
in O 0
children O 0
. O 0

However O 0
, O 0
combinations O 0
of O 0
different O 0
therapeutic O 0
regimens O 0
require O 0
consideration O 0
of O 0
potential O 0
adverse O 0
reactions O 0
. O 0

We O 0
describe O 0
a O 0
15 O 0
- O 0
yr O 0
- O 0
old O 0
girl O 0
who O 0
had O 0
orthotopic O 0
liver O 0
transplantation O 0
because O 0
of O 0
Wilson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

Tacrolimus B-Chemical 1
, O 0
MMF B-Chemical 1
, O 0
and O 0
steroids B-Chemical 1
were O 0
given O 0
as O 0
immunosuppressant O 0
. O 0

Lamivudine B-Chemical 1
was O 0
added O 0
because O 0
of O 0
de O 0
nova O 0
hepatitis B-Disease 1
B I-Disease 1
infection I-Disease 1
during O 0
her O 0
follow O 0
- O 0
up O 0
. O 0

Three O 0
yr O 0
after O 0
transplantation O 0
she O 0
developed O 0
renal B-Disease 1
Fanconi I-Disease 1
syndrome I-Disease 1
with O 0
severe O 0
metabolic B-Disease 1
acidosis I-Disease 1
, O 0
hypophosphatemia B-Disease 1
, O 0
glycosuria B-Disease 1
, O 0
and O 0
aminoaciduria B-Disease 1
. O 0

Although O 0
tacrolimus B-Chemical 1
was O 0
suspected O 0
to O 0
be O 0
the O 0
cause O 0
of O 0
late O 0
post O 0
- O 0
transplant O 0
renal O 0
acidosis B-Disease 1
and O 0
was O 0
replaced O 0
by O 0
sirolimus B-Chemical 1
, O 0
acidosis B-Disease 1
, O 0
and O 0
electrolyte O 0
imbalance O 0
got O 0
worse O 0
. O 0

Proximal O 0
muscle B-Disease 1
weakness I-Disease 1
has O 0
developed O 0
during O 0
her O 0
follow O 0
- O 0
up O 0
. O 0

Fanconi B-Disease 1
syndrome I-Disease 1
, O 0
as O 0
well O 0
as O 0
myopathy B-Disease 1
, O 0
is O 0
well O 0
recognized O 0
in O 0
patients O 0
with O 0
mitochondrial B-Disease 1
disorders I-Disease 1
and O 0
caused O 0
by O 0
depletion O 0
of O 0
mtDNA O 0
. O 0

We O 0
suggest O 0
that O 0
our O 0
patient O 0
' O 0
s O 0
tubular B-Disease 1
dysfunction I-Disease 1
and O 0
myopathy B-Disease 1
may O 0
have O 0
resulted O 0
from O 0
mitochondrial B-Disease 1
dysfunction I-Disease 1
which O 0
is O 0
triggered O 0
by O 0
tacrolimus B-Chemical 1
and O 0
augmented O 0
by O 0
lamivudine B-Chemical 1
. O 0

Higher O 0
optical O 0
density O 0
of O 0
an O 0
antigen O 0
assay O 0
predicts O 0
thrombosis B-Disease 1
in O 0
patients O 0
with O 0
heparin B-Chemical 1
- O 0
induced O 0
thrombocytopenia B-Disease 1
. O 0

OBJECTIVES O 0
: O 0
To O 0
correlate O 0
optical O 0
density O 0
and O 0
percent O 0
inhibition O 0
of O 0
a O 0
two O 0
- O 0
step O 0
heparin B-Chemical 1
- O 0
induced O 0
thrombocytopenia B-Disease 1
( O 0
HIT B-Disease 1
) O 0
antigen O 0
assay O 0
with O 0
thrombosis B-Disease 1
; O 0
the O 0
assay O 0
utilizes O 0
reaction O 0
inhibition O 0
characteristics O 0
of O 0
a O 0
high O 0
heparin B-Chemical 1
concentration O 0
. O 0

PATIENTS O 0
AND O 0
METHODS O 0
: O 0
Patients O 0
with O 0
more O 0
than O 0
50 O 0
% O 0
decrease O 0
in O 0
platelet O 0
count O 0
or O 0
thrombocytopenia B-Disease 1
( O 0
< O 0
150 O 0
x O 0
10 O 0
( O 0
9 O 0
) O 0
/ O 0
L O 0
) O 0
after O 0
exposure O 0
to O 0
heparin B-Chemical 1
, O 0
who O 0
had O 0
a O 0
positive O 0
two O 0
- O 0
step O 0
antigen O 0
assay O 0
[ O 0
optical O 0
density O 0
( O 0
OD O 0
) O 0
> O 0
0 O 0
. O 0
4 O 0
and O 0
> O 0
50 O 0
inhibition O 0
with O 0
high O 0
concentration O 0
of O 0
heparin B-Chemical 1
] O 0
were O 0
included O 0
in O 0
the O 0
study O 0
. O 0

RESULTS O 0
: O 0
Forty O 0
of O 0
94 O 0
HIT B-Disease 1
patients O 0
had O 0
thrombosis B-Disease 1
at O 0
diagnosis O 0
; O 0
54 O 0
/ O 0
94 O 0
had O 0
isolated O 0
- O 0
HIT B-Disease 1
without O 0
thrombosis B-Disease 1
. O 0

Eight O 0
of O 0
the O 0
isolated O 0
- O 0
HIT B-Disease 1
patients O 0
developed O 0
thrombosis B-Disease 1
within O 0
the O 0
next O 0
30 O 0
d O 0
; O 0
thus O 0
, O 0
a O 0
total O 0
of O 0
48 O 0
patients O 0
had O 0
thrombosis B-Disease 1
at O 0
day O 0
30 O 0
. O 0

At O 0
diagnosis O 0
there O 0
was O 0
no O 0
significant O 0
difference O 0
in O 0
OD O 0
between O 0
HIT B-Disease 1
patients O 0
with O 0
thrombosis B-Disease 1
and O 0
those O 0
with O 0
isolated O 0
- O 0
HIT B-Disease 1
. O 0

However O 0
, O 0
OD O 0
was O 0
significantly O 0
higher O 0
in O 0
all O 0
patients O 0
with O 0
thrombosis B-Disease 1
( O 0
n O 0
= O 0
48 O 0
, O 0
1 O 0
. O 0
34 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
89 O 0
) O 0
, O 0
including O 0
isolated O 0
- O 0
HIT B-Disease 1
patients O 0
who O 0
later O 0
developed O 0
thrombosis B-Disease 1
within O 0
30 O 0
d O 0
( O 0
n O 0
= O 0
8 O 0
, O 0
1 O 0
. O 0
84 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
64 O 0
) O 0
as O 0
compared O 0
to O 0
isolated O 0
- O 0
HIT B-Disease 1
patients O 0
who O 0
did O 0
not O 0
develop O 0
thrombosis B-Disease 1
( O 0
0 O 0
. O 0
96 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
75 O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
011 O 0
and O 0
P O 0
= O 0
0 O 0
. O 0
008 O 0
) O 0
. O 0

The O 0
Receiver O 0
Operative O 0
Characteristic O 0
Curve O 0
showed O 0
that O 0
OD O 0
> O 0
1 O 0
. O 0
27 O 0
in O 0
the O 0
isolated O 0
- O 0
HIT B-Disease 1
group O 0
had O 0
a O 0
significantly O 0
higher O 0
chance O 0
of O 0
developing O 0
thrombosis B-Disease 1
by O 0
day O 0
30 O 0
. O 0

None O 0
of O 0
these O 0
groups O 0
showed O 0
significant O 0
difference O 0
in O 0
percent O 0
inhibition O 0
. O 0

Multivariate O 0
analysis O 0
showed O 0
a O 0
2 O 0
. O 0
8 O 0
- O 0
fold O 0
increased O 0
risk O 0
of O 0
thrombosis B-Disease 1
in O 0
females O 0
. O 0

Similarly O 0
, O 0
thrombotic B-Disease 1
risk O 0
increased O 0
with O 0
age O 0
and O 0
OD O 0
values O 0
. O 0

CONCLUSION O 0
: O 0
Higher O 0
OD O 0
is O 0
associated O 0
with O 0
significant O 0
risk O 0
of O 0
subsequent O 0
thrombosis B-Disease 1
in O 0
patients O 0
with O 0
isolated O 0
- O 0
HIT B-Disease 1
; O 0
percent O 0
inhibition O 0
, O 0
however O 0
, O 0
was O 0
not O 0
predictive O 0
. O 0

Thalidomide B-Chemical 1
has O 0
limited O 0
single O 0
- O 0
agent O 0
activity O 0
in O 0
relapsed O 0
or O 0
refractory O 0
indolent O 0
non B-Disease 1
- I-Disease 1
Hodgkin I-Disease 1
lymphomas I-Disease 1
: O 0
a O 0
phase O 0
II O 0
trial O 0
of O 0
the O 0
Cancer B-Disease 1
and O 0
Leukemia B-Disease 1
Group O 0
B O 0
. O 0

Thalidomide B-Chemical 1
is O 0
an O 0
immunomodulatory O 0
agent O 0
with O 0
demonstrated O 0
activity O 0
in O 0
multiple B-Disease 1
myeloma I-Disease 1
, O 0
mantle B-Disease 1
cell I-Disease 1
lymphoma I-Disease 1
and O 0
lymphoplasmacytic B-Disease 1
lymphoma I-Disease 1
. O 0

Its O 0
activity O 0
is O 0
believed O 0
to O 0
be O 0
due O 0
modulation O 0
of O 0
the O 0
tumour B-Disease 1
milieu O 0
, O 0
including O 0
downregulation O 0
of O 0
angiogenesis O 0
and O 0
inflammatory O 0
cytokines O 0
. O 0

Between O 0
July O 0
2001 O 0
and O 0
April O 0
2004 O 0
, O 0
24 O 0
patients O 0
with O 0
relapsed O 0
/ O 0
refractory O 0
indolent O 0
lymphomas B-Disease 1
received O 0
thalidomide B-Chemical 1
200 O 0
mg O 0
daily O 0
with O 0
escalation O 0
by O 0
100 O 0
mg O 0
daily O 0
every O 0
1 O 0
- O 0
2 O 0
weeks O 0
as O 0
tolerated O 0
, O 0
up O 0
to O 0
a O 0
maximum O 0
of O 0
800 O 0
mg O 0
daily O 0
. O 0

Patients O 0
had O 0
received O 0
a O 0
median O 0
of O 0
2 O 0
( O 0
range O 0
, O 0
1 O 0
- O 0
4 O 0
) O 0
prior O 0
regimens O 0
. O 0

Of O 0
24 O 0
evaluable O 0
patients O 0
, O 0
two O 0
achieved O 0
a O 0
complete O 0
remission O 0
and O 0
one O 0
achieved O 0
a O 0
partial O 0
remission O 0
for O 0
an O 0
overall O 0
response O 0
rate O 0
of O 0
12 O 0
. O 0
5 O 0
% O 0
( O 0
95 O 0
% O 0
confidence O 0
interval O 0
: O 0
2 O 0
. O 0
6 O 0
- O 0
32 O 0
. O 0
4 O 0
% O 0
) O 0
. O 0

Eleven O 0
patients O 0
progressed O 0
during O 0
therapy O 0
. O 0

Grade O 0
3 O 0
- O 0
4 O 0
adverse O 0
effects O 0
included O 0
myelosuppression B-Disease 1
, O 0
fatigue B-Disease 1
, O 0
somnolence B-Disease 1
/ O 0
depressed B-Disease 1
mood I-Disease 1
, O 0
neuropathy B-Disease 1
and O 0
dyspnea B-Disease 1
. O 0

Of O 0
concern O 0
was O 0
the O 0
occurrence O 0
of O 0
four O 0
thromboembolic B-Disease 1
events O 0
. O 0

Our O 0
results O 0
failed O 0
to O 0
demonstrate O 0
an O 0
important O 0
response O 0
rate O 0
to O 0
single O 0
agent O 0
thalidomide B-Chemical 1
in O 0
indolent O 0
lymphomas B-Disease 1
and O 0
contrast O 0
with O 0
the O 0
higher O 0
activity O 0
level O 0
reported O 0
with O 0
the O 0
second O 0
generation O 0
immunomodulatory O 0
agent O 0
, O 0
lenalidomide B-Chemical 1
. O 0

Sex O 0
differences O 0
in O 0
NMDA B-Chemical 1
antagonist O 0
enhancement O 0
of O 0
morphine B-Chemical 1
antihyperalgesia O 0
in O 0
a O 0
capsaicin B-Chemical 1
model O 0
of O 0
persistent O 0
pain B-Disease 1
: O 0
comparisons O 0
to O 0
two O 0
models O 0
of O 0
acute B-Disease 1
pain I-Disease 1
. O 0

In O 0
acute B-Disease 1
pain I-Disease 1
models O 0
, O 0
N B-Chemical 1
- I-Chemical 1
methyl I-Chemical 1
- I-Chemical 1
D I-Chemical 1
- I-Chemical 1
aspartate I-Chemical 1
( O 0
NMDA B-Chemical 1
) O 0
antagonists O 0
enhance O 0
the O 0
antinociceptive O 0
effects O 0
of O 0
morphine B-Chemical 1
to O 0
a O 0
greater O 0
extent O 0
in O 0
males O 0
than O 0
females O 0
. O 0

The O 0
purpose O 0
of O 0
this O 0
investigation O 0
was O 0
to O 0
extend O 0
these O 0
findings O 0
to O 0
a O 0
persistent O 0
pain B-Disease 1
model O 0
which O 0
could O 0
be O 0
distinguished O 0
from O 0
acute B-Disease 1
pain I-Disease 1
models O 0
on O 0
the O 0
basis O 0
of O 0
the O 0
nociceptive O 0
fibers O 0
activated O 0
, O 0
neurochemical O 0
substrates O 0
, O 0
and O 0
duration O 0
of O 0
the O 0
nociceptive O 0
stimulus O 0
. O 0

To O 0
this O 0
end O 0
, O 0
persistent O 0
hyperalgesia B-Disease 1
was O 0
induced O 0
by O 0
administration O 0
of O 0
capsaicin B-Chemical 1
in O 0
the O 0
tail O 0
of O 0
gonadally O 0
intact O 0
F344 O 0
rats O 0
, O 0
following O 0
which O 0
the O 0
tail O 0
was O 0
immersed O 0
in O 0
a O 0
mildly O 0
noxious O 0
thermal O 0
stimulus O 0
, O 0
and O 0
tail O 0
- O 0
withdrawal O 0
latencies O 0
measured O 0
. O 0

For O 0
comparison O 0
, O 0
tests O 0
were O 0
conducted O 0
in O 0
two O 0
acute B-Disease 1
pain I-Disease 1
models O 0
, O 0
the O 0
hotplate O 0
and O 0
warm O 0
water O 0
tail O 0
- O 0
withdrawal O 0
procedures O 0
. O 0

In O 0
males O 0
, O 0
the O 0
non O 0
- O 0
competitive O 0
NMDA B-Chemical 1
antagonist O 0
dextromethorphan B-Chemical 1
enhanced O 0
the O 0
antihyperalgesic O 0
effect O 0
of O 0
low O 0
to O 0
moderate O 0
doses O 0
of O 0
morphine B-Chemical 1
in O 0
a O 0
dose O 0
- O 0
and O 0
time O 0
- O 0
dependent O 0
manner O 0
. O 0

Across O 0
the O 0
doses O 0
and O 0
pretreatment O 0
times O 0
examined O 0
, O 0
enhancement O 0
was O 0
not O 0
observed O 0
in O 0
females O 0
. O 0

Enhancement O 0
of O 0
morphine B-Chemical 1
antinociception O 0
by O 0
dextromethorphan B-Chemical 1
was O 0
seen O 0
in O 0
both O 0
males O 0
and O 0
females O 0
in O 0
the O 0
acute B-Disease 1
pain I-Disease 1
models O 0
, O 0
with O 0
the O 0
magnitude O 0
of O 0
this O 0
effect O 0
being O 0
greater O 0
in O 0
males O 0
. O 0

These O 0
findings O 0
demonstrate O 0
a O 0
sexually O 0
- O 0
dimorphic O 0
interaction O 0
between O 0
NMDA B-Chemical 1
antagonists O 0
and O 0
morphine B-Chemical 1
in O 0
a O 0
persistent O 0
pain B-Disease 1
model O 0
that O 0
can O 0
be O 0
distinguished O 0
from O 0
those O 0
observed O 0
in O 0
acute B-Disease 1
pain I-Disease 1
models O 0
. O 0

Development O 0
of O 0
proteinuria B-Disease 1
after O 0
switch O 0
to O 0
sirolimus B-Chemical 1
- O 0
based O 0
immunosuppression O 0
in O 0
long O 0
- O 0
term O 0
cardiac O 0
transplant O 0
patients O 0
. O 0

Calcineurin O 0
- O 0
inhibitor O 0
therapy O 0
can O 0
lead O 0
to O 0
renal B-Disease 1
dysfunction I-Disease 1
in O 0
heart O 0
transplantation O 0
patients O 0
. O 0

The O 0
novel O 0
immunosuppressive O 0
( O 0
IS O 0
) O 0
drug O 0
sirolmus B-Chemical 1
( O 0
Srl B-Chemical 1
) O 0
lacks O 0
nephrotoxic B-Disease 1
effects O 0
; O 0
however O 0
, O 0
proteinuria B-Disease 1
associated O 0
with O 0
Srl B-Chemical 1
has O 0
been O 0
reported O 0
following O 0
renal O 0
transplantation O 0
. O 0

In O 0
cardiac O 0
transplantation O 0
, O 0
the O 0
incidence O 0
of O 0
proteinuria B-Disease 1
associated O 0
with O 0
Srl B-Chemical 1
is O 0
unknown O 0
. O 0

In O 0
this O 0
study O 0
, O 0
long O 0
- O 0
term O 0
cardiac O 0
transplant O 0
patients O 0
were O 0
switched O 0
from O 0
cyclosporine B-Chemical 1
to O 0
Srl B-Chemical 1
- O 0
based O 0
IS O 0
. O 0

Concomitant O 0
IS O 0
consisted O 0
of O 0
mycophenolate B-Chemical 1
mofetil I-Chemical 1
+ O 0
/ O 0
- O 0
steroids B-Chemical 1
. O 0

Proteinuria O 0
increased O 0
significantly O 0
from O 0
a O 0
median O 0
of O 0
0 O 0
. O 0
13 O 0
g O 0
/ O 0
day O 0
( O 0
range O 0
0 O 0
- O 0
5 O 0
. O 0
7 O 0
) O 0
preswitch O 0
to O 0
0 O 0
. O 0
23 O 0
g O 0
/ O 0
day O 0
( O 0
0 O 0
- O 0
9 O 0
. O 0
88 O 0
) O 0
at O 0
24 O 0
months O 0
postswitch O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
0024 O 0
) O 0
. O 0

Before O 0
the O 0
switch O 0
, O 0
11 O 0
. O 0
5 O 0
% O 0
of O 0
patients O 0
had O 0
high O 0
- O 0
grade O 0
proteinuria B-Disease 1
( O 0
> O 0
1 O 0
. O 0
0 O 0
g O 0
/ O 0
day O 0
) O 0
; O 0
this O 0
increased O 0
to O 0
22 O 0
. O 0
9 O 0
% O 0
postswitch O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
006 O 0
) O 0
. O 0

ACE B-Chemical 1
inhibitor I-Chemical 1
and O 0
angiotensin B-Chemical 1
- I-Chemical 1
releasing I-Chemical 1
blocker I-Chemical 1
( O 0
ARB B-Chemical 1
) O 0
therapy O 0
reduced O 0
proteinuria B-Disease 1
development O 0
. O 0

Patients O 0
without O 0
proteinuria B-Disease 1
had O 0
increased O 0
renal O 0
function O 0
( O 0
median O 0
42 O 0
. O 0
5 O 0
vs O 0
. O 0
64 O 0
. O 0
1 O 0
, O 0
p O 0
= O 0
0 O 0
. O 0
25 O 0
) O 0
, O 0
whereas O 0
patients O 0
who O 0
developed O 0
high O 0
- O 0
grade O 0
proteinuria B-Disease 1
showed O 0
decreased O 0
renal O 0
function O 0
at O 0
the O 0
end O 0
of O 0
follow O 0
- O 0
up O 0
( O 0
median O 0
39 O 0
. O 0
6 O 0
vs O 0
. O 0
29 O 0
. O 0
2 O 0
, O 0
p O 0
= O 0
0 O 0
. O 0
125 O 0
) O 0
. O 0

Thus O 0
, O 0
proteinuria B-Disease 1
may O 0
develop O 0
in O 0
cardiac O 0
transplant O 0
patients O 0
after O 0
switch O 0
to O 0
Srl B-Chemical 1
, O 0
which O 0
may O 0
have O 0
an O 0
adverse O 0
effect O 0
on O 0
renal O 0
function O 0
in O 0
these O 0
patients O 0
. O 0

Srl B-Chemical 1
should O 0
be O 0
used O 0
with O 0
ACEi B-Chemical 1
/ O 0
ARB B-Chemical 1
therapy O 0
and O 0
patients O 0
monitored O 0
for O 0
proteinuria B-Disease 1
and O 0
increased O 0
renal B-Disease 1
dysfunction I-Disease 1
. O 0

Ginsenoside B-Chemical 1
Rg1 I-Chemical 1
restores O 0
the O 0
impairment B-Disease 1
of I-Disease 1
learning I-Disease 1
induced O 0
by O 0
chronic O 0
morphine B-Chemical 1
administration O 0
in O 0
rats O 0
. O 0

Rg1 B-Chemical 1
, O 0
as O 0
a O 0
ginsenoside B-Chemical 1
extracted O 0
from O 0
Panax O 0
ginseng O 0
, O 0
could O 0
ameliorate O 0
spatial O 0
learning B-Disease 1
impairment I-Disease 1
. O 0

Previous O 0
studies O 0
have O 0
demonstrated O 0
that O 0
Rg1 B-Chemical 1
might O 0
be O 0
a O 0
useful O 0
agent O 0
for O 0
the O 0
prevention O 0
and O 0
treatment O 0
of O 0
the O 0
adverse O 0
effects O 0
of O 0
morphine B-Chemical 1
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
investigate O 0
the O 0
effect O 0
of O 0
Rg1 B-Chemical 1
on O 0
learning B-Disease 1
impairment I-Disease 1
by O 0
chronic O 0
morphine B-Chemical 1
administration O 0
and O 0
the O 0
mechanism O 0
responsible O 0
for O 0
this O 0
effect O 0
. O 0

Male O 0
rats O 0
were O 0
subcutaneously O 0
injected O 0
with O 0
morphine B-Chemical 1
( O 0
10 O 0
mg O 0
/ O 0
kg O 0
) O 0
twice O 0
a O 0
day O 0
at O 0
12 O 0
hour O 0
intervals O 0
for O 0
10 O 0
days O 0
, O 0
and O 0
Rg1 B-Chemical 1
( O 0
30 O 0
mg O 0
/ O 0
kg O 0
) O 0
was O 0
intraperitoneally O 0
injected O 0
2 O 0
hours O 0
after O 0
the O 0
second O 0
injection O 0
of O 0
morphine B-Chemical 1
once O 0
a O 0
day O 0
for O 0
10 O 0
days O 0
. O 0

Spatial O 0
learning O 0
capacity O 0
was O 0
assessed O 0
in O 0
the O 0
Morris O 0
water O 0
maze O 0
. O 0

The O 0
results O 0
showed O 0
that O 0
rats O 0
treated O 0
with O 0
Morphine B-Chemical 1
/ O 0
Rg1 B-Chemical 1
decreased O 0
escape O 0
latency O 0
and O 0
increased O 0
the O 0
time O 0
spent O 0
in O 0
platform O 0
quadrant O 0
and O 0
entering O 0
frequency O 0
. O 0

By O 0
implantation O 0
of O 0
electrodes O 0
and O 0
electrophysiological O 0
recording O 0
in O 0
vivo O 0
, O 0
the O 0
results O 0
showed O 0
that O 0
Rg1 B-Chemical 1
restored O 0
the O 0
long O 0
- O 0
term O 0
potentiation O 0
( O 0
LTP O 0
) O 0
impaired O 0
by O 0
morphine B-Chemical 1
in O 0
both O 0
freely O 0
moving O 0
and O 0
anaesthetised O 0
rats O 0
. O 0

The O 0
electrophysiological O 0
recording O 0
in O 0
vitro O 0
showed O 0
that O 0
Rg1 B-Chemical 1
restored O 0
the O 0
LTP O 0
in O 0
slices O 0
from O 0
the O 0
rats O 0
treated O 0
with O 0
morphine B-Chemical 1
, O 0
but O 0
not O 0
changed O 0
LTP O 0
in O 0
the O 0
slices O 0
from O 0
normal O 0
saline O 0
- O 0
or O 0
morphine B-Chemical 1
/ O 0
Rg1 B-Chemical 1
- O 0
treated O 0
rats O 0
; O 0
this O 0
restoration O 0
could O 0
be O 0
inhibited O 0
by O 0
N B-Chemical 1
- I-Chemical 1
methyl I-Chemical 1
- I-Chemical 1
D I-Chemical 1
- I-Chemical 1
aspartate I-Chemical 1
( O 0
NMDA B-Chemical 1
) O 0
receptor O 0
antagonist O 0
MK801 B-Chemical 1
. O 0

We O 0
conclude O 0
that O 0
Rg1 B-Chemical 1
may O 0
significantly O 0
improve O 0
the O 0
spatial O 0
learning O 0
capacity O 0
impaired O 0
by O 0
chonic O 0
morphine B-Chemical 1
administration O 0
and O 0
restore O 0
the O 0
morphine B-Chemical 1
- O 0
inhibited O 0
LTP O 0
. O 0

This O 0
effect O 0
is O 0
NMDA B-Chemical 1
receptor O 0
dependent O 0
. O 0

Synthesis O 0
of O 0
N B-Chemical 1
- I-Chemical 1
pyrimidinyl I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
phenoxyacetamides I-Chemical 1
as O 0
adenosine B-Chemical 1
A2A O 0
receptor O 0
antagonists O 0
. O 0

A O 0
series O 0
of O 0
N B-Chemical 1
- I-Chemical 1
pyrimidinyl I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
phenoxyacetamide I-Chemical 1
adenosine B-Chemical 1
A O 0
( O 0
2A O 0
) O 0
antagonists O 0
is O 0
described O 0
. O 0

SAR O 0
studies O 0
led O 0
to O 0
compound O 0
14 O 0
with O 0
excellent O 0
potency O 0
( O 0
K O 0
( O 0
i O 0
) O 0
= O 0
0 O 0
. O 0
4 O 0
nM O 0
) O 0
, O 0
selectivity O 0
( O 0
A O 0
( O 0
1 O 0
) O 0
/ O 0
A O 0
( O 0
2A O 0
) O 0
> O 0
100 O 0
) O 0
, O 0
and O 0
efficacy O 0
( O 0
MED O 0
10 O 0
mg O 0
/ O 0
kg O 0
p O 0
. O 0
o O 0
. O 0
) O 0
in O 0
the O 0
rat O 0
haloperidol B-Chemical 1
- O 0
induced O 0
catalepsy B-Disease 1
model O 0
for O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

Evidence O 0
for O 0
an O 0
involvement O 0
of O 0
D1 O 0
and O 0
D2 O 0
dopamine B-Chemical 1
receptors O 0
in O 0
mediating O 0
nicotine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
in O 0
rats O 0
. O 0

Previous O 0
studies O 0
have O 0
suggested O 0
that O 0
repeated O 0
exposure O 0
of O 0
rats O 0
to O 0
the O 0
drug O 0
or O 0
to O 0
the O 0
experimental O 0
environment O 0
is O 0
necessary O 0
to O 0
observe O 0
nicotine B-Chemical 1
- O 0
induced O 0
locomotor O 0
stimulation O 0
. O 0

In O 0
the O 0
present O 0
study O 0
the O 0
role O 0
of O 0
habituation O 0
to O 0
the O 0
experimental O 0
environment O 0
on O 0
the O 0
stimulant O 0
effect O 0
of O 0
nicotine B-Chemical 1
in O 0
rats O 0
was O 0
examined O 0
. O 0

In O 0
addition O 0
, O 0
the O 0
role O 0
of O 0
dopamine B-Chemical 1
receptors O 0
in O 0
mediating O 0
nicotine B-Chemical 1
- O 0
induced O 0
locomotor O 0
stimulation O 0
was O 0
investigated O 0
by O 0
examining O 0
the O 0
effects O 0
of O 0
selective O 0
D1 O 0
and O 0
D2 O 0
dopamine B-Chemical 1
receptor O 0
antagonists O 0
on O 0
activity O 0
induced O 0
by O 0
nicotine B-Chemical 1
. O 0

Locomotor O 0
activity O 0
was O 0
assessed O 0
in O 0
male O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
tested O 0
in O 0
photocell O 0
cages O 0
. O 0

Nicotine B-Chemical 1
( O 0
1 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
) O 0
caused O 0
a O 0
significant O 0
increase B-Disease 1
in I-Disease 1
locomotor I-Disease 1
activity I-Disease 1
in O 0
rats O 0
that O 0
were O 0
habituated O 0
to O 0
the O 0
test O 0
environment O 0
, O 0
but O 0
had O 0
only O 0
a O 0
weak O 0
and O 0
delayed O 0
stimulant O 0
action O 0
in O 0
rats O 0
that O 0
were O 0
unfamiliar O 0
with O 0
the O 0
test O 0
environment O 0
. O 0

The O 0
stimulant O 0
action O 0
of O 0
nicotine B-Chemical 1
was O 0
blocked O 0
by O 0
the O 0
central O 0
nicotinic O 0
antagonist O 0
mecamylamine B-Chemical 1
but O 0
not O 0
by O 0
the O 0
peripheral O 0
nicotinic O 0
blocker O 0
hexamethonium B-Chemical 1
, O 0
indicating O 0
that O 0
the O 0
response O 0
is O 0
probably O 0
mediated O 0
by O 0
central O 0
nicotinic O 0
receptors O 0
. O 0

Nicotine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
was O 0
blocked O 0
by O 0
the O 0
selective O 0
D1 O 0
antagonist O 0
SCH B-Chemical 1
23390 I-Chemical 1
, O 0
the O 0
selective O 0
D2 O 0
antagonist O 0
raclopride B-Chemical 1
and O 0
the O 0
D1 O 0
/ O 0
D2 O 0
antagonist O 0
fluphenazine B-Chemical 1
. O 0

Pretreatment O 0
with O 0
the O 0
D2 O 0
agonist O 0
PHNO B-Chemical 1
enhanced O 0
nicotine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
, O 0
whereas O 0
the O 0
D1 O 0
agonist O 0
SKF B-Chemical 1
38393 I-Chemical 1
had O 0
no O 0
effect O 0
. O 0

The O 0
results O 0
indicate O 0
that O 0
acute O 0
nicotine B-Chemical 1
injection O 0
induces O 0
a O 0
pronounced O 0
hyperactivity B-Disease 1
in O 0
rats O 0
habituated O 0
to O 0
the O 0
test O 0
environment O 0
. O 0

The O 0
effect O 0
appears O 0
to O 0
be O 0
mediated O 0
by O 0
central O 0
nicotine B-Chemical 1
receptors O 0
, O 0
possibly O 0
located O 0
on O 0
dopaminergic O 0
neurons O 0
, O 0
and O 0
also O 0
requires O 0
the O 0
activation O 0
of O 0
both O 0
D1 O 0
and O 0
D2 O 0
dopamine B-Chemical 1
receptors O 0
. O 0

Central O 0
retinal B-Disease 1
vein I-Disease 1
occlusion I-Disease 1
associated O 0
with O 0
clomiphene B-Chemical 1
- O 0
induced O 0
ovulation O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
report O 0
a O 0
case O 0
of O 0
central O 0
retinal B-Disease 1
vein I-Disease 1
occlusion I-Disease 1
associated O 0
with O 0
clomiphene B-Chemical 1
citrate I-Chemical 1
( O 0
CC B-Chemical 1
) O 0
. O 0

DESIGN O 0
: O 0
Case O 0
study O 0
. O 0

SETTING O 0
: O 0
Ophthalmology O 0
clinic O 0
of O 0
an O 0
academic O 0
hospital O 0
. O 0

PATIENT O 0
( O 0
S O 0
) O 0
: O 0
A O 0
36 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
referred O 0
from O 0
the O 0
infertility B-Disease 1
clinic O 0
for O 0
blurred B-Disease 1
vision I-Disease 1
. O 0

INTERVENTION O 0
( O 0
S O 0
) O 0
: O 0
Ophthalmic O 0
examination O 0
after O 0
CC B-Chemical 1
therapy O 0
. O 0

MAIN O 0
OUTCOME O 0
MEASURE O 0
( O 0
S O 0
) O 0
: O 0
Central O 0
retinal B-Disease 1
vein I-Disease 1
occlusion I-Disease 1
after O 0
ovulation O 0
induction O 0
with O 0
CC B-Chemical 1
. O 0

RESULT O 0
( O 0
S O 0
) O 0
: O 0
A O 0
36 O 0
- O 0
year O 0
- O 0
old O 0
Chinese O 0
woman O 0
developed O 0
central O 0
retinal B-Disease 1
vein I-Disease 1
occlusion I-Disease 1
after O 0
eight O 0
courses O 0
of O 0
CC B-Chemical 1
. O 0

A O 0
search O 0
of O 0
the O 0
literature O 0
on O 0
the O 0
thromboembolic B-Disease 1
complications O 0
of O 0
CC B-Chemical 1
does O 0
not O 0
include O 0
this O 0
severe O 0
ophthalmic O 0
complication O 0
, O 0
although O 0
mild O 0
visual B-Disease 1
disturbance I-Disease 1
after O 0
CC B-Chemical 1
intake O 0
is O 0
not O 0
uncommon O 0
. O 0

CONCLUSION O 0
( O 0
S O 0
) O 0
: O 0
This O 0
is O 0
the O 0
first O 0
reported O 0
case O 0
of O 0
central O 0
retinal B-Disease 1
vein I-Disease 1
occlusion I-Disease 1
after O 0
treatment O 0
with O 0
CC B-Chemical 1
. O 0

Extra O 0
caution O 0
is O 0
warranted O 0
in O 0
treating O 0
infertility B-Disease 1
patients O 0
with O 0
CC B-Chemical 1
, O 0
and O 0
patients O 0
should O 0
be O 0
well O 0
informed O 0
of O 0
this O 0
side O 0
effect O 0
before O 0
commencement O 0
of O 0
therapy O 0
. O 0

Acute O 0
bronchodilating O 0
effects O 0
of O 0
ipratropium B-Chemical 1
bromide I-Chemical 1
and O 0
theophylline B-Chemical 1
in O 0
chronic B-Disease 1
obstructive I-Disease 1
pulmonary I-Disease 1
disease I-Disease 1
. O 0

The O 0
bronchodilator O 0
effects O 0
of O 0
a O 0
single O 0
dose O 0
of O 0
ipratropium B-Chemical 1
bromide I-Chemical 1
aerosol O 0
( O 0
36 O 0
micrograms O 0
) O 0
and O 0
short O 0
- O 0
acting O 0
theophylline B-Chemical 1
tablets O 0
( O 0
dose O 0
titrated O 0
to O 0
produce O 0
serum O 0
levels O 0
of O 0
10 O 0
- O 0
20 O 0
micrograms O 0
/ O 0
mL O 0
) O 0
were O 0
compared O 0
in O 0
a O 0
double O 0
- O 0
blind O 0
, O 0
placebo O 0
- O 0
controlled O 0
crossover O 0
study O 0
in O 0
21 O 0
patients O 0
with O 0
stable O 0
, O 0
chronic B-Disease 1
obstructive I-Disease 1
pulmonary I-Disease 1
disease I-Disease 1
. O 0

Mean O 0
peak O 0
forced O 0
expiratory O 0
volume O 0
in O 0
1 O 0
second O 0
( O 0
FEV1 O 0
) O 0
increases O 0
over O 0
baseline O 0
and O 0
the O 0
proportion O 0
of O 0
patients O 0
attaining O 0
at O 0
least O 0
a O 0
15 O 0
% O 0
increase O 0
in O 0
the O 0
FEV1 O 0
( O 0
responders O 0
) O 0
were O 0
31 O 0
% O 0
and O 0
90 O 0
% O 0
, O 0
respectively O 0
, O 0
for O 0
ipratropium B-Chemical 1
and O 0
17 O 0
% O 0
and O 0
50 O 0
% O 0
, O 0
respectively O 0
, O 0
for O 0
theophylline B-Chemical 1
. O 0

The O 0
average O 0
FEV1 O 0
increases O 0
during O 0
the O 0
6 O 0
- O 0
hour O 0
observation O 0
period O 0
were O 0
18 O 0
% O 0
for O 0
ipratropium B-Chemical 1
and O 0
8 O 0
% O 0
for O 0
theophylline B-Chemical 1
. O 0

The O 0
mean O 0
duration O 0
of O 0
action O 0
was O 0
3 O 0
. O 0
8 O 0
hours O 0
with O 0
ipratropium B-Chemical 1
and O 0
2 O 0
. O 0
4 O 0
hours O 0
with O 0
theophylline B-Chemical 1
. O 0

While O 0
side O 0
effects O 0
were O 0
rare O 0
, O 0
those O 0
experienced O 0
after O 0
theophylline B-Chemical 1
use O 0
did O 0
involve O 0
the O 0
cardiovascular B-Disease 1
and I-Disease 1
gastrointestinal I-Disease 1
systems I-Disease 1
. O 0

These O 0
results O 0
show O 0
that O 0
ipratropium B-Chemical 1
is O 0
a O 0
more O 0
potent O 0
bronchodilator O 0
than O 0
oral O 0
theophylline B-Chemical 1
in O 0
patients O 0
with O 0
chronic B-Disease 1
airflow I-Disease 1
obstruction I-Disease 1
. O 0

Methamphetamine B-Chemical 1
- O 0
induced O 0
neurotoxicity B-Disease 1
and O 0
microglial O 0
activation O 0
are O 0
not O 0
mediated O 0
by O 0
fractalkine O 0
receptor O 0
signaling O 0
. O 0

Methamphetamine B-Chemical 1
( O 0
METH B-Chemical 1
) O 0
damages O 0
dopamine B-Chemical 1
( O 0
DA B-Chemical 1
) O 0
nerve O 0
endings O 0
by O 0
a O 0
process O 0
that O 0
has O 0
been O 0
linked O 0
to O 0
microglial O 0
activation O 0
but O 0
the O 0
signaling O 0
pathways O 0
that O 0
mediate O 0
this O 0
response O 0
have O 0
not O 0
yet O 0
been O 0
delineated O 0
. O 0

Cardona O 0
et O 0
al O 0
. O 0

[ O 0
Nat O 0
. O 0
Neurosci O 0
. O 0
9 O 0
( O 0
2006 O 0
) O 0
, O 0
917 O 0
] O 0
recently O 0
identified O 0
the O 0
microglial O 0
- O 0
specific O 0
fractalkine O 0
receptor O 0
( O 0
CX3CR1 O 0
) O 0
as O 0
an O 0
important O 0
mediator O 0
of O 0
MPTP B-Chemical 1
- O 0
induced O 0
neurodegeneration B-Disease 1
of O 0
DA B-Chemical 1
neurons O 0
. O 0

Because O 0
the O 0
CNS B-Disease 1
damage I-Disease 1
caused O 0
by O 0
METH B-Chemical 1
and O 0
MPTP B-Chemical 1
is O 0
highly O 0
selective O 0
for O 0
the O 0
DA B-Chemical 1
neuronal O 0
system O 0
in O 0
mouse O 0
models O 0
of O 0
neurotoxicity B-Disease 1
, O 0
we O 0
hypothesized O 0
that O 0
the O 0
CX3CR1 O 0
plays O 0
a O 0
role O 0
in O 0
METH B-Chemical 1
- O 0
induced O 0
neurotoxicity B-Disease 1
and O 0
microglial O 0
activation O 0
. O 0

Mice O 0
in O 0
which O 0
the O 0
CX3CR1 O 0
gene O 0
has O 0
been O 0
deleted O 0
and O 0
replaced O 0
with O 0
a O 0
cDNA O 0
encoding O 0
enhanced O 0
green O 0
fluorescent O 0
protein O 0
( O 0
eGFP O 0
) O 0
were O 0
treated O 0
with O 0
METH B-Chemical 1
and O 0
examined O 0
for O 0
striatal O 0
neurotoxicity B-Disease 1
. O 0

METH B-Chemical 1
depleted O 0
DA B-Chemical 1
, O 0
caused O 0
microglial O 0
activation O 0
, O 0
and O 0
increased O 0
body O 0
temperature O 0
in O 0
CX3CR1 O 0
knockout O 0
mice O 0
to O 0
the O 0
same O 0
extent O 0
and O 0
over O 0
the O 0
same O 0
time O 0
course O 0
seen O 0
in O 0
wild O 0
- O 0
type O 0
controls O 0
. O 0

The O 0
effects O 0
of O 0
METH B-Chemical 1
in O 0
CX3CR1 O 0
knockout O 0
mice O 0
were O 0
not O 0
gender O 0
- O 0
dependent O 0
and O 0
did O 0
not O 0
extend O 0
beyond O 0
the O 0
striatum O 0
. O 0

Striatal O 0
microglia O 0
expressing O 0
eGFP O 0
constitutively O 0
show O 0
morphological O 0
changes O 0
after O 0
METH B-Chemical 1
that O 0
are O 0
characteristic O 0
of O 0
activation O 0
. O 0

This O 0
response O 0
was O 0
restricted O 0
to O 0
the O 0
striatum O 0
and O 0
contrasted O 0
sharply O 0
with O 0
unresponsive O 0
eGFP O 0
- O 0
microglia O 0
in O 0
surrounding O 0
brain O 0
areas O 0
that O 0
are O 0
not O 0
damaged O 0
by O 0
METH B-Chemical 1
. O 0

We O 0
conclude O 0
from O 0
these O 0
studies O 0
that O 0
CX3CR1 O 0
signaling O 0
does O 0
not O 0
modulate O 0
METH B-Chemical 1
neurotoxicity B-Disease 1
or O 0
microglial O 0
activation O 0
. O 0

Furthermore O 0
, O 0
it O 0
appears O 0
that O 0
striatal O 0
- O 0
resident O 0
microglia O 0
respond O 0
to O 0
METH B-Chemical 1
with O 0
an O 0
activation O 0
cascade O 0
and O 0
then O 0
return O 0
to O 0
a O 0
surveying O 0
state O 0
without O 0
undergoing O 0
apoptosis O 0
or O 0
migration O 0
. O 0

Nicotine B-Chemical 1
- O 0
induced O 0
nystagmus B-Disease 1
correlates O 0
with O 0
midpontine O 0
activation O 0
. O 0

The O 0
pathomechanism O 0
of O 0
nicotine B-Chemical 1
- O 0
induced O 0
nystagmus B-Disease 1
( O 0
NIN B-Disease 1
) O 0
is O 0
unknown O 0
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
delineate O 0
brain O 0
structures O 0
that O 0
are O 0
involved O 0
in O 0
NIN B-Disease 1
generation O 0
. O 0

Eight O 0
healthy O 0
volunteers O 0
inhaled O 0
nicotine B-Chemical 1
in O 0
darkness O 0
during O 0
a O 0
functional O 0
magnetic O 0
resonance O 0
imaging O 0
( O 0
fMRI O 0
) O 0
experiment O 0
; O 0
eye O 0
movements O 0
were O 0
registered O 0
using O 0
video O 0
- O 0
oculography O 0
. O 0

NIN B-Disease 1
correlated O 0
with O 0
blood O 0
oxygen B-Chemical 1
level O 0
- O 0
dependent O 0
( O 0
BOLD O 0
) O 0
activity O 0
levels O 0
in O 0
a O 0
midpontine O 0
site O 0
in O 0
the O 0
posterior O 0
basis O 0
pontis O 0
. O 0

NIN B-Disease 1
- O 0
induced O 0
midpontine O 0
activation O 0
may O 0
correspond O 0
to O 0
activation O 0
of O 0
the O 0
dorsomedial O 0
pontine O 0
nuclei O 0
and O 0
the O 0
nucleus O 0
reticularis O 0
tegmenti O 0
pontis O 0
, O 0
structures O 0
known O 0
to O 0
participate O 0
in O 0
the O 0
generation O 0
of O 0
multidirectional O 0
saccades O 0
and O 0
smooth O 0
pursuit O 0
eye O 0
movements O 0
. O 0

Acute O 0
effects O 0
of O 0
N B-Chemical 1
- I-Chemical 1
( I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
propylpentanoyl I-Chemical 1
) I-Chemical 1
urea I-Chemical 1
on O 0
hippocampal O 0
amino B-Chemical 1
acid I-Chemical 1
neurotransmitters O 0
in O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizure B-Disease 1
in O 0
rats O 0
. O 0

The O 0
present O 0
study O 0
aimed O 0
to O 0
investigate O 0
the O 0
anticonvulsant O 0
activity O 0
as O 0
well O 0
as O 0
the O 0
effects O 0
on O 0
the O 0
level O 0
of O 0
hippocampal O 0
amino B-Chemical 1
acid I-Chemical 1
neurotransmitters O 0
( O 0
glutamate B-Chemical 1
, O 0
aspartate B-Chemical 1
, O 0
glycine B-Chemical 1
and O 0
GABA B-Chemical 1
) O 0
of O 0
N B-Chemical 1
- I-Chemical 1
( I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
propylpentanoyl I-Chemical 1
) I-Chemical 1
urea I-Chemical 1
( O 0
VPU B-Chemical 1
) O 0
in O 0
comparison O 0
to O 0
its O 0
parent O 0
compound O 0
, O 0
valproic B-Chemical 1
acid I-Chemical 1
( O 0
VPA B-Chemical 1
) O 0
. O 0

VPU B-Chemical 1
was O 0
more O 0
potent O 0
than O 0
VPA B-Chemical 1
, O 0
exhibiting O 0
the O 0
median O 0
effective O 0
dose O 0
( O 0
ED O 0
( O 0
50 O 0
) O 0
) O 0
of O 0
49 O 0
mg O 0
/ O 0
kg O 0
in O 0
protecting O 0
rats O 0
against O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizure B-Disease 1
whereas O 0
the O 0
corresponding O 0
value O 0
for O 0
VPA B-Chemical 1
was O 0
322 O 0
mg O 0
/ O 0
kg O 0
. O 0

In O 0
vivo O 0
microdialysis O 0
demonstrated O 0
that O 0
an O 0
intraperitoneal O 0
administration O 0
of O 0
pilocarpine B-Chemical 1
induced O 0
a O 0
pronounced O 0
increment O 0
of O 0
hippocampal O 0
glutamate B-Chemical 1
and O 0
aspartate B-Chemical 1
whereas O 0
no O 0
significant O 0
change O 0
was O 0
observed O 0
on O 0
the O 0
level O 0
of O 0
glycine B-Chemical 1
and O 0
GABA B-Chemical 1
. O 0

Pretreatment O 0
with O 0
either O 0
VPU B-Chemical 1
( O 0
50 O 0
and O 0
100 O 0
mg O 0
/ O 0
kg O 0
) O 0
or O 0
VPA B-Chemical 1
( O 0
300 O 0
and O 0
600 O 0
mg O 0
/ O 0
kg O 0
) O 0
completely O 0
abolished O 0
pilocarpine B-Chemical 1
- O 0
evoked O 0
increases O 0
in O 0
extracellular O 0
glutamate B-Chemical 1
and O 0
aspartate B-Chemical 1
. O 0

In O 0
addition O 0
, O 0
a O 0
statistically O 0
significant O 0
reduction O 0
was O 0
also O 0
observed O 0
on O 0
the O 0
level O 0
of O 0
GABA B-Chemical 1
and O 0
glycine B-Chemical 1
but O 0
less O 0
than O 0
a O 0
drastic O 0
reduction O 0
of O 0
glutamate B-Chemical 1
and O 0
aspartate B-Chemical 1
level O 0
. O 0

Based O 0
on O 0
the O 0
finding O 0
that O 0
VPU B-Chemical 1
and O 0
VPA B-Chemical 1
could O 0
protect O 0
the O 0
animals O 0
against O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizure B-Disease 1
it O 0
is O 0
suggested O 0
that O 0
the O 0
reduction O 0
of O 0
inhibitory O 0
amino B-Chemical 1
acid I-Chemical 1
neurotransmitters O 0
was O 0
comparatively O 0
minor O 0
and O 0
offset O 0
by O 0
a O 0
pronounced O 0
reduction O 0
of O 0
glutamate B-Chemical 1
and O 0
aspartate B-Chemical 1
. O 0

Therefore O 0
, O 0
like O 0
VPA B-Chemical 1
, O 0
the O 0
finding O 0
that O 0
VPU B-Chemical 1
could O 0
drastically O 0
reduce O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
increases O 0
in O 0
glutamate B-Chemical 1
and O 0
aspartate B-Chemical 1
should O 0
account O 0
, O 0
at O 0
least O 0
partly O 0
, O 0
for O 0
its O 0
anticonvulsant O 0
activity O 0
observed O 0
in O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
seizure B-Disease 1
in O 0
experimental O 0
animals O 0
. O 0

Some O 0
other O 0
mechanism O 0
than O 0
those O 0
being O 0
reported O 0
herein O 0
should O 0
be O 0
further O 0
investigated O 0
. O 0

Protective O 0
effect O 0
of O 0
verapamil B-Chemical 1
on O 0
gastric B-Disease 1
hemorrhagic I-Disease 1
ulcers B-Disease 1
in O 0
severe O 0
atherosclerotic B-Disease 1
rats O 0
. O 0

Studies O 0
concerning O 0
with O 0
pathogenesis O 0
of O 0
gastric B-Disease 1
hemorrhage I-Disease 1
and O 0
mucosal O 0
ulceration O 0
produced O 0
in O 0
atherosclerotic B-Disease 1
rats O 0
are O 0
lacking O 0
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
is O 0
to O 0
examine O 0
the O 0
role O 0
of O 0
gastric O 0
acid O 0
back O 0
- O 0
diffusion O 0
, O 0
mast O 0
cell O 0
histamine B-Chemical 1
release O 0
, O 0
lipid O 0
peroxide O 0
( O 0
LPO O 0
) O 0
generation O 0
and O 0
mucosal O 0
microvascular O 0
permeability O 0
in O 0
modulating O 0
gastric B-Disease 1
hemorrhage I-Disease 1
and O 0
ulcer B-Disease 1
in O 0
rats O 0
with O 0
atherosclerosis B-Disease 1
induced O 0
by O 0
coadministration O 0
of O 0
vitamin B-Chemical 1
D2 I-Chemical 1
and O 0
cholesterol B-Chemical 1
. O 0

Additionally O 0
, O 0
the O 0
protective O 0
effect O 0
of O 0
verapamil B-Chemical 1
on O 0
this O 0
ulcer B-Disease 1
model O 0
was O 0
evaluated O 0
. O 0

Male O 0
Wistar O 0
rats O 0
were O 0
challenged O 0
intragastrically O 0
once O 0
daily O 0
for O 0
9 O 0
days O 0
with O 0
1 O 0
. O 0
0 O 0
ml O 0
/ O 0
kg O 0
of O 0
corn O 0
oil O 0
containing O 0
vitamin B-Chemical 1
D2 I-Chemical 1
and O 0
cholesterol B-Chemical 1
to O 0
induce O 0
atherosclerosis B-Disease 1
. O 0

Control O 0
rats O 0
received O 0
corn O 0
oil O 0
only O 0
. O 0

After O 0
gastric O 0
surgery O 0
, O 0
rat O 0
stomachs O 0
were O 0
irrigated O 0
for O 0
3 O 0
h O 0
with O 0
either O 0
simulated O 0
gastric O 0
juice O 0
or O 0
normal O 0
saline O 0
. O 0

Gastric O 0
acid O 0
back O 0
- O 0
diffusion O 0
, O 0
mucosal O 0
LPO O 0
generation O 0
, O 0
histamine B-Chemical 1
concentration O 0
, O 0
microvascular O 0
permeability O 0
, O 0
luminal B-Chemical 1
hemoglobin O 0
content O 0
and O 0
ulcer B-Disease 1
areas O 0
were O 0
determined O 0
. O 0

Elevated O 0
atherosclerotic B-Disease 1
parameters O 0
, O 0
such O 0
as O 0
serum O 0
calcium B-Chemical 1
, O 0
total O 0
cholesterol B-Chemical 1
and O 0
low O 0
- O 0
density O 0
lipoprotein O 0
concentration O 0
were O 0
obtained O 0
in O 0
atherosclerotic B-Disease 1
rats O 0
. O 0

Severe O 0
gastric O 0
ulcers B-Disease 1
accompanied O 0
with O 0
increased O 0
ulcerogenic O 0
factors O 0
, O 0
including O 0
gastric O 0
acid O 0
back O 0
- O 0
diffusion O 0
, O 0
histamine B-Chemical 1
release O 0
, O 0
LPO O 0
generation O 0
and O 0
luminal B-Chemical 1
hemoglobin O 0
content O 0
were O 0
also O 0
observed O 0
in O 0
these O 0
rats O 0
. O 0

Moreover O 0
, O 0
a O 0
positive O 0
correlation O 0
of O 0
histamine B-Chemical 1
to O 0
gastric B-Disease 1
hemorrhage I-Disease 1
and O 0
to O 0
ulcer B-Disease 1
was O 0
found O 0
in O 0
those O 0
atherosclerotic B-Disease 1
rats O 0
. O 0

This O 0
hemorrhagic B-Disease 1
ulcer B-Disease 1
and O 0
various O 0
ulcerogenic O 0
parameters O 0
were O 0
dose O 0
- O 0
dependently O 0
ameliorated O 0
by O 0
daily O 0
intragastric O 0
verapamil B-Chemical 1
. O 0

Atherosclerosis B-Disease 1
could O 0
produce O 0
gastric B-Disease 1
hemorrhagic I-Disease 1
ulcer B-Disease 1
via O 0
aggravation O 0
of O 0
gastric O 0
acid O 0
back O 0
- O 0
diffusion O 0
, O 0
LPO O 0
generation O 0
, O 0
histamine B-Chemical 1
release O 0
and O 0
microvascular O 0
permeability O 0
that O 0
could O 0
be O 0
ameliorated O 0
by O 0
verapamil B-Chemical 1
in O 0
rats O 0
. O 0

Lamivudine B-Chemical 1
for O 0
the O 0
prevention O 0
of O 0
hepatitis B-Disease 1
B I-Disease 1
virus O 0
reactivation O 0
in O 0
hepatitis B-Chemical 1
- I-Chemical 1
B I-Chemical 1
surface I-Chemical 1
antigen I-Chemical 1
( O 0
HBSAG B-Chemical 1
) O 0
seropositive O 0
cancer B-Disease 1
patients O 0
undergoing O 0
cytotoxic O 0
chemotherapy O 0
. O 0

Hepatitis B-Disease 1
B I-Disease 1
virus O 0
( O 0
HBV O 0
) O 0
is O 0
one O 0
of O 0
the O 0
major O 0
causes O 0
of O 0
chronic O 0
liver B-Disease 1
disease I-Disease 1
worldwide O 0
. O 0

Cancer B-Disease 1
patients O 0
who O 0
are O 0
chronic O 0
carriers O 0
of O 0
HBV O 0
have O 0
a O 0
higher O 0
hepatic B-Disease 1
complication I-Disease 1
rate O 0
while O 0
receiving O 0
cytotoxic O 0
chemotherapy O 0
( O 0
CT O 0
) O 0
and O 0
this O 0
has O 0
mainly O 0
been O 0
attributed O 0
to O 0
HBV O 0
reactivation O 0
. O 0

In O 0
this O 0
study O 0
, O 0
cancer B-Disease 1
patients O 0
who O 0
have O 0
solid O 0
and O 0
hematological B-Disease 1
malignancies I-Disease 1
with O 0
chronic O 0
HBV B-Disease 1
infection I-Disease 1
received O 0
the O 0
antiviral O 0
agent O 0
lamivudine B-Chemical 1
prior O 0
and O 0
during O 0
CT O 0
compared O 0
with O 0
historical O 0
control O 0
group O 0
who O 0
did O 0
not O 0
receive O 0
lamivudine B-Chemical 1
. O 0

The O 0
objectives O 0
were O 0
to O 0
assess O 0
the O 0
efficacy O 0
of O 0
lamivudine B-Chemical 1
in O 0
reducing O 0
the O 0
incidence O 0
of O 0
HBV O 0
reactivation O 0
, O 0
and O 0
diminishing O 0
morbidity O 0
and O 0
mortality O 0
during O 0
CT O 0
. O 0

Two O 0
groups O 0
were O 0
compared O 0
in O 0
this O 0
study O 0
. O 0

The O 0
prophylactic O 0
lamivudin B-Chemical 1
group O 0
consisted O 0
of O 0
37 O 0
patients O 0
who O 0
received O 0
prophylactic O 0
lamivudine B-Chemical 1
treatment O 0
. O 0

The O 0
historical O 0
controls O 0
consisted O 0
of O 0
50 O 0
consecutive O 0
patients O 0
who O 0
underwent O 0
CT O 0
without O 0
prophylactic O 0
lamivudine B-Chemical 1
. O 0

They O 0
were O 0
followed O 0
up O 0
during O 0
and O 0
for O 0
8 O 0
weeks O 0
after O 0
CT O 0
. O 0

The O 0
outcomes O 0
were O 0
compared O 0
for O 0
both O 0
groups O 0
. O 0

Of O 0
our O 0
control O 0
group O 0
( O 0
n O 0
= O 0
50 O 0
) O 0
, O 0
21 O 0
patients O 0
( O 0
42 O 0
% O 0
) O 0
were O 0
established O 0
hepatitis B-Disease 1
. O 0

Twelve O 0
( O 0
24 O 0
% O 0
) O 0
of O 0
them O 0
were O 0
evaluated O 0
as O 0
severe O 0
hepatitis B-Disease 1
. O 0

In O 0
the O 0
prophylactic O 0
lamivudine B-Chemical 1
group O 0
severe O 0
hepatitis B-Disease 1
were O 0
observed O 0
only O 0
in O 0
1 O 0
patient O 0
( O 0
2 O 0
. O 0
7 O 0
% O 0
) O 0
of O 0
37 O 0
patients O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
006 O 0
) O 0
. O 0

Comparison O 0
of O 0
the O 0
mean O 0
ALT O 0
values O 0
revealed O 0
significantly O 0
higher O 0
mean O 0
alanine B-Chemical 1
aminotransferase O 0
( O 0
ALT O 0
) O 0
values O 0
in O 0
the O 0
control O 0
group O 0
than O 0
the O 0
prophylactic O 0
lamivudine B-Chemical 1
group O 0
; O 0
154 O 0
: O 0
64 O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
32 O 0
) O 0
. O 0

Our O 0
study O 0
suggests O 0
that O 0
prophylactic O 0
lamivudine B-Chemical 1
significantly O 0
decreases O 0
the O 0
incidence O 0
of O 0
HBV O 0
reactivation O 0
and O 0
overall O 0
morbidity O 0
in O 0
cancer B-Disease 1
patients O 0
during O 0
and O 0
after O 0
immunosuppressive O 0
therapy O 0
. O 0

Further O 0
studies O 0
are O 0
needed O 0
to O 0
determine O 0
the O 0
most O 0
appropriate O 0
nucleoside B-Chemical 1
or O 0
nucleotide B-Chemical 1
analogue O 0
for O 0
antiviral O 0
prophylaxis O 0
during O 0
CT O 0
and O 0
the O 0
optimal O 0
duration O 0
of O 0
administration O 0
after O 0
completion O 0
of O 0
CT O 0
. O 0

Recovery O 0
of O 0
tacrolimus B-Chemical 1
- O 0
associated O 0
brachial B-Disease 1
neuritis I-Disease 1
after O 0
conversion O 0
to O 0
everolimus B-Chemical 1
in O 0
a O 0
pediatric O 0
renal O 0
transplant O 0
recipient O 0
- O 0
- O 0
case O 0
report O 0
and O 0
review O 0
of O 0
the O 0
literature O 0
. O 0

TAC B-Chemical 1
has O 0
been O 0
shown O 0
to O 0
be O 0
a O 0
potent O 0
immunosuppressive O 0
agent O 0
for O 0
solid O 0
organ O 0
transplantation O 0
in O 0
pediatrics O 0
. O 0

Neurotoxicity B-Disease 1
is O 0
a O 0
potentially O 0
serious O 0
toxic O 0
effect O 0
. O 0

It O 0
is O 0
characterized O 0
by O 0
encephalopathy B-Disease 1
, O 0
headaches B-Disease 1
, O 0
seizures B-Disease 1
, O 0
or O 0
neurological B-Disease 1
deficits I-Disease 1
. O 0

Here O 0
, O 0
we O 0
describe O 0
an O 0
eight O 0
- O 0
and O 0
- O 0
a O 0
- O 0
half O 0
- O 0
yr O 0
- O 0
old O 0
male O 0
renal O 0
transplant O 0
recipient O 0
with O 0
right O 0
BN O 0
. O 0

MRI O 0
demonstrated O 0
hyperintense O 0
T2 O 0
signals O 0
in O 0
the O 0
cervical O 0
cord O 0
and O 0
right O 0
brachial O 0
plexus O 0
roots O 0
indicative O 0
of O 0
both O 0
myelitis B-Disease 1
and O 0
right O 0
brachial B-Disease 1
plexitis I-Disease 1
. O 0

Symptoms O 0
persisted O 0
for O 0
three O 0
months O 0
despite O 0
TAC B-Chemical 1
dose O 0
reduction O 0
, O 0
administration O 0
of O 0
IVIG O 0
and O 0
four O 0
doses O 0
of O 0
methylprednisolone B-Chemical 1
pulse O 0
therapy O 0
. O 0

Improvement O 0
and O 0
eventually O 0
full O 0
recovery O 0
only O 0
occurred O 0
after O 0
TAC B-Chemical 1
was O 0
completely O 0
discontinued O 0
and O 0
successfully O 0
replaced O 0
by O 0
everolimus B-Chemical 1
. O 0

Omitting O 0
fentanyl B-Chemical 1
reduces O 0
nausea B-Disease 1
and O 0
vomiting B-Disease 1
, O 0
without O 0
increasing O 0
pain B-Disease 1
, O 0
after O 0
sevoflurane B-Chemical 1
for O 0
day O 0
surgery O 0
. O 0

BACKGROUND O 0
AND O 0
OBJECTIVE O 0
: O 0
Despite O 0
advantages O 0
of O 0
induction O 0
and O 0
maintenance O 0
of O 0
anaesthesia O 0
with O 0
sevoflurane B-Chemical 1
, O 0
postoperative B-Disease 1
nausea I-Disease 1
and I-Disease 1
vomiting I-Disease 1
occurs O 0
frequently O 0
. O 0

Fentanyl B-Chemical 1
is O 0
a O 0
commonly O 0
used O 0
supplement O 0
that O 0
may O 0
contribute O 0
to O 0
this O 0
, O 0
although O 0
it O 0
may O 0
also O 0
improve O 0
analgesia O 0
. O 0

METHODS O 0
: O 0
This O 0
double O 0
- O 0
blind O 0
study O 0
examined O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
postoperative B-Disease 1
nausea I-Disease 1
and I-Disease 1
vomiting I-Disease 1
and O 0
pain B-Disease 1
in O 0
the O 0
first O 0
24 O 0
h O 0
after O 0
sevoflurane B-Chemical 1
anaesthesia O 0
in O 0
216 O 0
adult O 0
day O 0
surgery O 0
patients O 0
. O 0

Patients O 0
were O 0
randomly O 0
allocated O 0
to O 0
either O 0
receive O 0
or O 0
not O 0
receive O 0
1 O 0
1 O 0
fentanyl B-Chemical 1
, O 0
while O 0
a O 0
third O 0
group O 0
received O 0
dexamethasone B-Chemical 1
in O 0
addition O 0
to O 0
fentanyl B-Chemical 1
. O 0

RESULTS O 0
: O 0
Omission O 0
of O 0
fentanyl B-Chemical 1
did O 0
not O 0
reduce O 0
the O 0
overall O 0
incidence O 0
of O 0
postoperative B-Disease 1
nausea I-Disease 1
and I-Disease 1
vomiting I-Disease 1
, O 0
but O 0
did O 0
reduce O 0
the O 0
incidence O 0
of O 0
vomiting B-Disease 1
and O 0
/ O 0
or O 0
moderate O 0
to O 0
severe O 0
nausea B-Disease 1
prior O 0
to O 0
discharge O 0
from O 0
20 O 0
% O 0
and O 0
17 O 0
% O 0
with O 0
fentanyl B-Chemical 1
and O 0
fentanyl B-Chemical 1
- O 0
dexamethasone B-Chemical 1
, O 0
respectively O 0
, O 0
to O 0
5 O 0
% O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
013 O 0
) O 0
. O 0

Antiemetic O 0
requirements O 0
were O 0
reduced O 0
from O 0
24 O 0
% O 0
and O 0
31 O 0
% O 0
to O 0
7 O 0
% O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
0012 O 0
) O 0
. O 0

Dexamethasone B-Chemical 1
had O 0
no O 0
significant O 0
effect O 0
on O 0
the O 0
incidence O 0
or O 0
severity O 0
of O 0
postoperative B-Disease 1
nausea I-Disease 1
and I-Disease 1
vomiting I-Disease 1
. O 0

Combining O 0
the O 0
two O 0
fentanyl B-Chemical 1
groups O 0
revealed O 0
further O 0
significant O 0
benefits O 0
from O 0
the O 0
avoidance O 0
of O 0
opioids O 0
, O 0
reducing O 0
postoperative B-Disease 1
nausea I-Disease 1
and I-Disease 1
vomiting I-Disease 1
and O 0
nausea B-Disease 1
prior O 0
to O 0
discharge O 0
from O 0
35 O 0
% O 0
and O 0
33 O 0
% O 0
to O 0
22 O 0
% O 0
and O 0
19 O 0
% O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
049 O 0
and O 0
P O 0
= O 0
0 O 0
. O 0
035 O 0
) O 0
, O 0
respectively O 0
, O 0
while O 0
nausea B-Disease 1
in O 0
the O 0
first O 0
24 O 0
h O 0
was O 0
decreased O 0
from O 0
42 O 0
% O 0
to O 0
27 O 0
% O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
034 O 0
) O 0
. O 0

Pain B-Disease 1
severity O 0
and O 0
analgesic O 0
requirements O 0
were O 0
unaffected O 0
by O 0
the O 0
omission O 0
of O 0
fentanyl B-Chemical 1
. O 0

Fentanyl B-Chemical 1
did O 0
reduce O 0
minor O 0
intraoperative O 0
movement O 0
but O 0
had O 0
no O 0
sevoflurane B-Chemical 1
- O 0
sparing O 0
effect O 0
and O 0
increased O 0
respiratory B-Disease 1
depression I-Disease 1
, O 0
hypotension B-Disease 1
and O 0
bradycardia B-Disease 1
. O 0

CONCLUSION O 0
: O 0
As O 0
fentanyl B-Chemical 1
exacerbated O 0
postoperative B-Disease 1
nausea I-Disease 1
and I-Disease 1
vomiting I-Disease 1
without O 0
an O 0
improvement O 0
in O 0
postoperative B-Disease 1
pain I-Disease 1
and O 0
also O 0
had O 0
adverse O 0
cardiorespiratory O 0
effects O 0
, O 0
it O 0
appears O 0
to O 0
be O 0
an O 0
unnecessary O 0
and O 0
possibly O 0
detrimental O 0
supplement O 0
to O 0
sevoflurane B-Chemical 1
in O 0
day O 0
surgery O 0
. O 0

Valvular B-Disease 1
heart I-Disease 1
disease I-Disease 1
in O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
treated O 0
with O 0
pergolide B-Chemical 1
. O 0

Course O 0
following O 0
treatment O 0
modifications O 0
. O 0

Valvular B-Disease 1
heart I-Disease 1
abnormalities I-Disease 1
have O 0
been O 0
reported O 0
in O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
( O 0
PD B-Disease 1
) O 0
treated O 0
with O 0
pergolide B-Chemical 1
. O 0

However O 0
, O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
these O 0
abnormalities O 0
vary O 0
from O 0
study O 0
to O 0
study O 0
and O 0
their O 0
course O 0
after O 0
drug O 0
withdrawal O 0
has O 0
not O 0
been O 0
systematically O 0
assessed O 0
. O 0

OBJECTIVES O 0
: O 0
To O 0
estimate O 0
the O 0
frequency O 0
and O 0
severity O 0
of O 0
valvular B-Disease 1
heart I-Disease 1
abnormality I-Disease 1
and O 0
its O 0
possible O 0
reversibility O 0
after O 0
drug O 0
withdrawal O 0
in O 0
a O 0
case O 0
- O 0
control O 0
study O 0
. O 0

METHODS O 0
: O 0
All O 0
PD B-Disease 1
patients O 0
in O 0
the O 0
Amiens O 0
area O 0
treated O 0
with O 0
pergolide B-Chemical 1
were O 0
invited O 0
to O 0
attend O 0
a O 0
cardiologic O 0
assessment O 0
including O 0
transthoracic O 0
echocardiography O 0
. O 0

Thirty O 0
PD B-Disease 1
patients O 0
participated O 0
in O 0
the O 0
study O 0
. O 0

A O 0
second O 0
echocardiography O 0
was O 0
performed O 0
( O 0
median O 0
interval O 0
: O 0
13 O 0
months O 0
) O 0
after O 0
pergolide B-Chemical 1
withdrawal O 0
( O 0
n O 0
= O 0
10 O 0
patients O 0
) O 0
. O 0

Controls O 0
were O 0
age O 0
- O 0
and O 0
sex O 0
- O 0
matched O 0
non O 0
- O 0
PD B-Disease 1
patients O 0
referred O 0
to O 0
the O 0
cardiology O 0
department O 0
. O 0

RESULTS O 0
: O 0
Compared O 0
to O 0
controls O 0
, O 0
aortic B-Disease 1
regurgitation I-Disease 1
( O 0
OR O 0
: O 0
3 O 0
. O 0
1 O 0
; O 0
95 O 0
% O 0
IC O 0
: O 0
1 O 0
. O 0
1 O 0
- O 0
8 O 0
. O 0
8 O 0
) O 0
and O 0
mitral B-Disease 1
regurgitation I-Disease 1
( O 0
OR O 0
: O 0
10 O 0
. O 0
7 O 0
; O 0
95 O 0
% O 0
IC O 0
: O 0
2 O 0
. O 0
1 O 0
- O 0
53 O 0
) O 0
were O 0
more O 0
frequent O 0
in O 0
PD B-Disease 1
patients O 0
( O 0
tricuspid O 0
: O 0
NS O 0
) O 0
. O 0

The O 0
number O 0
of O 0
affected O 0
valves O 0
( O 0
n O 0
= O 0
2 O 0
. O 0
4 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
7 O 0
) O 0
and O 0
the O 0
sum O 0
of O 0
regurgitation O 0
grades O 0
( O 0
n O 0
= O 0
2 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
09 O 0
) O 0
were O 0
higher O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
008 O 0
and O 0
p O 0
= O 0
0 O 0
. O 0
006 O 0
, O 0
respectively O 0
) O 0
in O 0
the O 0
pergolide B-Chemical 1
group O 0
. O 0

Severity O 0
of O 0
regurgitation O 0
was O 0
not O 0
correlated O 0
with O 0
pergolide B-Chemical 1
cumulative O 0
dose O 0
. O 0

A O 0
restrictive O 0
pattern O 0
of O 0
valvular B-Disease 1
regurgitation I-Disease 1
, O 0
suggestive O 0
of O 0
the O 0
role O 0
of O 0
pergolide B-Chemical 1
, O 0
was O 0
observed O 0
in O 0
12 O 0
/ O 0
30 O 0
( O 0
40 O 0
% O 0
) O 0
patients O 0
including O 0
two O 0
with O 0
heart B-Disease 1
failure I-Disease 1
. O 0

Pergolide B-Chemical 1
was O 0
discontinued O 0
in O 0
10 O 0
patients O 0
with O 0
valvular B-Disease 1
heart I-Disease 1
disease I-Disease 1
, O 0
resulting O 0
in O 0
a O 0
lower O 0
regurgitation O 0
grade O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
01 O 0
) O 0
at O 0
the O 0
second O 0
transthoracic O 0
echocardiography O 0
and O 0
the O 0
two O 0
patients O 0
with O 0
heart B-Disease 1
failure I-Disease 1
returned O 0
to O 0
nearly O 0
normal O 0
clinical O 0
examination O 0
. O 0

This O 0
study O 0
supports O 0
the O 0
high O 0
frequency O 0
of O 0
restrictive O 0
valve B-Disease 1
regurgitation I-Disease 1
in O 0
PD B-Disease 1
patients O 0
treated O 0
with O 0
pergolide B-Chemical 1
and O 0
reveals O 0
that O 0
a O 0
significant O 0
improvement O 0
is O 0
usual O 0
when O 0
the O 0
treatment O 0
is O 0
converted O 0
to O 0
non O 0
- O 0
ergot O 0
dopamine B-Chemical 1
agonists O 0
. O 0

Adriamycin B-Chemical 1
- O 0
induced O 0
autophagic O 0
cardiomyocyte O 0
death B-Disease 1
plays O 0
a O 0
pathogenic O 0
role O 0
in O 0
a O 0
rat O 0
model O 0
of O 0
heart B-Disease 1
failure I-Disease 1
. O 0

BACKGROUND O 0
: O 0
The O 0
mechanisms O 0
underlying O 0
heart B-Disease 1
failure I-Disease 1
induced O 0
by O 0
adriamycin B-Chemical 1
are O 0
very O 0
complicated O 0
and O 0
still O 0
unclear O 0
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
investigate O 0
whether O 0
autophagy O 0
was O 0
involved O 0
in O 0
the O 0
progression O 0
of O 0
heart B-Disease 1
failure I-Disease 1
induced O 0
by O 0
adriamycin B-Chemical 1
, O 0
so O 0
that O 0
we O 0
can O 0
develop O 0
a O 0
novel O 0
treatment O 0
strategy O 0
for O 0
heart B-Disease 1
failure I-Disease 1
. O 0

METHODS O 0
: O 0
3 B-Chemical 1
- I-Chemical 1
methyladenine I-Chemical 1
( O 0
3MA B-Chemical 1
) O 0
, O 0
a O 0
specific O 0
inhibitor O 0
on O 0
autophagy O 0
was O 0
used O 0
in O 0
a O 0
heart B-Disease 1
failure I-Disease 1
model O 0
of O 0
rats O 0
induced O 0
by O 0
adriamycin B-Chemical 1
. O 0

Neonatal O 0
cardiomyocytes O 0
were O 0
isolated O 0
from O 0
Sprague O 0
- O 0
Dawley O 0
rat O 0
hearts O 0
and O 0
randomly O 0
divided O 0
into O 0
controls O 0
, O 0
an O 0
adriamycin B-Chemical 1
- O 0
treated O 0
group O 0
, O 0
and O 0
a O 0
3MA B-Chemical 1
plus O 0
adriamycin B-Chemical 1
- O 0
treated O 0
group O 0
. O 0

We O 0
then O 0
examined O 0
the O 0
morphology O 0
, O 0
expression O 0
of O 0
beclin O 0
1 O 0
gene O 0
, O 0
mitochondrial O 0
permeability O 0
transition O 0
( O 0
MPT O 0
) O 0
, O 0
and O 0
Na O 0
+ O 0
- O 0
K B-Chemical 1
+ O 0
ATPase O 0
activity O 0
in O 0
vivo O 0
. O 0

We O 0
also O 0
assessed O 0
cell O 0
viability O 0
, O 0
mitochondrial O 0
membrane O 0
potential O 0
changes O 0
and O 0
counted O 0
autophagic O 0
vacuoles O 0
in O 0
cultured O 0
cardiomyocytes O 0
. O 0

In O 0
addition O 0
, O 0
we O 0
analyzed O 0
the O 0
expression O 0
of O 0
autophagy O 0
associated O 0
gene O 0
, O 0
beclin O 0
1 O 0
using O 0
RT O 0
- O 0
PCR O 0
and O 0
Western O 0
blotting O 0
in O 0
an O 0
animal O 0
model O 0
. O 0

RESULTS O 0
: O 0
3MA B-Chemical 1
significantly O 0
improved O 0
cardiac O 0
function O 0
and O 0
reduced O 0
mitochondrial O 0
injury O 0
. O 0

Furthermore O 0
, O 0
adriamycin B-Chemical 1
induced O 0
the O 0
formation O 0
of O 0
autophagic O 0
vacuoles O 0
, O 0
and O 0
3MA B-Chemical 1
strongly O 0
downregulated O 0
the O 0
expression O 0
of O 0
beclin O 0
1 O 0
in O 0
adriamycin B-Chemical 1
- O 0
induced O 0
failing O 0
heart O 0
and O 0
inhibited O 0
the O 0
formation O 0
of O 0
autophagic O 0
vacuoles O 0
. O 0

CONCLUSION O 0
: O 0
Autophagic O 0
cardiomyocyte O 0
death B-Disease 1
plays O 0
an O 0
important O 0
role O 0
in O 0
the O 0
pathogenesis O 0
of O 0
heart B-Disease 1
failure I-Disease 1
in O 0
rats O 0
induced O 0
by O 0
adriamycin B-Chemical 1
. O 0

Mitochondrial O 0
injury O 0
may O 0
be O 0
involved O 0
in O 0
the O 0
progression O 0
of O 0
heart B-Disease 1
failure I-Disease 1
caused O 0
by O 0
adriamycin B-Chemical 1
via O 0
the O 0
autophagy O 0
pathway O 0
. O 0

mToR O 0
inhibitors O 0
- O 0
induced O 0
proteinuria B-Disease 1
: O 0
mechanisms O 0
, O 0
significance O 0
, O 0
and O 0
management O 0
. O 0

Massive O 0
urinary O 0
protein O 0
excretion O 0
has O 0
been O 0
observed O 0
after O 0
conversion O 0
from O 0
calcineurin O 0
inhibitors O 0
to O 0
mammalian O 0
target O 0
of O 0
rapamycin B-Chemical 1
( O 0
mToR O 0
) O 0
inhibitors O 0
, O 0
especially O 0
sirolimus B-Chemical 1
, O 0
in O 0
renal O 0
transplant O 0
recipients O 0
with O 0
chronic B-Disease 1
allograft I-Disease 1
nephropathy I-Disease 1
. O 0

Because O 0
proteinuria B-Disease 1
is O 0
a O 0
major O 0
predictive O 0
factor O 0
of O 0
poor O 0
transplantation O 0
outcome O 0
, O 0
many O 0
studies O 0
focused O 0
on O 0
this O 0
adverse O 0
event O 0
during O 0
the O 0
past O 0
years O 0
. O 0

Whether O 0
proteinuria B-Disease 1
was O 0
due O 0
to O 0
sirolimus B-Chemical 1
or O 0
only O 0
a O 0
consequence O 0
of O 0
calcineurin O 0
inhibitors O 0
withdrawal O 0
remained O 0
unsolved O 0
until O 0
high O 0
range O 0
proteinuria B-Disease 1
has O 0
been O 0
observed O 0
during O 0
sirolimus B-Chemical 1
therapy O 0
in O 0
islet O 0
transplantation O 0
and O 0
in O 0
patients O 0
who O 0
received O 0
sirolimus B-Chemical 1
de O 0
novo O 0
. O 0

Podocyte O 0
injury O 0
and O 0
focal O 0
segmental O 0
glomerulosclerosis B-Disease 1
have O 0
been O 0
related O 0
to O 0
mToR O 0
inhibition O 0
in O 0
some O 0
patients O 0
, O 0
but O 0
the O 0
pathways O 0
underlying O 0
these O 0
lesions O 0
remain O 0
hypothetic O 0
. O 0

We O 0
discuss O 0
herein O 0
the O 0
possible O 0
mechanisms O 0
and O 0
the O 0
significance O 0
of O 0
mToR O 0
blockade O 0
- O 0
induced O 0
proteinuria B-Disease 1
. O 0

Neuropsychiatric O 0
side O 0
effects O 0
after O 0
the O 0
use O 0
of O 0
mefloquine B-Chemical 1
. O 0

This O 0
study O 0
describes O 0
neuropsychiatric O 0
side O 0
effects O 0
in O 0
patients O 0
after O 0
treatment O 0
with O 0
mefloquine B-Chemical 1
. O 0

Reactions O 0
consisted O 0
mainly O 0
of O 0
seizures B-Disease 1
, O 0
acute O 0
psychoses B-Disease 1
, O 0
anxiety B-Disease 1
neurosis I-Disease 1
, O 0
and O 0
major O 0
disturbances B-Disease 1
of I-Disease 1
sleep I-Disease 1
- I-Disease 1
wake I-Disease 1
rhythm I-Disease 1
. O 0

Side O 0
effects O 0
occurred O 0
after O 0
both O 0
therapeutic O 0
and O 0
prophylactic O 0
intake O 0
and O 0
were O 0
graded O 0
from O 0
moderate O 0
to O 0
severe O 0
. O 0

In O 0
a O 0
risk O 0
analysis O 0
of O 0
neuropsychiatric O 0
side O 0
effects O 0
in O 0
Germany O 0
, O 0
it O 0
is O 0
estimated O 0
that O 0
one O 0
of O 0
8 O 0
, O 0
000 O 0
mefloquine B-Chemical 1
users O 0
suffers O 0
from O 0
such O 0
reactions O 0
. O 0

The O 0
incidence O 0
calculation O 0
revealed O 0
that O 0
one O 0
of O 0
215 O 0
therapeutic O 0
users O 0
had O 0
reactions O 0
, O 0
compared O 0
with O 0
one O 0
of O 0
13 O 0
, O 0
000 O 0
in O 0
the O 0
prophylaxis O 0
group O 0
, O 0
making O 0
the O 0
risk O 0
of O 0
neuropsychiatric O 0
reactions O 0
after O 0
mefloquine B-Chemical 1
treatment O 0
60 O 0
times O 0
higher O 0
than O 0
after O 0
prophylaxis O 0
. O 0

Therefore O 0
, O 0
certain O 0
limitations O 0
for O 0
malaria B-Disease 1
prophylaxis O 0
and O 0
treatment O 0
with O 0
mefloquine B-Chemical 1
are O 0
recommended O 0
. O 0

Prenatal O 0
protein O 0
deprivation O 0
alters O 0
dopamine B-Chemical 1
- O 0
mediated O 0
behaviors O 0
and O 0
dopaminergic O 0
and O 0
glutamatergic O 0
receptor O 0
binding O 0
. O 0

Epidemiological O 0
evidence O 0
indicates O 0
that O 0
prenatal O 0
nutritional O 0
deprivation O 0
may O 0
increase O 0
the O 0
risk O 0
of O 0
schizophrenia B-Disease 1
. O 0

The O 0
goal O 0
of O 0
these O 0
studies O 0
was O 0
to O 0
use O 0
an O 0
animal O 0
model O 0
to O 0
examine O 0
the O 0
effects O 0
of O 0
prenatal O 0
protein O 0
deprivation O 0
on O 0
behaviors O 0
and O 0
receptor O 0
binding O 0
with O 0
relevance O 0
to O 0
schizophrenia B-Disease 1
. O 0

We O 0
report O 0
that O 0
prenatally O 0
protein O 0
deprived O 0
( O 0
PD O 0
) O 0
female O 0
rats O 0
showed O 0
an O 0
increased O 0
stereotypic O 0
response O 0
to O 0
apomorphine B-Chemical 1
and O 0
an O 0
increased O 0
locomotor O 0
response O 0
to O 0
amphetamine B-Chemical 1
in O 0
adulthood O 0
. O 0

These O 0
differences O 0
were O 0
not O 0
observed O 0
during O 0
puberty O 0
. O 0

No O 0
changes O 0
in O 0
haloperidol B-Chemical 1
- O 0
induced O 0
catalepsy B-Disease 1
or O 0
MK B-Chemical 1
- I-Chemical 1
801 I-Chemical 1
- O 0
induced O 0
locomotion O 0
were O 0
seen O 0
following O 0
PD O 0
. O 0

In O 0
addition O 0
, O 0
PD O 0
female O 0
rats O 0
showed O 0
increased O 0
( O 0
3 O 0
) O 0
H B-Chemical 1
- O 0
MK B-Chemical 1
- I-Chemical 1
801 I-Chemical 1
binding O 0
in O 0
the O 0
striatum O 0
and O 0
hippocampus O 0
, O 0
but O 0
not O 0
in O 0
the O 0
cortex O 0
. O 0

PD O 0
female O 0
rats O 0
also O 0
showed O 0
increased O 0
( O 0
3 O 0
) O 0
H B-Chemical 1
- O 0
haloperidol B-Chemical 1
binding O 0
and O 0
decreased O 0
dopamine B-Chemical 1
transporter O 0
binding O 0
in O 0
striatum O 0
. O 0

No O 0
statistically O 0
significant O 0
changes O 0
in O 0
behavior O 0
or O 0
receptor O 0
binding O 0
were O 0
found O 0
in O 0
PD O 0
males O 0
with O 0
the O 0
exception O 0
of O 0
increased O 0
( O 0
3 O 0
) O 0
H B-Chemical 1
- O 0
MK B-Chemical 1
- I-Chemical 1
801 I-Chemical 1
binding O 0
in O 0
cortex O 0
. O 0

This O 0
animal O 0
model O 0
may O 0
be O 0
useful O 0
to O 0
explore O 0
the O 0
mechanisms O 0
by O 0
which O 0
prenatal O 0
nutritional B-Disease 1
deficiency I-Disease 1
enhances O 0
risk O 0
for O 0
schizophrenia B-Disease 1
in O 0
humans O 0
and O 0
may O 0
also O 0
have O 0
implications O 0
for O 0
developmental O 0
processes O 0
leading O 0
to O 0
differential O 0
sensitivity O 0
to O 0
drugs O 0
of O 0
abuse O 0
. O 0

Adverse O 0
effects O 0
of O 0
topical O 0
papaverine B-Chemical 1
on O 0
auditory O 0
nerve O 0
function O 0
. O 0

BACKGROUND O 0
: O 0
Papaverine B-Chemical 1
hydrochloride I-Chemical 1
is O 0
a O 0
direct O 0
- O 0
acting O 0
vasodilator O 0
used O 0
to O 0
manage O 0
vasospasm B-Disease 1
during O 0
various O 0
neurosurgical O 0
operations O 0
. O 0

Transient O 0
cranial B-Disease 1
nerve I-Disease 1
dysfunction I-Disease 1
has O 0
been O 0
described O 0
in O 0
a O 0
few O 0
cases O 0
with O 0
topical O 0
papaverine B-Chemical 1
. O 0

This O 0
study O 0
supports O 0
previous O 0
reports O 0
and O 0
provides O 0
neurophysiological O 0
evidence O 0
of O 0
an O 0
adverse O 0
effect O 0
on O 0
the O 0
auditory O 0
nerve O 0
. O 0

METHODS O 0
: O 0
We O 0
conducted O 0
a O 0
retrospective O 0
review O 0
of O 0
70 O 0
consecutive O 0
microvascular O 0
decompression O 0
operations O 0
and O 0
studied O 0
those O 0
patients O 0
who O 0
received O 0
topical O 0
papaverine B-Chemical 1
for O 0
vasospasm B-Disease 1
. O 0

Topical O 0
papaverine B-Chemical 1
was O 0
used O 0
as O 0
a O 0
direct O 0
therapeutic O 0
action O 0
to O 0
manage O 0
vasospasm B-Disease 1
in O 0
a O 0
total O 0
of O 0
11 O 0
patients O 0
. O 0

The O 0
timing O 0
of O 0
papaverine B-Chemical 1
application O 0
and O 0
ongoing O 0
operative O 0
events O 0
was O 0
reviewed O 0
relative O 0
to O 0
changes O 0
in O 0
neurophysiological O 0
recordings O 0
. O 0

Brainstem O 0
auditory O 0
evoked O 0
potentials O 0
( O 0
BAEPs O 0
) O 0
were O 0
routinely O 0
used O 0
to O 0
monitor O 0
cochlear O 0
nerve O 0
function O 0
during O 0
these O 0
operations O 0
. O 0

FINDINGS O 0
: O 0
A O 0
temporal O 0
relationship O 0
was O 0
found O 0
between O 0
topical O 0
papaverine B-Chemical 1
and O 0
BAEP O 0
changes O 0
leading O 0
to O 0
complete O 0
waveform O 0
loss O 0
. O 0

The O 0
average O 0
temporal O 0
delay O 0
between O 0
papaverine B-Chemical 1
and O 0
the O 0
onset O 0
of O 0
an O 0
adverse O 0
BAEP O 0
change O 0
was O 0
5 O 0
min O 0
. O 0

In O 0
10 O 0
of O 0
11 O 0
patients O 0
, O 0
BAEP O 0
waves O 0
II O 0
/ O 0
III O 0
- O 0
V O 0
completely O 0
disappeared O 0
within O 0
2 O 0
to O 0
25 O 0
min O 0
after O 0
papaverine B-Chemical 1
. O 0

Eight O 0
of O 0
these O 0
10 O 0
patients O 0
had O 0
complete O 0
loss O 0
of O 0
BAEP O 0
waveforms O 0
within O 0
10 O 0
min O 0
. O 0

One O 0
patient O 0
showed O 0
no O 0
recovery O 0
of O 0
later O 0
waves O 0
and O 0
a O 0
delayed O 0
profound O 0
sensorineural B-Disease 1
hearing I-Disease 1
loss I-Disease 1
. O 0

The O 0
average O 0
recovery O 0
time O 0
of O 0
BAEP O 0
waveforms O 0
to O 0
pre O 0
- O 0
papaverine B-Chemical 1
baseline O 0
values O 0
was O 0
39 O 0
min O 0
. O 0

CONCLUSIONS O 0
: O 0
Topical O 0
papaverine B-Chemical 1
for O 0
the O 0
treatment O 0
of O 0
vasospasm B-Disease 1
was O 0
associated O 0
with O 0
the O 0
onset O 0
of O 0
a O 0
transient O 0
disturbance O 0
in O 0
neurophysiological O 0
function O 0
of O 0
the O 0
ascending O 0
auditory O 0
brainstem O 0
pathway O 0
. O 0

The O 0
complete O 0
disappearance O 0
of O 0
BAEP O 0
waveforms O 0
with O 0
a O 0
consistent O 0
temporal O 0
delay O 0
suggests O 0
a O 0
possible O 0
adverse B-Disease 1
effect I-Disease 1
on I-Disease 1
the I-Disease 1
proximal I-Disease 1
eighth I-Disease 1
nerve I-Disease 1
. O 0

Recommendations O 0
to O 0
avoid O 0
potential O 0
cranial B-Disease 1
nerve I-Disease 1
deficits I-Disease 1
from O 0
papaverine B-Chemical 1
are O 0
provided O 0
. O 0

Simvastatin B-Chemical 1
- I-Chemical 1
ezetimibe I-Chemical 1
- O 0
induced O 0
hepatic B-Disease 1
failure I-Disease 1
necessitating O 0
liver O 0
transplantation O 0
. O 0

Abstract O 0
Serum O 0
aminotransferase O 0
elevations O 0
are O 0
a O 0
commonly O 0
known O 0
adverse O 0
effect O 0
of O 0
3 O 0
- O 0
hydroxy O 0
- O 0
3 O 0
- O 0
methylglutaryl O 0
coenzyme O 0
A O 0
reductase O 0
inhibitor O 0
( O 0
statin B-Chemical 1
) O 0
therapy O 0
. O 0

However O 0
, O 0
hepatotoxic B-Disease 1
events O 0
have O 0
not O 0
been O 0
widely O 0
published O 0
with O 0
ezetimibe B-Chemical 1
or O 0
the O 0
combination O 0
agent O 0
simvastatin B-Chemical 1
- I-Chemical 1
ezetimibe I-Chemical 1
. O 0

We O 0
describe O 0
a O 0
70 O 0
- O 0
year O 0
- O 0
old O 0
Hispanic O 0
woman O 0
who O 0
developed O 0
fulminant B-Disease 1
hepatic I-Disease 1
failure I-Disease 1
necessitating O 0
liver O 0
transplantation O 0
10 O 0
weeks O 0
after O 0
conversion O 0
from O 0
simvastatin B-Chemical 1
40 O 0
mg O 0
/ O 0
day O 0
to O 0
simvastatin B-Chemical 1
10 I-Chemical 1
mg I-Chemical 1
- I-Chemical 1
ezetimibe I-Chemical 1
40 I-Chemical 1
mg I-Chemical 1
/ O 0
day O 0
. O 0

The O 0
patient O 0
' O 0
s O 0
lipid O 0
panel O 0
had O 0
been O 0
maintained O 0
with O 0
simvastatin B-Chemical 1
for O 0
18 O 0
months O 0
before O 0
the O 0
conversion O 0
without O 0
evidence O 0
of O 0
hepatotoxicity B-Disease 1
. O 0

A O 0
routine O 0
laboratory O 0
work O 0
- O 0
up O 0
10 O 0
weeks O 0
after O 0
conversion O 0
revealed O 0
elevated O 0
serum O 0
aminotransferase O 0
levels O 0
. O 0

Simvastatinezetimibe B-Chemical 1
and O 0
escitalopram B-Chemical 1
( O 0
which O 0
she O 0
was O 0
taking O 0
for O 0
depression B-Disease 1
) O 0
were O 0
discontinued O 0
, O 0
and O 0
other O 0
potential O 0
causes O 0
of O 0
hepatotoxicity B-Disease 1
were O 0
excluded O 0
. O 0

A O 0
repeat O 0
work O 0
- O 0
up O 0
revealed O 0
further O 0
elevations O 0
in O 0
aminotransferase O 0
levels O 0
, O 0
and O 0
liver O 0
biopsy O 0
revealed O 0
evidence O 0
of O 0
moderate O 0
- O 0
to O 0
- O 0
severe O 0
drug B-Disease 1
toxicity I-Disease 1
. O 0

She O 0
underwent O 0
liver O 0
transplantation O 0
with O 0
an O 0
uneventful O 0
postoperative O 0
course O 0
. O 0

Her O 0
aminotransferase O 0
levels O 0
returned O 0
to O 0
normal O 0
by O 0
postoperative O 0
day O 0
23 O 0
, O 0
and O 0
her O 0
2 O 0
- O 0
year O 0
follow O 0
- O 0
up O 0
showed O 0
no O 0
adverse O 0
events O 0
. O 0

Ezetimibe B-Chemical 1
undergoes O 0
extensive O 0
glucuronidation O 0
by O 0
uridine B-Chemical 1
diphosphate I-Chemical 1
glucoronosyltransferases O 0
( O 0
UGT O 0
) O 0
in O 0
the O 0
intestine O 0
and O 0
liver O 0
and O 0
may O 0
have O 0
inhibited O 0
the O 0
glucuronidation O 0
of O 0
simvastatin B-Chemical 1
hydroxy I-Chemical 1
acid I-Chemical 1
, O 0
resulting O 0
in O 0
increased O 0
simvastatin B-Chemical 1
exposure O 0
and O 0
subsequent O 0
hepatotoxicity B-Disease 1
. O 0

To O 0
our O 0
knowledge O 0
, O 0
this O 0
is O 0
the O 0
first O 0
case O 0
report O 0
of O 0
simvastatin B-Chemical 1
- I-Chemical 1
ezetimibe I-Chemical 1
- O 0
induced O 0
liver B-Disease 1
failure I-Disease 1
that O 0
resulted O 0
in O 0
liver O 0
transplantation O 0
. O 0

We O 0
postulate O 0
that O 0
the O 0
mechanism O 0
of O 0
the O 0
simvastatinezetimibe B-Chemical 1
- O 0
induced O 0
hepatotoxicity B-Disease 1
is O 0
the O 0
increased O 0
simvastatin B-Chemical 1
exposure O 0
by O 0
ezetimibe B-Chemical 1
inhibition O 0
of O 0
UGT O 0
enzymes O 0
. O 0

Clinicians O 0
should O 0
be O 0
aware O 0
of O 0
potential O 0
hepatotoxicity B-Disease 1
with O 0
simvastatin B-Chemical 1
- I-Chemical 1
ezetimibe I-Chemical 1
especially O 0
in O 0
elderly O 0
patients O 0
and O 0
should O 0
carefully O 0
monitor O 0
serum O 0
aminotransferase O 0
levels O 0
when O 0
starting O 0
therapy O 0
and O 0
titrating O 0
the O 0
dosage O 0
. O 0

Massive O 0
proteinuria B-Disease 1
and O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
after O 0
oral O 0
bisphosphonate B-Chemical 1
( O 0
alendronate B-Chemical 1
) O 0
administration O 0
in O 0
a O 0
patient O 0
with O 0
focal B-Disease 1
segmental I-Disease 1
glomerulosclerosis I-Disease 1
. O 0

A O 0
61 O 0
- O 0
year O 0
- O 0
old O 0
Japanese O 0
man O 0
with O 0
nephrotic B-Disease 1
syndrome I-Disease 1
due O 0
to O 0
focal B-Disease 1
segmental I-Disease 1
glomerulosclerosis I-Disease 1
was O 0
initially O 0
responding O 0
well O 0
to O 0
steroid B-Chemical 1
therapy O 0
. O 0

The O 0
amount O 0
of O 0
daily O 0
urinary O 0
protein O 0
decreased O 0
from O 0
15 O 0
. O 0
6 O 0
to O 0
2 O 0
. O 0
8 O 0
g O 0
. O 0

Within O 0
14 O 0
days O 0
of O 0
the O 0
oral O 0
bisphosphonate B-Chemical 1
( O 0
alendronate B-Chemical 1
sodium I-Chemical 1
) O 0
administration O 0
, O 0
the O 0
amount O 0
of O 0
daily O 0
urinary O 0
protein O 0
increased O 0
rapidly O 0
up O 0
to O 0
12 O 0
. O 0
8 O 0
g O 0
with O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
. O 0

After O 0
discontinuing O 0
the O 0
oral O 0
alendronate B-Chemical 1
, O 0
the O 0
patient O 0
underwent O 0
six O 0
cycles O 0
of O 0
hemodialysis O 0
and O 0
four O 0
cycles O 0
of O 0
LDL O 0
apheresis O 0
. O 0

Urinary O 0
volume O 0
and O 0
serum O 0
creatinine B-Chemical 1
levels O 0
recovered O 0
to O 0
the O 0
normal O 0
range O 0
, O 0
with O 0
urinary O 0
protein O 0
disappearing O 0
completely O 0
within O 0
40 O 0
days O 0
. O 0

This O 0
report O 0
demonstrates O 0
that O 0
not O 0
only O 0
intravenous O 0
, O 0
but O 0
also O 0
oral O 0
bisphosphonates B-Chemical 1
can O 0
aggravate O 0
proteinuria B-Disease 1
and O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
. O 0

Serum O 0
- O 0
and O 0
glucocorticoid O 0
- O 0
inducible O 0
kinase O 0
1 O 0
in O 0
doxorubicin B-Chemical 1
- O 0
induced O 0
nephrotic B-Disease 1
syndrome I-Disease 1
. O 0

Doxorubicin B-Chemical 1
- O 0
induced O 0
nephropathy B-Disease 1
leads O 0
to O 0
epithelial O 0
sodium B-Chemical 1
channel O 0
( O 0
ENaC O 0
) O 0
- O 0
dependent O 0
volume B-Disease 1
retention I-Disease 1
and O 0
renal O 0
fibrosis B-Disease 1
. O 0

The O 0
aldosterone B-Chemical 1
- O 0
sensitive O 0
serum O 0
- O 0
and O 0
glucocorticoid O 0
- O 0
inducible O 0
kinase O 0
SGK1 O 0
has O 0
been O 0
shown O 0
to O 0
participate O 0
in O 0
the O 0
stimulation O 0
of O 0
ENaC O 0
and O 0
to O 0
mediate O 0
renal O 0
fibrosis B-Disease 1
following O 0
mineralocorticoid O 0
and O 0
salt O 0
excess O 0
. O 0

The O 0
present O 0
study O 0
was O 0
performed O 0
to O 0
elucidate O 0
the O 0
role O 0
of O 0
SGK1 O 0
in O 0
the O 0
volume B-Disease 1
retention I-Disease 1
and O 0
fibrosis B-Disease 1
during O 0
nephrotic B-Disease 1
syndrome I-Disease 1
. O 0

To O 0
this O 0
end O 0
, O 0
doxorubicin B-Chemical 1
( O 0
15 O 0
mug O 0
/ O 0
g O 0
body O 0
wt O 0
) O 0
was O 0
injected O 0
intravenously O 0
into O 0
gene O 0
- O 0
targeted O 0
mice O 0
lacking O 0
SGK1 O 0
( O 0
sgk1 O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
) O 0
and O 0
their O 0
wild O 0
- O 0
type O 0
littermates O 0
( O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
) O 0
. O 0

Doxorubicin B-Chemical 1
treatment O 0
resulted O 0
in O 0
heavy O 0
proteinuria B-Disease 1
( O 0
> O 0
100 O 0
mg O 0
protein O 0
/ O 0
mg O 0
crea O 0
) O 0
in O 0
15 O 0
/ O 0
44 O 0
of O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
and O 0
15 O 0
/ O 0
44 O 0
of O 0
sgk1 O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
leading O 0
to O 0
severe O 0
nephrotic B-Disease 1
syndrome I-Disease 1
with O 0
ascites B-Disease 1
, O 0
lipidemia B-Disease 1
, O 0
and O 0
hypoalbuminemia B-Disease 1
in O 0
both O 0
genotypes O 0
. O 0

Plasma O 0
aldosterone B-Chemical 1
levels O 0
increased O 0
in O 0
nephrotic B-Disease 1
mice O 0
of O 0
both O 0
genotypes O 0
and O 0
was O 0
followed O 0
by O 0
increased O 0
SGK1 O 0
protein O 0
expression O 0
in O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
mice O 0
. O 0

Urinary O 0
sodium B-Chemical 1
excretion O 0
reached O 0
signficantly O 0
lower O 0
values O 0
in O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
mice O 0
( O 0
15 O 0
+ O 0
/ O 0
- O 0
5 O 0
mumol O 0
/ O 0
mg O 0
crea O 0
) O 0
than O 0
in O 0
sgk1 O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
( O 0
35 O 0
+ O 0
/ O 0
- O 0
5 O 0
mumol O 0
/ O 0
mg O 0
crea O 0
) O 0
and O 0
was O 0
associated O 0
with O 0
a O 0
significantly O 0
higher O 0
body O 0
weight B-Disease 1
gain I-Disease 1
in O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
compared O 0
with O 0
sgk1 O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
( O 0
+ O 0
6 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
7 O 0
vs O 0
. O 0
+ O 0
4 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
8 O 0
g O 0
) O 0
. O 0

During O 0
the O 0
course O 0
of O 0
nephrotic B-Disease 1
syndrome I-Disease 1
, O 0
serum O 0
urea B-Chemical 1
concentrations O 0
increased O 0
significantly O 0
faster O 0
in O 0
sgk1 O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
than O 0
in O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
mice O 0
leading O 0
to O 0
uremia B-Disease 1
and O 0
a O 0
reduced O 0
median O 0
survival O 0
in O 0
sgk1 O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
( O 0
29 O 0
vs O 0
. O 0
40 O 0
days O 0
in O 0
sgk1 O 0
( O 0
+ O 0
/ O 0
+ O 0
) O 0
mice O 0
) O 0
. O 0

In O 0
conclusion O 0
, O 0
gene O 0
- O 0
targeted O 0
mice O 0
lacking O 0
SGK1 O 0
showed O 0
blunted O 0
volume B-Disease 1
retention I-Disease 1
, O 0
yet O 0
were O 0
not O 0
protected O 0
against O 0
renal O 0
fibrosis B-Disease 1
during O 0
experimental O 0
nephrotic B-Disease 1
syndrome I-Disease 1
. O 0

Severe O 0
thrombocytopenia B-Disease 1
and O 0
haemolytic B-Disease 1
anaemia I-Disease 1
associated O 0
with O 0
ciprofloxacin B-Chemical 1
: O 0
a O 0
case O 0
report O 0
with O 0
fatal O 0
outcome O 0
. O 0

Haematological O 0
adverse O 0
reactions O 0
associated O 0
with O 0
fatal O 0
outcome O 0
are O 0
rare O 0
during O 0
treatment O 0
with O 0
ciprofloxacin B-Chemical 1
. O 0

A O 0
30 O 0
- O 0
year O 0
old O 0
Caucasian O 0
man O 0
reported O 0
with O 0
abdominal B-Disease 1
pain I-Disease 1
and O 0
jaundice B-Disease 1
after O 0
3 O 0
- O 0
day O 0
administration O 0
of O 0
oral O 0
ciprofloxacin B-Chemical 1
for O 0
a O 0
suspect O 0
of O 0
urinary B-Disease 1
tract I-Disease 1
infection I-Disease 1
. O 0

Clinical O 0
evaluations O 0
suggested O 0
an O 0
initial O 0
diagnosis O 0
of O 0
severe O 0
thrombocytopenia B-Disease 1
and O 0
haemolysis B-Disease 1
. O 0

The O 0
patient O 0
progressively O 0
developed O 0
petechiae B-Disease 1
and O 0
purpura B-Disease 1
on O 0
thorax O 0
and O 0
lower O 0
limbs O 0
. O 0

Despite O 0
pharmacological O 0
and O 0
supportive O 0
interventions O 0
, O 0
laboratory O 0
parameters O 0
worsened O 0
and O 0
the O 0
patient O 0
died O 0
17 O 0
hours O 0
after O 0
admission O 0
. O 0

An O 0
accurate O 0
autopsy O 0
revealed O 0
most O 0
organs O 0
with O 0
diffuse O 0
petechial O 0
haemorrhages B-Disease 1
. O 0

No O 0
signs O 0
of O 0
bone B-Disease 1
marrow I-Disease 1
depression I-Disease 1
were O 0
found O 0
. O 0

No O 0
thrombi B-Disease 1
or O 0
signs O 0
of O 0
microangiopathies B-Disease 1
were O 0
observed O 0
in O 0
arterial O 0
vessels O 0
. O 0

Blood O 0
and O 0
urine O 0
cultures O 0
did O 0
not O 0
show O 0
any O 0
bacterial O 0
growth O 0
. O 0

This O 0
case O 0
report O 0
shows O 0
that O 0
ciprofloxacin B-Chemical 1
may O 0
precipitate O 0
life O 0
- O 0
threatening O 0
thrombocytopenia B-Disease 1
and O 0
haemolytic B-Disease 1
anaemia I-Disease 1
, O 0
even O 0
in O 0
the O 0
early O 0
phases O 0
of O 0
treatment O 0
and O 0
without O 0
apparent O 0
previous O 0
exposures O 0
. O 0

Alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
prevents O 0
mitochondrial B-Disease 1
damage I-Disease 1
and O 0
neurotoxicity B-Disease 1
in O 0
experimental O 0
chemotherapy O 0
neuropathy B-Disease 1
. O 0

The O 0
study O 0
investigates O 0
if O 0
alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
is O 0
neuroprotective O 0
against O 0
chemotherapy O 0
induced O 0
neurotoxicity B-Disease 1
, O 0
if O 0
mitochondrial B-Disease 1
damage I-Disease 1
plays O 0
a O 0
critical O 0
role O 0
in O 0
toxic B-Disease 1
neurodegenerative I-Disease 1
cascade I-Disease 1
, O 0
and O 0
if O 0
neuroprotective O 0
effects O 0
of O 0
alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
depend O 0
on O 0
mitochondria O 0
protection O 0
. O 0

We O 0
used O 0
an O 0
in O 0
vitro O 0
model O 0
of O 0
chemotherapy O 0
induced O 0
peripheral B-Disease 1
neuropathy I-Disease 1
that O 0
closely O 0
mimic O 0
the O 0
in O 0
vivo O 0
condition O 0
by O 0
exposing O 0
primary O 0
cultures O 0
of O 0
dorsal O 0
root O 0
ganglion O 0
( O 0
DRG O 0
) O 0
sensory O 0
neurons O 0
to O 0
paclitaxel B-Chemical 1
and O 0
cisplatin B-Chemical 1
, O 0
two O 0
widely O 0
used O 0
and O 0
highly O 0
effective O 0
chemotherapeutic O 0
drugs O 0
. O 0

This O 0
approach O 0
allowed O 0
investigating O 0
the O 0
efficacy O 0
of O 0
alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
in O 0
preventing O 0
axonal B-Disease 1
damage I-Disease 1
and O 0
apoptosis O 0
and O 0
the O 0
function O 0
and O 0
ultrastructural O 0
morphology O 0
of O 0
mitochondria O 0
after O 0
exposure O 0
to O 0
toxic O 0
agents O 0
and O 0
alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
. O 0

Our O 0
results O 0
demonstrate O 0
that O 0
both O 0
cisplatin B-Chemical 1
and O 0
paclitaxel B-Chemical 1
cause O 0
early O 0
mitochondrial B-Disease 1
impairment I-Disease 1
with O 0
loss O 0
of O 0
membrane O 0
potential O 0
and O 0
induction O 0
of O 0
autophagic O 0
vacuoles O 0
in O 0
neurons O 0
. O 0

Alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
exerts O 0
neuroprotective O 0
effects O 0
against O 0
chemotherapy O 0
induced O 0
neurotoxicity B-Disease 1
in O 0
sensory O 0
neurons O 0
: O 0
it O 0
rescues O 0
the O 0
mitochondrial B-Disease 1
toxicity I-Disease 1
and O 0
induces O 0
the O 0
expression O 0
of O 0
frataxin O 0
, O 0
an O 0
essential O 0
mitochondrial O 0
protein O 0
with O 0
anti O 0
- O 0
oxidant O 0
and O 0
chaperone O 0
properties O 0
. O 0

In O 0
conclusion O 0
mitochondrial B-Disease 1
toxicity I-Disease 1
is O 0
an O 0
early O 0
common O 0
event O 0
both O 0
in O 0
paclitaxel B-Chemical 1
and O 0
cisplatin B-Chemical 1
induced O 0
neurotoxicity B-Disease 1
. O 0

Alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
protects O 0
sensory O 0
neurons O 0
through O 0
its O 0
anti O 0
- O 0
oxidant O 0
and O 0
mitochondrial O 0
regulatory O 0
functions O 0
, O 0
possibly O 0
inducing O 0
the O 0
expression O 0
of O 0
frataxin O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
alpha B-Chemical 1
- I-Chemical 1
lipoic I-Chemical 1
acid I-Chemical 1
might O 0
reduce O 0
the O 0
risk O 0
of O 0
developing O 0
peripheral B-Disease 1
nerve I-Disease 1
toxicity I-Disease 1
in O 0
patients O 0
undergoing O 0
chemotherapy O 0
and O 0
encourage O 0
further O 0
confirmatory O 0
clinical O 0
trials O 0
. O 0

Toxicity B-Disease 1
in O 0
rhesus O 0
monkeys O 0
following O 0
administration O 0
of O 0
the O 0
8 B-Chemical 1
- I-Chemical 1
aminoquinoline I-Chemical 1
8 B-Chemical 1
- I-Chemical 1
[ I-Chemical 1
( I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
amino I-Chemical 1
- I-Chemical 1
l I-Chemical 1
- I-Chemical 1
methylbutyl I-Chemical 1
) I-Chemical 1
amino I-Chemical 1
] I-Chemical 1
- I-Chemical 1
5 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
l I-Chemical 1
- I-Chemical 1
hexyloxy I-Chemical 1
) I-Chemical 1
- I-Chemical 1
6 I-Chemical 1
- I-Chemical 1
methoxy I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
methylquinoline I-Chemical 1
( O 0
WR242511 B-Chemical 1
) O 0
. O 0

INTRODUCTION O 0
: O 0
Many O 0
substances O 0
that O 0
form O 0
methemoglobin O 0
( O 0
MHb O 0
) O 0
effectively O 0
counter O 0
cyanide O 0
( O 0
CN O 0
) O 0
toxicity B-Disease 1
. O 0

Although O 0
MHb O 0
formers O 0
are O 0
generally O 0
applied O 0
as O 0
treatments O 0
for O 0
CN O 0
poisoning B-Disease 1
, O 0
it O 0
has O 0
been O 0
proposed O 0
that O 0
a O 0
stable O 0
, O 0
long O 0
- O 0
acting O 0
MHb O 0
former O 0
could O 0
serve O 0
as O 0
a O 0
CN O 0
pretreatment O 0
. O 0

Using O 0
this O 0
rationale O 0
, O 0
the O 0
8 B-Chemical 1
- I-Chemical 1
aminoquinoline I-Chemical 1
WR242511 B-Chemical 1
, O 0
a O 0
potent O 0
long O 0
- O 0
lasting O 0
MHb O 0
former O 0
in O 0
rodents O 0
and O 0
beagle O 0
dogs O 0
, O 0
was O 0
studied O 0
in O 0
the O 0
rhesus O 0
monkey O 0
for O 0
advanced O 0
development O 0
as O 0
a O 0
potential O 0
CN O 0
pretreatment O 0
. O 0

METHODS O 0
: O 0
In O 0
this O 0
study O 0
, O 0
WR242511 B-Chemical 1
was O 0
administered O 0
intravenously O 0
( O 0
IV O 0
) O 0
in O 0
2 O 0
female O 0
and O 0
4 O 0
male O 0
rhesus O 0
monkeys O 0
in O 0
doses O 0
of O 0
3 O 0
. O 0
5 O 0
and O 0
/ O 0
or O 0
7 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
; O 0
a O 0
single O 0
male O 0
also O 0
received O 0
WR242511 B-Chemical 1
orally O 0
( O 0
PO O 0
) O 0
at O 0
7 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
. O 0

Health O 0
status O 0
and O 0
MHb O 0
levels O 0
were O 0
monitored O 0
following O 0
exposure O 0
. O 0

RESULTS O 0
: O 0
The O 0
selected O 0
doses O 0
of O 0
WR242511 B-Chemical 1
, O 0
which O 0
produced O 0
significant O 0
methemoglobinemia B-Disease 1
in O 0
beagle O 0
dogs O 0
in O 0
earlier O 0
studies O 0
conducted O 0
elsewhere O 0
, O 0
produced O 0
very O 0
little O 0
MHb O 0
( O 0
mean O 0
< O 0
2 O 0
. O 0
0 O 0
% O 0
) O 0
in O 0
the O 0
rhesus O 0
monkey O 0
. O 0

Furthermore O 0
, O 0
transient O 0
hemoglobinuria B-Disease 1
was O 0
noted O 0
approximately O 0
60 O 0
minutes O 0
postinjection O 0
of O 0
WR242511 B-Chemical 1
( O 0
3 O 0
. O 0
5 O 0
or O 0
7 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
) O 0
, O 0
and O 0
2 O 0
lethalities O 0
occurred O 0
( O 0
one O 0
IV O 0
and O 0
one O 0
PO O 0
) O 0
following O 0
the O 0
7 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
dose O 0
. O 0

Myoglobinuria B-Disease 1
was O 0
also O 0
observed O 0
following O 0
the O 0
7 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
dose O 0
. O 0

Histopathology O 0
analyses O 0
in O 0
the O 0
2 O 0
animals O 0
that O 0
died O 0
revealed O 0
liver B-Disease 1
and I-Disease 1
kidney I-Disease 1
toxicity I-Disease 1
, O 0
with O 0
greater O 0
severity O 0
in O 0
the O 0
orally O 0
- O 0
treated O 0
animal O 0
. O 0

CONCLUSIONS O 0
: O 0
These O 0
data O 0
demonstrate O 0
direct O 0
and O 0
/ O 0
or O 0
indirect O 0
drug O 0
- O 0
induced O 0
toxicity B-Disease 1
. O 0

It O 0
is O 0
concluded O 0
that O 0
WR242511 B-Chemical 1
should O 0
not O 0
be O 0
pursued O 0
as O 0
a O 0
pretreatment O 0
for O 0
CN O 0
poisoning B-Disease 1
unless O 0
the O 0
anti O 0
- O 0
CN O 0
characteristics O 0
of O 0
this O 0
compound O 0
can O 0
be O 0
successfully O 0
dissociated O 0
from O 0
those O 0
producing O 0
undesirable O 0
toxicity B-Disease 1
. O 0

Repetitive O 0
transcranial O 0
magnetic O 0
stimulation O 0
for O 0
levodopa B-Chemical 1
- O 0
induced O 0
dyskinesias B-Disease 1
in O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

In O 0
a O 0
placebo O 0
- O 0
controlled O 0
, O 0
single O 0
- O 0
blinded O 0
, O 0
crossover O 0
study O 0
, O 0
we O 0
assessed O 0
the O 0
effect O 0
of O 0
" O 0
real O 0
" O 0
repetitive O 0
transcranial O 0
magnetic O 0
stimulation O 0
( O 0
rTMS O 0
) O 0
versus O 0
" O 0
sham O 0
" O 0
rTMS O 0
( O 0
placebo O 0
) O 0
on O 0
peak O 0
dose O 0
dyskinesias B-Disease 1
in O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
( O 0
PD B-Disease 1
) O 0
. O 0

Ten O 0
patients O 0
with O 0
PD B-Disease 1
and O 0
prominent O 0
dyskinesias B-Disease 1
had O 0
rTMS O 0
( O 0
1 O 0
, O 0
800 O 0
pulses O 0
; O 0
1 O 0
Hz O 0
rate O 0
) O 0
delivered O 0
over O 0
the O 0
motor O 0
cortex O 0
for O 0
4 O 0
consecutive O 0
days O 0
twice O 0
, O 0
once O 0
real O 0
stimuli O 0
and O 0
once O 0
sham O 0
stimulation O 0
were O 0
used O 0
; O 0
evaluations O 0
were O 0
done O 0
at O 0
the O 0
baseline O 0
and O 0
1 O 0
day O 0
after O 0
the O 0
end O 0
of O 0
each O 0
of O 0
the O 0
treatment O 0
series O 0
. O 0

Direct O 0
comparison O 0
between O 0
sham O 0
and O 0
real O 0
rTMS O 0
effects O 0
showed O 0
no O 0
significant O 0
difference O 0
in O 0
clinician O 0
- O 0
assessed O 0
dyskinesia B-Disease 1
severity O 0
. O 0

However O 0
, O 0
comparison O 0
with O 0
the O 0
baseline O 0
showed O 0
small O 0
but O 0
significant O 0
reduction O 0
in O 0
dyskinesia B-Disease 1
severity O 0
following O 0
real O 0
rTMS O 0
but O 0
not O 0
placebo O 0
. O 0

The O 0
major O 0
effect O 0
was O 0
on O 0
dystonia B-Disease 1
subscore O 0
. O 0

Similarly O 0
, O 0
in O 0
patient O 0
diaries O 0
, O 0
although O 0
both O 0
treatments O 0
caused O 0
reduction O 0
in O 0
subjective O 0
dyskinesia B-Disease 1
scores O 0
during O 0
the O 0
days O 0
of O 0
intervention O 0
, O 0
the O 0
effect O 0
was O 0
sustained O 0
for O 0
3 O 0
days O 0
after O 0
the O 0
intervention O 0
for O 0
the O 0
real O 0
rTMS O 0
only O 0
. O 0

Following O 0
rTMS O 0
, O 0
no O 0
side O 0
effects O 0
and O 0
no O 0
adverse O 0
effects O 0
on O 0
motor O 0
function O 0
and O 0
PD B-Disease 1
symptoms O 0
were O 0
noted O 0
. O 0

The O 0
results O 0
suggest O 0
the O 0
existence O 0
of O 0
residual O 0
beneficial O 0
clinical O 0
aftereffects O 0
of O 0
consecutive O 0
daily O 0
applications O 0
of O 0
low O 0
- O 0
frequency O 0
rTMS O 0
on O 0
dyskinesias B-Disease 1
in O 0
PD B-Disease 1
. O 0

The O 0
effects O 0
may O 0
be O 0
further O 0
exploited O 0
for O 0
potential O 0
therapeutic O 0
uses O 0
. O 0

Intracavernous O 0
epinephrine B-Chemical 1
: O 0
a O 0
minimally O 0
invasive O 0
treatment O 0
for O 0
priapism B-Disease 1
in O 0
the O 0
emergency O 0
department O 0
. O 0

Priapism B-Disease 1
is O 0
the O 0
prolonged O 0
erection O 0
of O 0
the O 0
penis O 0
in O 0
the O 0
absence O 0
of O 0
sexual O 0
arousal O 0
. O 0

A O 0
45 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
, O 0
an O 0
admitted O 0
frequent O 0
cocaine B-Chemical 1
user O 0
, O 0
presented O 0
to O 0
the O 0
Emergency O 0
Department O 0
( O 0
ED O 0
) O 0
on O 0
two O 0
separate O 0
occasions O 0
with O 0
a O 0
history O 0
of O 0
priapism B-Disease 1
after O 0
cocaine B-Chemical 1
use O 0
. O 0

The O 0
management O 0
options O 0
in O 0
the O 0
ED O 0
, O 0
as O 0
exemplified O 0
by O 0
four O 0
individual O 0
case O 0
reports O 0
, O 0
in O 0
particular O 0
the O 0
use O 0
of O 0
a O 0
minimally O 0
invasive O 0
method O 0
of O 0
intracorporal O 0
epinephrine B-Chemical 1
instillation O 0
, O 0
are O 0
discussed O 0
. O 0

Prophylactic O 0
use O 0
of O 0
lamivudine B-Chemical 1
with O 0
chronic O 0
immunosuppressive O 0
therapy O 0
for O 0
rheumatologic B-Disease 1
disorders I-Disease 1
. O 0

The O 0
objective O 0
of O 0
this O 0
study O 0
was O 0
to O 0
report O 0
our O 0
experience O 0
concerning O 0
the O 0
effectiveness O 0
of O 0
the O 0
prophylactic O 0
administration O 0
of O 0
lamivudine B-Chemical 1
in O 0
hepatitis B-Chemical 1
B I-Chemical 1
virus I-Chemical 1
surface I-Chemical 1
antigen I-Chemical 1
( O 0
HBs B-Chemical 1
Ag I-Chemical 1
) O 0
positive O 0
patients O 0
with O 0
rheumatologic B-Disease 1
disease I-Disease 1
. O 0

From O 0
June O 0
2004 O 0
to O 0
October O 0
2006 O 0
, O 0
11 O 0
HBs B-Chemical 1
Ag I-Chemical 1
positive O 0
patients O 0
with O 0
rheumatologic B-Disease 1
diseases I-Disease 1
, O 0
who O 0
were O 0
on O 0
both O 0
immunosuppressive O 0
and O 0
prophylactic O 0
lamivudine B-Chemical 1
therapies O 0
, O 0
were O 0
retrospectively O 0
assessed O 0
. O 0

Liver O 0
function O 0
tests O 0
, O 0
hepatitis B-Disease 1
B I-Disease 1
virus O 0
( O 0
HBV O 0
) O 0
serologic O 0
markers O 0
, O 0
and O 0
HBV O 0
DNA O 0
levels O 0
of O 0
the O 0
patients O 0
during O 0
follow O 0
- O 0
up O 0
were O 0
obtained O 0
from O 0
hospital O 0
file O 0
records O 0
. O 0

Eleven O 0
patients O 0
( O 0
six O 0
male O 0
) O 0
with O 0
median O 0
age O 0
47 O 0
years O 0
( O 0
range O 0
27 O 0
- O 0
73 O 0
) O 0
, O 0
median O 0
disease O 0
duration O 0
50 O 0
months O 0
( O 0
range O 0
9 O 0
- O 0
178 O 0
) O 0
and O 0
median O 0
follow O 0
- O 0
up O 0
period O 0
of O 0
patients O 0
13 O 0
. O 0
8 O 0
months O 0
( O 0
range O 0
5 O 0
- O 0
27 O 0
) O 0
were O 0
enrolled O 0
in O 0
this O 0
study O 0
. O 0

Lamivudine B-Chemical 1
therapy O 0
was O 0
started O 0
3 O 0
- O 0
7 O 0
days O 0
prior O 0
to O 0
immunosuppressive O 0
therapy O 0
in O 0
all O 0
patients O 0
. O 0

Baseline O 0
, O 0
liver O 0
function O 0
tests O 0
were O 0
elevated O 0
in O 0
two O 0
patients O 0
( O 0
fourth O 0
patient O 0
: O 0
ALT O 0
: O 0
122 O 0
IU O 0
/ O 0
l O 0
, O 0
AST O 0
: O 0
111 O 0
IU O 0
/ O 0
l O 0
, O 0
tenth O 0
patient O 0
: O 0
ALT O 0
: O 0
294 O 0
IU O 0
/ O 0
l O 0
, O 0
AST O 0
: O 0
274 O 0
IU O 0
/ O 0
l O 0
, O 0
with O 0
minimal O 0
changes O 0
in O 0
the O 0
liver O 0
biopsy O 0
in O 0
both O 0
) O 0
. O 0

Shortly O 0
after O 0
treatment O 0
their O 0
tests O 0
normalized O 0
and O 0
during O 0
follow O 0
- O 0
up O 0
period O 0
none O 0
of O 0
the O 0
patients O 0
had O 0
abnormal B-Disease 1
liver I-Disease 1
function I-Disease 1
tests O 0
. O 0

In O 0
four O 0
patients O 0
HBV O 0
DNA O 0
levels O 0
were O 0
higher O 0
than O 0
normal O 0
at O 0
baseline O 0
. O 0

Two O 0
of O 0
these O 0
normalized O 0
and O 0
the O 0
others O 0
increased O 0
later O 0
. O 0

In O 0
three O 0
additional O 0
patients O 0
, O 0
HBV O 0
DNA O 0
levels O 0
were O 0
increased O 0
during O 0
follow O 0
- O 0
up O 0
. O 0

None O 0
of O 0
the O 0
patients O 0
had O 0
significant O 0
clinical O 0
sings O 0
of O 0
HBV O 0
activation O 0
. O 0

Lamivudine B-Chemical 1
was O 0
well O 0
tolerated O 0
and O 0
was O 0
continued O 0
in O 0
all O 0
patients O 0
. O 0

Prophylactic O 0
administration O 0
of O 0
lamivudine B-Chemical 1
in O 0
patients O 0
who O 0
required O 0
immunosuppressive O 0
therapy O 0
seems O 0
to O 0
be O 0
safe O 0
, O 0
well O 0
tolerated O 0
and O 0
effective O 0
in O 0
preventing O 0
HBV O 0
reactivation O 0
. O 0

Effect O 0
of O 0
green B-Chemical 1
tea I-Chemical 1
and O 0
vitamin B-Chemical 1
E I-Chemical 1
combination O 0
in O 0
isoproterenol B-Chemical 1
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

The O 0
present O 0
study O 0
was O 0
aimed O 0
to O 0
investigate O 0
the O 0
combined O 0
effects O 0
of O 0
green B-Chemical 1
tea I-Chemical 1
and O 0
vitamin B-Chemical 1
E I-Chemical 1
on O 0
heart O 0
weight O 0
, O 0
body O 0
weight O 0
, O 0
serum O 0
marker O 0
enzymes O 0
, O 0
lipid O 0
peroxidation O 0
, O 0
endogenous O 0
antioxidants O 0
and O 0
membrane O 0
bound O 0
ATPases O 0
in O 0
isoproterenol B-Chemical 1
( O 0
ISO B-Chemical 1
) O 0
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

Adult O 0
male O 0
albino O 0
rats O 0
, O 0
treated O 0
with O 0
ISO B-Chemical 1
( O 0
200 O 0
mg O 0
/ O 0
kg O 0
, O 0
s O 0
. O 0
c O 0
. O 0
) O 0
for O 0
2 O 0
days O 0
at O 0
an O 0
interval O 0
of O 0
24 O 0
h O 0
caused O 0
a O 0
significant O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
elevation O 0
of O 0
heart O 0
weight O 0
, O 0
serum O 0
marker O 0
enzymes O 0
, O 0
lipid O 0
peroxidation O 0
and O 0
Ca B-Chemical 1
+ O 0
2 O 0
ATPase O 0
level O 0
whereas O 0
there O 0
was O 0
a O 0
significant O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
decrease O 0
in O 0
body O 0
weight O 0
, O 0
endogenous O 0
antioxidants O 0
, O 0
Na B-Chemical 1
+ O 0
/ O 0
K B-Chemical 1
+ O 0
ATPase O 0
and O 0
Mg B-Chemical 1
+ O 0
2 O 0
ATPase O 0
levels O 0
. O 0

Administration O 0
of O 0
green B-Chemical 1
tea I-Chemical 1
( O 0
100 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
, O 0
p O 0
. O 0
o O 0
. O 0
) O 0
and O 0
vitamin B-Chemical 1
E I-Chemical 1
( O 0
100 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
, O 0
p O 0
. O 0
o O 0
. O 0
) O 0
together O 0
for O 0
30 O 0
consecutive O 0
days O 0
and O 0
challenged O 0
with O 0
ISO B-Chemical 1
on O 0
the O 0
day O 0
29th O 0
and O 0
30th O 0
, O 0
showed O 0
a O 0
significant O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
decrease O 0
in O 0
heart O 0
weight O 0
, O 0
serum O 0
marker O 0
enzymes O 0
, O 0
lipid O 0
peroxidation O 0
, O 0
Ca B-Chemical 1
+ O 0
2 O 0
ATPase O 0
and O 0
a O 0
significant O 0
increase O 0
in O 0
the O 0
body O 0
weight O 0
, O 0
endogenous O 0
antioxidants O 0
, O 0
Na B-Chemical 1
+ O 0
/ O 0
K B-Chemical 1
+ O 0
ATPase O 0
and O 0
Mg B-Chemical 1
+ O 0
2 O 0
ATPase O 0
when O 0
compared O 0
with O 0
ISO B-Chemical 1
treated O 0
group O 0
and O 0
green B-Chemical 1
tea I-Chemical 1
or O 0
vitamin B-Chemical 1
E I-Chemical 1
alone O 0
treated O 0
groups O 0
. O 0

These O 0
findings O 0
indicate O 0
the O 0
synergistic O 0
protective O 0
effect O 0
of O 0
green B-Chemical 1
tea I-Chemical 1
and O 0
vitamin B-Chemical 1
E I-Chemical 1
during O 0
ISO B-Chemical 1
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

Irreversible O 0
damage O 0
to O 0
the O 0
medullary O 0
interstitium O 0
in O 0
experimental O 0
analgesic O 0
nephropathy B-Disease 1
in O 0
F344 O 0
rats O 0
. O 0

Renal B-Disease 1
papillary I-Disease 1
necrosis I-Disease 1
( O 0
RPN B-Disease 1
) O 0
and O 0
a O 0
decreased O 0
urinary O 0
concentrating O 0
ability O 0
developed O 0
during O 0
continuous O 0
long O 0
- O 0
term O 0
treatment O 0
with O 0
aspirin B-Chemical 1
and O 0
paracetamol B-Chemical 1
in O 0
female O 0
Fischer O 0
344 O 0
rats O 0
. O 0

Renal O 0
structure O 0
and O 0
concentrating O 0
ability O 0
were O 0
examined O 0
after O 0
a O 0
recovery O 0
period O 0
of O 0
up O 0
to O 0
18 O 0
weeks O 0
, O 0
when O 0
no O 0
analgesics O 0
were O 0
given O 0
, O 0
to O 0
investigate O 0
whether O 0
the O 0
analgesic O 0
- O 0
induced O 0
changes O 0
were O 0
reversible O 0
. O 0

There O 0
was O 0
no O 0
evidence O 0
of O 0
repair O 0
to O 0
the O 0
damaged O 0
medullary O 0
interstitial O 0
matrix O 0
, O 0
or O 0
proliferation O 0
of O 0
remaining O 0
undamaged O 0
type O 0
1 O 0
medullary O 0
interstitial O 0
cells O 0
after O 0
the O 0
recovery O 0
period O 0
following O 0
analgesic O 0
treatment O 0
. O 0

The O 0
recovery O 0
of O 0
urinary O 0
concentrating O 0
ability O 0
was O 0
related O 0
to O 0
the O 0
length O 0
of O 0
analgesic O 0
treatment O 0
and O 0
the O 0
extent O 0
of O 0
the O 0
resulting O 0
inner O 0
medullary O 0
structural O 0
damage O 0
. O 0

During O 0
the O 0
early O 0
stages O 0
of O 0
analgesic O 0
treatment O 0
, O 0
the O 0
changes O 0
in O 0
urinary O 0
concentrating O 0
ability O 0
were O 0
reversible O 0
, O 0
but O 0
after O 0
prolonged O 0
analgesic O 0
treatment O 0
, O 0
maximum O 0
urinary O 0
concentrating O 0
ability O 0
failed O 0
to O 0
recover O 0
. O 0

This O 0
study O 0
shows O 0
that O 0
prolonged O 0
analgesic O 0
treatment O 0
in O 0
Fischer O 0
344 O 0
rats O 0
causes O 0
progressive O 0
and O 0
irreversible O 0
damage O 0
to O 0
the O 0
interstitial O 0
matrix O 0
and O 0
type O 0
1 O 0
interstitial O 0
cells O 0
leading O 0
to O 0
RPN B-Disease 1
. O 0

The O 0
associated O 0
urinary O 0
concentrating O 0
defect O 0
is O 0
reversible O 0
only O 0
during O 0
the O 0
early O 0
stages O 0
of O 0
structural O 0
damage O 0
to O 0
the O 0
inner O 0
medulla O 0
. O 0

Testosterone B-Chemical 1
- O 0
dependent O 0
hypertension B-Disease 1
and O 0
upregulation O 0
of O 0
intrarenal O 0
angiotensinogen O 0
in O 0
Dahl O 0
salt B-Chemical 1
- O 0
sensitive O 0
rats O 0
. O 0

Blood O 0
pressure O 0
( O 0
BP O 0
) O 0
is O 0
more O 0
salt B-Chemical 1
sensitive O 0
in O 0
men O 0
than O 0
in O 0
premenopausal O 0
women O 0
. O 0

In O 0
Dahl O 0
salt B-Chemical 1
- O 0
sensitive O 0
rats O 0
( O 0
DS O 0
) O 0
, O 0
high O 0
- O 0
salt B-Chemical 1
( O 0
HS O 0
) O 0
diet O 0
increases O 0
BP O 0
more O 0
in O 0
males O 0
than O 0
females O 0
. O 0

In O 0
contrast O 0
to O 0
the O 0
systemic O 0
renin O 0
- O 0
angiotensin B-Chemical 1
system O 0
, O 0
which O 0
is O 0
suppressed O 0
in O 0
response O 0
to O 0
HS O 0
in O 0
male O 0
DS O 0
, O 0
intrarenal O 0
angiotensinogen O 0
expression O 0
is O 0
increased O 0
, O 0
and O 0
intrarenal O 0
levels O 0
of O 0
ANG O 0
II O 0
are O 0
not O 0
suppressed O 0
. O 0

In O 0
this O 0
study O 0
, O 0
the O 0
hypothesis O 0
was O 0
tested O 0
that O 0
there O 0
is O 0
a O 0
sexual O 0
dimorphism O 0
in O 0
HS O 0
- O 0
induced O 0
upregulation O 0
of O 0
intrarenal O 0
angiotensinogen O 0
mediated O 0
by O 0
testosterone B-Chemical 1
that O 0
also O 0
causes O 0
increases O 0
in O 0
BP O 0
and O 0
renal B-Disease 1
injury I-Disease 1
. O 0

On O 0
a O 0
low O 0
- O 0
salt B-Chemical 1
( O 0
LS O 0
) O 0
diet O 0
, O 0
male O 0
DS O 0
had O 0
higher O 0
levels O 0
of O 0
intrarenal O 0
angiotensinogen O 0
mRNA O 0
than O 0
females O 0
. O 0

HS O 0
diet O 0
for O 0
4 O 0
wk O 0
increased O 0
renal O 0
cortical O 0
angiotensinogen O 0
mRNA O 0
and O 0
protein O 0
only O 0
in O 0
male O 0
DS O 0
, O 0
which O 0
was O 0
prevented O 0
by O 0
castration O 0
. O 0

Ovariectomy O 0
of O 0
female O 0
DS O 0
had O 0
no O 0
effect O 0
on O 0
intrarenal O 0
angiotensinogen O 0
expression O 0
on O 0
either O 0
diet O 0
. O 0

Radiotelemetric O 0
BP O 0
was O 0
similar O 0
between O 0
males O 0
and O 0
castrated O 0
rats O 0
on O 0
LS O 0
diet O 0
. O 0

HS O 0
diet O 0
for O 0
4 O 0
wk O 0
caused O 0
a O 0
progressive O 0
increase O 0
in O 0
BP O 0
, O 0
protein O 0
and O 0
albumin O 0
excretion O 0
, O 0
and O 0
glomerular B-Disease 1
sclerosis I-Disease 1
in O 0
male O 0
DS O 0
rats O 0
, O 0
which O 0
were O 0
attenuated O 0
by O 0
castration O 0
. O 0

Testosterone B-Chemical 1
replacement O 0
in O 0
castrated O 0
DS O 0
rats O 0
increased O 0
BP O 0
, O 0
renal B-Disease 1
injury I-Disease 1
, O 0
and O 0
upregulation O 0
of O 0
renal O 0
angiotensinogen O 0
associated O 0
with O 0
HS O 0
diet O 0
. O 0

Testosterone B-Chemical 1
contributes O 0
to O 0
the O 0
development O 0
of O 0
hypertension B-Disease 1
and O 0
renal B-Disease 1
injury I-Disease 1
in O 0
male O 0
DS O 0
rats O 0
on O 0
HS O 0
diet O 0
possibly O 0
through O 0
upregulation O 0
of O 0
the O 0
intrarenal O 0
renin O 0
- O 0
angiotensin B-Chemical 1
system O 0
. O 0

Explicit O 0
episodic O 0
memory O 0
for O 0
sensory O 0
- O 0
discriminative O 0
components O 0
of O 0
capsaicin B-Chemical 1
- O 0
induced O 0
pain B-Disease 1
: O 0
immediate O 0
and O 0
delayed O 0
ratings O 0
. O 0

Pain B-Disease 1
memory O 0
is O 0
thought O 0
to O 0
affect O 0
future O 0
pain B-Disease 1
sensitivity O 0
and O 0
thus O 0
contribute O 0
to O 0
clinical O 0
pain B-Disease 1
conditions O 0
. O 0

Systematic O 0
investigations O 0
of O 0
the O 0
human O 0
capacity O 0
to O 0
remember O 0
sensory O 0
features O 0
of O 0
experimental O 0
pain B-Disease 1
are O 0
sparse O 0
. O 0

In O 0
order O 0
to O 0
address O 0
long O 0
- O 0
term O 0
pain B-Disease 1
memory O 0
, O 0
nine O 0
healthy O 0
male O 0
volunteers O 0
received O 0
intradermal O 0
injections O 0
of O 0
three O 0
doses O 0
of O 0
capsaicin B-Chemical 1
( O 0
0 O 0
. O 0
05 O 0
, O 0
1 O 0
and O 0
20 O 0
microg O 0
, O 0
separated O 0
by O 0
15 O 0
min O 0
breaks O 0
) O 0
, O 0
each O 0
given O 0
three O 0
times O 0
in O 0
a O 0
balanced O 0
design O 0
across O 0
three O 0
sessions O 0
at O 0
one O 0
week O 0
intervals O 0
. O 0

Pain B-Disease 1
rating O 0
was O 0
performed O 0
using O 0
a O 0
computerized O 0
visual O 0
analogue O 0
scale O 0
( O 0
0 O 0
- O 0
100 O 0
) O 0
digitized O 0
at O 0
1 O 0
/ O 0
s O 0
, O 0
either O 0
immediately O 0
online O 0
or O 0
one O 0
hour O 0
or O 0
one O 0
day O 0
after O 0
injection O 0
. O 0

Subjects O 0
also O 0
recalled O 0
their O 0
pains B-Disease 1
one O 0
week O 0
later O 0
. O 0

Capsaicin B-Chemical 1
injection O 0
reliably O 0
induced O 0
a O 0
dose O 0
- O 0
dependent O 0
flare O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
without O 0
any O 0
difference O 0
within O 0
or O 0
across O 0
sessions O 0
. O 0

The O 0
strong O 0
burning O 0
pain B-Disease 1
decayed O 0
exponentially O 0
within O 0
a O 0
few O 0
minutes O 0
. O 0

Subjects O 0
were O 0
able O 0
to O 0
reliably O 0
discriminate O 0
pain B-Disease 1
magnitude O 0
and O 0
duration O 0
across O 0
capsaicin B-Chemical 1
doses O 0
( O 0
both O 0
p O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
regardless O 0
of O 0
whether O 0
first O 0
- O 0
time O 0
ratings O 0
were O 0
requested O 0
immediately O 0
, O 0
after O 0
one O 0
hour O 0
or O 0
after O 0
one O 0
day O 0
. O 0

Pain B-Disease 1
recall O 0
after O 0
one O 0
week O 0
was O 0
similarly O 0
precise O 0
( O 0
magnitude O 0
: O 0
p O 0
< O 0
0 O 0
. O 0
01 O 0
, O 0
duration O 0
: O 0
p O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Correlation O 0
with O 0
rating O 0
recall O 0
after O 0
one O 0
week O 0
was O 0
best O 0
when O 0
first O 0
- O 0
time O 0
ratings O 0
were O 0
requested O 0
as O 0
late O 0
as O 0
one O 0
day O 0
after O 0
injection O 0
( O 0
R O 0
( O 0
2 O 0
) O 0
= O 0
0 O 0
. O 0
79 O 0
) O 0
indicating O 0
that O 0
both O 0
rating O 0
retrievals O 0
utilized O 0
similar O 0
memory O 0
traces O 0
. O 0

These O 0
results O 0
indicate O 0
a O 0
reliable O 0
memory O 0
for O 0
magnitude O 0
and O 0
duration O 0
of O 0
experimentally O 0
induced O 0
pain B-Disease 1
. O 0

The O 0
data O 0
further O 0
suggest O 0
that O 0
the O 0
consolidation O 0
of O 0
this O 0
memory O 0
is O 0
an O 0
important O 0
interim O 0
stage O 0
, O 0
and O 0
may O 0
take O 0
up O 0
to O 0
one O 0
day O 0
. O 0

Severe O 0
and O 0
long O 0
lasting O 0
cholestasis B-Disease 1
after O 0
high O 0
- O 0
dose O 0
co B-Chemical 1
- I-Chemical 1
trimoxazole I-Chemical 1
treatment O 0
for O 0
Pneumocystis B-Disease 1
pneumonia I-Disease 1
in O 0
HIV B-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
- O 0
- O 0
a O 0
report O 0
of O 0
two O 0
cases O 0
. O 0

Pneumocystis B-Disease 1
pneumonia I-Disease 1
( O 0
PCP B-Disease 1
) O 0
, O 0
a O 0
common O 0
opportunistic B-Disease 1
infection I-Disease 1
in O 0
HIV B-Disease 1
- I-Disease 1
infected I-Disease 1
individuals O 0
, O 0
is O 0
generally O 0
treated O 0
with O 0
high O 0
doses O 0
of O 0
co B-Chemical 1
- I-Chemical 1
trimoxazole I-Chemical 1
. O 0

However O 0
, O 0
treatment O 0
is O 0
often O 0
limited O 0
by O 0
adverse O 0
effects O 0
. O 0

Here O 0
, O 0
we O 0
report O 0
two O 0
cases O 0
of O 0
severely O 0
immunocompromised O 0
HIV B-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
who O 0
developed O 0
severe O 0
intrahepatic B-Disease 1
cholestasis I-Disease 1
, O 0
and O 0
in O 0
one O 0
patient O 0
lesions O 0
mimicking O 0
liver B-Disease 1
abscess I-Disease 1
formation O 0
on O 0
radiologic O 0
exams O 0
, O 0
during O 0
co B-Chemical 1
- I-Chemical 1
trimoxazole I-Chemical 1
treatment O 0
for O 0
PCP B-Disease 1
. O 0

Whereas O 0
patient O 0
1 O 0
showed O 0
lesions O 0
of O 0
up O 0
to O 0
1 O 0
cm O 0
readily O 0
detectable O 0
on O 0
magnetic O 0
resonance O 0
imaging O 0
under O 0
prolonged O 0
co B-Chemical 1
- I-Chemical 1
trimoxazole I-Chemical 1
treatment O 0
, O 0
therapy O 0
of O 0
patient O 0
2 O 0
was O 0
switched O 0
early O 0
. O 0

Bradykinin B-Chemical 1
receptors O 0
antagonists O 0
and O 0
nitric B-Chemical 1
oxide I-Chemical 1
synthase O 0
inhibitors O 0
in O 0
vincristine B-Chemical 1
and O 0
streptozotocin B-Chemical 1
induced O 0
hyperalgesia B-Disease 1
in O 0
chemotherapy O 0
and O 0
diabetic B-Disease 1
neuropathy I-Disease 1
rat O 0
model O 0
. O 0

PURPOSE O 0
: O 0
The O 0
influence O 0
of O 0
an O 0
irreversible O 0
inhibitor O 0
of O 0
constitutive O 0
NO B-Chemical 1
synthase O 0
( O 0
L O 0
- O 0
NOArg O 0
; O 0
1 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
ip O 0
) O 0
, O 0
a O 0
relatively O 0
selective O 0
inhibitor O 0
of O 0
inducible O 0
NO B-Chemical 1
synthase O 0
( O 0
L O 0
- O 0
NIL O 0
; O 0
1 O 0
. O 0
0 O 0
mg O 0
/ O 0
kg O 0
ip O 0
) O 0
and O 0
a O 0
relatively O 0
specific O 0
inhibitor O 0
of O 0
neuronal O 0
NO B-Chemical 1
synthase O 0
( O 0
7 O 0
- O 0
NI O 0
; O 0
0 O 0
. O 0
1 O 0
mg O 0
/ O 0
kg O 0
ip O 0
) O 0
, O 0
on O 0
antihyperalgesic O 0
action O 0
of O 0
selective O 0
antagonists O 0
of O 0
B2 O 0
and O 0
B1 O 0
receptors O 0
: O 0
D O 0
- O 0
Arg O 0
- O 0
[ O 0
Hyp3 O 0
, O 0
Thi5 O 0
, O 0
D O 0
- O 0
Tic7 O 0
, O 0
Oic8 O 0
] O 0
bradykinin B-Chemical 1
( O 0
HOE B-Chemical 1
140 I-Chemical 1
; O 0
70 O 0
nmol O 0
/ O 0
kg O 0
ip O 0
) O 0
or O 0
des B-Chemical 1
Arg10 I-Chemical 1
HOE I-Chemical 1
140 I-Chemical 1
( O 0
70 O 0
nmol O 0
/ O 0
kg O 0
ip O 0
) O 0
respectively O 0
, O 0
in O 0
model O 0
of O 0
diabetic B-Disease 1
( I-Disease 1
streptozotocin I-Disease 1
- I-Disease 1
induced I-Disease 1
) I-Disease 1
and I-Disease 1
toxic I-Disease 1
( I-Disease 1
vincristine I-Disease 1
- I-Disease 1
induced I-Disease 1
) I-Disease 1
neuropathy I-Disease 1
was O 0
investigated O 0
. O 0

METHODS O 0
: O 0
The O 0
changes O 0
in O 0
pain B-Disease 1
thresholds O 0
were O 0
determined O 0
using O 0
mechanical O 0
stimuli O 0
- O 0
- O 0
the O 0
modification O 0
of O 0
the O 0
classic O 0
paw O 0
withdrawal O 0
test O 0
described O 0
by O 0
Randall O 0
- O 0
Selitto O 0
. O 0

RESULTS O 0
: O 0
The O 0
results O 0
of O 0
this O 0
paper O 0
confirm O 0
that O 0
inhibition O 0
of O 0
bradykinin B-Chemical 1
receptors O 0
and O 0
inducible O 0
NO B-Chemical 1
synthase O 0
but O 0
not O 0
neuronal O 0
NO B-Chemical 1
synthase O 0
activity O 0
reduces O 0
diabetic B-Disease 1
hyperalgesia I-Disease 1
. O 0

Pretreatment O 0
with O 0
L O 0
- O 0
NOArg O 0
and O 0
L O 0
- O 0
NIL O 0
but O 0
not O 0
7 O 0
- O 0
NI O 0
, O 0
significantly O 0
increases O 0
antihyperalgesic O 0
activity O 0
both O 0
HOE B-Chemical 1
140 I-Chemical 1
and O 0
des B-Chemical 1
Arg10 I-Chemical 1
HOE I-Chemical 1
140 I-Chemical 1
. O 0

It O 0
was O 0
also O 0
shown O 0
that O 0
both O 0
products O 0
of O 0
inducible O 0
NO B-Chemical 1
synthase O 0
and O 0
neuronal O 0
NO B-Chemical 1
synthase O 0
activation O 0
as O 0
well O 0
as O 0
bradykinin B-Chemical 1
are O 0
involved O 0
in O 0
hyperalgesia B-Disease 1
produced O 0
by O 0
vincristine B-Chemical 1
. O 0

Moreover O 0
, O 0
L O 0
- O 0
NOArg O 0
and O 0
7 O 0
- O 0
NI O 0
but O 0
not O 0
L O 0
- O 0
NIL O 0
intensify O 0
antihyperalgesic O 0
activity O 0
of O 0
HOE B-Chemical 1
140 I-Chemical 1
or O 0
des B-Chemical 1
- I-Chemical 1
Arg10HOE I-Chemical 1
140 I-Chemical 1
in O 0
toxic B-Disease 1
neuropathy I-Disease 1
. O 0

CONCLUSIONS O 0
: O 0
Results O 0
of O 0
these O 0
studies O 0
suggest O 0
that O 0
B1 O 0
and O 0
B2 O 0
receptors O 0
are O 0
engaged O 0
in O 0
transmission O 0
of O 0
nociceptive O 0
stimuli O 0
in O 0
both O 0
diabetic B-Disease 1
and I-Disease 1
toxic I-Disease 1
neuropathy I-Disease 1
. O 0

In O 0
streptozotocin B-Chemical 1
- O 0
induced O 0
hyperalgesia B-Disease 1
, O 0
inducible O 0
NO B-Chemical 1
synthase O 0
participates O 0
in O 0
pronociceptive O 0
activity O 0
of O 0
bradykinin B-Chemical 1
, O 0
whereas O 0
in O 0
vincristine B-Chemical 1
- O 0
induced O 0
hyperalgesia B-Disease 1
bradykinin B-Chemical 1
seemed O 0
to O 0
activate O 0
neuronal O 0
NO B-Chemical 1
synthase O 0
pathway O 0
. O 0

Therefore O 0
, O 0
concomitant O 0
administration O 0
of O 0
small O 0
doses O 0
of O 0
bradykinin B-Chemical 1
receptor O 0
antagonists O 0
and O 0
NO B-Chemical 1
synthase O 0
inhibitors O 0
can O 0
be O 0
effective O 0
in O 0
alleviation O 0
of O 0
neuropathic B-Disease 1
pain I-Disease 1
, O 0
even O 0
in O 0
hospital O 0
care O 0
. O 0

Confusion B-Disease 1
, O 0
a O 0
rather O 0
serious O 0
adverse O 0
drug O 0
reaction O 0
with O 0
valproic B-Chemical 1
acid I-Chemical 1
: O 0
a O 0
review O 0
of O 0
the O 0
French O 0
Pharmacovigilance O 0
database O 0
. O 0

INTRODUCTION O 0
: O 0
Confusion B-Disease 1
is O 0
an O 0
adverse O 0
drug O 0
reaction O 0
frequently O 0
observed O 0
with O 0
valproic B-Chemical 1
acid I-Chemical 1
. O 0

Some O 0
case O 0
reports O 0
are O 0
published O 0
in O 0
the O 0
literature O 0
but O 0
no O 0
systematic O 0
study O 0
from O 0
a O 0
sample O 0
of O 0
patients O 0
has O 0
been O 0
published O 0
. O 0

We O 0
performed O 0
this O 0
study O 0
in O 0
order O 0
to O 0
describe O 0
the O 0
main O 0
characteristics O 0
of O 0
this O 0
adverse O 0
drug O 0
reaction O 0
. O 0

METHODS O 0
: O 0
Using O 0
the O 0
French O 0
Pharmacovigilance O 0
database O 0
, O 0
we O 0
selected O 0
the O 0
cases O 0
of O 0
confusion B-Disease 1
reported O 0
since O 0
1985 O 0
with O 0
valproic B-Chemical 1
acid I-Chemical 1
. O 0

RESULTS O 0
: O 0
272 O 0
cases O 0
of O 0
confusion B-Disease 1
were O 0
reported O 0
with O 0
valproic B-Chemical 1
acid I-Chemical 1
: O 0
153 O 0
women O 0
and O 0
119 O 0
men O 0
. O 0

Confusion B-Disease 1
mostly O 0
occurred O 0
during O 0
the O 0
two O 0
first O 0
weeks O 0
following O 0
valproic B-Chemical 1
acid I-Chemical 1
exposure O 0
( O 0
39 O 0
. O 0
7 O 0
% O 0
) O 0
. O 0

It O 0
was O 0
" O 0
serious O 0
" O 0
for O 0
almost O 0
2 O 0
/ O 0
3 O 0
of O 0
the O 0
patients O 0
( O 0
62 O 0
. O 0
5 O 0
% O 0
) O 0
and O 0
its O 0
outcome O 0
favourable O 0
in O 0
most O 0
of O 0
the O 0
cases O 0
( O 0
82 O 0
% O 0
) O 0
. O 0

The O 0
occurrence O 0
of O 0
this O 0
ADR O 0
was O 0
more O 0
frequent O 0
in O 0
patients O 0
aged O 0
between O 0
61 O 0
and O 0
80 O 0
years O 0
. O 0

CONCLUSION O 0
: O 0
This O 0
work O 0
shows O 0
that O 0
confusion B-Disease 1
with O 0
valproic B-Chemical 1
acid I-Chemical 1
is O 0
a O 0
serious O 0
, O 0
rather O 0
frequent O 0
but O 0
reversible O 0
adverse O 0
drug O 0
reaction O 0
. O 0

It O 0
occurs O 0
especially O 0
in O 0
older O 0
patients O 0
and O 0
during O 0
the O 0
first O 0
two O 0
weeks O 0
of O 0
treatment O 0
. O 0

Reversible O 0
inferior B-Disease 1
colliculus I-Disease 1
lesion I-Disease 1
in O 0
metronidazole B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
: O 0
magnetic O 0
resonance O 0
findings O 0
on O 0
diffusion O 0
- O 0
weighted O 0
and O 0
fluid O 0
attenuated O 0
inversion O 0
recovery O 0
imaging O 0
. O 0

OBJECTIVE O 0
: O 0
This O 0
is O 0
to O 0
present O 0
reversible O 0
inferior B-Disease 1
colliculus I-Disease 1
lesions I-Disease 1
in O 0
metronidazole B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
, O 0
to O 0
focus O 0
on O 0
the O 0
diffusion O 0
- O 0
weighted O 0
imaging O 0
( O 0
DWI O 0
) O 0
and O 0
fluid O 0
attenuated O 0
inversion O 0
recovery O 0
( O 0
FLAIR O 0
) O 0
imaging O 0
. O 0

MATERIALS O 0
AND O 0
METHODS O 0
: O 0
From O 0
November O 0
2005 O 0
to O 0
September O 0
2007 O 0
, O 0
8 O 0
patients O 0
( O 0
5 O 0
men O 0
and O 0
3 O 0
women O 0
) O 0
were O 0
diagnosed O 0
as O 0
having O 0
metronidazole B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
( O 0
age O 0
range O 0
; O 0
43 O 0
- O 0
78 O 0
years O 0
) O 0
. O 0

They O 0
had O 0
been O 0
taking O 0
metronidazole B-Chemical 1
( O 0
total O 0
dosage O 0
, O 0
45 O 0
- O 0
120 O 0
g O 0
; O 0
duration O 0
, O 0
30 O 0
days O 0
to O 0
2 O 0
months O 0
) O 0
to O 0
treat O 0
the O 0
infection B-Disease 1
in O 0
various O 0
organs O 0
. O 0

Initial O 0
brain O 0
magnetic O 0
resonance O 0
imaging O 0
( O 0
MRI O 0
) O 0
were O 0
obtained O 0
after O 0
the O 0
hospitalization O 0
, O 0
including O 0
DWI O 0
( O 0
8 O 0
/ O 0
8 O 0
) O 0
, O 0
apparent O 0
diffusion O 0
coefficient O 0
( O 0
ADC O 0
) O 0
map O 0
( O 0
4 O 0
/ O 0
8 O 0
) O 0
, O 0
FLAIR O 0
( O 0
7 O 0
/ O 0
8 O 0
) O 0
, O 0
and O 0
T2 O 0
- O 0
weighted O 0
image O 0
( O 0
8 O 0
/ O 0
8 O 0
) O 0
. O 0

Follow O 0
- O 0
up O 0
MRIs O 0
were O 0
performed O 0
on O 0
5 O 0
patients O 0
from O 0
third O 0
to O 0
14th O 0
days O 0
after O 0
discontinuation O 0
of O 0
metronidazole B-Chemical 1
administration O 0
. O 0

Findings O 0
of O 0
initial O 0
and O 0
follow O 0
- O 0
up O 0
MRIs O 0
were O 0
retrospectively O 0
evaluated O 0
by O 0
2 O 0
neuroradiologists O 0
by O 0
consensus O 0
, O 0
to O 0
analyze O 0
the O 0
presence O 0
of O 0
abnormal O 0
signal O 0
intensities O 0
, O 0
their O 0
locations O 0
, O 0
and O 0
signal O 0
changes O 0
on O 0
follow O 0
- O 0
up O 0
images O 0
. O 0

RESULTS O 0
: O 0
Initial O 0
MRIs O 0
showed O 0
abnormal O 0
high O 0
signal O 0
intensities O 0
on O 0
DWI O 0
and O 0
FLAIR O 0
( O 0
or O 0
T2 O 0
- O 0
weighted O 0
image O 0
) O 0
at O 0
the O 0
dentate O 0
nucleus O 0
( O 0
8 O 0
/ O 0
8 O 0
) O 0
, O 0
inferior O 0
colliculus O 0
( O 0
6 O 0
/ O 0
8 O 0
) O 0
, O 0
corpus O 0
callosum O 0
( O 0
2 O 0
/ O 0
8 O 0
) O 0
, O 0
pons O 0
( O 0
2 O 0
/ O 0
8 O 0
) O 0
, O 0
medulla O 0
( O 0
1 O 0
/ O 0
8 O 0
) O 0
, O 0
and O 0
bilateral O 0
cerebral O 0
white O 0
matter O 0
( O 0
1 O 0
/ O 0
8 O 0
) O 0
. O 0

High O 0
- O 0
signal O 0
intensity O 0
lesions O 0
on O 0
DWI O 0
tended O 0
to O 0
show O 0
low O 0
signal O 0
intensity O 0
on O 0
ADC O 0
map O 0
( O 0
3 O 0
/ O 0
4 O 0
) O 0
, O 0
but O 0
in O 0
one O 0
patient O 0
, O 0
high O 0
signal O 0
intensity O 0
was O 0
shown O 0
at O 0
bilateral O 0
dentate O 0
nuclei O 0
on O 0
not O 0
only O 0
DWI O 0
but O 0
also O 0
ADC O 0
map O 0
. O 0

All O 0
the O 0
lesions O 0
in O 0
dentate O 0
, O 0
inferior O 0
colliculus O 0
, O 0
pons O 0
, O 0
and O 0
medullas O 0
had O 0
been O 0
resolved O 0
completely O 0
on O 0
follow O 0
- O 0
up O 0
MRIs O 0
in O 0
5 O 0
patients O 0
, O 0
but O 0
in O 0
1 O 0
patient O 0
of O 0
them O 0
, O 0
corpus O 0
callosal B-Disease 1
lesion I-Disease 1
persisted O 0
. O 0

CONCLUSIONS O 0
: O 0
Reversible O 0
inferior B-Disease 1
colliculus I-Disease 1
lesions I-Disease 1
could O 0
be O 0
considered O 0
as O 0
the O 0
characteristic O 0
for O 0
metronidazole B-Chemical 1
- O 0
induced O 0
encephalopathy B-Disease 1
, O 0
next O 0
to O 0
the O 0
dentate O 0
nucleus O 0
involvement O 0
. O 0

Clinically O 0
significant O 0
proteinuria B-Disease 1
following O 0
the O 0
administration O 0
of O 0
sirolimus B-Chemical 1
to O 0
renal O 0
transplant O 0
recipients O 0
. O 0

BACKGROUND O 0
: O 0
Sirolimus B-Chemical 1
is O 0
the O 0
latest O 0
immunosuppressive O 0
agent O 0
used O 0
to O 0
prevent O 0
rejection O 0
, O 0
and O 0
may O 0
have O 0
less O 0
nephrotoxicity B-Disease 1
than O 0
calcineurin O 0
inhibitor O 0
( O 0
CNI O 0
) O 0
- O 0
based O 0
regimens O 0
. O 0

To O 0
date O 0
there O 0
has O 0
been O 0
little O 0
documentation O 0
of O 0
clinically O 0
significant O 0
proteinuria B-Disease 1
linked O 0
with O 0
the O 0
use O 0
of O 0
sirolimus B-Chemical 1
. O 0

We O 0
have O 0
encountered O 0
several O 0
patients O 0
who O 0
developed O 0
substantial O 0
proteinuria B-Disease 1
associated O 0
with O 0
sirolimus B-Chemical 1
use O 0
. O 0

In O 0
each O 0
patient O 0
, O 0
the O 0
close O 0
temporal O 0
association O 0
between O 0
the O 0
commencement O 0
of O 0
sirolimus B-Chemical 1
therapy O 0
and O 0
proteinuria B-Disease 1
implicated O 0
sirolimus B-Chemical 1
as O 0
the O 0
most O 0
likely O 0
etiology O 0
of O 0
the O 0
proteinuria B-Disease 1
. O 0

METHODS O 0
: O 0
We O 0
analyzed O 0
the O 0
clinical O 0
and O 0
laboratory O 0
information O 0
available O 0
for O 0
all O 0
119 O 0
patients O 0
transplanted O 0
at O 0
the O 0
Washington O 0
Hospital O 0
Center O 0
between O 0
1999 O 0
- O 0
2003 O 0
for O 0
whom O 0
sirolimus B-Chemical 1
was O 0
a O 0
component O 0
of O 0
their O 0
immunosuppressant O 0
regimen O 0
. O 0

In O 0
these O 0
patients O 0
, O 0
the O 0
magnitude O 0
of O 0
proteinuria B-Disease 1
was O 0
assessed O 0
on O 0
morning O 0
urine O 0
samples O 0
by O 0
turbidometric O 0
measurement O 0
or O 0
random O 0
urine O 0
protein O 0
: O 0
creatinine B-Chemical 1
ratios O 0
, O 0
an O 0
estimate O 0
of O 0
grams O 0
of O 0
proteinuria B-Disease 1
/ O 0
day O 0
. O 0

Laboratory O 0
results O 0
were O 0
compared O 0
between O 0
prior O 0
, O 0
during O 0
and O 0
following O 0
sirolimus B-Chemical 1
use O 0
. O 0

RESULTS O 0
: O 0
Twenty O 0
- O 0
eight O 0
patients O 0
( O 0
24 O 0
% O 0
) O 0
developed O 0
increased O 0
proteinuria B-Disease 1
from O 0
baseline O 0
during O 0
their O 0
post O 0
- O 0
transplantation O 0
course O 0
. O 0

In O 0
21 O 0
patients O 0
an O 0
alternative O 0
cause O 0
of O 0
proteinuria B-Disease 1
was O 0
either O 0
obvious O 0
or O 0
insufficient O 0
data O 0
was O 0
available O 0
to O 0
be O 0
conclusive O 0
. O 0

In O 0
7 O 0
of O 0
the O 0
28 O 0
patients O 0
there O 0
was O 0
a O 0
striking O 0
temporal O 0
association O 0
between O 0
the O 0
initiation O 0
of O 0
sirolimus B-Chemical 1
and O 0
the O 0
development O 0
of O 0
nephrotic B-Disease 1
- O 0
range O 0
proteinuria B-Disease 1
. O 0

Proteinuria B-Disease 1
correlated O 0
most O 0
strongly O 0
with O 0
sirolimus B-Chemical 1
therapy O 0
when O 0
compared O 0
to O 0
other O 0
demographic O 0
and O 0
clinical O 0
variables O 0
. O 0

In O 0
most O 0
patients O 0
, O 0
discontinuation O 0
of O 0
sirolimus B-Chemical 1
resulted O 0
in O 0
a O 0
decrease O 0
, O 0
but O 0
not O 0
resolution O 0
, O 0
of O 0
proteinuria B-Disease 1
. O 0

CONCLUSIONS O 0
: O 0
Sirolimus B-Chemical 1
induces O 0
or O 0
aggravates O 0
pre O 0
- O 0
existing O 0
proteinuria B-Disease 1
in O 0
an O 0
unpredictable O 0
subset O 0
of O 0
renal O 0
allograft O 0
recipients O 0
. O 0

Proteinuria B-Disease 1
may O 0
improve O 0
, O 0
but O 0
does O 0
not O 0
resolve O 0
, O 0
when O 0
sirolimus B-Chemical 1
is O 0
withdrawn O 0
. O 0

Components O 0
of O 0
lemon O 0
essential O 0
oil O 0
attenuate O 0
dementia B-Disease 1
induced O 0
by O 0
scopolamine B-Chemical 1
. O 0

The O 0
anti O 0
- O 0
dementia B-Disease 1
effects O 0
of O 0
s B-Chemical 1
- I-Chemical 1
limonene I-Chemical 1
and O 0
s B-Chemical 1
- I-Chemical 1
perillyl I-Chemical 1
alcohol I-Chemical 1
were O 0
observed O 0
using O 0
the O 0
passive O 0
avoidance O 0
test O 0
( O 0
PA O 0
) O 0
and O 0
the O 0
open O 0
field O 0
habituation O 0
test O 0
( O 0
OFH O 0
) O 0
. O 0

These O 0
lemon O 0
essential O 0
oils O 0
showed O 0
strong O 0
ability O 0
to O 0
improve O 0
memory B-Disease 1
impaired I-Disease 1
by O 0
scopolamine B-Chemical 1
; O 0
however O 0
, O 0
s B-Chemical 1
- I-Chemical 1
perillyl I-Chemical 1
alcohol I-Chemical 1
relieved O 0
the O 0
deficit B-Disease 1
of I-Disease 1
associative I-Disease 1
memory I-Disease 1
in O 0
PA O 0
only O 0
, O 0
and O 0
did O 0
not O 0
improve O 0
non O 0
- O 0
associative O 0
memory O 0
significantly O 0
in O 0
OFH O 0
. O 0

Analysis O 0
of O 0
neurotransmitter O 0
concentration O 0
in O 0
some O 0
brain O 0
regions O 0
on O 0
the O 0
test O 0
day O 0
showed O 0
that O 0
dopamine B-Chemical 1
concentration O 0
of O 0
the O 0
vehicle O 0
/ O 0
scopolamine B-Chemical 1
group O 0
was O 0
significantly O 0
lower O 0
than O 0
that O 0
of O 0
the O 0
vehicle O 0
/ O 0
vehicle O 0
group O 0
, O 0
but O 0
this O 0
phenomenon O 0
was O 0
reversed O 0
when O 0
s B-Chemical 1
- I-Chemical 1
limonene I-Chemical 1
or O 0
s B-Chemical 1
- I-Chemical 1
perillyl I-Chemical 1
alcohol I-Chemical 1
were O 0
administered O 0
before O 0
the O 0
injection O 0
of O 0
scopolamine B-Chemical 1
. O 0

Simultaneously O 0
, O 0
we O 0
found O 0
that O 0
these O 0
two O 0
lemon O 0
essential O 0
oil O 0
components O 0
could O 0
inhibit O 0
acetylcholinesterase O 0
activity O 0
in O 0
vitro O 0
using O 0
the O 0
Ellman O 0
method O 0
. O 0

Attentional O 0
modulation O 0
of O 0
perceived O 0
pain B-Disease 1
intensity O 0
in O 0
capsaicin B-Chemical 1
- O 0
induced O 0
secondary O 0
hyperalgesia B-Disease 1
. O 0

Perceived O 0
pain B-Disease 1
intensity O 0
is O 0
modulated O 0
by O 0
attention O 0
. O 0

However O 0
, O 0
it O 0
is O 0
not O 0
known O 0
that O 0
how O 0
pain B-Disease 1
intensity O 0
ratings O 0
are O 0
affected O 0
by O 0
attention O 0
in O 0
capsaicin B-Chemical 1
- O 0
induced O 0
secondary O 0
hyperalgesia B-Disease 1
. O 0

Here O 0
we O 0
show O 0
that O 0
perceived O 0
pain B-Disease 1
intensity O 0
in O 0
secondary O 0
hyperalgesia B-Disease 1
is O 0
decreased O 0
when O 0
attention O 0
is O 0
distracted O 0
away O 0
from O 0
the O 0
painful O 0
pinprick O 0
stimulus O 0
with O 0
a O 0
visual O 0
task O 0
. O 0

Furthermore O 0
, O 0
it O 0
was O 0
found O 0
that O 0
the O 0
magnitude O 0
of O 0
attentional O 0
modulation O 0
in O 0
secondary O 0
hyperalgesia B-Disease 1
is O 0
very O 0
similar O 0
to O 0
that O 0
of O 0
capsaicin B-Chemical 1
- O 0
untreated O 0
, O 0
control O 0
condition O 0
. O 0

Our O 0
findings O 0
, O 0
showing O 0
no O 0
interaction O 0
between O 0
capsaicin B-Chemical 1
treatment O 0
and O 0
attentional O 0
modulation O 0
suggest O 0
that O 0
capsaicin B-Chemical 1
- O 0
induced O 0
secondary O 0
hyperalgesia B-Disease 1
and O 0
attention O 0
might O 0
affect O 0
mechanical O 0
pain B-Disease 1
through O 0
independent O 0
mechanisms O 0
. O 0

Cardioprotective O 0
effect O 0
of O 0
salvianolic B-Chemical 1
acid I-Chemical 1
A I-Chemical 1
on O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

The O 0
present O 0
study O 0
was O 0
designed O 0
to O 0
evaluate O 0
the O 0
cardioprotective O 0
potential O 0
of O 0
salvianolic B-Chemical 1
acid I-Chemical 1
A I-Chemical 1
on O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
rats O 0
. O 0

Hemodynamic O 0
parameters O 0
and O 0
lead O 0
II O 0
electrocardiograph O 0
were O 0
monitored O 0
and O 0
recorded O 0
continuously O 0
. O 0

Cardiac O 0
marker O 0
enzymes O 0
and O 0
antioxidative O 0
parameters O 0
in O 0
serum O 0
and O 0
heart O 0
tissues O 0
were O 0
measured O 0
. O 0

Assay O 0
for O 0
mitochondrial O 0
respiratory O 0
function O 0
and O 0
histopathological O 0
examination O 0
of O 0
heart O 0
tissues O 0
were O 0
performed O 0
. O 0

Isoproterenol B-Chemical 1
- O 0
treated O 0
rats O 0
showed O 0
significant O 0
increases O 0
in O 0
the O 0
levels O 0
of O 0
lactate B-Chemical 1
dehydrogenase O 0
, O 0
aspartate B-Chemical 1
transaminase O 0
, O 0
creatine B-Chemical 1
kinase O 0
and O 0
malondialdehyde B-Chemical 1
and O 0
significant O 0
decreases O 0
in O 0
the O 0
activities O 0
of O 0
superoxide B-Chemical 1
dismutase O 0
, O 0
catalase O 0
and O 0
glutathione B-Chemical 1
peroxidase O 0
in O 0
serum O 0
and O 0
heart O 0
. O 0

These O 0
rats O 0
also O 0
showed O 0
declines O 0
in O 0
left O 0
ventricular O 0
systolic O 0
pressure O 0
, O 0
maximum O 0
and O 0
minimum O 0
rate O 0
of O 0
developed O 0
left O 0
ventricular O 0
pressure O 0
, O 0
and O 0
elevation O 0
of O 0
left O 0
ventricular O 0
end O 0
- O 0
diastolic O 0
pressure O 0
and O 0
ST O 0
- O 0
segment O 0
. O 0

In O 0
addition O 0
, O 0
mitochondrial O 0
respiratory B-Disease 1
dysfunction I-Disease 1
characterized O 0
by O 0
decreased O 0
respiratory O 0
control O 0
ratio O 0
and O 0
ADP B-Chemical 1
/ O 0
O O 0
was O 0
observed O 0
in O 0
isoproterenol B-Chemical 1
- O 0
treated O 0
rats O 0
. O 0

Administration O 0
of O 0
salvianolic B-Chemical 1
acid I-Chemical 1
A I-Chemical 1
for O 0
a O 0
period O 0
of O 0
8 O 0
days O 0
significantly O 0
attenuated O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
cardiac B-Disease 1
dysfunction I-Disease 1
and O 0
myocardial B-Disease 1
injury I-Disease 1
and O 0
improved O 0
mitochondrial O 0
respiratory O 0
function O 0
. O 0

The O 0
protective O 0
role O 0
of O 0
salvianolic B-Chemical 1
acid I-Chemical 1
A I-Chemical 1
against O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
damage I-Disease 1
was O 0
further O 0
confirmed O 0
by O 0
histopathological O 0
examination O 0
. O 0

The O 0
results O 0
of O 0
our O 0
study O 0
suggest O 0
that O 0
salvianolic B-Chemical 1
acid I-Chemical 1
A I-Chemical 1
possessing O 0
antioxidant O 0
activity O 0
has O 0
a O 0
significant O 0
protective O 0
effect O 0
against O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

Long O 0
- O 0
term O 0
glutamate B-Chemical 1
supplementation O 0
failed O 0
to O 0
protect O 0
against O 0
peripheral B-Disease 1
neurotoxicity I-Disease 1
of O 0
paclitaxel B-Chemical 1
. O 0

Toxic O 0
peripheral B-Disease 1
neuropathy I-Disease 1
is O 0
still O 0
a O 0
significant O 0
limiting O 0
factor O 0
for O 0
chemotherapy O 0
with O 0
paclitaxel B-Chemical 1
( O 0
PAC B-Chemical 1
) O 0
, O 0
although O 0
glutamate B-Chemical 1
and O 0
its O 0
closely O 0
related O 0
amino B-Chemical 1
acid I-Chemical 1
glutamine B-Chemical 1
were O 0
claimed O 0
to O 0
ameliorate O 0
PAC B-Chemical 1
neurotoxicity B-Disease 1
. O 0

This O 0
pilot O 0
trial O 0
aimed O 0
to O 0
evaluate O 0
the O 0
role O 0
of O 0
glutamate B-Chemical 1
supplementation O 0
for O 0
preventing O 0
PAC B-Chemical 1
- O 0
induced O 0
peripheral B-Disease 1
neuropathy I-Disease 1
in O 0
a O 0
randomized O 0
, O 0
placebo O 0
- O 0
controlled O 0
, O 0
double O 0
- O 0
blinded O 0
clinical O 0
and O 0
electro O 0
- O 0
diagnostic O 0
study O 0
. O 0

Forty O 0
- O 0
three O 0
ovarian B-Disease 1
cancer I-Disease 1
patients O 0
were O 0
available O 0
for O 0
analysis O 0
following O 0
six O 0
cycles O 0
of O 0
the O 0
same O 0
PAC B-Chemical 1
- O 0
containing O 0
regimen O 0
: O 0
23 O 0
had O 0
been O 0
supplemented O 0
by O 0
glutamate B-Chemical 1
all O 0
along O 0
the O 0
treatment O 0
period O 0
, O 0
at O 0
a O 0
daily O 0
dose O 0
of O 0
three O 0
times O 0
500 O 0
mg O 0
( O 0
group O 0
G O 0
) O 0
, O 0
and O 0
20 O 0
had O 0
received O 0
a O 0
placebo O 0
( O 0
group O 0
P O 0
) O 0
. O 0

Patients O 0
were O 0
evaluated O 0
by O 0
neurological O 0
examinations O 0
, O 0
questionnaires O 0
and O 0
sensory O 0
- O 0
motor O 0
nerve O 0
conduction O 0
studies O 0
. O 0

There O 0
was O 0
no O 0
significant O 0
difference O 0
in O 0
the O 0
frequency O 0
of O 0
signs O 0
or O 0
symptoms O 0
between O 0
the O 0
two O 0
groups O 0
although O 0
neurotoxicity B-Disease 1
symptoms O 0
presented O 0
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However O 0
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This O 0
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Development O 0
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A O 0
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Ophthalmologic O 0
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The O 0
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The O 0
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In O 0
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To O 0
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Deficits B-Disease 1
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Ecstasy B-Chemical 1
users O 0
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A O 0
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Ecstasy B-Chemical 1
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Hydrogen B-Chemical 1
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Contact O 0
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The O 0
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hydrogen B-Chemical 1
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. O 0

The O 0
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59 O 0
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alcohol B-Chemical 1
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In O 0
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he O 0
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flushing B-Disease 1
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, O 0
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. O 0

Manifestations O 0
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. O 0

The O 0
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Five O 0
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The O 0
patient O 0
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. O 0

These O 0
cases O 0
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. O 0

Sulpiride B-Chemical 1
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. O 0

Sulpiride B-Chemical 1
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Although O 0
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have O 0
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We O 0
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within O 0
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We O 0
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. O 0

Comparative O 0
cognitive O 0
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oxycodone B-Chemical 1
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This O 0
study O 0
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Seventy O 0
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Plasma O 0
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Significant O 0
declines B-Disease 1
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, I-Disease 1
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, I-Disease 1
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were O 0
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. O 0

For O 0
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This O 0
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, O 0
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PERSPECTIVE O 0
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Study O 0
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. O 0

Therefore O 0
, O 0
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older O 0
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. O 0

The O 0
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transporter O 0
- O 0
1 O 0
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SSR103800 B-Chemical 1
displays O 0
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normal O 0
and O 0
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Schizophrenia B-Disease 1
has O 0
been O 0
initially O 0
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with O 0
dysfunction O 0
in O 0
dopamine B-Chemical 1
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. O 0

However O 0
, O 0
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N B-Chemical 1
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methyl I-Chemical 1
- I-Chemical 1
D I-Chemical 1
- I-Chemical 1
aspartate I-Chemical 1
( O 0
NMDA B-Chemical 1
) O 0
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produce O 0
schizophrenic B-Disease 1
- O 0
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symptoms O 0
in O 0
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has O 0
led O 0
to O 0
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. O 0

As O 0
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result O 0
, O 0
there O 0
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a O 0
growing O 0
interest O 0
in O 0
the O 0
development O 0
of O 0
pharmacological O 0
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activity O 0
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. O 0

Among O 0
them O 0
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glycine B-Chemical 1
transporter O 0
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NMDA B-Chemical 1
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increasing O 0
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glycine B-Chemical 1
( O 0
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co O 0
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agonist O 0
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NMDA B-Chemical 1
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levels O 0
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. O 0

This O 0
study O 0
aimed O 0
at O 0
investigating O 0
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antipsychotic O 0
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SSR103800 B-Chemical 1
, O 0
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particular O 0
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hyperactivity B-Disease 1
, O 0
involving O 0
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, O 0
amphetamine B-Chemical 1
and O 0
MK B-Chemical 1
- I-Chemical 1
801 I-Chemical 1
) O 0
or O 0
transgenic O 0
mice O 0
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, O 0
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/ O 0
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) O 0
and O 0
DAT O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
) O 0
. O 0

Results O 0
showed O 0
that O 0
SSR103800 B-Chemical 1
( O 0
10 O 0
- O 0
30 O 0
mg O 0
/ O 0
kg O 0
p O 0
. O 0
o O 0
. O 0
) O 0
blocked O 0
hyperactivity B-Disease 1
induced O 0
by O 0
the O 0
non O 0
- O 0
competitive O 0
NMDA B-Chemical 1
receptor O 0
antagonist O 0
, O 0
MK B-Chemical 1
- I-Chemical 1
801 I-Chemical 1
and O 0
partially O 0
reversed O 0
spontaneous O 0
hyperactivity B-Disease 1
of O 0
NMDA B-Chemical 1
Nr1 O 0
( O 0
neo O 0
- O 0
/ O 0
- O 0
) O 0
mice O 0
. O 0

In O 0
contrast O 0
, O 0
SSR103800 B-Chemical 1
failed O 0
to O 0
affect O 0
hyperactivity B-Disease 1
induced O 0
by O 0
amphetamine B-Chemical 1
or O 0
naturally O 0
observed O 0
in O 0
dopamine B-Chemical 1
transporter O 0
( O 0
DAT O 0
( O 0
- O 0
/ O 0
- O 0
) O 0
) O 0
knockout O 0
mice O 0
( O 0
10 O 0
- O 0
30 O 0
mg O 0
/ O 0
kg O 0
p O 0
. O 0
o O 0
. O 0
) O 0
. O 0

Importantly O 0
, O 0
both O 0
classical O 0
( O 0
haloperidol B-Chemical 1
) O 0
and O 0
atypical O 0
( O 0
olanzapine B-Chemical 1
, O 0
clozapine B-Chemical 1
and O 0
aripiprazole B-Chemical 1
) O 0
antipsychotics O 0
were O 0
effective O 0
in O 0
all O 0
these O 0
models O 0
of O 0
hyperactivity B-Disease 1
. O 0

However O 0
, O 0
unlike O 0
these O 0
latter O 0
, O 0
SSR103800 B-Chemical 1
did O 0
not O 0
produce O 0
catalepsy B-Disease 1
( O 0
retention O 0
on O 0
the O 0
bar O 0
test O 0
) O 0
up O 0
to O 0
30 O 0
mg O 0
/ O 0
kg O 0
p O 0
. O 0
o O 0
. O 0

Together O 0
these O 0
findings O 0
show O 0
that O 0
the O 0
GlyT1 O 0
inhibitor O 0
, O 0
SSR103800 B-Chemical 1
, O 0
produces O 0
antipsychotic O 0
- O 0
like O 0
effects O 0
, O 0
which O 0
differ O 0
from O 0
those O 0
observed O 0
with O 0
compounds O 0
primarily O 0
targeting O 0
the O 0
dopaminergic O 0
system O 0
, O 0
and O 0
has O 0
a O 0
reduced O 0
side O 0
- O 0
effect O 0
potential O 0
as O 0
compared O 0
with O 0
these O 0
latter O 0
drugs O 0
. O 0

Pyrrolidine B-Chemical 1
dithiocarbamate I-Chemical 1
protects O 0
the O 0
piriform O 0
cortex O 0
in O 0
the O 0
pilocarpine B-Chemical 1
status B-Disease 1
epilepticus I-Disease 1
model O 0
. O 0

Pyrrolidine B-Chemical 1
dithiocarbamate I-Chemical 1
( O 0
PDTC B-Chemical 1
) O 0
has O 0
a O 0
dual O 0
mechanism O 0
of O 0
action O 0
as O 0
an O 0
antioxidant O 0
and O 0
an O 0
inhibitor O 0
of O 0
the O 0
transcription O 0
factor O 0
kappa O 0
- O 0
beta O 0
. O 0

Both O 0
, O 0
production O 0
of O 0
reactive O 0
oxygen B-Chemical 1
species O 0
as O 0
well O 0
as O 0
activation O 0
of O 0
NF O 0
- O 0
kappaB O 0
have O 0
been O 0
implicated O 0
in O 0
severe O 0
neuronal B-Disease 1
damage I-Disease 1
in O 0
different O 0
sub O 0
- O 0
regions O 0
of O 0
the O 0
hippocampus O 0
as O 0
well O 0
as O 0
in O 0
the O 0
surrounding O 0
cortices O 0
. O 0

The O 0
effect O 0
of O 0
PDTC B-Chemical 1
on O 0
status B-Disease 1
epilepticus I-Disease 1
- O 0
associated O 0
cell O 0
loss O 0
in O 0
the O 0
hippocampus O 0
and O 0
piriform O 0
cortex O 0
was O 0
evaluated O 0
in O 0
the O 0
rat O 0
fractionated O 0
pilocarpine B-Chemical 1
model O 0
. O 0

Treatment O 0
with O 0
150 O 0
mg O 0
/ O 0
kg O 0
PDTC B-Chemical 1
before O 0
and O 0
following O 0
status B-Disease 1
epilepticus I-Disease 1
significantly O 0
increased O 0
the O 0
mortality O 0
rate O 0
to O 0
100 O 0
% O 0
. O 0

Administration O 0
of O 0
50 O 0
mg O 0
/ O 0
kg O 0
PDTC B-Chemical 1
( O 0
low O 0
- O 0
dose O 0
) O 0
did O 0
not O 0
exert O 0
major O 0
effects O 0
on O 0
the O 0
development O 0
of O 0
a O 0
status B-Disease 1
epilepticus I-Disease 1
or O 0
the O 0
mortality O 0
rate O 0
. O 0

In O 0
vehicle O 0
- O 0
treated O 0
rats O 0
, O 0
status B-Disease 1
epilepticus I-Disease 1
caused O 0
pronounced O 0
neuronal B-Disease 1
damage I-Disease 1
in O 0
the O 0
piriform O 0
cortex O 0
comprising O 0
both O 0
pyramidal O 0
cells O 0
and O 0
interneurons O 0
. O 0

Low O 0
- O 0
dose O 0
PDTC B-Chemical 1
treatment O 0
almost O 0
completely O 0
protected O 0
from O 0
lesions O 0
in O 0
the O 0
piriform O 0
cortex O 0
. O 0

A O 0
significant O 0
decrease O 0
in O 0
neuronal O 0
density O 0
of O 0
the O 0
hippocampal O 0
hilar O 0
formation O 0
was O 0
identified O 0
in O 0
vehicle O 0
- O 0
and O 0
PDTC B-Chemical 1
- O 0
treated O 0
rats O 0
following O 0
status B-Disease 1
epilepticus I-Disease 1
. O 0

In O 0
conclusion O 0
, O 0
the O 0
NF O 0
- O 0
kappaB O 0
inhibitor O 0
and O 0
antioxidant O 0
PDTC B-Chemical 1
protected O 0
the O 0
piriform O 0
cortex O 0
, O 0
whereas O 0
it O 0
did O 0
not O 0
affect O 0
hilar O 0
neuronal B-Disease 1
loss I-Disease 1
. O 0

These O 0
data O 0
might O 0
indicate O 0
that O 0
the O 0
generation O 0
of O 0
reactive O 0
oxygen B-Chemical 1
species O 0
and O 0
activation O 0
of O 0
NF O 0
- O 0
kappaB O 0
plays O 0
a O 0
more O 0
central O 0
role O 0
in O 0
seizure B-Disease 1
- O 0
associated O 0
neuronal B-Disease 1
damage I-Disease 1
in O 0
the O 0
temporal O 0
cortex O 0
as O 0
compared O 0
to O 0
the O 0
hippocampal O 0
hilus O 0
. O 0

However O 0
, O 0
future O 0
investigations O 0
are O 0
necessary O 0
to O 0
exactly O 0
analyze O 0
the O 0
biochemical O 0
mechanisms O 0
by O 0
which O 0
PDTC B-Chemical 1
exerted O 0
its O 0
beneficial O 0
effects O 0
in O 0
the O 0
piriform O 0
cortex O 0
. O 0

Anaesthetists O 0
' O 0
nightmare O 0
: O 0
masseter B-Disease 1
spasm I-Disease 1
after O 0
induction O 0
in O 0
an O 0
undiagnosed O 0
case O 0
of O 0
myotonia B-Disease 1
congenita I-Disease 1
. O 0

We O 0
report O 0
an O 0
undiagnosed O 0
case O 0
of O 0
myotonia B-Disease 1
congenita I-Disease 1
in O 0
a O 0
24 O 0
- O 0
year O 0
- O 0
old O 0
previously O 0
healthy O 0
primigravida O 0
, O 0
who O 0
developed O 0
life O 0
threatening O 0
masseter B-Disease 1
spasm I-Disease 1
following O 0
a O 0
standard O 0
dose O 0
of O 0
intravenous O 0
suxamethonium B-Chemical 1
for O 0
induction O 0
of O 0
anaesthesia O 0
. O 0

Neither O 0
the O 0
patient O 0
nor O 0
the O 0
anaesthetist O 0
was O 0
aware O 0
of O 0
the O 0
diagnosis O 0
before O 0
this O 0
potentially O 0
lethal O 0
complication O 0
occurred O 0
. O 0

Twin O 0
preterm O 0
neonates O 0
with O 0
cardiac B-Disease 1
toxicity I-Disease 1
related O 0
to O 0
lopinavir B-Chemical 1
/ I-Chemical 1
ritonavir I-Chemical 1
therapy O 0
. O 0

We O 0
report O 0
twin O 0
neonates O 0
who O 0
were O 0
born O 0
prematurely O 0
at O 0
32 O 0
weeks O 0
of O 0
gestation O 0
to O 0
a O 0
mother O 0
with O 0
human B-Disease 1
immunodeficiency I-Disease 1
virus I-Disease 1
infection I-Disease 1
. O 0

One O 0
of O 0
the O 0
twins O 0
developed O 0
complete O 0
heart B-Disease 1
block I-Disease 1
and O 0
dilated B-Disease 1
cardiomyopathy I-Disease 1
related O 0
to O 0
lopinavir B-Chemical 1
/ I-Chemical 1
ritonavir I-Chemical 1
therapy O 0
, O 0
a O 0
boosted O 0
protease O 0
- O 0
inhibitor O 0
agent O 0
, O 0
while O 0
the O 0
other O 0
twin O 0
developed O 0
mild O 0
bradycardia B-Disease 1
. O 0

We O 0
recommend O 0
caution O 0
in O 0
the O 0
use O 0
of O 0
lopinavir B-Chemical 1
/ I-Chemical 1
ritonavir I-Chemical 1
in O 0
the O 0
immediate O 0
neonatal O 0
period O 0
. O 0

When O 0
drugs O 0
disappear O 0
from O 0
the O 0
patient O 0
: O 0
elimination O 0
of O 0
intravenous O 0
medication O 0
by O 0
hemodiafiltration O 0
. O 0

Twenty O 0
- O 0
three O 0
hours O 0
after O 0
heart O 0
transplantation O 0
, O 0
life O 0
- O 0
threatening O 0
acute O 0
right B-Disease 1
heart I-Disease 1
failure I-Disease 1
was O 0
diagnosed O 0
in O 0
a O 0
patient O 0
requiring O 0
continuous O 0
venovenous O 0
hemodiafiltration O 0
( O 0
CVVHDF O 0
) O 0
. O 0

Increasing O 0
doses O 0
of O 0
catecholamines B-Chemical 1
, O 0
sedatives O 0
, O 0
and O 0
muscle O 0
relaxants O 0
administered O 0
through O 0
a O 0
central O 0
venous O 0
catheter O 0
were O 0
ineffective O 0
. O 0

However O 0
, O 0
a O 0
bolus O 0
of O 0
epinephrine B-Chemical 1
injected O 0
through O 0
an O 0
alternative O 0
catheter O 0
provoked O 0
a O 0
hypertensive B-Disease 1
crisis O 0
. O 0

Thus O 0
, O 0
interference O 0
with O 0
the O 0
central O 0
venous O 0
infusion O 0
by O 0
the O 0
dialysis O 0
catheter O 0
was O 0
suspected O 0
. O 0

The O 0
catheters O 0
were O 0
changed O 0
, O 0
and O 0
hemodynamics O 0
stabilized O 0
at O 0
lower O 0
catecholamine B-Chemical 1
doses O 0
. O 0

When O 0
the O 0
effects O 0
of O 0
IV O 0
drugs O 0
are O 0
inadequate O 0
in O 0
patients O 0
receiving O 0
CVVHDF O 0
, O 0
interference O 0
with O 0
adjacent O 0
catheters O 0
resulting O 0
in O 0
elimination O 0
of O 0
the O 0
drug O 0
by O 0
CVVHDF O 0
should O 0
be O 0
suspected O 0
. O 0

Less O 0
frequent O 0
lithium B-Chemical 1
administration O 0
and O 0
lower O 0
urine O 0
volume O 0
. O 0

OBJECTIVE O 0
: O 0
This O 0
study O 0
was O 0
designed O 0
to O 0
determine O 0
whether O 0
patients O 0
maintained O 0
on O 0
a O 0
regimen O 0
of O 0
lithium B-Chemical 1
on O 0
a O 0
once O 0
- O 0
per O 0
- O 0
day O 0
schedule O 0
have O 0
lower O 0
urine O 0
volumes O 0
than O 0
do O 0
patients O 0
receiving O 0
multiple O 0
doses O 0
per O 0
day O 0
. O 0

METHOD O 0
: O 0
This O 0
was O 0
a O 0
cross O 0
- O 0
sectional O 0
study O 0
of O 0
85 O 0
patients O 0
from O 0
a O 0
lithium B-Chemical 1
clinic O 0
who O 0
received O 0
different O 0
dose O 0
schedules O 0
. O 0

Patients O 0
were O 0
admitted O 0
to O 0
the O 0
hospital O 0
for O 0
measurement O 0
of O 0
lithium B-Chemical 1
level O 0
, O 0
creatinine B-Chemical 1
clearance O 0
, O 0
urine O 0
volume O 0
, O 0
and O 0
maximum O 0
osmolality O 0
. O 0

RESULTS O 0
: O 0
Multiple O 0
daily O 0
doses O 0
of O 0
lithium B-Chemical 1
were O 0
associated O 0
with O 0
higher O 0
urine O 0
volumes O 0
. O 0

The O 0
dosing O 0
schedule O 0
, O 0
duration O 0
of O 0
lithium B-Chemical 1
treatment O 0
, O 0
and O 0
daily O 0
dose O 0
of O 0
lithium B-Chemical 1
did O 0
not O 0
affect O 0
maximum O 0
osmolality O 0
or O 0
creatinine B-Chemical 1
clearance O 0
. O 0

CONCLUSIONS O 0
: O 0
Urine O 0
volume O 0
can O 0
be O 0
reduced O 0
by O 0
giving O 0
lithium B-Chemical 1
once O 0
daily O 0
and O 0
/ O 0
or O 0
by O 0
lowering O 0
the O 0
total O 0
daily O 0
dose O 0
. O 0

Lithium B-Chemical 1
- O 0
induced O 0
polyuria B-Disease 1
seems O 0
to O 0
be O 0
related O 0
to O 0
extrarenal O 0
as O 0
well O 0
as O 0
to O 0
renal O 0
effects O 0
. O 0

Antibacterial O 0
medication O 0
use O 0
during O 0
pregnancy O 0
and O 0
risk O 0
of O 0
birth B-Disease 1
defects I-Disease 1
: O 0
National O 0
Birth B-Disease 1
Defects I-Disease 1
Prevention O 0
Study O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
estimate O 0
the O 0
association O 0
between O 0
antibacterial O 0
medications O 0
and O 0
selected O 0
birth B-Disease 1
defects I-Disease 1
. O 0

DESIGN O 0
, O 0
SETTING O 0
, O 0
AND O 0
PARTICIPANTS O 0
: O 0
Population O 0
- O 0
based O 0
, O 0
multisite O 0
, O 0
case O 0
- O 0
control O 0
study O 0
of O 0
women O 0
who O 0
had O 0
pregnancies O 0
affected O 0
by O 0
1 O 0
of O 0
more O 0
than O 0
30 O 0
eligible O 0
major O 0
birth B-Disease 1
defects I-Disease 1
identified O 0
via O 0
birth B-Disease 1
defect I-Disease 1
surveillance O 0
programs O 0
in O 0
10 O 0
states O 0
( O 0
n O 0
= O 0
13 O 0
155 O 0
) O 0
and O 0
control O 0
women O 0
randomly O 0
selected O 0
from O 0
the O 0
same O 0
geographical O 0
regions O 0
( O 0
n O 0
= O 0
4941 O 0
) O 0
. O 0

MAIN O 0
EXPOSURE O 0
: O 0
Reported O 0
maternal O 0
use O 0
of O 0
antibacterials O 0
( O 0
1 O 0
month O 0
before O 0
pregnancy O 0
through O 0
the O 0
end O 0
of O 0
the O 0
first O 0
trimester O 0
) O 0
. O 0

MAIN O 0
OUTCOME O 0
MEASURE O 0
: O 0
Odds O 0
ratios O 0
( O 0
ORs O 0
) O 0
measuring O 0
the O 0
association O 0
between O 0
antibacterial O 0
use O 0
and O 0
selected O 0
birth B-Disease 1
defects I-Disease 1
adjusted O 0
for O 0
potential O 0
confounders O 0
. O 0

RESULTS O 0
: O 0
The O 0
reported O 0
use O 0
of O 0
antibacterials O 0
increased O 0
during O 0
pregnancy O 0
, O 0
peaking O 0
during O 0
the O 0
third O 0
month O 0
. O 0

Sulfonamides B-Chemical 1
were O 0
associated O 0
with O 0
anencephaly B-Disease 1
( O 0
adjusted O 0
OR O 0
[ O 0
AOR O 0
] O 0
= O 0
3 O 0
. O 0
4 O 0
; O 0
95 O 0
% O 0
confidence O 0
interval O 0
[ O 0
CI O 0
] O 0
, O 0
1 O 0
. O 0
3 O 0
- O 0
8 O 0
. O 0
8 O 0
) O 0
, O 0
hypoplastic B-Disease 1
left I-Disease 1
heart I-Disease 1
syndrome I-Disease 1
( O 0
AOR O 0
= O 0
3 O 0
. O 0
2 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
3 O 0
- O 0
7 O 0
. O 0
6 O 0
) O 0
, O 0
coarctation B-Disease 1
of I-Disease 1
the I-Disease 1
aorta I-Disease 1
( O 0
AOR O 0
= O 0
2 O 0
. O 0
7 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
3 O 0
- O 0
5 O 0
. O 0
6 O 0
) O 0
, O 0
choanal B-Disease 1
atresia I-Disease 1
( O 0
AOR O 0
= O 0
8 O 0
. O 0
0 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
2 O 0
. O 0
7 O 0
- O 0
23 O 0
. O 0
5 O 0
) O 0
, O 0
transverse B-Disease 1
limb I-Disease 1
deficiency I-Disease 1
( O 0
AOR O 0
= O 0
2 O 0
. O 0
5 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
0 O 0
- O 0
5 O 0
. O 0
9 O 0
) O 0
, O 0
and O 0
diaphragmatic B-Disease 1
hernia I-Disease 1
( O 0
AOR O 0
= O 0
2 O 0
. O 0
4 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
1 O 0
- O 0
5 O 0
. O 0
4 O 0
) O 0
. O 0

Nitrofurantoins B-Chemical 1
were O 0
associated O 0
with O 0
anophthalmia B-Disease 1
or O 0
microphthalmos B-Disease 1
( O 0
AOR O 0
= O 0
3 O 0
. O 0
7 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
1 O 0
- O 0
12 O 0
. O 0
2 O 0
) O 0
, O 0
hypoplastic B-Disease 1
left I-Disease 1
heart I-Disease 1
syndrome I-Disease 1
( O 0
AOR O 0
= O 0
4 O 0
. O 0
2 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
9 O 0
- O 0
9 O 0
. O 0
1 O 0
) O 0
, O 0
atrial B-Disease 1
septal I-Disease 1
defects I-Disease 1
( O 0
AOR O 0
= O 0
1 O 0
. O 0
9 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
1 O 0
- O 0
3 O 0
. O 0
4 O 0
) O 0
, O 0
and O 0
cleft B-Disease 1
lip I-Disease 1
with O 0
cleft B-Disease 1
palate I-Disease 1
( O 0
AOR O 0
= O 0
2 O 0
. O 0
1 O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
1 O 0
. O 0
2 O 0
- O 0
3 O 0
. O 0
9 O 0
) O 0
. O 0

Other O 0
antibacterial O 0
agents O 0
that O 0
showed O 0
associations O 0
included O 0
erythromycins B-Chemical 1
( O 0
2 O 0
defects O 0
) O 0
, O 0
penicillins B-Chemical 1
( O 0
1 O 0
defect O 0
) O 0
, O 0
cephalosporins B-Chemical 1
( O 0
1 O 0
defect O 0
) O 0
, O 0
and O 0
quinolones B-Chemical 1
( O 0
1 O 0
defect O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
Reassuringly O 0
, O 0
penicillins B-Chemical 1
, O 0
erythromycins B-Chemical 1
, O 0
and O 0
cephalosporins B-Chemical 1
, O 0
although O 0
used O 0
commonly O 0
by O 0
pregnant O 0
women O 0
, O 0
were O 0
not O 0
associated O 0
with O 0
many O 0
birth B-Disease 1
defects I-Disease 1
. O 0

Sulfonamides B-Chemical 1
and O 0
nitrofurantoins B-Chemical 1
were O 0
associated O 0
with O 0
several O 0
birth B-Disease 1
defects I-Disease 1
, O 0
indicating O 0
a O 0
need O 0
for O 0
additional O 0
scrutiny O 0
. O 0

Differential O 0
impact O 0
of O 0
immune O 0
escape O 0
mutations O 0
G145R O 0
and O 0
P120T O 0
on O 0
the O 0
replication O 0
of O 0
lamivudine B-Chemical 1
- O 0
resistant O 0
hepatitis B-Chemical 1
B I-Chemical 1
virus I-Chemical 1
e I-Chemical 1
antigen I-Chemical 1
- O 0
positive O 0
and O 0
- O 0
negative O 0
strains O 0
. O 0

Immune O 0
escape O 0
variants O 0
of O 0
the O 0
hepatitis B-Disease 1
B I-Disease 1
virus O 0
( O 0
HBV O 0
) O 0
represent O 0
an O 0
emerging O 0
clinical O 0
challenge O 0
, O 0
because O 0
they O 0
can O 0
be O 0
associated O 0
with O 0
vaccine O 0
escape O 0
, O 0
HBV O 0
reactivation O 0
, O 0
and O 0
failure O 0
of O 0
diagnostic O 0
tests O 0
. O 0

Recent O 0
data O 0
suggest O 0
a O 0
preferential O 0
selection O 0
of O 0
immune O 0
escape O 0
mutants O 0
in O 0
distinct O 0
peripheral O 0
blood O 0
leukocyte O 0
compartments O 0
of O 0
infected O 0
individuals O 0
. O 0

We O 0
therefore O 0
systematically O 0
analyzed O 0
the O 0
functional O 0
impact O 0
of O 0
the O 0
most O 0
prevalent O 0
immune O 0
escape O 0
variants O 0
, O 0
the O 0
sG145R O 0
and O 0
sP120T O 0
mutants O 0
, O 0
on O 0
the O 0
viral O 0
replication O 0
efficacy O 0
and O 0
antiviral O 0
drug O 0
susceptibility O 0
of O 0
common O 0
treatment O 0
- O 0
associated O 0
mutants O 0
with O 0
resistance O 0
to O 0
lamivudine B-Chemical 1
( O 0
LAM B-Chemical 1
) O 0
and O 0
/ O 0
or O 0
HBeAg B-Chemical 1
negativity O 0
. O 0

Replication O 0
- O 0
competent O 0
HBV O 0
strains O 0
with O 0
sG145R O 0
or O 0
sP120T O 0
and O 0
LAM B-Chemical 1
resistance O 0
( O 0
rtM204I O 0
or O 0
rtL180M O 0
/ O 0
rtM204V O 0
) O 0
were O 0
generated O 0
on O 0
an O 0
HBeAg B-Chemical 1
- O 0
positive O 0
and O 0
an O 0
HBeAg B-Chemical 1
- O 0
negative O 0
background O 0
with O 0
precore O 0
( O 0
PC O 0
) O 0
and O 0
basal O 0
core O 0
promoter O 0
( O 0
BCP O 0
) O 0
mutants O 0
. O 0

The O 0
sG145R O 0
mutation O 0
strongly O 0
reduced O 0
HBsAg B-Chemical 1
levels O 0
and O 0
was O 0
able O 0
to O 0
fully O 0
restore O 0
the O 0
impaired O 0
replication O 0
of O 0
LAM B-Chemical 1
- O 0
resistant O 0
HBV O 0
mutants O 0
to O 0
the O 0
levels O 0
of O 0
wild O 0
- O 0
type O 0
HBV O 0
, O 0
and O 0
PC O 0
or O 0
BCP O 0
mutations O 0
further O 0
enhanced O 0
viral O 0
replication O 0
. O 0

Although O 0
the O 0
sP120T O 0
substitution O 0
also O 0
impaired O 0
HBsAg B-Chemical 1
secretion O 0
, O 0
it O 0
did O 0
not O 0
enhance O 0
the O 0
replication O 0
of O 0
LAM B-Chemical 1
- O 0
resistant O 0
clones O 0
. O 0

However O 0
, O 0
the O 0
concomitant O 0
occurrence O 0
of O 0
HBeAg B-Chemical 1
negativity O 0
( O 0
PC O 0
/ O 0
BCP O 0
) O 0
, O 0
sP120T O 0
, O 0
and O 0
LAM B-Chemical 1
resistance O 0
resulted O 0
in O 0
the O 0
restoration O 0
of O 0
replication O 0
to O 0
levels O 0
of O 0
wild O 0
- O 0
type O 0
HBV O 0
. O 0

In O 0
all O 0
clones O 0
with O 0
combined O 0
immune O 0
escape O 0
and O 0
LAM B-Chemical 1
resistance O 0
mutations O 0
, O 0
the O 0
nucleotide B-Chemical 1
analogues O 0
adefovir B-Chemical 1
and O 0
tenofovir B-Chemical 1
remained O 0
effective O 0
in O 0
suppressing O 0
viral O 0
replication O 0
in O 0
vitro O 0
. O 0

These O 0
findings O 0
reveal O 0
the O 0
differential O 0
impact O 0
of O 0
immune O 0
escape O 0
variants O 0
on O 0
the O 0
replication O 0
and O 0
drug O 0
susceptibility O 0
of O 0
complex O 0
HBV O 0
mutants O 0
, O 0
supporting O 0
the O 0
need O 0
of O 0
close O 0
surveillance O 0
and O 0
treatment O 0
adjustment O 0
in O 0
response O 0
to O 0
the O 0
selection O 0
of O 0
distinct O 0
mutational O 0
patterns O 0
. O 0

Hemolytic B-Disease 1
anemia I-Disease 1
associated O 0
with O 0
the O 0
use O 0
of O 0
omeprazole B-Chemical 1
. O 0

Omeprazole B-Chemical 1
is O 0
the O 0
first O 0
drug O 0
designed O 0
to O 0
block O 0
the O 0
final O 0
step O 0
in O 0
the O 0
acid O 0
secretory O 0
process O 0
within O 0
the O 0
parietal O 0
cell O 0
. O 0

It O 0
has O 0
been O 0
shown O 0
to O 0
be O 0
extremely O 0
effective O 0
in O 0
the O 0
treatment O 0
of O 0
peptic B-Disease 1
ulcer I-Disease 1
disease I-Disease 1
, O 0
reflux B-Disease 1
esophagitis I-Disease 1
, O 0
and O 0
the O 0
Zollinger B-Disease 1
- I-Disease 1
Ellison I-Disease 1
syndrome I-Disease 1
. O 0

Although O 0
clinical O 0
experience O 0
with O 0
omeprazole B-Chemical 1
is O 0
still O 0
limited O 0
, O 0
many O 0
controlled O 0
studies O 0
have O 0
established O 0
the O 0
short O 0
- O 0
term O 0
safety O 0
of O 0
this O 0
drug O 0
. O 0

We O 0
report O 0
the O 0
first O 0
case O 0
of O 0
a O 0
serious O 0
short O 0
- O 0
term O 0
adverse O 0
reaction O 0
with O 0
the O 0
use O 0
of O 0
omeprazole B-Chemical 1
: O 0
hemolytic B-Disease 1
anemia I-Disease 1
. O 0

The O 0
patient O 0
developed O 0
weakness O 0
, O 0
lethargy B-Disease 1
, O 0
and O 0
shortness B-Disease 1
of I-Disease 1
breath I-Disease 1
2 O 0
days O 0
after O 0
starting O 0
therapy O 0
with O 0
omeprazole B-Chemical 1
. O 0

Two O 0
weeks O 0
after O 0
the O 0
initiation O 0
of O 0
therapy O 0
, O 0
her O 0
hematocrit O 0
had O 0
decreased O 0
from O 0
44 O 0
. O 0
1 O 0
% O 0
to O 0
20 O 0
. O 0
4 O 0
% O 0
, O 0
and O 0
she O 0
had O 0
a O 0
positive O 0
direct O 0
Coombs O 0
antiglobulin O 0
test O 0
and O 0
an O 0
elevated O 0
indirect O 0
bilirubin B-Chemical 1
. O 0

After O 0
she O 0
discontinued O 0
the O 0
omeprazole B-Chemical 1
, O 0
her O 0
hemoglobin O 0
and O 0
hematocrit O 0
gradually O 0
returned O 0
to O 0
normal O 0
. O 0

The O 0
mechanism O 0
by O 0
which O 0
omeprazole B-Chemical 1
caused O 0
the O 0
patient O 0
' O 0
s O 0
hemolytic B-Disease 1
anemia I-Disease 1
is O 0
uncertain O 0
, O 0
but O 0
physicians O 0
should O 0
be O 0
alerted O 0
to O 0
this O 0
possible O 0
adverse O 0
effect O 0
. O 0

Phenylephrine B-Chemical 1
but O 0
not O 0
ephedrine B-Chemical 1
reduces B-Disease 1
frontal I-Disease 1
lobe I-Disease 1
oxygenation I-Disease 1
following O 0
anesthesia O 0
- O 0
induced O 0
hypotension B-Disease 1
. O 0

BACKGROUND O 0
: O 0
Vasopressor O 0
agents O 0
are O 0
used O 0
to O 0
correct O 0
anesthesia O 0
- O 0
induced O 0
hypotension B-Disease 1
. O 0

We O 0
describe O 0
the O 0
effect O 0
of O 0
phenylephrine B-Chemical 1
and O 0
ephedrine B-Chemical 1
on O 0
frontal O 0
lobe O 0
oxygenation O 0
( O 0
S O 0
( O 0
c O 0
) O 0
O O 0
( O 0
2 O 0
) O 0
) O 0
following O 0
anesthesia O 0
- O 0
induced O 0
hypotension B-Disease 1
. O 0

METHODS O 0
: O 0
Following O 0
induction O 0
of O 0
anesthesia O 0
by O 0
fentanyl B-Chemical 1
( O 0
0 O 0
. O 0
15 O 0
mg O 0
kg O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
and O 0
propofol B-Chemical 1
( O 0
2 O 0
. O 0
0 O 0
mg O 0
kg O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
, O 0
13 O 0
patients O 0
received O 0
phenylephrine B-Chemical 1
( O 0
0 O 0
. O 0
1 O 0
mg O 0
iv O 0
) O 0
and O 0
12 O 0
patients O 0
received O 0
ephedrine B-Chemical 1
( O 0
10 O 0
mg O 0
iv O 0
) O 0
to O 0
restore O 0
mean O 0
arterial O 0
pressure O 0
( O 0
MAP O 0
) O 0
. O 0

Heart O 0
rate O 0
( O 0
HR O 0
) O 0
, O 0
MAP O 0
, O 0
stroke B-Disease 1
volume O 0
( O 0
SV O 0
) O 0
, O 0
cardiac O 0
output O 0
( O 0
CO O 0
) O 0
, O 0
and O 0
frontal O 0
lobe O 0
oxygenation O 0
( O 0
S O 0
( O 0
c O 0
) O 0
O O 0
( O 0
2 O 0
) O 0
) O 0
were O 0
registered O 0
. O 0

RESULTS O 0
: O 0
Induction O 0
of O 0
anesthesia O 0
was O 0
followed O 0
by O 0
a B-Disease 1
decrease I-Disease 1
in I-Disease 1
MAP I-Disease 1
, I-Disease 1
HR I-Disease 1
, I-Disease 1
SV I-Disease 1
, I-Disease 1
and I-Disease 1
CO I-Disease 1
concomitant O 0
with O 0
an O 0
elevation O 0
in O 0
S O 0
( O 0
c O 0
) O 0
O O 0
( O 0
2 O 0
) O 0
. O 0

After O 0
administration O 0
of O 0
phenylephrine B-Chemical 1
, O 0
MAP O 0
increased O 0
( O 0
51 O 0
+ O 0
/ O 0
- O 0
12 O 0
to O 0
81 O 0
+ O 0
/ O 0
- O 0
13 O 0
mmHg O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
; O 0
mean O 0
+ O 0
/ O 0
- O 0
SD O 0
) O 0
. O 0

However O 0
, O 0
a O 0
14 O 0
% O 0
( O 0
from O 0
70 O 0
+ O 0
/ O 0
- O 0
8 O 0
% O 0
to O 0
60 O 0
+ O 0
/ O 0
- O 0
7 O 0
% O 0
) O 0
reduction O 0
in O 0
S O 0
( O 0
c O 0
) O 0
O O 0
( O 0
2 O 0
) O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
followed O 0
with O 0
no O 0
change O 0
in O 0
CO O 0
( O 0
3 O 0
. O 0
7 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
1 O 0
to O 0
3 O 0
. O 0
4 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
9 O 0
l O 0
min O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
. O 0

The O 0
administration O 0
of O 0
ephedrine B-Chemical 1
led O 0
to O 0
a O 0
similar O 0
increase O 0
in O 0
MAP O 0
( O 0
53 O 0
+ O 0
/ O 0
- O 0
9 O 0
to O 0
79 O 0
+ O 0
/ O 0
- O 0
8 O 0
mmHg O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
restored O 0
CO O 0
( O 0
3 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
2 O 0
to O 0
5 O 0
. O 0
0 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
3 O 0
l O 0
min O 0
( O 0
- O 0
1 O 0
) O 0
) O 0
, O 0
and O 0
preserved O 0
S O 0
( O 0
c O 0
) O 0
O O 0
( O 0
2 O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
utilization O 0
of O 0
phenylephrine B-Chemical 1
to O 0
correct O 0
hypotension B-Disease 1
induced O 0
by O 0
anesthesia O 0
has O 0
a O 0
negative O 0
impact O 0
on O 0
S O 0
( O 0
c O 0
) O 0
O O 0
( O 0
2 O 0
) O 0
while O 0
ephedrine B-Chemical 1
maintains O 0
frontal O 0
lobe O 0
oxygenation O 0
potentially O 0
related O 0
to O 0
an O 0
increase O 0
in O 0
CO O 0
. O 0

Prolonged O 0
elevation O 0
of O 0
plasma O 0
argatroban B-Chemical 1
in O 0
a O 0
cardiac O 0
transplant O 0
patient O 0
with O 0
a O 0
suspected O 0
history O 0
of O 0
heparin B-Chemical 1
- O 0
induced O 0
thrombocytopenia B-Disease 1
with O 0
thrombosis B-Disease 1
. O 0

BACKGROUND O 0
: O 0
Direct O 0
thrombin O 0
inhibitors O 0
( O 0
DTIs O 0
) O 0
provide O 0
an O 0
alternative O 0
method O 0
of O 0
anticoagulation O 0
for O 0
patients O 0
with O 0
a O 0
history O 0
of O 0
heparin B-Chemical 1
- O 0
induced O 0
thrombocytopenia B-Disease 1
( O 0
HIT B-Disease 1
) O 0
or O 0
HIT B-Disease 1
with O 0
thrombosis B-Disease 1
( O 0
HITT B-Disease 1
) O 0
undergoing O 0
cardiopulmonary O 0
bypass O 0
( O 0
CPB O 0
) O 0
. O 0

In O 0
the O 0
following O 0
report O 0
, O 0
a O 0
65 O 0
- O 0
year O 0
- O 0
old O 0
critically B-Disease 1
ill I-Disease 1
patient O 0
with O 0
a O 0
suspected O 0
history O 0
of O 0
HITT B-Disease 1
was O 0
administered O 0
argatroban B-Chemical 1
for O 0
anticoagulation O 0
on O 0
bypass O 0
during O 0
heart O 0
transplantation O 0
. O 0

The O 0
patient O 0
required O 0
massive O 0
transfusion O 0
support O 0
( O 0
55 O 0
units O 0
of O 0
red O 0
blood O 0
cells O 0
, O 0
42 O 0
units O 0
of O 0
fresh O 0
- O 0
frozen O 0
plasma O 0
, O 0
40 O 0
units O 0
of O 0
cryoprecipitate O 0
, O 0
40 O 0
units O 0
of O 0
platelets O 0
, O 0
and O 0
three O 0
doses O 0
of O 0
recombinant O 0
Factor O 0
VIIa O 0
) O 0
for O 0
severe O 0
intraoperative B-Disease 1
and I-Disease 1
postoperative I-Disease 1
bleeding I-Disease 1
. O 0

STUDY O 0
DESIGN O 0
AND O 0
METHODS O 0
: O 0
Plasma O 0
samples O 0
from O 0
before O 0
and O 0
after O 0
CPB O 0
were O 0
analyzed O 0
postoperatively O 0
for O 0
argatroban B-Chemical 1
concentration O 0
using O 0
a O 0
modified O 0
ecarin O 0
clotting O 0
time O 0
( O 0
ECT O 0
) O 0
assay O 0
. O 0

RESULTS O 0
: O 0
Unexpectedly O 0
high O 0
concentrations O 0
of O 0
argatroban B-Chemical 1
were O 0
measured O 0
in O 0
these O 0
samples O 0
( O 0
range O 0
, O 0
0 O 0
- O 0
32 O 0
microg O 0
/ O 0
mL O 0
) O 0
, O 0
and O 0
a O 0
prolonged O 0
plasma O 0
argatroban B-Chemical 1
half O 0
life O 0
( O 0
t O 0
( O 0
1 O 0
/ O 0
2 O 0
) O 0
) O 0
of O 0
514 O 0
minutes O 0
was O 0
observed O 0
( O 0
published O 0
elimination O 0
t O 0
( O 0
1 O 0
/ O 0
2 O 0
) O 0
is O 0
39 O 0
- O 0
51 O 0
minutes O 0
[ O 0
< O 0
or O 0
= O 0
181 O 0
minutes O 0
with O 0
hepatic B-Disease 1
impairment I-Disease 1
] O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
Correlation O 0
of O 0
plasma O 0
argatroban B-Chemical 1
concentration O 0
versus O 0
the O 0
patient O 0
' O 0
s O 0
coagulation O 0
variables O 0
and O 0
clinical O 0
course O 0
suggest O 0
that O 0
prolonged O 0
elevated O 0
levels O 0
of O 0
plasma O 0
argatroban B-Chemical 1
may O 0
have O 0
contributed O 0
to O 0
the O 0
patient O 0
' O 0
s O 0
extended O 0
coagulopathy B-Disease 1
. O 0

Because O 0
DTIs O 0
do O 0
not O 0
have O 0
reversal O 0
agents O 0
, O 0
surgical O 0
teams O 0
and O 0
transfusion O 0
services O 0
should O 0
remain O 0
aware O 0
of O 0
the O 0
possibility O 0
of O 0
massive O 0
transfusion O 0
events O 0
during O 0
anticoagulation O 0
with O 0
these O 0
agents O 0
. O 0

This O 0
is O 0
the O 0
first O 0
report O 0
to O 0
measure O 0
plasma O 0
argatroban B-Chemical 1
concentration O 0
in O 0
the O 0
context O 0
of O 0
CPB O 0
and O 0
extended O 0
coagulopathy B-Disease 1
. O 0

The O 0
effects O 0
of O 0
the O 0
adjunctive O 0
bupropion B-Chemical 1
on O 0
male O 0
sexual B-Disease 1
dysfunction I-Disease 1
induced O 0
by O 0
a O 0
selective B-Chemical 1
serotonin I-Chemical 1
reuptake I-Chemical 1
inhibitor I-Chemical 1
: O 0
a O 0
double O 0
- O 0
blind O 0
placebo O 0
- O 0
controlled O 0
and O 0
randomized O 0
study O 0
. O 0

OBJECTIVE O 0
: O 0
To O 0
determine O 0
the O 0
safety O 0
and O 0
efficacy O 0
of O 0
adjunctive O 0
bupropion B-Chemical 1
sustained O 0
- O 0
release O 0
( O 0
SR O 0
) O 0
on O 0
male O 0
sexual B-Disease 1
dysfunction I-Disease 1
( O 0
SD B-Disease 1
) O 0
induced O 0
by O 0
a O 0
selective B-Chemical 1
serotonin I-Chemical 1
reuptake I-Chemical 1
inhibitor I-Chemical 1
( O 0
SSRI B-Chemical 1
) O 0
, O 0
as O 0
SD B-Disease 1
is O 0
a O 0
common O 0
side O 0
- O 0
effect O 0
of O 0
SSRIs B-Chemical 1
and O 0
the O 0
most O 0
effective O 0
treatments O 0
have O 0
yet O 0
to O 0
be O 0
determined O 0
. O 0

PATIENTS O 0
AND O 0
METHODS O 0
: O 0
The O 0
randomized O 0
sample O 0
consisted O 0
of O 0
234 O 0
euthymic O 0
men O 0
who O 0
were O 0
receiving O 0
some O 0
type O 0
of O 0
SSRI B-Chemical 1
. O 0

The O 0
men O 0
were O 0
randomly O 0
assigned O 0
to O 0
bupropion B-Chemical 1
SR O 0
( O 0
150 O 0
mg O 0
twice O 0
daily O 0
, O 0
117 O 0
) O 0
or O 0
placebo O 0
( O 0
twice O 0
daily O 0
, O 0
117 O 0
) O 0
for O 0
12 O 0
weeks O 0
. O 0

Efficacy O 0
was O 0
evaluated O 0
using O 0
the O 0
Clinical O 0
Global O 0
Impression O 0
- O 0
Sexual O 0
Function O 0
( O 0
CGI O 0
- O 0
SF O 0
; O 0
the O 0
primary O 0
outcome O 0
measure O 0
) O 0
, O 0
the O 0
International O 0
Index O 0
of O 0
Erectile O 0
Function O 0
( O 0
IIEF O 0
) O 0
, O 0
Arizona O 0
Sexual O 0
Experience O 0
Scale O 0
( O 0
ASEX O 0
) O 0
, O 0
and O 0
Erectile B-Disease 1
Dysfunction I-Disease 1
Inventory O 0
of O 0
Treatment O 0
Satisfaction O 0
( O 0
EDITS O 0
) O 0
( O 0
secondary O 0
outcome O 0
measures O 0
) O 0
. O 0

Participants O 0
were O 0
followed O 0
biweekly O 0
during O 0
study O 0
period O 0
. O 0

RESULTS O 0
: O 0
After O 0
12 O 0
weeks O 0
of O 0
treatment O 0
, O 0
the O 0
mean O 0
( O 0
sd O 0
) O 0
scores O 0
for O 0
CGI O 0
- O 0
SF O 0
were O 0
significantly O 0
lower O 0
, O 0
i O 0
. O 0
e O 0
. O 0
better O 0
, O 0
in O 0
patients O 0
on O 0
bupropion B-Chemical 1
SR O 0
, O 0
at O 0
2 O 0
. O 0
4 O 0
( O 0
1 O 0
. O 0
2 O 0
) O 0
, O 0
than O 0
in O 0
the O 0
placebo O 0
group O 0
, O 0
at O 0
3 O 0
. O 0
9 O 0
( O 0
1 O 0
. O 0
1 O 0
) O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

Men O 0
who O 0
received O 0
bupropion B-Chemical 1
had O 0
a O 0
significant O 0
increase O 0
in O 0
the O 0
total O 0
IIEF O 0
score O 0
( O 0
54 O 0
. O 0
4 O 0
% O 0
vs O 0
1 O 0
. O 0
2 O 0
% O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
003 O 0
) O 0
, O 0
and O 0
in O 0
the O 0
five O 0
different O 0
domains O 0
of O 0
the O 0
IIEF O 0
. O 0

Total O 0
ASEX O 0
scores O 0
were O 0
significantly O 0
lower O 0
, O 0
i O 0
. O 0
e O 0
. O 0
better O 0
, O 0
among O 0
men O 0
who O 0
received O 0
bupropion B-Chemical 1
than O 0
placebo O 0
, O 0
at O 0
15 O 0
. O 0
5 O 0
( O 0
4 O 0
. O 0
3 O 0
) O 0
vs O 0
21 O 0
. O 0
5 O 0
( O 0
4 O 0
. O 0
7 O 0
) O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
002 O 0
) O 0
. O 0

The O 0
EDITS O 0
scores O 0
were O 0
67 O 0
. O 0
4 O 0
( O 0
10 O 0
. O 0
2 O 0
) O 0
for O 0
the O 0
bupropion B-Chemical 1
and O 0
36 O 0
. O 0
3 O 0
( O 0
11 O 0
. O 0
7 O 0
) O 0
for O 0
the O 0
placebo O 0
group O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

The O 0
ASEX O 0
score O 0
and O 0
CGI O 0
- O 0
SF O 0
score O 0
were O 0
correlated O 0
( O 0
P O 0
= O 0
0 O 0
. O 0
003 O 0
) O 0
. O 0

In O 0
linear O 0
regression O 0
analyses O 0
the O 0
CGI O 0
- O 0
SF O 0
score O 0
was O 0
not O 0
affected O 0
significantly O 0
by O 0
the O 0
duration O 0
of O 0
SD B-Disease 1
, O 0
type O 0
of O 0
SSRI B-Chemical 1
used O 0
and O 0
age O 0
. O 0

CONCLUSIONS O 0
: O 0
Bupropion B-Chemical 1
is O 0
an O 0
effective O 0
treatment O 0
for O 0
male O 0
SD B-Disease 1
induced O 0
by O 0
SSRIs B-Chemical 1
. O 0

These O 0
results O 0
provide O 0
empirical O 0
support O 0
for O 0
conducting O 0
a O 0
further O 0
study O 0
of O 0
bupropion B-Chemical 1
. O 0

Prevention O 0
of O 0
seizures B-Disease 1
and O 0
reorganization O 0
of O 0
hippocampal O 0
functions O 0
by O 0
transplantation O 0
of O 0
bone O 0
marrow O 0
cells O 0
in O 0
the O 0
acute O 0
phase O 0
of O 0
experimental O 0
epilepsy B-Disease 1
. O 0

In O 0
this O 0
study O 0
, O 0
we O 0
investigated O 0
the O 0
therapeutic O 0
potential O 0
of O 0
bone O 0
marrow O 0
mononuclear O 0
cells O 0
( O 0
BMCs O 0
) O 0
in O 0
a O 0
model O 0
of O 0
epilepsy B-Disease 1
induced O 0
by O 0
pilocarpine B-Chemical 1
in O 0
rats O 0
. O 0

BMCs O 0
obtained O 0
from O 0
green O 0
fluorescent O 0
protein O 0
( O 0
GFP O 0
) O 0
transgenic O 0
mice O 0
or O 0
rats O 0
were O 0
transplanted O 0
intravenously O 0
after O 0
induction O 0
of O 0
status B-Disease 1
epilepticus I-Disease 1
( O 0
SE B-Disease 1
) O 0
. O 0

Spontaneous B-Disease 1
recurrent I-Disease 1
seizures I-Disease 1
( O 0
SRS B-Disease 1
) O 0
were O 0
monitored O 0
using O 0
Racine O 0
' O 0
s O 0
seizure B-Disease 1
severity O 0
scale O 0
. O 0

All O 0
of O 0
the O 0
rats O 0
in O 0
the O 0
saline O 0
- O 0
treated O 0
epileptic B-Disease 1
control O 0
group O 0
developed O 0
SRS B-Disease 1
, O 0
whereas O 0
none O 0
of O 0
the O 0
BMC O 0
- O 0
treated O 0
epileptic B-Disease 1
animals O 0
had O 0
seizures B-Disease 1
in O 0
the O 0
short O 0
term O 0
( O 0
15 O 0
days O 0
after O 0
transplantation O 0
) O 0
, O 0
regardless O 0
of O 0
the O 0
BMC O 0
source O 0
. O 0

Over O 0
the O 0
long O 0
- O 0
term O 0
chronic O 0
phase O 0
( O 0
120 O 0
days O 0
after O 0
transplantation O 0
) O 0
, O 0
only O 0
25 O 0
% O 0
of O 0
BMC O 0
- O 0
treated O 0
epileptic B-Disease 1
animals O 0
had O 0
seizures B-Disease 1
, O 0
but O 0
with O 0
a O 0
lower O 0
frequency O 0
and O 0
duration O 0
compared O 0
to O 0
the O 0
epileptic B-Disease 1
control O 0
group O 0
. O 0

The O 0
density O 0
of O 0
hippocampal O 0
neurons O 0
in O 0
the O 0
brains O 0
of O 0
animals O 0
treated O 0
with O 0
BMCs O 0
was O 0
markedly O 0
preserved O 0
. O 0

At O 0
hippocampal O 0
Schaeffer O 0
collateral O 0
- O 0
CA1 O 0
synapses O 0
, O 0
long O 0
- O 0
term O 0
potentiation O 0
was O 0
preserved O 0
in O 0
BMC O 0
- O 0
transplanted O 0
rats O 0
compared O 0
to O 0
epileptic B-Disease 1
controls O 0
. O 0

The O 0
donor O 0
- O 0
derived O 0
GFP O 0
( O 0
+ O 0
) O 0
cells O 0
were O 0
rarely O 0
found O 0
in O 0
the O 0
brains O 0
of O 0
transplanted O 0
epileptic B-Disease 1
rats O 0
. O 0

In O 0
conclusion O 0
, O 0
treatment O 0
with O 0
BMCs O 0
can O 0
prevent O 0
the O 0
development O 0
of O 0
chronic O 0
seizures B-Disease 1
, O 0
reduce O 0
neuronal B-Disease 1
loss I-Disease 1
, O 0
and O 0
influence O 0
the O 0
reorganization O 0
of O 0
the O 0
hippocampal O 0
neuronal O 0
network O 0
. O 0

Normalizing O 0
effects O 0
of O 0
modafinil B-Chemical 1
on O 0
sleep O 0
in O 0
chronic O 0
cocaine B-Chemical 1
users O 0
. O 0

OBJECTIVE O 0
: O 0
The O 0
purpose O 0
of O 0
the O 0
present O 0
study O 0
was O 0
to O 0
determine O 0
the O 0
effect O 0
of O 0
morning O 0
- O 0
dosed O 0
modafinil B-Chemical 1
on O 0
sleep O 0
and O 0
daytime B-Disease 1
sleepiness I-Disease 1
in O 0
chronic O 0
cocaine B-Chemical 1
users O 0
. O 0

METHOD O 0
: O 0
Twenty O 0
cocaine B-Chemical 1
- O 0
dependent O 0
participants O 0
were O 0
randomly O 0
assigned O 0
to O 0
receive O 0
modafinil B-Chemical 1
, O 0
400 O 0
mg O 0
( O 0
N O 0
= O 0
10 O 0
) O 0
, O 0
or O 0
placebo O 0
( O 0
N O 0
= O 0
10 O 0
) O 0
every O 0
morning O 0
at O 0
7 O 0
: O 0
30 O 0
a O 0
. O 0
m O 0
. O 0
for O 0
16 O 0
days O 0
in O 0
an O 0
inpatient O 0
, O 0
double O 0
- O 0
blind O 0
randomized O 0
trial O 0
. O 0

Participants O 0
underwent O 0
polysomnographic O 0
sleep O 0
recordings O 0
on O 0
days O 0
1 O 0
to O 0
3 O 0
, O 0
7 O 0
to O 0
9 O 0
, O 0
and O 0
14 O 0
to O 0
16 O 0
( O 0
first O 0
, O 0
second O 0
, O 0
and O 0
third O 0
weeks O 0
of O 0
abstinence O 0
) O 0
. O 0

The O 0
Multiple O 0
Sleep O 0
Latency O 0
Test O 0
was O 0
performed O 0
at O 0
11 O 0
: O 0
30 O 0
a O 0
. O 0
m O 0
. O 0
, O 0
2 O 0
: O 0
00 O 0
p O 0
. O 0
m O 0
. O 0
, O 0
and O 0
4 O 0
: O 0
30 O 0
p O 0
. O 0
m O 0
. O 0
on O 0
days O 0
2 O 0
, O 0
8 O 0
, O 0
and O 0
15 O 0
. O 0

For O 0
comparison O 0
of O 0
sleep O 0
architecture O 0
variables O 0
, O 0
12 O 0
healthy O 0
comparison O 0
participants O 0
underwent O 0
a O 0
single O 0
night O 0
of O 0
experimental O 0
polysomnography O 0
that O 0
followed O 0
1 O 0
night O 0
of O 0
accommodation O 0
polysomnography O 0
. O 0

RESULTS O 0
: O 0
Progressive O 0
abstinence O 0
from O 0
cocaine B-Chemical 1
was O 0
associated O 0
with O 0
worsening O 0
of O 0
all O 0
measured O 0
polysomnographic O 0
sleep O 0
outcomes O 0
. O 0

Compared O 0
with O 0
placebo O 0
, O 0
modafinil B-Chemical 1
decreased O 0
nighttime O 0
sleep O 0
latency O 0
and O 0
increased O 0
slow O 0
- O 0
wave O 0
sleep O 0
time O 0
in O 0
cocaine B-Chemical 1
- O 0
dependent O 0
participants O 0
. O 0

The O 0
effect O 0
of O 0
modafinil B-Chemical 1
interacted O 0
with O 0
the O 0
abstinence O 0
week O 0
and O 0
was O 0
associated O 0
with O 0
longer O 0
total O 0
sleep O 0
time O 0
and O 0
shorter O 0
REM O 0
sleep O 0
latency O 0
in O 0
the O 0
third O 0
week O 0
of O 0
abstinence O 0
. O 0

Comparison O 0
of O 0
slow O 0
- O 0
wave O 0
sleep O 0
time O 0
, O 0
total O 0
sleep O 0
time O 0
, O 0
and O 0
sleep O 0
latency O 0
in O 0
cocaine B-Chemical 1
- O 0
dependent O 0
and O 0
healthy O 0
participants O 0
revealed O 0
a O 0
normalizing O 0
effect O 0
of O 0
modafinil B-Chemical 1
in O 0
cocaine B-Chemical 1
- O 0
dependent O 0
participants O 0
. O 0

Modafinil B-Chemical 1
was O 0
associated O 0
with O 0
increased O 0
daytime O 0
sleep O 0
latency O 0
, O 0
as O 0
measured O 0
by O 0
the O 0
Multiple O 0
Sleep O 0
Latency O 0
Test O 0
, O 0
and O 0
a O 0
nearly O 0
significant O 0
decrease O 0
in O 0
subjective O 0
daytime B-Disease 1
sleepiness I-Disease 1
. O 0

CONCLUSIONS O 0
: O 0
Morning O 0
- O 0
dosed O 0
modafinil B-Chemical 1
promotes O 0
nocturnal O 0
sleep O 0
, O 0
normalizes O 0
sleep O 0
architecture O 0
, O 0
and O 0
decreases O 0
daytime B-Disease 1
sleepiness I-Disease 1
in O 0
abstinent O 0
cocaine B-Chemical 1
users O 0
. O 0

These O 0
effects O 0
may O 0
be O 0
relevant O 0
in O 0
the O 0
treatment O 0
of O 0
cocaine B-Chemical 1
dependence O 0
. O 0

Safety O 0
of O 0
transesophageal O 0
echocardiography O 0
in O 0
adults O 0
: O 0
study O 0
in O 0
a O 0
multidisciplinary O 0
hospital O 0
. O 0

BACKGROUND O 0
: O 0
TEE O 0
is O 0
a O 0
semi O 0
- O 0
invasive O 0
tool O 0
broadly O 0
used O 0
and O 0
its O 0
utilization O 0
associated O 0
to O 0
sedatives O 0
drugs O 0
might O 0
to O 0
affect O 0
the O 0
procedure O 0
safety O 0
. O 0

OBJECTIVE O 0
: O 0
to O 0
analyze O 0
aspects O 0
of O 0
TEE O 0
safety O 0
associated O 0
to O 0
the O 0
use O 0
of O 0
Midazolan B-Chemical 1
( O 0
MZ B-Chemical 1
) O 0
and O 0
Flumazenil B-Chemical 1
( O 0
FL B-Chemical 1
) O 0
and O 0
the O 0
influence O 0
of O 0
the O 0
clinical O 0
variables O 0
on O 0
the O 0
event O 0
rate O 0
. O 0

METHOD O 0
: O 0
prospective O 0
study O 0
with O 0
137 O 0
patients O 0
that O 0
underwent O 0
TEE O 0
with O 0
MZ B-Chemical 1
associated O 0
to O 0
moderate O 0
sedation O 0
. O 0

We O 0
analyzed O 0
the O 0
following O 0
events O 0
: O 0
complications O 0
related O 0
with O 0
the O 0
topical O 0
anesthesia O 0
, O 0
with O 0
MZ B-Chemical 1
use O 0
and O 0
with O 0
the O 0
procedure O 0
. O 0

Uni O 0
- O 0
and O 0
multivariate O 0
analyses O 0
were O 0
used O 0
to O 0
test O 0
the O 0
influence O 0
of O 0
the O 0
clinical O 0
variables O 0
: O 0
age O 0
, O 0
sex O 0
, O 0
stroke B-Disease 1
, O 0
myocardiopathy B-Disease 1
( O 0
MP B-Disease 1
) O 0
, O 0
duration O 0
of O 0
the O 0
test O 0
, O 0
mitral B-Disease 1
regurgitation I-Disease 1
( O 0
MR B-Disease 1
) O 0
and O 0
the O 0
MZ B-Chemical 1
dose O 0
. O 0

RESULTS O 0
: O 0
All O 0
patients O 0
( O 0
65 O 0
+ O 0
/ O 0
- O 0
16 O 0
yrs O 0
; O 0
58 O 0
% O 0
males O 0
) O 0
finished O 0
the O 0
examination O 0
. O 0

The O 0
mean O 0
doses O 0
of O 0
MZ B-Chemical 1
and O 0
FL B-Chemical 1
were O 0
4 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
9 O 0
mg O 0
and O 0
0 O 0
. O 0
28 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
2 O 0
mg O 0
, O 0
respectively O 0
. O 0

The O 0
duration O 0
of O 0
the O 0
examination O 0
and O 0
the O 0
mean O 0
ejection O 0
fraction O 0
( O 0
EF O 0
) O 0
were O 0
16 O 0
. O 0
4 O 0
+ O 0
/ O 0
- O 0
6 O 0
. O 0
1 O 0
minutes O 0
and O 0
60 O 0
+ O 0
/ O 0
- O 0
9 O 0
% O 0
, O 0
respectively O 0
. O 0

Mild O 0
hypoxia B-Disease 1
( O 0
SO2 O 0
< O 0
90 O 0
% O 0
) O 0
was O 0
the O 0
most O 0
common O 0
event O 0
( O 0
11 O 0
patients O 0
) O 0
; O 0
3 O 0
patients O 0
( O 0
2 O 0
% O 0
) O 0
presented O 0
transient O 0
hypoxia B-Disease 1
due O 0
to O 0
upper O 0
airway B-Disease 1
obstruction I-Disease 1
by O 0
probe O 0
introduction O 0
and O 0
8 O 0
( O 0
5 O 0
. O 0
8 O 0
% O 0
) O 0
due O 0
to O 0
hypoxia B-Disease 1
caused O 0
by O 0
MZ B-Chemical 1
use O 0
. O 0

Transient O 0
hypotension B-Disease 1
( O 0
SAP O 0
< O 0
90mmHg O 0
) O 0
occurred O 0
in O 0
1 O 0
patient O 0
( O 0
0 O 0
. O 0
7 O 0
% O 0
) O 0
. O 0

The O 0
multivariate O 0
analysis O 0
showed O 0
that O 0
severe O 0
MR B-Disease 1
, O 0
MP B-Disease 1
( O 0
EF O 0
< O 0
45 O 0
% O 0
) O 0
and O 0
high O 0
doses O 0
of O 0
MZ B-Chemical 1
( O 0
> O 0
5mg O 0
) O 0
were O 0
associated O 0
with O 0
events O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

The O 0
EF O 0
was O 0
40 O 0
% O 0
, O 0
in O 0
the O 0
group O 0
with O 0
MP B-Disease 1
and O 0
44 O 0
% O 0
in O 0
the O 0
group O 0
with O 0
severe O 0
MR B-Disease 1
and O 0
it O 0
can O 0
be O 0
a O 0
factor O 0
associated O 0
with O 0
clinical O 0
events O 0
in O 0
the O 0
last O 0
group O 0
. O 0

CONCLUSION O 0
: O 0
TEE O 0
with O 0
sedation O 0
presents O 0
a O 0
low O 0
rate O 0
of O 0
events O 0
. O 0

There O 0
were O 0
no O 0
severe O 0
events O 0
and O 0
there O 0
was O 0
no O 0
need O 0
to O 0
interrupt O 0
the O 0
examinations O 0
. O 0

Effect O 0
of O 0
direct O 0
intracoronary O 0
administration O 0
of O 0
methylergonovine B-Chemical 1
in O 0
patients O 0
with O 0
and O 0
without O 0
variant B-Disease 1
angina I-Disease 1
. O 0

The O 0
effects O 0
of O 0
intracoronary O 0
administration O 0
of O 0
methylergonovine B-Chemical 1
were O 0
studied O 0
in O 0
21 O 0
patients O 0
with O 0
variant B-Disease 1
angina I-Disease 1
and O 0
22 O 0
patients O 0
with O 0
atypical O 0
chest B-Disease 1
pain I-Disease 1
and O 0
in O 0
others O 0
without O 0
angina B-Disease 1
pectoris I-Disease 1
( O 0
control O 0
group O 0
) O 0
. O 0

Methylergonovine B-Chemical 1
was O 0
administered O 0
continuously O 0
at O 0
a O 0
rate O 0
of O 0
10 O 0
micrograms O 0
/ O 0
min O 0
up O 0
to O 0
50 O 0
micrograms O 0
. O 0

In O 0
all O 0
patients O 0
with O 0
variant B-Disease 1
angina I-Disease 1
, O 0
coronary B-Disease 1
spasm I-Disease 1
was O 0
provoked O 0
at O 0
a O 0
mean O 0
dose O 0
of O 0
28 O 0
+ O 0
/ O 0
- O 0
13 O 0
micrograms O 0
( O 0
mean O 0
+ O 0
/ O 0
- O 0
SD O 0
) O 0
. O 0

In O 0
the O 0
control O 0
group O 0
neither O 0
ischemic O 0
ST O 0
change O 0
nor O 0
localized O 0
spasm B-Disease 1
occurred O 0
. O 0

The O 0
basal O 0
tone O 0
of O 0
the O 0
right O 0
coronary O 0
artery O 0
was O 0
significantly O 0
lower O 0
than O 0
that O 0
of O 0
the O 0
left O 0
coronary O 0
artery O 0
. O 0

The O 0
percentage O 0
of O 0
vasoconstriction O 0
of O 0
the O 0
right O 0
coronary O 0
artery O 0
was O 0
significantly O 0
higher O 0
than O 0
that O 0
of O 0
the O 0
left O 0
coronary O 0
artery O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
spasm B-Disease 1
provocation O 0
tests O 0
, O 0
which O 0
use O 0
an O 0
intracoronary O 0
injection O 0
of O 0
a O 0
relatively O 0
low O 0
dose O 0
of O 0
methylergonovine B-Chemical 1
, O 0
have O 0
a O 0
high O 0
sensitivity O 0
in O 0
variant B-Disease 1
angina I-Disease 1
and O 0
the O 0
vasoreactivity O 0
of O 0
the O 0
right O 0
coronary O 0
artery O 0
may O 0
be O 0
greater O 0
than O 0
that O 0
of O 0
the O 0
other O 0
coronary O 0
arteries O 0
. O 0

Oral O 0
manifestations O 0
of O 0
" O 0
meth B-Disease 1
mouth I-Disease 1
" O 0
: O 0
a O 0
case O 0
report O 0
. O 0

AIM O 0
: O 0
The O 0
aim O 0
of O 0
the O 0
documentation O 0
of O 0
this O 0
clinical O 0
case O 0
is O 0
to O 0
make O 0
clinicians O 0
aware O 0
of O 0
" O 0
meth B-Disease 1
mouth I-Disease 1
" O 0
and O 0
the O 0
medical O 0
risks O 0
associated O 0
with O 0
this O 0
serious O 0
condition O 0
. O 0

BACKGROUND O 0
: O 0
Methamphetamine B-Chemical 1
is O 0
a O 0
very O 0
addictive O 0
, O 0
powerful O 0
stimulant O 0
that O 0
increases O 0
wakefulness O 0
and O 0
physical O 0
activity O 0
and O 0
can O 0
produce O 0
other O 0
effects O 0
such O 0
as O 0
cardiac B-Disease 1
dysrhythmias I-Disease 1
, O 0
hypertension B-Disease 1
, O 0
hallucinations B-Disease 1
, O 0
and O 0
violent B-Disease 1
behavior I-Disease 1
. O 0

Dental O 0
patients O 0
abusing O 0
methamphetamine B-Chemical 1
can O 0
present O 0
with O 0
poor O 0
oral O 0
hygiene O 0
, O 0
xerostomia B-Disease 1
, O 0
rampant O 0
caries B-Disease 1
( O 0
" O 0
meth B-Disease 1
mouth I-Disease 1
" O 0
) O 0
, O 0
and O 0
excessive O 0
tooth B-Disease 1
wear I-Disease 1
. O 0

Oral O 0
rehabilitation O 0
of O 0
patients O 0
using O 0
methamphetamine B-Chemical 1
can O 0
be O 0
challenging O 0
. O 0

CASE O 0
DESCRIPTION O 0
: O 0
A O 0
30 O 0
- O 0
year O 0
- O 0
old O 0
Caucasian O 0
woman O 0
presented O 0
with O 0
dental O 0
pain B-Disease 1
, O 0
bad B-Disease 1
breath I-Disease 1
, O 0
and O 0
self O 0
- O 0
reported O 0
poor O 0
esthetics O 0
. O 0

A O 0
comprehensive O 0
examination O 0
including O 0
her O 0
medical O 0
history O 0
, O 0
panoramic O 0
radiograph O 0
, O 0
and O 0
intraoral O 0
examination O 0
revealed O 0
19 O 0
carious B-Disease 1
lesions I-Disease 1
, O 0
which O 0
is O 0
not O 0
very O 0
common O 0
for O 0
a O 0
healthy O 0
adult O 0
. O 0

She O 0
reported O 0
her O 0
use O 0
of O 0
methamphetamine B-Chemical 1
for O 0
five O 0
years O 0
and O 0
had O 0
not O 0
experienced O 0
any O 0
major O 0
carious B-Disease 1
episodes I-Disease 1
before O 0
she O 0
started O 0
using O 0
the O 0
drug O 0
. O 0

SUMMARY O 0
: O 0
The O 0
patient O 0
' O 0
s O 0
medical O 0
and O 0
dental O 0
histories O 0
along O 0
with O 0
radiographic O 0
and O 0
clinical O 0
findings O 0
lead O 0
to O 0
a O 0
diagnosis O 0
of O 0
" O 0
meth B-Disease 1
mouth I-Disease 1
. O 0
" O 0
Although O 0
three O 0
different O 0
dental O 0
treatment O 0
modalities O 0
( O 0
either O 0
conventional O 0
or O 0
implant O 0
- O 0
supported O 0
) O 0
have O 0
been O 0
offered O 0
to O 0
the O 0
patient O 0
since O 0
August O 0
2007 O 0
, O 0
the O 0
patient O 0
has O 0
yet O 0
to O 0
initiate O 0
any O 0
treatment O 0
. O 0

CLINICAL O 0
SIGNIFICANCE O 0
: O 0
This O 0
clinical O 0
case O 0
showing O 0
oral O 0
manifestations O 0
of O 0
meth B-Disease 1
mouth I-Disease 1
was O 0
presented O 0
to O 0
help O 0
dental O 0
practitioners O 0
recognize O 0
and O 0
manage O 0
patients O 0
who O 0
may O 0
be O 0
abusing O 0
methamphetamines B-Chemical 1
. O 0

Dental O 0
practitioners O 0
also O 0
may O 0
be O 0
skeptical O 0
about O 0
the O 0
reliability O 0
of O 0
appointment O 0
keeping O 0
by O 0
these O 0
patients O 0
, O 0
as O 0
they O 0
frequently O 0
miss O 0
their O 0
appointments O 0
without O 0
reasonable O 0
justification O 0
. O 0

Antituberculosis B-Chemical 1
therapy O 0
- O 0
induced O 0
acute B-Disease 1
liver I-Disease 1
failure I-Disease 1
: O 0
magnitude O 0
, O 0
profile O 0
, O 0
prognosis O 0
, O 0
and O 0
predictors O 0
of O 0
outcome O 0
. O 0

Antituberculosis B-Chemical 1
therapy O 0
( O 0
ATT O 0
) O 0
- O 0
associated O 0
acute B-Disease 1
liver I-Disease 1
failure I-Disease 1
( O 0
ATT O 0
- O 0
ALF B-Disease 1
) O 0
is O 0
the O 0
commonest O 0
drug O 0
- O 0
induced O 0
ALF B-Disease 1
in O 0
South O 0
Asia O 0
. O 0

Prospective O 0
studies O 0
on O 0
ATT O 0
- O 0
ALF B-Disease 1
are O 0
lacking O 0
. O 0

The O 0
current O 0
study O 0
prospectively O 0
evaluated O 0
the O 0
magnitude O 0
, O 0
clinical O 0
course O 0
, O 0
outcome O 0
, O 0
and O 0
prognostic O 0
factors O 0
in O 0
ATT O 0
- O 0
ALF B-Disease 1
. O 0

From O 0
January O 0
1986 O 0
to O 0
January O 0
2009 O 0
, O 0
1223 O 0
consecutive O 0
ALF B-Disease 1
patients O 0
were O 0
evaluated O 0
: O 0
ATT O 0
alone O 0
was O 0
the O 0
cause O 0
in O 0
70 O 0
( O 0
5 O 0
. O 0
7 O 0
% O 0
) O 0
patients O 0
. O 0

Another O 0
15 O 0
( O 0
1 O 0
. O 0
2 O 0
% O 0
) O 0
had O 0
ATT O 0
and O 0
simultaneous O 0
hepatitis B-Disease 1
virus I-Disease 1
infection I-Disease 1
. O 0

In O 0
44 O 0
( O 0
62 O 0
. O 0
8 O 0
% O 0
) O 0
patients O 0
, O 0
ATT O 0
was O 0
prescribed O 0
empirically O 0
without O 0
definitive O 0
evidence O 0
of O 0
tuberculosis B-Disease 1
. O 0

ATT O 0
- O 0
ALF B-Disease 1
patients O 0
were O 0
younger O 0
( O 0
32 O 0
. O 0
87 O 0
[ O 0
+ O 0
/ O 0
- O 0
15 O 0
. O 0
8 O 0
] O 0
years O 0
) O 0
, O 0
and O 0
49 O 0
( O 0
70 O 0
% O 0
) O 0
of O 0
them O 0
were O 0
women O 0
. O 0

Most O 0
had O 0
hyperacute O 0
presentation O 0
; O 0
the O 0
median O 0
icterus B-Disease 1
encephalopathy B-Disease 1
interval O 0
was O 0
4 O 0
. O 0
5 O 0
( O 0
0 O 0
- O 0
30 O 0
) O 0
days O 0
. O 0

The O 0
median O 0
duration O 0
of O 0
ATT O 0
before O 0
ALF B-Disease 1
was O 0
30 O 0
( O 0
7 O 0
- O 0
350 O 0
) O 0
days O 0
. O 0

At O 0
presentation O 0
, O 0
advanced O 0
encephalopathy B-Disease 1
and O 0
cerebral B-Disease 1
edema I-Disease 1
were O 0
present O 0
in O 0
51 O 0
( O 0
76 O 0
% O 0
) O 0
and O 0
29 O 0
( O 0
41 O 0
. O 0
4 O 0
% O 0
) O 0
patients O 0
, O 0
respectively O 0
. O 0

Gastrointestinal B-Disease 1
bleed I-Disease 1
, O 0
seizures B-Disease 1
, O 0
infection B-Disease 1
, O 0
and O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
were O 0
documented O 0
in O 0
seven O 0
( O 0
10 O 0
% O 0
) O 0
, O 0
five O 0
( O 0
7 O 0
. O 0
1 O 0
% O 0
) O 0
, O 0
26 O 0
( O 0
37 O 0
. O 0
1 O 0
% O 0
) O 0
, O 0
and O 0
seven O 0
( O 0
10 O 0
% O 0
) O 0
patients O 0
, O 0
respectively O 0
. O 0

Compared O 0
with O 0
hepatitis B-Disease 1
E I-Disease 1
virus O 0
( O 0
HEV O 0
) O 0
and O 0
non O 0
- O 0
A O 0
non O 0
- O 0
E O 0
- O 0
induced O 0
ALF B-Disease 1
, O 0
ATT O 0
- O 0
ALF B-Disease 1
patients O 0
had O 0
nearly O 0
similar O 0
presentations O 0
except O 0
for O 0
older O 0
age O 0
and O 0
less O 0
elevation O 0
of O 0
liver O 0
enzymes O 0
. O 0

The O 0
mortality O 0
rate O 0
among O 0
patients O 0
with O 0
ATT O 0
- O 0
ALF B-Disease 1
was O 0
high O 0
( O 0
67 O 0
. O 0
1 O 0
% O 0
, O 0
n O 0
= O 0
47 O 0
) O 0
, O 0
and O 0
only O 0
23 O 0
( O 0
32 O 0
. O 0
9 O 0
% O 0
) O 0
patients O 0
recovered O 0
with O 0
medical O 0
treatment O 0
. O 0

In O 0
multivariate O 0
analysis O 0
, O 0
three O 0
factors O 0
independently O 0
predicted O 0
mortality O 0
: O 0
serum O 0
bilirubin B-Chemical 1
( O 0
> O 0
or O 0
= O 0
10 O 0
. O 0
8 O 0
mg O 0
/ O 0
dL O 0
) O 0
, O 0
prothrombin O 0
time O 0
( O 0
PT O 0
) O 0
prolongation O 0
( O 0
> O 0
or O 0
= O 0
26 O 0
seconds O 0
) O 0
, O 0
and O 0
grade O 0
III O 0
/ O 0
IV O 0
encephalopathy B-Disease 1
at O 0
presentation O 0
. O 0

CONCLUSION O 0
: O 0
ATT O 0
- O 0
ALF B-Disease 1
constituted O 0
5 O 0
. O 0
7 O 0
% O 0
of O 0
ALF B-Disease 1
at O 0
our O 0
center O 0
and O 0
had O 0
a O 0
high O 0
mortality O 0
rate O 0
. O 0

Because O 0
the O 0
mortality O 0
rate O 0
is O 0
so O 0
high O 0
, O 0
determining O 0
which O 0
factors O 0
are O 0
predictors O 0
is O 0
less O 0
important O 0
. O 0

A O 0
high O 0
proportion O 0
of O 0
patients O 0
had O 0
consumed O 0
ATT O 0
empirically O 0
, O 0
which O 0
could O 0
have O 0
been O 0
prevented O 0
. O 0

Design O 0
and O 0
analysis O 0
of O 0
the O 0
HYPREN O 0
- O 0
trial O 0
: O 0
safety O 0
of O 0
enalapril B-Chemical 1
and O 0
prazosin B-Chemical 1
in O 0
the O 0
initial O 0
treatment O 0
phase O 0
of O 0
patients O 0
with O 0
congestive B-Disease 1
heart I-Disease 1
failure I-Disease 1
. O 0

Since O 0
the O 0
introduction O 0
of O 0
angiotensin B-Chemical 1
converting I-Chemical 1
enzyme I-Chemical 1
( I-Chemical 1
ACE I-Chemical 1
) I-Chemical 1
inhibitors I-Chemical 1
into O 0
the O 0
adjunctive O 0
treatment O 0
of O 0
patients O 0
with O 0
congestive B-Disease 1
heart I-Disease 1
failure I-Disease 1
, O 0
cases O 0
of O 0
severe O 0
hypotension B-Disease 1
, O 0
especially O 0
on O 0
the O 0
first O 0
day O 0
of O 0
treatment O 0
, O 0
have O 0
occasionally O 0
been O 0
reported O 0
. O 0

To O 0
assess O 0
the O 0
safety O 0
of O 0
the O 0
ACE B-Chemical 1
inhibitor I-Chemical 1
enalapril B-Chemical 1
a O 0
multicenter O 0
, O 0
randomized O 0
, O 0
prazosin B-Chemical 1
- O 0
controlled O 0
trial O 0
was O 0
designed O 0
that O 0
compared O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
symptomatic O 0
hypotension B-Disease 1
on O 0
the O 0
first O 0
day O 0
of O 0
treatment O 0
. O 0

Trial O 0
medication O 0
was O 0
2 O 0
. O 0
5 O 0
mg O 0
enalapril B-Chemical 1
or O 0
0 O 0
. O 0
5 O 0
prazosin B-Chemical 1
. O 0

Subjects O 0
were O 0
1210 O 0
inpatients O 0
with O 0
New O 0
York O 0
Heart O 0
Association O 0
( O 0
NYHA O 0
) O 0
functional O 0
class O 0
II O 0
and O 0
III O 0
. O 0

Patients O 0
who O 0
received O 0
enalapril B-Chemical 1
experienced O 0
clinically O 0
and O 0
statistically O 0
significantly O 0
less O 0
symptomatic O 0
hypotension B-Disease 1
( O 0
5 O 0
. O 0
2 O 0
% O 0
) O 0
than O 0
the O 0
patients O 0
who O 0
received O 0
prazosin B-Chemical 1
( O 0
12 O 0
. O 0
9 O 0
% O 0
) O 0
. O 0

All O 0
patients O 0
recovered O 0
. O 0

It O 0
was O 0
concluded O 0
that O 0
treatment O 0
with O 0
enalapril B-Chemical 1
was O 0
well O 0
tolerated O 0
and O 0
it O 0
is O 0
, O 0
therefore O 0
, O 0
unreasonable O 0
to O 0
restrict O 0
the O 0
initiation O 0
of O 0
treatment O 0
with O 0
enalapril B-Chemical 1
to O 0
inpatients O 0
. O 0

Central B-Disease 1
nervous I-Disease 1
system I-Disease 1
complications I-Disease 1
during O 0
treatment O 0
of O 0
acute B-Disease 1
lymphoblastic I-Disease 1
leukemia I-Disease 1
in O 0
a O 0
single O 0
pediatric O 0
institution O 0
. O 0

Central B-Disease 1
nervous I-Disease 1
system I-Disease 1
( I-Disease 1
CNS I-Disease 1
) I-Disease 1
complications I-Disease 1
during O 0
treatment O 0
of O 0
childhood O 0
acute B-Disease 1
lymphoblastic I-Disease 1
leukemia I-Disease 1
( O 0
ALL B-Disease 1
) O 0
remain O 0
a O 0
challenging O 0
clinical O 0
problem O 0
. O 0

Outcome O 0
improvement O 0
with O 0
more O 0
intensive O 0
chemotherapy O 0
has O 0
significantly O 0
increased O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
adverse O 0
events O 0
. O 0

This O 0
study O 0
analyzed O 0
the O 0
incidence O 0
of O 0
neurological B-Disease 1
complications I-Disease 1
during O 0
ALL B-Disease 1
treatment O 0
in O 0
a O 0
single O 0
pediatric O 0
institution O 0
, O 0
focusing O 0
on O 0
clinical O 0
, O 0
radiological O 0
, O 0
and O 0
electrophysiological O 0
findings O 0
. O 0

Exclusion O 0
criteria O 0
included O 0
CNS O 0
leukemic B-Disease 1
infiltration I-Disease 1
at O 0
diagnosis O 0
, O 0
therapy O 0
- O 0
related O 0
peripheral B-Disease 1
neuropathy I-Disease 1
, O 0
late O 0
- O 0
onset O 0
encephalopathy B-Disease 1
, O 0
or O 0
long O 0
- O 0
term O 0
neurocognitive B-Disease 1
defects I-Disease 1
. O 0

During O 0
a O 0
9 O 0
- O 0
year O 0
period O 0
, O 0
we O 0
retrospectively O 0
collected O 0
27 O 0
neurological O 0
events O 0
( O 0
11 O 0
% O 0
) O 0
in O 0
as O 0
many O 0
patients O 0
, O 0
from O 0
253 O 0
children O 0
enrolled O 0
in O 0
the O 0
ALL B-Disease 1
front O 0
- O 0
line O 0
protocol O 0
. O 0

CNS O 0
complications O 0
included O 0
posterior O 0
reversible O 0
leukoencephalopathy B-Disease 1
syndrome O 0
( O 0
n O 0
= O 0
10 O 0
) O 0
, O 0
stroke B-Disease 1
( O 0
n O 0
= O 0
5 O 0
) O 0
, O 0
temporal B-Disease 1
lobe I-Disease 1
epilepsy I-Disease 1
( O 0
n O 0
= O 0
2 O 0
) O 0
, O 0
high O 0
- O 0
dose O 0
methotrexate B-Chemical 1
toxicity B-Disease 1
( O 0
n O 0
= O 0
2 O 0
) O 0
, O 0
syndrome O 0
of O 0
inappropriate B-Disease 1
antidiuretic I-Disease 1
hormone I-Disease 1
secretion I-Disease 1
( O 0
n O 0
= O 0
1 O 0
) O 0
, O 0
and O 0
other O 0
unclassified O 0
events O 0
( O 0
n O 0
= O 0
7 O 0
) O 0
. O 0

In O 0
conclusion O 0
, O 0
CNS O 0
complications O 0
are O 0
frequent O 0
events O 0
during O 0
ALL B-Disease 1
therapy O 0
, O 0
and O 0
require O 0
rapid O 0
detection O 0
and O 0
prompt O 0
treatment O 0
to O 0
limit O 0
permanent O 0
damage O 0
. O 0

Cocaine B-Chemical 1
causes O 0
memory B-Disease 1
and I-Disease 1
learning I-Disease 1
impairments I-Disease 1
in O 0
rats O 0
: O 0
involvement O 0
of O 0
nuclear O 0
factor O 0
kappa O 0
B O 0
and O 0
oxidative O 0
stress O 0
, O 0
and O 0
prevention O 0
by O 0
topiramate B-Chemical 1
. O 0

Different O 0
mechanisms O 0
have O 0
been O 0
suggested O 0
for O 0
cocaine B-Chemical 1
toxicity B-Disease 1
including O 0
an O 0
increase O 0
in O 0
oxidative O 0
stress O 0
but O 0
the O 0
association O 0
between O 0
oxidative O 0
status O 0
in O 0
the O 0
brain O 0
and O 0
cocaine B-Chemical 1
induced O 0
- O 0
behaviour O 0
is O 0
poorly O 0
understood O 0
. O 0

Nuclear O 0
factor O 0
kappa O 0
B O 0
( O 0
NFkappaB O 0
) O 0
is O 0
a O 0
sensor O 0
of O 0
oxidative O 0
stress O 0
and O 0
participates O 0
in O 0
memory O 0
formation O 0
that O 0
could O 0
be O 0
involved O 0
in O 0
drug O 0
toxicity B-Disease 1
and O 0
addiction O 0
mechanisms O 0
. O 0

Therefore O 0
NFkappaB O 0
activity O 0
, O 0
oxidative O 0
stress O 0
, O 0
neuronal O 0
nitric B-Chemical 1
oxide I-Chemical 1
synthase O 0
( O 0
nNOS O 0
) O 0
activity O 0
, O 0
spatial O 0
learning O 0
and O 0
memory O 0
as O 0
well O 0
as O 0
the O 0
effect O 0
of O 0
topiramate B-Chemical 1
, O 0
a O 0
previously O 0
proposed O 0
therapy O 0
for O 0
cocaine B-Disease 1
addiction I-Disease 1
, O 0
were O 0
evaluated O 0
in O 0
an O 0
experimental O 0
model O 0
of O 0
cocaine B-Chemical 1
administration O 0
in O 0
rats O 0
. O 0

NFkappaB O 0
activity O 0
was O 0
decreased O 0
in O 0
the O 0
frontal O 0
cortex O 0
of O 0
cocaine B-Chemical 1
treated O 0
rats O 0
, O 0
as O 0
well O 0
as O 0
GSH B-Chemical 1
concentration O 0
and O 0
glutathione B-Chemical 1
peroxidase O 0
activity O 0
in O 0
the O 0
hippocampus O 0
, O 0
whereas O 0
nNOS O 0
activity O 0
in O 0
the O 0
hippocampus O 0
was O 0
increased O 0
. O 0

Memory O 0
retrieval O 0
of O 0
experiences O 0
acquired O 0
prior O 0
to O 0
cocaine B-Chemical 1
administration O 0
was O 0
impaired O 0
and O 0
negatively O 0
correlated O 0
with O 0
NFkappaB O 0
activity O 0
in O 0
the O 0
frontal O 0
cortex O 0
. O 0

In O 0
contrast O 0
, O 0
learning O 0
of O 0
new O 0
tasks O 0
was O 0
enhanced O 0
and O 0
correlated O 0
with O 0
the O 0
increase O 0
of O 0
nNOS O 0
activity O 0
and O 0
the O 0
decrease O 0
of O 0
glutathione B-Chemical 1
peroxidase O 0
. O 0

These O 0
results O 0
provide O 0
evidence O 0
for O 0
a O 0
possible O 0
mechanistic O 0
role O 0
of O 0
oxidative O 0
and O 0
nitrosative O 0
stress O 0
and O 0
NFkappaB O 0
in O 0
the O 0
alterations O 0
induced O 0
by O 0
cocaine B-Chemical 1
. O 0

Topiramate B-Chemical 1
prevented O 0
all O 0
the O 0
alterations O 0
observed O 0
, O 0
showing O 0
novel O 0
neuroprotective O 0
properties O 0
. O 0

Efficacy O 0
and O 0
safety O 0
of O 0
asenapine B-Chemical 1
in O 0
a O 0
placebo O 0
- O 0
and O 0
haloperidol B-Chemical 1
- O 0
controlled O 0
trial O 0
in O 0
patients O 0
with O 0
acute O 0
exacerbation O 0
of O 0
schizophrenia B-Disease 1
. O 0

Asenapine B-Chemical 1
is O 0
approved O 0
by O 0
the O 0
Food O 0
and O 0
Drugs O 0
Administration O 0
in O 0
adults O 0
for O 0
acute O 0
treatment O 0
of O 0
schizophrenia B-Disease 1
or O 0
of O 0
manic B-Disease 1
or O 0
mixed O 0
episodes O 0
associated O 0
with O 0
bipolar B-Disease 1
I I-Disease 1
disorder I-Disease 1
with O 0
or O 0
without O 0
psychotic B-Disease 1
features O 0
. O 0

In O 0
a O 0
double O 0
- O 0
blind O 0
6 O 0
- O 0
week O 0
trial O 0
, O 0
458 O 0
patients O 0
with O 0
acute O 0
schizophrenia B-Disease 1
were O 0
randomly O 0
assigned O 0
to O 0
fixed O 0
- O 0
dose O 0
treatment O 0
with O 0
asenapine B-Chemical 1
at O 0
5 O 0
mg O 0
twice O 0
daily O 0
( O 0
BID O 0
) O 0
, O 0
asenapine B-Chemical 1
at O 0
10 O 0
mg O 0
BID O 0
, O 0
placebo O 0
, O 0
or O 0
haloperidol B-Chemical 1
at O 0
4 O 0
mg O 0
BID O 0
( O 0
to O 0
verify O 0
assay O 0
sensitivity O 0
) O 0
. O 0

With O 0
last O 0
observations O 0
carried O 0
forward O 0
( O 0
LOCF O 0
) O 0
, O 0
mean O 0
Positive O 0
and O 0
Negative O 0
Syndrome O 0
Scale O 0
total O 0
score O 0
reductions O 0
from O 0
baseline O 0
to O 0
endpoint O 0
were O 0
significantly O 0
greater O 0
with O 0
asenapine B-Chemical 1
at O 0
5 O 0
mg O 0
BID O 0
( O 0
- O 0
16 O 0
. O 0
2 O 0
) O 0
and O 0
haloperidol B-Chemical 1
( O 0
- O 0
15 O 0
. O 0
4 O 0
) O 0
than O 0
placebo O 0
( O 0
- O 0
10 O 0
. O 0
7 O 0
; O 0
both O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
; O 0
using O 0
mixed O 0
model O 0
for O 0
repeated O 0
measures O 0
( O 0
MMRM O 0
) O 0
, O 0
changes O 0
at O 0
day O 0
42 O 0
were O 0
significantly O 0
greater O 0
with O 0
asenapine B-Chemical 1
at O 0
5 O 0
and O 0
10 O 0
mg O 0
BID O 0
( O 0
- O 0
21 O 0
. O 0
3 O 0
and O 0
- O 0
19 O 0
. O 0
4 O 0
, O 0
respectively O 0
) O 0
and O 0
haloperidol B-Chemical 1
( O 0
- O 0
20 O 0
. O 0
0 O 0
) O 0
than O 0
placebo O 0
( O 0
- O 0
14 O 0
. O 0
6 O 0
; O 0
all O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

On O 0
the O 0
Positive O 0
and O 0
Negative O 0
Syndrome O 0
Scale O 0
positive O 0
subscale O 0
, O 0
all O 0
treatments O 0
were O 0
superior O 0
to O 0
placebo O 0
with O 0
LOCF O 0
and O 0
MMRM O 0
; O 0
asenapine B-Chemical 1
at O 0
5 O 0
mg O 0
BID O 0
was O 0
superior O 0
to O 0
placebo O 0
on O 0
the O 0
negative O 0
subscale O 0
with O 0
MMRM O 0
and O 0
on O 0
the O 0
general O 0
psychopathology O 0
subscale O 0
with O 0
LOCF O 0
and O 0
MMRM O 0
. O 0

Treatment O 0
- O 0
related O 0
adverse O 0
events O 0
( O 0
AEs O 0
) O 0
occurred O 0
in O 0
44 O 0
% O 0
and O 0
52 O 0
% O 0
, O 0
57 O 0
% O 0
, O 0
and O 0
41 O 0
% O 0
of O 0
the O 0
asenapine B-Chemical 1
at O 0
5 O 0
and O 0
10 O 0
mg O 0
BID O 0
, O 0
haloperidol B-Chemical 1
, O 0
and O 0
placebo O 0
groups O 0
, O 0
respectively O 0
. O 0

Extrapyramidal B-Disease 1
symptoms I-Disease 1
reported O 0
as O 0
AEs O 0
occurred O 0
in O 0
15 O 0
% O 0
and O 0
18 O 0
% O 0
, O 0
34 O 0
% O 0
, O 0
and O 0
10 O 0
% O 0
of O 0
the O 0
asenapine B-Chemical 1
at O 0
5 O 0
and O 0
10 O 0
mg O 0
BID O 0
, O 0
haloperidol B-Chemical 1
, O 0
and O 0
placebo O 0
groups O 0
, O 0
respectively O 0
. O 0

Across O 0
all O 0
groups O 0
, O 0
no O 0
more O 0
than O 0
5 O 0
% O 0
of O 0
patients O 0
had O 0
clinically O 0
significant O 0
weight O 0
change O 0
. O 0

Post O 0
hoc O 0
analyses O 0
indicated O 0
that O 0
efficacy O 0
was O 0
similar O 0
with O 0
asenapine B-Chemical 1
and O 0
haloperidol B-Chemical 1
; O 0
greater O 0
contrasts O 0
were O 0
seen O 0
in O 0
AEs O 0
, O 0
especially O 0
extrapyramidal B-Disease 1
symptoms I-Disease 1
. O 0

Salvage O 0
therapy O 0
with O 0
nelarabine B-Chemical 1
, O 0
etoposide B-Chemical 1
, O 0
and O 0
cyclophosphamide B-Chemical 1
in O 0
relapsed O 0
/ O 0
refractory O 0
paediatric O 0
T B-Disease 1
- I-Disease 1
cell I-Disease 1
lymphoblastic I-Disease 1
leukaemia I-Disease 1
and I-Disease 1
lymphoma I-Disease 1
. O 0

A O 0
combination O 0
of O 0
5 O 0
d O 0
of O 0
nelarabine B-Chemical 1
( O 0
AraG B-Chemical 1
) O 0
with O 0
5 O 0
d O 0
of O 0
etoposide B-Chemical 1
( O 0
VP B-Chemical 1
) O 0
and O 0
cyclophosphamide B-Chemical 1
( O 0
CPM B-Chemical 1
) O 0
and O 0
prophylactic O 0
intrathecal O 0
chemotherapy O 0
was O 0
used O 0
as O 0
salvage O 0
therapy O 0
in O 0
seven O 0
children O 0
with O 0
refractory O 0
or O 0
relapsed O 0
T B-Disease 1
- I-Disease 1
cell I-Disease 1
leukaemia I-Disease 1
or I-Disease 1
lymphoma I-Disease 1
. O 0

The O 0
most O 0
common O 0
side O 0
effects O 0
attributable O 0
to O 0
the O 0
AraG B-Chemical 1
included O 0
Grade O 0
2 O 0
and O 0
3 O 0
sensory O 0
and O 0
motor O 0
neuropathy B-Disease 1
and O 0
musculoskeletal B-Disease 1
pain I-Disease 1
. O 0

Haematological B-Disease 1
toxicity I-Disease 1
was O 0
greater O 0
for O 0
the O 0
combination O 0
than O 0
AraG B-Chemical 1
alone O 0
, O 0
although O 0
median O 0
time O 0
to O 0
neutrophil O 0
and O 0
platelet O 0
recovery O 0
was O 0
consistent O 0
with O 0
other O 0
salvage O 0
therapies O 0
. O 0

All O 0
patients O 0
had O 0
some O 0
response O 0
to O 0
the O 0
combined O 0
therapy O 0
and O 0
five O 0
of O 0
the O 0
seven O 0
went O 0
into O 0
complete O 0
remission O 0
after O 0
one O 0
or O 0
two O 0
courses O 0
of O 0
AraG B-Chemical 1
/ O 0
VP B-Chemical 1
/ O 0
CPM B-Chemical 1
. O 0

Our O 0
experience O 0
supports O 0
the O 0
safety O 0
of O 0
giving O 0
AraG B-Chemical 1
as O 0
salvage O 0
therapy O 0
in O 0
synchrony O 0
with O 0
etoposide B-Chemical 1
and O 0
cyclophosphamide B-Chemical 1
, O 0
although O 0
neurological B-Disease 1
toxicity I-Disease 1
must O 0
be O 0
closely O 0
monitored O 0
. O 0

Effect O 0
of O 0
adriamycin B-Chemical 1
combined O 0
with O 0
whole O 0
body O 0
hyperthermia B-Disease 1
on O 0
tumor B-Disease 1
and O 0
normal O 0
tissues O 0
. O 0

Thermal O 0
enhancement O 0
of O 0
Adriamycin B-Chemical 1
- O 0
mediated O 0
antitumor O 0
activity O 0
and O 0
normal O 0
tissue O 0
toxicities B-Disease 1
by O 0
whole O 0
body O 0
hyperthermia B-Disease 1
were O 0
compared O 0
using O 0
a O 0
F344 O 0
rat O 0
model O 0
. O 0

Antitumor O 0
activity O 0
was O 0
studied O 0
using O 0
a O 0
tumor B-Disease 1
growth O 0
delay O 0
assay O 0
. O 0

Acute O 0
normal O 0
tissue O 0
toxicities B-Disease 1
( O 0
i O 0
. O 0
e O 0
. O 0
, O 0
leukopenia B-Disease 1
and O 0
thrombocytopenia B-Disease 1
) O 0
and O 0
late O 0
normal O 0
tissue O 0
toxicities B-Disease 1
( O 0
i O 0
. O 0
e O 0
. O 0
, O 0
myocardial B-Disease 1
and I-Disease 1
kidney I-Disease 1
injury I-Disease 1
) O 0
were O 0
evaluated O 0
by O 0
functional O 0
/ O 0
physiological O 0
assays O 0
and O 0
by O 0
morphological O 0
techniques O 0
. O 0

Whole O 0
body O 0
hyperthermia B-Disease 1
( O 0
120 O 0
min O 0
at O 0
41 O 0
. O 0
5 O 0
degrees O 0
C O 0
) O 0
enhanced O 0
both O 0
Adriamycin B-Chemical 1
- O 0
mediated O 0
antitumor O 0
activity O 0
and O 0
toxic O 0
side O 0
effects O 0
. O 0

The O 0
thermal O 0
enhancement O 0
ratio O 0
calculated O 0
for O 0
antitumor O 0
activity O 0
was O 0
1 O 0
. O 0
6 O 0
. O 0

Thermal O 0
enhancement O 0
ratios O 0
estimated O 0
for O 0
" O 0
acute O 0
" O 0
hematological O 0
changes O 0
were O 0
1 O 0
. O 0
3 O 0
, O 0
whereas O 0
those O 0
estimated O 0
for O 0
" O 0
late O 0
" O 0
damage O 0
( O 0
based O 0
on O 0
morphological O 0
cardiac B-Disease 1
and I-Disease 1
renal I-Disease 1
lesions I-Disease 1
) O 0
varied O 0
between O 0
2 O 0
. O 0
4 O 0
and O 0
4 O 0
. O 0
3 O 0
. O 0

Thus O 0
, O 0
while O 0
whole O 0
body O 0
hyperthermia B-Disease 1
enhances O 0
Adriamycin B-Chemical 1
- O 0
mediated O 0
antitumor O 0
effect O 0
, O 0
normal O 0
tissue O 0
toxicity B-Disease 1
is O 0
also O 0
increased O 0
, O 0
and O 0
the O 0
potential O 0
therapeutic O 0
gain O 0
of O 0
the O 0
combined O 0
modality O 0
treatment O 0
is O 0
eroded O 0
. O 0

Permeability O 0
, O 0
ultrastructural O 0
changes O 0
, O 0
and O 0
distribution O 0
of O 0
novel O 0
proteins O 0
in O 0
the O 0
glomerular O 0
barrier O 0
in O 0
early O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
nephrosis B-Disease 1
. O 0

BACKGROUND O 0
/ O 0
AIMS O 0
: O 0
It O 0
is O 0
still O 0
unclear O 0
what O 0
happens O 0
in O 0
the O 0
glomerulus O 0
when O 0
proteinuria B-Disease 1
starts O 0
. O 0

Using O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
nephrosis B-Disease 1
( O 0
PAN O 0
) O 0
rats O 0
, O 0
we O 0
studied O 0
early O 0
ultrastructural O 0
and O 0
permeability O 0
changes O 0
in O 0
relation O 0
to O 0
the O 0
expression O 0
of O 0
the O 0
podocyte O 0
- O 0
associated O 0
molecules O 0
nephrin O 0
, O 0
a O 0
- O 0
actinin O 0
, O 0
dendrin O 0
, O 0
and O 0
plekhh2 O 0
, O 0
the O 0
last O 0
two O 0
of O 0
which O 0
were O 0
only O 0
recently O 0
discovered O 0
in O 0
podocytes O 0
. O 0

METHODS O 0
: O 0
Using O 0
immune O 0
stainings O 0
, O 0
semiquantitative O 0
measurement O 0
was O 0
performed O 0
under O 0
the O 0
electron O 0
microscope O 0
. O 0

Permeability O 0
was O 0
assessed O 0
using O 0
isolated O 0
kidney O 0
perfusion O 0
with O 0
tracers O 0
. O 0

Possible O 0
effects O 0
of O 0
ACE O 0
inhibition O 0
were O 0
tested O 0
. O 0

RESULTS O 0
: O 0
By O 0
day O 0
2 O 0
, O 0
some O 0
patchy O 0
foot O 0
process O 0
effacement O 0
, O 0
but O 0
no O 0
proteinuria B-Disease 1
, O 0
appeared O 0
. O 0

The O 0
amount O 0
of O 0
nephrin O 0
was O 0
reduced O 0
in O 0
both O 0
diseased O 0
and O 0
normal O 0
areas O 0
. O 0

The O 0
other O 0
proteins O 0
showed O 0
few O 0
changes O 0
, O 0
which O 0
were O 0
limited O 0
to O 0
diseased O 0
areas O 0
. O 0

By O 0
day O 0
4 O 0
, O 0
foot O 0
process O 0
effacement O 0
was O 0
complete O 0
and O 0
proteinuria B-Disease 1
appeared O 0
in O 0
parallel O 0
with O 0
signs O 0
of O 0
size O 0
barrier O 0
damage O 0
. O 0

Nephrin O 0
decreased O 0
further O 0
, O 0
while O 0
dendrin O 0
and O 0
plekhh2 O 0
also O 0
decreased O 0
but O 0
a O 0
- O 0
actinin O 0
remained O 0
unchanged O 0
. O 0

ACE O 0
inhibition O 0
had O 0
no O 0
significant O 0
protective O 0
effect O 0
. O 0

CONCLUSIONS O 0
: O 0
PAN O 0
glomeruli O 0
already O 0
showed O 0
significant O 0
pathology O 0
by O 0
day O 0
4 O 0
, O 0
despite O 0
relatively O 0
mild O 0
proteinuria B-Disease 1
. O 0

This O 0
was O 0
preceded O 0
by O 0
altered O 0
nephrin O 0
expression O 0
, O 0
supporting O 0
its O 0
pivotal O 0
role O 0
in O 0
podocyte O 0
morphology O 0
. O 0

The O 0
novel O 0
proteins O 0
dendrin O 0
and O 0
plekhh2 O 0
were O 0
both O 0
reduced O 0
, O 0
suggesting O 0
roles O 0
in O 0
PAN O 0
, O 0
whereas O 0
a O 0
- O 0
actinin O 0
was O 0
unchanged O 0
. O 0

A O 0
novel O 0
, O 0
multiple O 0
symptom O 0
model O 0
of O 0
obsessive B-Disease 1
- I-Disease 1
compulsive I-Disease 1
- I-Disease 1
like I-Disease 1
behaviors I-Disease 1
in O 0
animals O 0
. O 0

BACKGROUND O 0
: O 0
Current O 0
animal O 0
models O 0
of O 0
obsessive B-Disease 1
- I-Disease 1
compulsive I-Disease 1
disorder I-Disease 1
( O 0
OCD B-Disease 1
) O 0
typically O 0
involve O 0
acute O 0
, O 0
drug O 0
- O 0
induced O 0
symptom O 0
provocation O 0
or O 0
a O 0
genetic O 0
association O 0
with O 0
stereotypies O 0
or O 0
anxiety B-Disease 1
. O 0

None O 0
of O 0
these O 0
current O 0
models O 0
demonstrate O 0
multiple O 0
OCD B-Disease 1
- O 0
like O 0
behaviors O 0
. O 0

METHODS O 0
: O 0
Neonatal O 0
rats O 0
were O 0
treated O 0
with O 0
the O 0
tricyclic O 0
antidepressant B-Chemical 1
clomipramine B-Chemical 1
or O 0
vehicle O 0
between O 0
days O 0
9 O 0
and O 0
16 O 0
twice O 0
daily O 0
and O 0
behaviorally O 0
tested O 0
in O 0
adulthood O 0
. O 0

RESULTS O 0
: O 0
Clomipramine B-Chemical 1
exposure O 0
in O 0
immature O 0
rats O 0
produced O 0
significant O 0
behavioral O 0
and O 0
biochemical O 0
changes O 0
that O 0
include O 0
enhanced O 0
anxiety B-Disease 1
( O 0
elevated O 0
plus O 0
maze O 0
and O 0
marble O 0
burying O 0
) O 0
, O 0
behavioral B-Disease 1
inflexibility I-Disease 1
( O 0
perseveration O 0
in O 0
the O 0
spontaneous O 0
alternation O 0
task O 0
and O 0
impaired O 0
reversal O 0
learning O 0
) O 0
, O 0
working O 0
memory B-Disease 1
impairment I-Disease 1
( O 0
e O 0
. O 0
g O 0
. O 0
, O 0
win O 0
- O 0
shift O 0
paradigm O 0
) O 0
, O 0
hoarding B-Disease 1
, O 0
and O 0
corticostriatal B-Disease 1
dysfunction I-Disease 1
. O 0

Dopamine B-Chemical 1
D2 O 0
receptors O 0
were O 0
elevated O 0
in O 0
the O 0
striatum O 0
, O 0
whereas O 0
serotonin B-Chemical 1
2C O 0
, O 0
but O 0
not O 0
serotonin B-Chemical 1
1A O 0
, O 0
receptors O 0
were O 0
elevated O 0
in O 0
the O 0
orbital O 0
frontal O 0
cortex O 0
. O 0

CONCLUSIONS O 0
: O 0
This O 0
is O 0
the O 0
first O 0
demonstration O 0
of O 0
multiple O 0
symptoms O 0
consistent O 0
with O 0
an O 0
OCD B-Disease 1
- O 0
like O 0
profile O 0
in O 0
animals O 0
. O 0

Moreover O 0
, O 0
these O 0
behaviors O 0
are O 0
accompanied O 0
by O 0
biochemical O 0
changes O 0
in O 0
brain O 0
regions O 0
previously O 0
identified O 0
as O 0
relevant O 0
to O 0
OCD B-Disease 1
. O 0

This O 0
novel O 0
model O 0
of O 0
OCD B-Disease 1
demonstrates O 0
that O 0
drug O 0
exposure O 0
during O 0
a O 0
sensitive O 0
period O 0
can O 0
program O 0
disease O 0
- O 0
like O 0
systems O 0
permanently O 0
, O 0
which O 0
could O 0
have O 0
implications O 0
for O 0
current O 0
and O 0
future O 0
therapeutic O 0
strategies O 0
for O 0
this O 0
and O 0
other O 0
psychiatric B-Disease 1
disorders I-Disease 1
. O 0

Elevation O 0
of O 0
ADAM10 O 0
, O 0
ADAM17 O 0
, O 0
MMP O 0
- O 0
2 O 0
and O 0
MMP O 0
- O 0
9 O 0
expression O 0
with O 0
media O 0
degeneration O 0
features O 0
CaCl2 B-Chemical 1
- O 0
induced O 0
thoracic B-Disease 1
aortic I-Disease 1
aneurysm I-Disease 1
in O 0
a O 0
rat O 0
model O 0
. O 0

PURPOSE O 0
: O 0
This O 0
study O 0
was O 0
designed O 0
to O 0
establish O 0
a O 0
rat O 0
model O 0
of O 0
thoracic B-Disease 1
aortic I-Disease 1
aneurysm I-Disease 1
( O 0
TAA B-Disease 1
) O 0
by O 0
calcium B-Chemical 1
chloride I-Chemical 1
( O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
) O 0
- O 0
induced O 0
arterial B-Disease 1
injury I-Disease 1
and O 0
to O 0
explore O 0
the O 0
potential O 0
role O 0
of O 0
a O 0
disintegrin O 0
and O 0
metalloproteinase O 0
( O 0
ADAM O 0
) O 0
, O 0
matrix O 0
metalloproteinases O 0
( O 0
MMPs O 0
) O 0
and O 0
their O 0
endogenous O 0
inhibitors O 0
( O 0
TIMPs O 0
) O 0
in O 0
TAA B-Disease 1
formation O 0
. O 0

METHODS O 0
: O 0
Thoracic O 0
aorta O 0
of O 0
male O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
was O 0
exposed O 0
to O 0
0 O 0
. O 0
5M O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
or O 0
normal O 0
saline O 0
( O 0
NaCl B-Chemical 1
) O 0
. O 0

After O 0
12weeks O 0
, O 0
animals O 0
were O 0
euthanized O 0
, O 0
and O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
treated O 0
, O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
untreated O 0
( O 0
n O 0
= O 0
12 O 0
) O 0
and O 0
NaCl B-Chemical 1
- O 0
treated O 0
aortic O 0
segments O 0
( O 0
n O 0
= O 0
12 O 0
) O 0
were O 0
collected O 0
for O 0
histological O 0
and O 0
molecular O 0
assessments O 0
. O 0

MMP O 0
- O 0
TIMP O 0
and O 0
ADAM O 0
mRNAs O 0
were O 0
semi O 0
- O 0
quantitatively O 0
analyzed O 0
and O 0
protein O 0
expressions O 0
were O 0
determined O 0
by O 0
immunohistochemistry O 0
. O 0

RESULTS O 0
: O 0
Despite O 0
similar O 0
external O 0
diameters O 0
among O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
treated O 0
, O 0
non O 0
- O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
treated O 0
and O 0
NaCl B-Chemical 1
- O 0
treated O 0
segments O 0
, O 0
aneurymal O 0
alteration O 0
( O 0
n O 0
= O 0
6 O 0
, O 0
50 O 0
% O 0
) O 0
, O 0
media O 0
degeneration O 0
with O 0
regional O 0
disruption O 0
, O 0
fragmentation O 0
of O 0
elastic O 0
fiber O 0
, O 0
and O 0
increased O 0
collagen O 0
deposition O 0
( O 0
n O 0
= O 0
12 O 0
, O 0
100 O 0
% O 0
) O 0
were O 0
demonstrated O 0
in O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
treated O 0
segments O 0
. O 0

MMP O 0
- O 0
2 O 0
, O 0
MMP O 0
- O 0
9 O 0
, O 0
ADAM O 0
- O 0
10 O 0
and O 0
ADAM O 0
- O 0
17 O 0
mRNA O 0
levels O 0
were O 0
increased O 0
in O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
treated O 0
segments O 0
( O 0
all O 0
p O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
, O 0
with O 0
trends O 0
of O 0
elevation O 0
in O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
untreated O 0
segments O 0
, O 0
as O 0
compared O 0
with O 0
NaCl B-Chemical 1
- O 0
treated O 0
segments O 0
. O 0

Immunohistochemistry O 0
displayed O 0
significantly O 0
increased O 0
expressions O 0
of O 0
MMP O 0
- O 0
2 O 0
, O 0
MMP O 0
- O 0
9 O 0
, O 0
ADAM O 0
- O 0
10 O 0
and O 0
ADAM O 0
- O 0
17 O 0
( O 0
all O 0
p O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
in O 0
intima O 0
and O 0
media O 0
for O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
- O 0
treated O 0
segments O 0
. O 0

TIMP O 0
mRNA O 0
and O 0
tissue O 0
levels O 0
did O 0
not O 0
differ O 0
obviously O 0
among O 0
the O 0
three O 0
aortic O 0
segments O 0
. O 0

CONCLUSION O 0
: O 0
This O 0
study O 0
establishes O 0
a O 0
TAA B-Disease 1
model O 0
by O 0
periarterial O 0
CaCl B-Chemical 1
( I-Chemical 1
2 I-Chemical 1
) I-Chemical 1
exposure O 0
in O 0
rats O 0
, O 0
and O 0
demonstrates O 0
a O 0
significant O 0
elevation O 0
of O 0
expression O 0
of O 0
MMP O 0
- O 0
2 O 0
, O 0
MMP O 0
- O 0
9 O 0
, O 0
ADAM10 O 0
and O 0
ADAM17 O 0
in O 0
the O 0
pathogenesis O 0
of O 0
vascular O 0
remodeling O 0
. O 0

Suxamethonium B-Chemical 1
induced O 0
prolonged O 0
apnea B-Disease 1
in O 0
a O 0
patient O 0
receiving O 0
electroconvulsive O 0
therapy O 0
. O 0

Suxamethonium B-Chemical 1
causes O 0
prolonged O 0
apnea B-Disease 1
in O 0
patients O 0
in O 0
whom O 0
pseudocholinesterase O 0
enzyme O 0
gets O 0
deactivated O 0
by O 0
organophosphorus B-Chemical 1
( I-Chemical 1
OP I-Chemical 1
) I-Chemical 1
poisons I-Chemical 1
. O 0

Here O 0
, O 0
we O 0
present O 0
a O 0
similar O 0
incident O 0
in O 0
a O 0
severely O 0
depressed B-Disease 1
patient O 0
who O 0
received O 0
electroconvulsive O 0
therapy O 0
( O 0
ECT O 0
) O 0
. O 0

Prolonged O 0
apnea B-Disease 1
in O 0
our O 0
case O 0
ensued O 0
because O 0
the O 0
information O 0
about O 0
suicidal O 0
attempt O 0
by O 0
OP B-Chemical 1
compound I-Chemical 1
was O 0
concealed O 0
from O 0
the O 0
treating O 0
team O 0
. O 0

Curcumin B-Chemical 1
ameliorates O 0
cognitive B-Disease 1
dysfunction I-Disease 1
and O 0
oxidative O 0
damage O 0
in O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
administered O 0
rats O 0
. O 0

The O 0
antiepileptic O 0
drugs O 0
, O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
are O 0
well O 0
known O 0
to O 0
cause O 0
cognitive B-Disease 1
impairment I-Disease 1
on O 0
chronic O 0
use O 0
. O 0

The O 0
increase O 0
in O 0
free O 0
radical O 0
generation O 0
has O 0
been O 0
implicated O 0
as O 0
one O 0
of O 0
the O 0
important O 0
mechanisms O 0
of O 0
cognitive B-Disease 1
impairment I-Disease 1
by O 0
antiepileptic O 0
drugs O 0
. O 0

Curcumin B-Chemical 1
has O 0
shown O 0
antioxidant O 0
, O 0
anti O 0
- O 0
inflammatory O 0
and O 0
neuro O 0
- O 0
protective O 0
properties O 0
. O 0

Therefore O 0
, O 0
the O 0
present O 0
study O 0
was O 0
carried O 0
out O 0
to O 0
investigate O 0
the O 0
effect O 0
of O 0
chronic O 0
curcumin B-Chemical 1
administration O 0
on O 0
phenobarbitone B-Chemical 1
- O 0
and O 0
carbamazepine B-Chemical 1
- O 0
induced O 0
cognitive B-Disease 1
impairment I-Disease 1
and O 0
oxidative O 0
stress O 0
in O 0
rats O 0
. O 0

Pharmacokinetic O 0
interactions O 0
of O 0
curcumin B-Chemical 1
with O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
were O 0
also O 0
studied O 0
. O 0

Vehicle O 0
/ O 0
drugs O 0
were O 0
administered O 0
daily O 0
for O 0
21days O 0
to O 0
male O 0
Wistar O 0
rats O 0
. O 0

Passive O 0
avoidance O 0
paradigm O 0
and O 0
elevated O 0
plus O 0
maze O 0
test O 0
were O 0
used O 0
to O 0
assess O 0
cognitive O 0
function O 0
. O 0

At O 0
the O 0
end O 0
of O 0
study O 0
period O 0
, O 0
serum O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
, O 0
whole O 0
brain O 0
malondialdehyde B-Chemical 1
and O 0
reduced O 0
glutathione B-Chemical 1
levels O 0
were O 0
estimated O 0
. O 0

The O 0
administration O 0
of O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
for O 0
21days O 0
caused O 0
a O 0
significant O 0
impairment B-Disease 1
of I-Disease 1
learning I-Disease 1
and I-Disease 1
memory I-Disease 1
as O 0
well O 0
as O 0
an O 0
increased O 0
oxidative O 0
stress O 0
. O 0

Concomitant O 0
curcumin B-Chemical 1
administration O 0
prevented O 0
the O 0
cognitive B-Disease 1
impairment I-Disease 1
and O 0
decreased O 0
the O 0
increased O 0
oxidative O 0
stress O 0
induced O 0
by O 0
these O 0
antiepileptic O 0
drugs O 0
. O 0

Curcumin B-Chemical 1
co O 0
- O 0
administration O 0
did O 0
not O 0
cause O 0
any O 0
significant O 0
alteration O 0
in O 0
the O 0
serum O 0
concentrations O 0
of O 0
both O 0
phenobarbitone B-Chemical 1
as O 0
well O 0
as O 0
carbamazepine B-Chemical 1
. O 0

These O 0
results O 0
show O 0
that O 0
curcumin B-Chemical 1
has O 0
beneficial O 0
effect O 0
in O 0
mitigating O 0
the O 0
deterioration B-Disease 1
of I-Disease 1
cognitive I-Disease 1
functions I-Disease 1
and O 0
oxidative O 0
damage O 0
in O 0
rats O 0
treated O 0
with O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
without O 0
significantly O 0
altering O 0
their O 0
serum O 0
concentrations O 0
. O 0

The O 0
findings O 0
suggest O 0
that O 0
curcumin B-Chemical 1
can O 0
be O 0
considered O 0
as O 0
a O 0
potential O 0
safe O 0
and O 0
effective O 0
adjuvant O 0
to O 0
phenobarbitone B-Chemical 1
and O 0
carbamazepine B-Chemical 1
therapy O 0
in O 0
preventing O 0
cognitive B-Disease 1
impairment I-Disease 1
associated O 0
with O 0
these O 0
drugs O 0
. O 0

Can O 0
angiogenesis O 0
be O 0
a O 0
target O 0
of O 0
treatment O 0
for O 0
ribavirin B-Chemical 1
associated O 0
hemolytic B-Disease 1
anemia I-Disease 1
? O 0

BACKGROUND O 0
/ O 0
AIMS O 0
: O 0
Recently O 0
ribavirin B-Chemical 1
has O 0
been O 0
found O 0
to O 0
inhibit O 0
angiogenesis O 0
and O 0
a O 0
number O 0
of O 0
angiogenesis O 0
inhibitors O 0
such O 0
as O 0
sunitinib B-Chemical 1
and O 0
sorafenib B-Chemical 1
have O 0
been O 0
found O 0
to O 0
cause O 0
acute O 0
hemolysis B-Disease 1
. O 0

We O 0
aimed O 0
to O 0
investigate O 0
whether O 0
there O 0
is O 0
a O 0
relation O 0
between O 0
hemoglobin O 0
, O 0
haptoglobin O 0
and O 0
angiogenesis O 0
soluble O 0
markers O 0
which O 0
are O 0
modifiable O 0
and O 0
can O 0
help O 0
in O 0
developing O 0
strategies O 0
against O 0
anemia B-Disease 1
. O 0

METHODS O 0
: O 0
Fourteen O 0
patients O 0
chronically B-Disease 1
infected I-Disease 1
with I-Disease 1
hepatitis I-Disease 1
C I-Disease 1
virus I-Disease 1
were O 0
treated O 0
by O 0
pegylated B-Chemical 1
interferon I-Chemical 1
alpha I-Chemical 1
2a I-Chemical 1
and O 0
ribavirin B-Chemical 1
. O 0

Serum O 0
hemoglobin O 0
, O 0
haptoglobin O 0
and O 0
angiogenesis O 0
markers O 0
of O 0
vascular O 0
endothelial O 0
growth O 0
factor O 0
and O 0
angiopoetin O 0
- O 0
2 O 0
were O 0
investigated O 0
before O 0
and O 0
after O 0
therapy O 0
. O 0

RESULTS O 0
: O 0
We O 0
observed O 0
a O 0
significant O 0
decrease O 0
in O 0
haptoglobin O 0
levels O 0
at O 0
the O 0
end O 0
of O 0
the O 0
treatment O 0
period O 0
. O 0

Hemoglobin O 0
levels O 0
also O 0
decreased O 0
but O 0
insignificantly O 0
by O 0
treatment O 0
. O 0

In O 0
contrast O 0
with O 0
the O 0
literature O 0
, O 0
serum O 0
levels O 0
of O 0
angiogenesis O 0
factors O 0
did O 0
not O 0
change O 0
significantly O 0
by O 0
pegylated B-Chemical 1
interferon I-Chemical 1
and O 0
ribavirin B-Chemical 1
therapy O 0
. O 0

We O 0
found O 0
no O 0
correlation O 0
of O 0
angiogenesis O 0
soluble O 0
markers O 0
with O 0
either O 0
hemoglobin O 0
or O 0
haptoglobin O 0
. O 0

CONCLUSION O 0
: O 0
This O 0
is O 0
the O 0
first O 0
study O 0
in O 0
the O 0
literature O 0
investigating O 0
a O 0
link O 0
between O 0
angiogenesis O 0
soluble O 0
markers O 0
and O 0
ribavirin B-Chemical 1
induced O 0
anemia B-Disease 1
in O 0
patients O 0
with O 0
hepatitis B-Disease 1
C I-Disease 1
and O 0
we O 0
could O 0
not O 0
find O 0
any O 0
relation O 0
. O 0

Future O 0
research O 0
with O 0
larger O 0
number O 0
of O 0
patients O 0
is O 0
needed O 0
to O 0
find O 0
out O 0
modifiable O 0
factors O 0
that O 0
will O 0
improve O 0
the O 0
safety O 0
of O 0
ribavirin B-Chemical 1
therapy O 0
. O 0

Reduction O 0
in O 0
injection O 0
pain B-Disease 1
using O 0
buffered O 0
lidocaine B-Chemical 1
as O 0
a O 0
local O 0
anesthetic O 0
before O 0
cardiac O 0
catheterization O 0
. O 0

Previous O 0
reports O 0
have O 0
suggested O 0
that O 0
pain B-Disease 1
associated O 0
with O 0
the O 0
injection O 0
of O 0
lidocaine B-Chemical 1
is O 0
related O 0
to O 0
the O 0
acidic O 0
pH O 0
of O 0
the O 0
solution O 0
. O 0

To O 0
determine O 0
if O 0
the O 0
addition O 0
of O 0
a O 0
buffering O 0
solution O 0
to O 0
adjust O 0
the O 0
pH O 0
of O 0
lidocaine B-Chemical 1
into O 0
the O 0
physiologic O 0
range O 0
would O 0
reduce O 0
pain B-Disease 1
during O 0
injection O 0
, O 0
we O 0
performed O 0
a O 0
blinded O 0
randomized O 0
study O 0
in O 0
patients O 0
undergoing O 0
cardiac O 0
catheterization O 0
. O 0

Twenty O 0
patients O 0
were O 0
asked O 0
to O 0
quantify O 0
the O 0
severity O 0
of O 0
pain B-Disease 1
after O 0
receiving O 0
standard O 0
lidocaine B-Chemical 1
in O 0
one O 0
femoral O 0
area O 0
and O 0
buffered O 0
lidocaine B-Chemical 1
in O 0
the O 0
opposite O 0
femoral O 0
area O 0
. O 0

The O 0
mean O 0
pain B-Disease 1
score O 0
for O 0
buffered O 0
lidocaine B-Chemical 1
was O 0
significantly O 0
lower O 0
than O 0
the O 0
mean O 0
score O 0
for O 0
standard O 0
lidocaine B-Chemical 1
( O 0
2 O 0
. O 0
7 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
9 O 0
vs O 0
. O 0
3 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
2 O 0
, O 0
P O 0
= O 0
0 O 0
. O 0
03 O 0
) O 0
. O 0

The O 0
pH O 0
adjustment O 0
of O 0
standard O 0
lidocaine B-Chemical 1
can O 0
be O 0
accomplished O 0
easily O 0
in O 0
the O 0
catheterization O 0
laboratory O 0
before O 0
injection O 0
and O 0
results O 0
in O 0
a O 0
reduction O 0
of O 0
the O 0
pain B-Disease 1
occurring O 0
during O 0
the O 0
infiltration O 0
of O 0
tissues O 0
. O 0

Effect O 0
of O 0
L B-Chemical 1
- I-Chemical 1
alpha I-Chemical 1
- I-Chemical 1
glyceryl I-Chemical 1
- I-Chemical 1
phosphorylcholine I-Chemical 1
on O 0
amnesia B-Disease 1
caused O 0
by O 0
scopolamine B-Chemical 1
. O 0

The O 0
present O 0
study O 0
was O 0
carried O 0
out O 0
to O 0
test O 0
the O 0
effects O 0
of O 0
L B-Chemical 1
- I-Chemical 1
alpha I-Chemical 1
- I-Chemical 1
glycerylphosphorylcholine I-Chemical 1
( O 0
L B-Chemical 1
- I-Chemical 1
alpha I-Chemical 1
- I-Chemical 1
GFC I-Chemical 1
) O 0
on O 0
memory B-Disease 1
impairment I-Disease 1
induced O 0
by O 0
scopolamine B-Chemical 1
in O 0
man O 0
. O 0

Thirty O 0
- O 0
two O 0
healthy O 0
young O 0
volunteers O 0
were O 0
randomly O 0
allocated O 0
to O 0
four O 0
different O 0
groups O 0
. O 0

They O 0
were O 0
given O 0
a O 0
ten O 0
day O 0
pretreatment O 0
with O 0
either O 0
L B-Chemical 1
- I-Chemical 1
alpha I-Chemical 1
- I-Chemical 1
GFC I-Chemical 1
or O 0
placebo O 0
, O 0
p O 0
. O 0
o O 0
. O 0
, O 0
and O 0
on O 0
the O 0
eleventh O 0
day O 0
either O 0
scopolamine B-Chemical 1
or O 0
placebo O 0
, O 0
i O 0
. O 0
m O 0
. O 0

Before O 0
and O 0
0 O 0
. O 0
5 O 0
, O 0
1 O 0
, O 0
2 O 0
, O 0
3 O 0
, O 0
and O 0
6 O 0
h O 0
after O 0
injection O 0
the O 0
subjects O 0
were O 0
given O 0
attention O 0
and O 0
mnemonic O 0
tests O 0
. O 0

The O 0
findings O 0
of O 0
this O 0
study O 0
indicate O 0
that O 0
the O 0
drug O 0
is O 0
able O 0
to O 0
antagonize O 0
impairment B-Disease 1
of I-Disease 1
attention I-Disease 1
and I-Disease 1
memory I-Disease 1
induced O 0
by O 0
scopolamine B-Chemical 1
. O 0

Safety O 0
of O 0
capecitabine B-Chemical 1
: O 0
a O 0
review O 0
. O 0

IMPORTANCE O 0
OF O 0
THE O 0
FIELD O 0
: O 0
Fluoropyrimidines B-Chemical 1
, O 0
in O 0
particular O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
( O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
) O 0
, O 0
have O 0
been O 0
the O 0
mainstay O 0
of O 0
treatment O 0
for O 0
several O 0
solid O 0
tumors B-Disease 1
, O 0
including O 0
colorectal B-Disease 1
, I-Disease 1
breast I-Disease 1
and I-Disease 1
head I-Disease 1
and I-Disease 1
neck I-Disease 1
cancers I-Disease 1
, O 0
for O 0
> O 0
40 O 0
years O 0
. O 0

AREAS O 0
COVERED O 0
IN O 0
THIS O 0
REVIEW O 0
: O 0
This O 0
article O 0
reviews O 0
the O 0
pharmacology O 0
and O 0
efficacy O 0
of O 0
capecitabine B-Chemical 1
with O 0
a O 0
special O 0
emphasis O 0
on O 0
its O 0
safety O 0
. O 0

WHAT O 0
THE O 0
READER O 0
WILL O 0
GAIN O 0
: O 0
The O 0
reader O 0
will O 0
gain O 0
better O 0
insight O 0
into O 0
the O 0
safety O 0
of O 0
capecitabine B-Chemical 1
in O 0
special O 0
populations O 0
such O 0
as O 0
patients O 0
with O 0
advanced O 0
age O 0
, O 0
renal B-Disease 1
and I-Disease 1
kidney I-Disease 1
disease I-Disease 1
. O 0

We O 0
also O 0
explore O 0
different O 0
dosing O 0
and O 0
schedules O 0
of O 0
capecitabine B-Chemical 1
administration O 0
. O 0

TAKE O 0
HOME O 0
MESSAGE O 0
: O 0
Capecitabine B-Chemical 1
is O 0
an O 0
oral O 0
prodrug O 0
of O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
and O 0
was O 0
developed O 0
to O 0
fulfill O 0
the O 0
need O 0
for O 0
a O 0
more O 0
convenient O 0
therapy O 0
and O 0
provide O 0
an O 0
improved O 0
safety O 0
/ O 0
efficacy O 0
profile O 0
. O 0

It O 0
has O 0
shown O 0
promising O 0
results O 0
alone O 0
or O 0
in O 0
combination O 0
with O 0
other O 0
chemotherapeutic O 0
agents O 0
in O 0
colorectal B-Disease 1
, I-Disease 1
breast I-Disease 1
, I-Disease 1
pancreaticobiliary I-Disease 1
, I-Disease 1
gastric I-Disease 1
, I-Disease 1
renal I-Disease 1
cell I-Disease 1
and I-Disease 1
head I-Disease 1
and I-Disease 1
neck I-Disease 1
cancers I-Disease 1
. O 0

The O 0
most O 0
commonly O 0
reported O 0
toxic O 0
effects O 0
of O 0
capecitabine B-Chemical 1
are O 0
diarrhea B-Disease 1
, O 0
nausea B-Disease 1
, O 0
vomiting B-Disease 1
, O 0
stomatitis B-Disease 1
and O 0
hand B-Disease 1
- I-Disease 1
foot I-Disease 1
syndrome I-Disease 1
. O 0

Capecitabine B-Chemical 1
has O 0
a O 0
well O 0
- O 0
established O 0
safety O 0
profile O 0
and O 0
can O 0
be O 0
given O 0
safely O 0
to O 0
patients O 0
with O 0
advanced O 0
age O 0
, O 0
hepatic B-Disease 1
and I-Disease 1
renal I-Disease 1
dysfunctions I-Disease 1
. O 0

Levodopa B-Chemical 1
- O 0
induced O 0
dyskinesias B-Disease 1
in O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
: O 0
filling O 0
the O 0
bench O 0
- O 0
to O 0
- O 0
bedside O 0
gap O 0
. O 0

Levodopa B-Chemical 1
is O 0
the O 0
most O 0
effective O 0
drug O 0
for O 0
the O 0
treatment O 0
of O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

However O 0
, O 0
the O 0
long O 0
- O 0
term O 0
use O 0
of O 0
this O 0
dopamine B-Chemical 1
precursor O 0
is O 0
complicated O 0
by O 0
highly O 0
disabling O 0
fluctuations O 0
and O 0
dyskinesias B-Disease 1
. O 0

Although O 0
preclinical O 0
and O 0
clinical O 0
findings O 0
suggest O 0
pulsatile O 0
stimulation O 0
of O 0
striatal O 0
postsynaptic O 0
receptors O 0
as O 0
a O 0
key O 0
mechanism O 0
underlying O 0
levodopa B-Chemical 1
- O 0
induced O 0
dyskinesias B-Disease 1
, O 0
their O 0
pathogenesis O 0
is O 0
still O 0
unclear O 0
. O 0

In O 0
recent O 0
years O 0
, O 0
evidence O 0
from O 0
animal O 0
models O 0
of O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
has O 0
provided O 0
important O 0
information O 0
to O 0
understand O 0
the O 0
effect O 0
of O 0
specific O 0
receptor O 0
and O 0
post O 0
- O 0
receptor O 0
molecular O 0
mechanisms O 0
underlying O 0
the O 0
development O 0
of O 0
dyskinetic B-Disease 1
movements I-Disease 1
. O 0

Recent O 0
preclinical O 0
and O 0
clinical O 0
data O 0
from O 0
promising O 0
lines O 0
of O 0
research O 0
focus O 0
on O 0
the O 0
differential O 0
role O 0
of O 0
presynaptic O 0
versus O 0
postsynaptic O 0
mechanisms O 0
, O 0
dopamine B-Chemical 1
receptor O 0
subtypes O 0
, O 0
ionotropic O 0
and O 0
metabotropic O 0
glutamate B-Chemical 1
receptors O 0
, O 0
and O 0
non O 0
- O 0
dopaminergic O 0
neurotransmitter O 0
systems O 0
in O 0
the O 0
pathophysiology O 0
of O 0
levodopa B-Chemical 1
- O 0
induced O 0
dyskinesias B-Disease 1
. O 0

Effects O 0
of O 0
pallidal O 0
neurotensin B-Chemical 1
on O 0
haloperidol B-Chemical 1
- O 0
induced O 0
parkinsonian B-Disease 1
catalepsy I-Disease 1
: O 0
behavioral O 0
and O 0
electrophysiological O 0
studies O 0
. O 0

OBJECTIVE O 0
: O 0
The O 0
globus O 0
pallidus O 0
plays O 0
a O 0
critical O 0
role O 0
in O 0
movement O 0
regulation O 0
. O 0

Previous O 0
studies O 0
have O 0
indicated O 0
that O 0
the O 0
globus O 0
pallidus O 0
receives O 0
neurotensinergic O 0
innervation O 0
from O 0
the O 0
striatum O 0
, O 0
and O 0
systemic O 0
administration O 0
of O 0
a O 0
neurotensin B-Chemical 1
analog O 0
could O 0
produce O 0
antiparkinsonian O 0
effects O 0
. O 0

The O 0
present O 0
study O 0
aimed O 0
to O 0
investigate O 0
the O 0
effects O 0
of O 0
pallidal O 0
neurotensin B-Chemical 1
on O 0
haloperidol B-Chemical 1
- O 0
induced O 0
parkinsonian B-Disease 1
symptoms I-Disease 1
. O 0

METHODS O 0
: O 0
Behavioral O 0
experiments O 0
and O 0
electrophysiological O 0
recordings O 0
were O 0
performed O 0
in O 0
the O 0
present O 0
study O 0
. O 0

RESULTS O 0
: O 0
Bilateral O 0
infusions O 0
of O 0
neurotensin B-Chemical 1
into O 0
the O 0
globus O 0
pallidus O 0
reversed O 0
haloperidol B-Chemical 1
- O 0
induced O 0
parkinsonian B-Disease 1
catalepsy I-Disease 1
in O 0
rats O 0
. O 0

Electrophysiological O 0
recordings O 0
showed O 0
that O 0
microinjection O 0
of O 0
neurotensin B-Chemical 1
induced O 0
excitation O 0
of O 0
pallidal O 0
neurons O 0
in O 0
the O 0
presence O 0
of O 0
systemic O 0
haloperidol B-Chemical 1
administration O 0
. O 0

The O 0
neurotensin B-Chemical 1
type I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
receptor I-Chemical 1
antagonist I-Chemical 1
SR48692 B-Chemical 1
blocked O 0
both O 0
the O 0
behavioral O 0
and O 0
the O 0
electrophysiological O 0
effects O 0
induced O 0
by O 0
neurotensin B-Chemical 1
. O 0

CONCLUSION O 0
: O 0
Activation O 0
of O 0
pallidal O 0
neurotensin B-Chemical 1
receptors O 0
may O 0
be O 0
involved O 0
in O 0
neurotensin B-Chemical 1
- O 0
induced O 0
antiparkinsonian O 0
effects O 0
. O 0

Carmofur B-Chemical 1
- O 0
induced O 0
organic B-Disease 1
mental I-Disease 1
disorders I-Disease 1
. O 0

Organic B-Disease 1
mental I-Disease 1
disorder I-Disease 1
was O 0
observed O 0
in O 0
a O 0
29 O 0
- O 0
year O 0
- O 0
old O 0
female O 0
in O 0
the O 0
prognostic O 0
period O 0
after O 0
the O 0
onset O 0
of O 0
carmofur B-Chemical 1
- O 0
induced O 0
leukoencephalopathy B-Disease 1
. O 0

Symptoms O 0
such O 0
as O 0
euphoria O 0
, O 0
emotional O 0
lability O 0
and O 0
puerile O 0
attitude O 0
noted O 0
in O 0
the O 0
patient O 0
were O 0
diagnosed O 0
as O 0
organic B-Disease 1
personality I-Disease 1
syndrome I-Disease 1
according O 0
to O 0
the O 0
criteria O 0
defined O 0
in O 0
the O 0
DSM O 0
- O 0
III O 0
- O 0
R O 0
. O 0

It O 0
is O 0
referred O 0
to O 0
as O 0
a O 0
frontal B-Disease 1
lobe I-Disease 1
syndrome I-Disease 1
. O 0

Brain O 0
CT O 0
revealed O 0
a O 0
periventricular O 0
low O 0
density O 0
area O 0
in O 0
the O 0
frontal O 0
white O 0
matter O 0
and O 0
moderate O 0
dilatation O 0
of O 0
the O 0
lateral O 0
ventricles O 0
especially O 0
at O 0
the O 0
bilateral O 0
anterior O 0
horns O 0
. O 0

Consequently O 0
, O 0
carmofur B-Chemical 1
- O 0
induced O 0
leukoencephalopathy B-Disease 1
may O 0
uncommonly O 0
result O 0
in O 0
organic B-Disease 1
personality I-Disease 1
syndrome I-Disease 1
in O 0
the O 0
residual O 0
state O 0
. O 0

It O 0
may O 0
be O 0
attributed O 0
to O 0
the O 0
structural B-Disease 1
damage I-Disease 1
to I-Disease 1
the I-Disease 1
frontal I-Disease 1
lobe I-Disease 1
. O 0

Butyrylcholinesterase O 0
gene O 0
mutations O 0
in O 0
patients O 0
with O 0
prolonged O 0
apnea B-Disease 1
after O 0
succinylcholine B-Chemical 1
for O 0
electroconvulsive O 0
therapy O 0
. O 0

BACKGROUND O 0
: O 0
patients O 0
undergoing O 0
electroconvulsive O 0
therapy O 0
( O 0
ECT O 0
) O 0
often O 0
receive O 0
succinylcholine B-Chemical 1
as O 0
part O 0
of O 0
the O 0
anesthetic O 0
procedure O 0
. O 0

The O 0
duration O 0
of O 0
action O 0
may O 0
be O 0
prolonged O 0
in O 0
patients O 0
with O 0
genetic O 0
variants O 0
of O 0
the O 0
butyrylcholinesterase O 0
enzyme O 0
( O 0
BChE O 0
) O 0
, O 0
the O 0
most O 0
common O 0
being O 0
the O 0
K O 0
- O 0
and O 0
the O 0
A O 0
- O 0
variants O 0
. O 0

The O 0
aim O 0
of O 0
the O 0
study O 0
was O 0
to O 0
assess O 0
the O 0
clinical O 0
significance O 0
of O 0
genetic O 0
variants O 0
in O 0
butyrylcholinesterase O 0
gene O 0
( O 0
BCHE O 0
) O 0
in O 0
patients O 0
with O 0
a O 0
suspected O 0
prolonged O 0
duration O 0
of O 0
action O 0
of O 0
succinylcholine B-Chemical 1
after O 0
ECT O 0
. O 0

METHODS O 0
: O 0
a O 0
total O 0
of O 0
13 O 0
patients O 0
were O 0
referred O 0
to O 0
the O 0
Danish O 0
Cholinesterase O 0
Research O 0
Unit O 0
after O 0
ECT O 0
during O 0
38 O 0
months O 0
. O 0

We O 0
determined O 0
the O 0
BChE O 0
activity O 0
and O 0
the O 0
BCHE O 0
genotype O 0
using O 0
molecular O 0
genetic O 0
methods O 0
, O 0
the O 0
duration O 0
of O 0
apnea B-Disease 1
, O 0
time O 0
to O 0
sufficient O 0
spontaneous O 0
ventilation O 0
and O 0
whether O 0
neuromuscular O 0
monitoring O 0
was O 0
used O 0
. O 0

The O 0
duration O 0
of O 0
apnea B-Disease 1
was O 0
compared O 0
with O 0
published O 0
data O 0
on O 0
normal O 0
subjects O 0
. O 0

RESULTS O 0
: O 0
in O 0
11 O 0
patients O 0
, O 0
mutations O 0
were O 0
found O 0
in O 0
the O 0
BCHE O 0
gene O 0
, O 0
the O 0
K O 0
- O 0
variant O 0
being O 0
the O 0
most O 0
frequent O 0
. O 0

The O 0
duration O 0
of O 0
apnea B-Disease 1
was O 0
5 O 0
- O 0
15 O 0
min O 0
compared O 0
with O 0
3 O 0
- O 0
5 O 0
. O 0
3 O 0
min O 0
from O 0
the O 0
literature O 0
. O 0

Severe O 0
distress O 0
was O 0
noted O 0
in O 0
the O 0
recovery O 0
phase O 0
in O 0
two O 0
patients O 0
. O 0

Neuromuscular O 0
monitoring O 0
was O 0
used O 0
in O 0
two O 0
patients O 0
. O 0

CONCLUSION O 0
: O 0
eleven O 0
of O 0
13 O 0
patients O 0
with O 0
a O 0
prolonged O 0
duration O 0
of O 0
action O 0
of O 0
succinylcholine B-Chemical 1
had O 0
mutations O 0
in O 0
BCHE O 0
, O 0
indicating O 0
that O 0
this O 0
is O 0
the O 0
possible O 0
reason O 0
for O 0
a O 0
prolonged O 0
period O 0
of O 0
apnea B-Disease 1
. O 0

We O 0
recommend O 0
objective O 0
neuromuscular O 0
monitoring O 0
during O 0
the O 0
first O 0
ECT O 0
. O 0

Perhexiline B-Chemical 1
maleate I-Chemical 1
and O 0
peripheral B-Disease 1
neuropathy I-Disease 1
. O 0

Peripheral B-Disease 1
neuropathy I-Disease 1
has O 0
been O 0
noted O 0
as O 0
a O 0
complication O 0
of O 0
therapy O 0
with O 0
perhexiline B-Chemical 1
maleate I-Chemical 1
, O 0
a O 0
drug O 0
widely O 0
used O 0
in O 0
France O 0
( O 0
and O 0
in O 0
clinical O 0
trials O 0
in O 0
the O 0
United O 0
States O 0
) O 0
for O 0
the O 0
prophylactic O 0
treatment O 0
of O 0
angina B-Disease 1
pectoris I-Disease 1
. O 0

In O 0
24 O 0
patients O 0
with O 0
this O 0
complication O 0
, O 0
the O 0
marked O 0
slowing O 0
of O 0
motor O 0
nerve O 0
conduction O 0
velocity O 0
and O 0
the O 0
electromyographic O 0
changes O 0
imply O 0
mainly O 0
a O 0
demyelinating B-Disease 1
disorder I-Disease 1
. O 0

Improvement O 0
was O 0
noted O 0
with O 0
cessation O 0
of O 0
therapy O 0
. O 0

In O 0
a O 0
few O 0
cases O 0
the O 0
presence O 0
of O 0
active O 0
denervation O 0
signified O 0
a O 0
poor O 0
prognosis O 0
, O 0
with O 0
only O 0
slight O 0
improvement O 0
. O 0

The O 0
underlying O 0
mechanism O 0
causing O 0
the O 0
neuropathy B-Disease 1
is O 0
not O 0
yet O 0
fully O 0
known O 0
, O 0
although O 0
some O 0
evidence O 0
indicates O 0
that O 0
it O 0
may O 0
be O 0
a O 0
lipid O 0
storage O 0
process O 0
. O 0

A O 0
phase O 0
I O 0
study O 0
of O 0
4 B-Chemical 1
' I-Chemical 1
- I-Chemical 1
0 I-Chemical 1
- I-Chemical 1
tetrahydropyranyladriamycin I-Chemical 1
. O 0

Clinical O 0
pharmacology O 0
and O 0
pharmacokinetics O 0
. O 0

A O 0
Phase O 0
I O 0
study O 0
of O 0
intravenous O 0
( O 0
IV O 0
) O 0
bolus O 0
4 B-Chemical 1
' I-Chemical 1
- I-Chemical 1
0 I-Chemical 1
- I-Chemical 1
tetrahydropyranyladriamycin I-Chemical 1
( O 0
Pirarubicin B-Chemical 1
) O 0
was O 0
done O 0
in O 0
55 O 0
patients O 0
in O 0
good O 0
performance O 0
status O 0
with O 0
refractory O 0
tumors B-Disease 1
. O 0

Twenty O 0
- O 0
six O 0
had O 0
minimal O 0
prior O 0
therapy O 0
( O 0
good O 0
risk O 0
) O 0
, O 0
23 O 0
had O 0
extensive O 0
prior O 0
therapy O 0
( O 0
poor O 0
risk O 0
) O 0
, O 0
and O 0
six O 0
had O 0
renal B-Disease 1
and I-Disease 1
/ I-Disease 1
or I-Disease 1
hepatic I-Disease 1
dysfunction I-Disease 1
. O 0

A O 0
total O 0
of O 0
167 O 0
courses O 0
at O 0
doses O 0
of O 0
15 O 0
to O 0
70 O 0
mg O 0
/ O 0
m2 O 0
were O 0
evaluable O 0
. O 0

Maximum O 0
tolerated O 0
dose O 0
in O 0
good O 0
- O 0
risk O 0
patients O 0
was O 0
70 O 0
mg O 0
/ O 0
m2 O 0
, O 0
and O 0
in O 0
poor O 0
- O 0
risk O 0
patients O 0
, O 0
60 O 0
mg O 0
/ O 0
m2 O 0
. O 0

The O 0
dose O 0
- O 0
limiting O 0
toxic O 0
effect O 0
was O 0
transient O 0
noncumulative O 0
granulocytopenia B-Disease 1
. O 0

Granulocyte O 0
nadir O 0
was O 0
on O 0
day O 0
14 O 0
( O 0
range O 0
, O 0
4 O 0
- O 0
22 O 0
) O 0
. O 0

Less O 0
frequent O 0
toxic O 0
effects O 0
included O 0
thrombocytopenia B-Disease 1
, O 0
anemia B-Disease 1
, O 0
nausea B-Disease 1
, O 0
mild O 0
alopecia B-Disease 1
, O 0
phlebitis B-Disease 1
, O 0
and O 0
mucositis B-Disease 1
. O 0

Myelosuppression B-Disease 1
was O 0
more O 0
in O 0
patients O 0
with O 0
hepatic B-Disease 1
dysfunction I-Disease 1
. O 0

Pharmacokinetic O 0
analyses O 0
in O 0
21 O 0
patients O 0
revealed O 0
Pirarubicin B-Chemical 1
plasma O 0
T O 0
1 O 0
/ O 0
2 O 0
alpha O 0
( O 0
+ O 0
/ O 0
- O 0
SE O 0
) O 0
of O 0
2 O 0
. O 0
5 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
85 O 0
minutes O 0
, O 0
T O 0
beta O 0
1 O 0
/ O 0
2 O 0
of O 0
25 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
6 O 0
. O 0
5 O 0
minutes O 0
, O 0
and O 0
T O 0
1 O 0
/ O 0
2 O 0
gamma O 0
of O 0
23 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
7 O 0
. O 0
6 O 0
hours O 0
. O 0

The O 0
area O 0
under O 0
the O 0
curve O 0
was O 0
537 O 0
+ O 0
/ O 0
- O 0
149 O 0
ng O 0
/ O 0
ml O 0
x O 0
hours O 0
, O 0
volume O 0
of O 0
distribution O 0
( O 0
Vd O 0
) O 0
3504 O 0
+ O 0
/ O 0
- O 0
644 O 0
l O 0
/ O 0
m2 O 0
, O 0
and O 0
total O 0
clearance O 0
( O 0
ClT O 0
) O 0
was O 0
204 O 0
+ O 0
39 O 0
. O 0
3 O 0
l O 0
/ O 0
hour O 0
/ O 0
m2 O 0
. O 0

Adriamycinol B-Chemical 1
, O 0
doxorubicin B-Chemical 1
, O 0
adriamycinone B-Chemical 1
, O 0
and O 0
tetrahydropyranyladriamycinol B-Chemical 1
were O 0
the O 0
metabolites O 0
detected O 0
in O 0
plasma O 0
and O 0
the O 0
amount O 0
of O 0
doxorubicin B-Chemical 1
was O 0
less O 0
than O 0
or O 0
equal O 0
to O 0
10 O 0
% O 0
of O 0
the O 0
total O 0
metabolites O 0
. O 0

Urinary O 0
excretion O 0
of O 0
Pirarubicin B-Chemical 1
in O 0
the O 0
first O 0
24 O 0
hours O 0
was O 0
less O 0
than O 0
or O 0
equal O 0
to O 0
10 O 0
% O 0
. O 0

Activity O 0
was O 0
noted O 0
in O 0
mesothelioma B-Disease 1
, O 0
leiomyosarcoma B-Disease 1
, O 0
and O 0
basal B-Disease 1
cell I-Disease 1
carcinoma I-Disease 1
. O 0

The O 0
recommended O 0
starting O 0
dose O 0
for O 0
Phase O 0
II O 0
trials O 0
is O 0
60 O 0
mg O 0
/ O 0
m2 O 0
IV O 0
bolus O 0
every O 0
3 O 0
weeks O 0
. O 0

Ocular B-Disease 1
and I-Disease 1
auditory I-Disease 1
toxicity I-Disease 1
in O 0
hemodialyzed O 0
patients O 0
receiving O 0
desferrioxamine B-Chemical 1
. O 0

During O 0
an O 0
18 O 0
- O 0
month O 0
period O 0
of O 0
study O 0
41 O 0
hemodialyzed O 0
patients O 0
receiving O 0
desferrioxamine B-Chemical 1
( O 0
10 O 0
- O 0
40 O 0
mg O 0
/ O 0
kg O 0
BW O 0
/ O 0
3 O 0
times O 0
weekly O 0
) O 0
for O 0
the O 0
first O 0
time O 0
were O 0
monitored O 0
for O 0
detection O 0
of O 0
audiovisual B-Disease 1
toxicity I-Disease 1
. O 0

6 O 0
patients O 0
presented O 0
clinical O 0
symptoms O 0
of O 0
visual B-Disease 1
or I-Disease 1
auditory I-Disease 1
toxicity I-Disease 1
. O 0

Moreover O 0
, O 0
detailed O 0
ophthalmologic O 0
and O 0
audiologic O 0
studies O 0
disclosed O 0
abnormalities O 0
in O 0
7 O 0
more O 0
asymptomatic O 0
patients O 0
. O 0

Visual B-Disease 1
toxicity I-Disease 1
was O 0
of O 0
retinal O 0
origin O 0
and O 0
was O 0
characterized O 0
by O 0
a O 0
tritan O 0
- O 0
type O 0
dyschromatopsy B-Disease 1
, O 0
sometimes O 0
associated O 0
with O 0
a B-Disease 1
loss I-Disease 1
of I-Disease 1
visual I-Disease 1
acuity I-Disease 1
and O 0
pigmentary B-Disease 1
retinal I-Disease 1
deposits I-Disease 1
. O 0

Auditory B-Disease 1
toxicity I-Disease 1
was O 0
characterized O 0
by O 0
a O 0
mid O 0
- O 0
to O 0
high O 0
- O 0
frequency O 0
neurosensorial B-Disease 1
hearing I-Disease 1
loss I-Disease 1
and O 0
the O 0
lesion O 0
was O 0
of O 0
the O 0
cochlear O 0
type O 0
. O 0

Desferrioxamine B-Chemical 1
withdrawal O 0
resulted O 0
in O 0
a O 0
complete O 0
recovery O 0
of O 0
visual O 0
function O 0
in O 0
1 O 0
patient O 0
and O 0
partial O 0
recovery O 0
in O 0
3 O 0
, O 0
and O 0
a O 0
complete O 0
reversal O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
in O 0
3 O 0
patients O 0
and O 0
partial O 0
recovery O 0
in O 0
3 O 0
. O 0

This O 0
toxicity B-Disease 1
appeared O 0
in O 0
patients O 0
receiving O 0
the O 0
higher O 0
doses O 0
of O 0
desferrioxamine B-Chemical 1
or O 0
coincided O 0
with O 0
the O 0
normalization O 0
of O 0
ferritin O 0
or O 0
aluminium B-Chemical 1
serum O 0
levels O 0
. O 0

The O 0
data O 0
indicate O 0
that O 0
audiovisual B-Disease 1
toxicity I-Disease 1
is O 0
not O 0
an O 0
infrequent O 0
complication O 0
in O 0
hemodialyzed O 0
patients O 0
receiving O 0
desferrioxamine B-Chemical 1
. O 0

Periodical O 0
audiovisual O 0
monitoring O 0
should O 0
be O 0
performed O 0
on O 0
hemodialyzed O 0
patients O 0
receiving O 0
the O 0
drug O 0
in O 0
order O 0
to O 0
detect O 0
adverse O 0
effects O 0
as O 0
early O 0
as O 0
possible O 0
. O 0

Serial O 0
epilepsy B-Disease 1
caused O 0
by O 0
levodopa B-Chemical 1
/ I-Chemical 1
carbidopa I-Chemical 1
administration O 0
in O 0
two O 0
patients O 0
on O 0
hemodialysis O 0
. O 0

Two O 0
patients O 0
with O 0
similar O 0
clinical O 0
features O 0
are O 0
presented O 0
: O 0
both O 0
patients O 0
had O 0
chronic B-Disease 1
renal I-Disease 1
failure I-Disease 1
, O 0
on O 0
hemodialysis O 0
for O 0
many O 0
years O 0
but O 0
recently O 0
begun O 0
on O 0
a O 0
high O 0
- O 0
flux O 0
dialyzer O 0
; O 0
both O 0
had O 0
been O 0
receiving O 0
a O 0
carbidopa B-Chemical 1
/ I-Chemical 1
levodopa I-Chemical 1
preparation O 0
; O 0
and O 0
both O 0
had O 0
the O 0
onset O 0
of O 0
hallucinosis B-Disease 1
and O 0
recurrent O 0
seizures B-Disease 1
, O 0
which O 0
were O 0
refractory O 0
to O 0
anticonvulsants O 0
. O 0

The O 0
first O 0
patient O 0
died O 0
without O 0
a O 0
diagnosis O 0
; O 0
the O 0
second O 0
patient O 0
had O 0
a O 0
dramatic O 0
recovery O 0
following O 0
the O 0
administration O 0
of O 0
vitamin B-Chemical 1
B6 I-Chemical 1
. O 0

Neither O 0
patient O 0
was O 0
considered O 0
to O 0
have O 0
a O 0
renal O 0
state O 0
sufficiently O 0
severe O 0
enough O 0
to O 0
explain O 0
their O 0
presentation O 0
. O 0

Randomized O 0
, O 0
double O 0
- O 0
blind O 0
trial O 0
of O 0
mazindol B-Chemical 1
in O 0
Duchenne B-Disease 1
dystrophy I-Disease 1
. O 0

There O 0
is O 0
evidence O 0
that O 0
growth O 0
hormone O 0
may O 0
be O 0
related O 0
to O 0
the O 0
progression O 0
of O 0
weakness B-Disease 1
in O 0
Duchenne B-Disease 1
dystrophy I-Disease 1
. O 0

We O 0
conducted O 0
a O 0
12 O 0
- O 0
month O 0
controlled O 0
trial O 0
of O 0
mazindol B-Chemical 1
, O 0
a O 0
putative O 0
growth O 0
hormone O 0
secretion O 0
inhibitor O 0
, O 0
in O 0
83 O 0
boys O 0
with O 0
Duchenne B-Disease 1
dystrophy I-Disease 1
. O 0

Muscle O 0
strength O 0
, O 0
contractures O 0
, O 0
functional O 0
ability O 0
and O 0
pulmonary O 0
function O 0
were O 0
tested O 0
at O 0
baseline O 0
, O 0
and O 0
6 O 0
and O 0
12 O 0
months O 0
after O 0
treatment O 0
with O 0
mazindol B-Chemical 1
( O 0
3 O 0
mg O 0
/ O 0
d O 0
) O 0
or O 0
placebo O 0
. O 0

The O 0
study O 0
was O 0
designed O 0
to O 0
have O 0
a O 0
power O 0
of O 0
greater O 0
than O 0
0 O 0
. O 0
90 O 0
to O 0
detect O 0
a O 0
slowing O 0
to O 0
25 O 0
% O 0
of O 0
the O 0
expected O 0
rate O 0
of O 0
progression O 0
of O 0
weakness B-Disease 1
at O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
. O 0

Mazindol B-Chemical 1
did O 0
not O 0
benefit O 0
strength O 0
at O 0
any O 0
point O 0
in O 0
the O 0
study O 0
. O 0

Side O 0
effects O 0
attributable O 0
to O 0
mazindol B-Chemical 1
included O 0
decreased B-Disease 1
appetite I-Disease 1
( O 0
36 O 0
% O 0
) O 0
, O 0
dry B-Disease 1
mouth I-Disease 1
( O 0
10 O 0
% O 0
) O 0
, O 0
behavioral O 0
change O 0
( O 0
22 O 0
% O 0
) O 0
, O 0
and O 0
gastrointestinal B-Disease 1
symptoms I-Disease 1
( O 0
18 O 0
% O 0
) O 0
; O 0
mazindol B-Chemical 1
dosage O 0
was O 0
reduced O 0
in O 0
43 O 0
% O 0
of O 0
patients O 0
. O 0

The O 0
effect O 0
of O 0
mazindol B-Chemical 1
on O 0
GH O 0
secretion O 0
was O 0
estimated O 0
indirectly O 0
by O 0
comparing O 0
the O 0
postabsorptive O 0
IGF O 0
- O 0
I O 0
levels O 0
obtained O 0
following O 0
3 O 0
, O 0
6 O 0
, O 0
9 O 0
, O 0
and O 0
12 O 0
months O 0
in O 0
the O 0
mazindol B-Chemical 1
treated O 0
to O 0
those O 0
in O 0
the O 0
placebo O 0
groups O 0
. O 0

Although O 0
mazindol B-Chemical 1
- O 0
treated O 0
patients O 0
gained O 0
less O 0
weight O 0
and O 0
height O 0
than O 0
placebo O 0
- O 0
treated O 0
patients O 0
, O 0
no O 0
significant O 0
effect O 0
on O 0
IGF O 0
- O 0
I O 0
levels O 0
was O 0
observed O 0
. O 0

Mazindol B-Chemical 1
doses O 0
not O 0
slow O 0
the O 0
progression O 0
of O 0
weakness B-Disease 1
in O 0
Duchenne B-Disease 1
dystrophy I-Disease 1
. O 0

Facilitation O 0
of O 0
memory O 0
retrieval O 0
by O 0
pre O 0
- O 0
test O 0
morphine B-Chemical 1
and O 0
its O 0
state O 0
dependency O 0
in O 0
the O 0
step O 0
- O 0
through O 0
type O 0
passive O 0
avoidance O 0
learning O 0
test O 0
in O 0
mice O 0
. O 0

Amnesia B-Disease 1
produced O 0
by O 0
scopolamine B-Chemical 1
and O 0
cycloheximide B-Chemical 1
were O 0
reversed O 0
by O 0
morphine B-Chemical 1
given O 0
30 O 0
min O 0
before O 0
the O 0
test O 0
trial O 0
( O 0
pre O 0
- O 0
test O 0
) O 0
, O 0
and O 0
pre O 0
- O 0
test O 0
morphine B-Chemical 1
also O 0
facilitated O 0
the O 0
memory O 0
retrieval O 0
in O 0
the O 0
animals O 0
administered O 0
naloxone B-Chemical 1
during O 0
the O 0
training O 0
trial O 0
. O 0

Similarly O 0
, O 0
pre O 0
- O 0
test O 0
scopolamine B-Chemical 1
partially O 0
reversed O 0
the O 0
scopolamine B-Chemical 1
- O 0
induced O 0
amnesia B-Disease 1
, O 0
but O 0
not O 0
significantly O 0
; O 0
and O 0
pre O 0
- O 0
test O 0
cycloheximide B-Chemical 1
failed O 0
to O 0
reverse O 0
the O 0
cycloheximide B-Chemical 1
- O 0
induced O 0
amnesia B-Disease 1
. O 0

These O 0
results O 0
suggest O 0
that O 0
the O 0
facilitation O 0
of O 0
memory O 0
retrieval O 0
by O 0
pre O 0
- O 0
test O 0
morphine B-Chemical 1
might O 0
be O 0
the O 0
direct O 0
action O 0
of O 0
morphine B-Chemical 1
rather O 0
than O 0
a O 0
state O 0
dependent O 0
effect O 0
. O 0

Naloxone B-Chemical 1
reverses O 0
the O 0
antihypertensive O 0
effect O 0
of O 0
clonidine B-Chemical 1
. O 0

In O 0
unanesthetized O 0
, O 0
spontaneously O 0
hypertensive B-Disease 1
rats O 0
the O 0
decrease O 0
in O 0
blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
produced O 0
by O 0
intravenous O 0
clonidine B-Chemical 1
, O 0
5 O 0
to O 0
20 O 0
micrograms O 0
/ O 0
kg O 0
, O 0
was O 0
inhibited O 0
or O 0
reversed O 0
by O 0
nalozone B-Chemical 1
, O 0
0 O 0
. O 0
2 O 0
to O 0
2 O 0
mg O 0
/ O 0
kg O 0
. O 0

The O 0
hypotensive B-Disease 1
effect O 0
of O 0
100 O 0
mg O 0
/ O 0
kg O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
was O 0
also O 0
partially O 0
reversed O 0
by O 0
naloxone B-Chemical 1
. O 0

Naloxone B-Chemical 1
alone O 0
did O 0
not O 0
affect O 0
either O 0
blood O 0
pressure O 0
or O 0
heart O 0
rate O 0
. O 0

In O 0
brain O 0
membranes O 0
from O 0
spontaneously O 0
hypertensive B-Disease 1
rats O 0
clonidine B-Chemical 1
, O 0
10 O 0
( O 0
- O 0
8 O 0
) O 0
to O 0
10 O 0
( O 0
- O 0
5 O 0
) O 0
M O 0
, O 0
did O 0
not O 0
influence O 0
stereoselective O 0
binding O 0
of O 0
[ B-Chemical 1
3H I-Chemical 1
] I-Chemical 1
- I-Chemical 1
naloxone I-Chemical 1
( O 0
8 O 0
nM O 0
) O 0
, O 0
and O 0
naloxone B-Chemical 1
, O 0
10 O 0
( O 0
- O 0
8 O 0
) O 0
to O 0
10 O 0
( O 0
- O 0
4 O 0
) O 0
M O 0
, O 0
did O 0
not O 0
influence O 0
clonidine B-Chemical 1
- O 0
suppressible O 0
binding O 0
of O 0
[ B-Chemical 1
3H I-Chemical 1
] I-Chemical 1
- I-Chemical 1
dihydroergocryptine I-Chemical 1
( O 0
1 O 0
nM O 0
) O 0
. O 0

These O 0
findings O 0
indicate O 0
that O 0
in O 0
spontaneously O 0
hypertensive B-Disease 1
rats O 0
the O 0
effects O 0
of O 0
central O 0
alpha O 0
- O 0
adrenoceptor O 0
stimulation O 0
involve O 0
activation O 0
of O 0
opiate O 0
receptors O 0
. O 0

As O 0
naloxone B-Chemical 1
and O 0
clonidine B-Chemical 1
do O 0
not O 0
appear O 0
to O 0
interact O 0
with O 0
the O 0
same O 0
receptor O 0
site O 0
, O 0
the O 0
observed O 0
functional O 0
antagonism O 0
suggests O 0
the O 0
release O 0
of O 0
an O 0
endogenous O 0
opiate O 0
by O 0
clonidine B-Chemical 1
or O 0
alpha B-Chemical 1
- I-Chemical 1
methyldopa I-Chemical 1
and O 0
the O 0
possible O 0
role O 0
of O 0
the O 0
opiate O 0
in O 0
the O 0
central O 0
control O 0
of O 0
sympathetic O 0
tone O 0
. O 0

Neurotoxicity B-Disease 1
of O 0
halogenated B-Chemical 1
hydroxyquinolines I-Chemical 1
: O 0
clinical O 0
analysis O 0
of O 0
cases O 0
reported O 0
outside O 0
Japan O 0
. O 0

An O 0
analysis O 0
is O 0
presented O 0
of O 0
220 O 0
cases O 0
of O 0
possible O 0
neurotoxic B-Disease 1
reactions O 0
to O 0
halogenated B-Chemical 1
hydroxyquinolines I-Chemical 1
reported O 0
from O 0
outside O 0
Japan O 0
. O 0

In O 0
80 O 0
cases O 0
insufficient O 0
information O 0
was O 0
available O 0
for O 0
adequate O 0
comment O 0
and O 0
in O 0
29 O 0
a O 0
relationship O 0
to O 0
the O 0
administration O 0
of O 0
clioquinol B-Chemical 1
could O 0
be O 0
excluded O 0
. O 0

Of O 0
the O 0
remainder O 0
, O 0
a O 0
relationship O 0
to O 0
clioquinol B-Chemical 1
was O 0
considered O 0
probable O 0
in O 0
42 O 0
and O 0
possible O 0
in O 0
69 O 0
cases O 0
. O 0

In O 0
six O 0
of O 0
the O 0
probable O 0
cases O 0
the O 0
neurological B-Disease 1
disturbance I-Disease 1
consisted O 0
of O 0
an O 0
acute O 0
reversible O 0
encephalopathy B-Disease 1
usually O 0
related O 0
to O 0
the O 0
ingestion O 0
of O 0
a O 0
high O 0
dose O 0
of O 0
clioquinol B-Chemical 1
over O 0
a O 0
short O 0
period O 0
. O 0

The O 0
most O 0
common O 0
manifestation O 0
, O 0
observed O 0
in O 0
15 O 0
further O 0
cases O 0
, O 0
was O 0
isolated O 0
optic B-Disease 1
atrophy I-Disease 1
. O 0

This O 0
was O 0
most O 0
frequently O 0
found O 0
in O 0
children O 0
, O 0
many O 0
of O 0
whom O 0
had O 0
received O 0
clioquinol B-Chemical 1
as O 0
treatment O 0
for O 0
acrodermatitis B-Disease 1
enteropathica I-Disease 1
. O 0

In O 0
the O 0
remaining O 0
cases O 0
, O 0
a O 0
combination O 0
of O 0
myelopathy B-Disease 1
, O 0
visual B-Disease 1
disturbance I-Disease 1
, O 0
and O 0
peripheral B-Disease 1
neuropathy I-Disease 1
was O 0
the O 0
most O 0
common O 0
manifestation O 0
. O 0

Isolated O 0
myelopathy B-Disease 1
or O 0
peripheral B-Disease 1
neuropathy I-Disease 1
, O 0
or O 0
these O 0
manifestations O 0
occurring O 0
together O 0
, O 0
were O 0
infrequent O 0
. O 0

The O 0
onset O 0
of O 0
all O 0
manifestations O 0
( O 0
except O 0
toxic O 0
encephalopathy B-Disease 1
) O 0
was O 0
usually O 0
subacute O 0
, O 0
with O 0
subsequent O 0
partial O 0
recovery O 0
. O 0

Older O 0
subjects O 0
tended O 0
to O 0
display O 0
more O 0
side O 0
effects O 0
. O 0

The O 0
full O 0
syndrome O 0
of O 0
subacute O 0
myelo B-Disease 1
- I-Disease 1
optic I-Disease 1
neuropathy I-Disease 1
was O 0
more O 0
frequent O 0
in O 0
women O 0
, O 0
but O 0
they O 0
tended O 0
to O 0
have O 0
taken O 0
greater O 0
quantities O 0
of O 0
the O 0
drug O 0
. O 0

Prazosin B-Chemical 1
- O 0
induced O 0
stress B-Disease 1
incontinence I-Disease 1
. O 0

A O 0
case O 0
of O 0
genuine O 0
stress B-Disease 1
incontinence I-Disease 1
due O 0
to O 0
prazosin B-Chemical 1
, O 0
a O 0
common O 0
antihypertensive O 0
drug O 0
, O 0
is O 0
presented O 0
. O 0

Prazosin B-Chemical 1
exerts O 0
its O 0
antihypertensive O 0
effects O 0
through O 0
vasodilatation O 0
caused O 0
by O 0
selective O 0
blockade O 0
of O 0
postsynaptic O 0
alpha O 0
- O 0
1 O 0
adrenergic O 0
receptors O 0
. O 0

As O 0
an O 0
alpha O 0
- O 0
blocker O 0
, O 0
it O 0
also O 0
exerts O 0
a O 0
significant O 0
relaxant O 0
effect O 0
on O 0
the O 0
bladder O 0
neck O 0
and O 0
urethra O 0
. O 0

The O 0
patient O 0
' O 0
s O 0
clinical O 0
course O 0
is O 0
described O 0
and O 0
correlated O 0
with O 0
initial O 0
urodynamic O 0
studies O 0
while O 0
on O 0
prazosin B-Chemical 1
and O 0
subsequent O 0
studies O 0
while O 0
taking O 0
verapamil B-Chemical 1
. O 0

Her O 0
incontinence B-Disease 1
resolved O 0
with O 0
the O 0
change O 0
of O 0
medication O 0
. O 0

The O 0
restoration O 0
of O 0
continence O 0
was O 0
accompanied O 0
by O 0
a O 0
substantial O 0
rise O 0
in O 0
maximum O 0
urethral O 0
pressure O 0
, O 0
maximum O 0
urethral O 0
closure O 0
pressure O 0
, O 0
and O 0
functional O 0
urethral O 0
length O 0
. O 0

Patients O 0
who O 0
present O 0
with O 0
stress B-Disease 1
incontinence I-Disease 1
while O 0
taking O 0
prazosin B-Chemical 1
should O 0
change O 0
their O 0
antihypertensive O 0
medication O 0
before O 0
considering O 0
surgery O 0
, O 0
because O 0
their O 0
incontinence B-Disease 1
may O 0
resolve O 0
spontaneously O 0
with O 0
a O 0
change O 0
in O 0
drug O 0
therapy O 0
. O 0

Myocardial B-Disease 1
infarction I-Disease 1
following O 0
sublingual O 0
administration O 0
of O 0
isosorbide B-Chemical 1
dinitrate I-Chemical 1
. O 0

A O 0
78 O 0
- O 0
year O 0
- O 0
old O 0
with O 0
healed O 0
septal O 0
necrosis B-Disease 1
suffered O 0
a O 0
recurrent O 0
myocardial B-Disease 1
infarction I-Disease 1
of O 0
the O 0
anterior O 0
wall O 0
following O 0
the O 0
administration O 0
of O 0
isosorbide B-Chemical 1
dinitrate I-Chemical 1
5 O 0
mg O 0
sublingually O 0
. O 0

After O 0
detailing O 0
the O 0
course O 0
of O 0
events O 0
, O 0
we O 0
discuss O 0
the O 0
role O 0
of O 0
paradoxical O 0
coronary O 0
spasm B-Disease 1
and O 0
hypotension B-Disease 1
- O 0
mediated O 0
myocardial B-Disease 1
ischemia I-Disease 1
occurring O 0
downstream O 0
to O 0
significant O 0
coronary B-Disease 1
arterial I-Disease 1
stenosis I-Disease 1
in O 0
the O 0
pathophysiology O 0
of O 0
acute B-Disease 1
coronary I-Disease 1
insufficiency I-Disease 1
. O 0

Comparison O 0
of O 0
the O 0
respiratory O 0
effects O 0
of O 0
i O 0
. O 0
v O 0
. O 0
infusions O 0
of O 0
morphine B-Chemical 1
and O 0
regional O 0
analgesia O 0
by O 0
extradural O 0
block O 0
. O 0

The O 0
incidence O 0
of O 0
postoperative O 0
respiratory O 0
apnoea B-Disease 1
was O 0
compared O 0
between O 0
five O 0
patients O 0
receiving O 0
a O 0
continuous O 0
i O 0
. O 0
v O 0
. O 0
infusion O 0
of O 0
morphine B-Chemical 1
( O 0
mean O 0
73 O 0
. O 0
6 O 0
mg O 0
) O 0
and O 0
five O 0
patients O 0
receiving O 0
a O 0
continuous O 0
extradural O 0
infusion O 0
of O 0
0 O 0
. O 0
25 O 0
% O 0
bupivacaine B-Chemical 1
( O 0
mean O 0
192 O 0
mg O 0
) O 0
in O 0
the O 0
24 O 0
- O 0
h O 0
period O 0
following O 0
upper O 0
abdominal O 0
surgery O 0
. O 0

Monitoring O 0
consisted O 0
of O 0
airflow O 0
detection O 0
by O 0
a O 0
carbon B-Chemical 1
dioxide I-Chemical 1
analyser O 0
, O 0
chest O 0
wall O 0
movement O 0
detected O 0
by O 0
pneumatic O 0
capsules O 0
, O 0
and O 0
continuous O 0
electrocardiograph O 0
recorded O 0
with O 0
a O 0
Holter O 0
ambulatory O 0
monitor O 0
. O 0

Both O 0
obstructive B-Disease 1
( I-Disease 1
P I-Disease 1
less I-Disease 1
than I-Disease 1
0 I-Disease 1
. I-Disease 1
05 I-Disease 1
) I-Disease 1
and I-Disease 1
central I-Disease 1
apnoea I-Disease 1
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
occurred O 0
more O 0
frequently O 0
in O 0
patients O 0
who O 0
had O 0
a O 0
morphine B-Chemical 1
infusion O 0
. O 0

There O 0
was O 0
also O 0
a O 0
higher O 0
incidence O 0
of O 0
tachyarrhythmias B-Disease 1
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
and O 0
ventricular B-Disease 1
ectopic I-Disease 1
beats I-Disease 1
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
in O 0
the O 0
morphine B-Chemical 1
infusion O 0
group O 0
. O 0

Effects O 0
of O 0
aminophylline B-Chemical 1
on O 0
the O 0
threshold O 0
for O 0
initiating O 0
ventricular B-Disease 1
fibrillation I-Disease 1
during O 0
respiratory B-Disease 1
failure I-Disease 1
. O 0

Cardiac B-Disease 1
arrhythmias I-Disease 1
have O 0
frequently O 0
been O 0
reported O 0
in O 0
association O 0
with O 0
respiratory B-Disease 1
failure I-Disease 1
. O 0

The O 0
possible O 0
additive O 0
role O 0
of O 0
pharmacologic O 0
agents O 0
in O 0
precipitating O 0
cardiac B-Disease 1
disturbances I-Disease 1
in O 0
patients O 0
with O 0
respiratory B-Disease 1
failure I-Disease 1
has O 0
only O 0
recently O 0
been O 0
emphasized O 0
. O 0

The O 0
effects O 0
of O 0
aminophylline B-Chemical 1
on O 0
the O 0
ventricular B-Disease 1
fibrillation I-Disease 1
threshold O 0
during O 0
normal O 0
acid O 0
- O 0
base O 0
conditions O 0
and O 0
during O 0
respiratory B-Disease 1
failure I-Disease 1
were O 0
studied O 0
in O 0
anesthetized O 0
open O 0
chest O 0
dogs O 0
. O 0

The O 0
ventricular B-Disease 1
fibrillation I-Disease 1
threshold O 0
was O 0
measured O 0
by O 0
passing O 0
a O 0
gated O 0
train O 0
of O 0
12 O 0
constant O 0
current O 0
pulses O 0
through O 0
the O 0
ventricular O 0
myocardium O 0
during O 0
the O 0
vulnerable O 0
period O 0
of O 0
the O 0
cardiac O 0
cycle O 0
. O 0

During O 0
the O 0
infusion O 0
of O 0
aminophylline B-Chemical 1
, O 0
the O 0
ventricular B-Disease 1
fibrillation I-Disease 1
threshold O 0
was O 0
reduced O 0
by O 0
30 O 0
to O 0
40 O 0
percent O 0
of O 0
the O 0
control O 0
when O 0
pH O 0
and O 0
partial O 0
pressures O 0
of O 0
oxygen B-Chemical 1
( O 0
PO2 B-Chemical 1
) O 0
and O 0
carbon B-Chemical 1
dioxide I-Chemical 1
( O 0
CO2 B-Chemical 1
) O 0
were O 0
kept O 0
within O 0
normal O 0
limits O 0
. O 0

When O 0
respiratory B-Disease 1
failure I-Disease 1
was O 0
produced O 0
by O 0
hypoventilation B-Disease 1
( O 0
pH O 0
7 O 0
. O 0
05 O 0
to O 0
7 O 0
. O 0
25 O 0
; O 0
PC02 O 0
70 O 0
to O 0
100 O 0
mm O 0
Hg O 0
: O 0
P02 O 0
20 O 0
to O 0
40 O 0
mm O 0
Hg O 0
) O 0
, O 0
infusion O 0
of O 0
aminophylline B-Chemical 1
resulted O 0
in O 0
an O 0
even O 0
greater O 0
decrease O 0
in O 0
ventricular B-Disease 1
fibrillation I-Disease 1
threshold O 0
to O 0
60 O 0
percent O 0
of O 0
the O 0
control O 0
level O 0
. O 0

These O 0
experiments O 0
suggest O 0
that O 0
although O 0
many O 0
factors O 0
may O 0
contribute O 0
to O 0
the O 0
increased O 0
incidence O 0
of O 0
ventricular B-Disease 1
arrhythmias I-Disease 1
in O 0
respiratory B-Disease 1
failure I-Disease 1
, O 0
pharmacologic O 0
agents O 0
, O 0
particularly O 0
aminophylline B-Chemical 1
, O 0
may O 0
play O 0
a O 0
significant O 0
role O 0
. O 0

Pentoxifylline B-Chemical 1
( O 0
Trental B-Chemical 1
) O 0
does O 0
not O 0
inhibit O 0
dipyridamole B-Chemical 1
- O 0
induced O 0
coronary O 0
hyperemia B-Disease 1
: O 0
implications O 0
for O 0
dipyridamole B-Chemical 1
- O 0
thallium B-Chemical 1
- O 0
201 O 0
myocardial O 0
imaging O 0
. O 0

Dipyridamole B-Chemical 1
- O 0
thallium B-Chemical 1
- O 0
201 O 0
imaging O 0
is O 0
often O 0
performed O 0
in O 0
patients O 0
unable O 0
to O 0
exercise O 0
because O 0
of O 0
peripheral B-Disease 1
vascular I-Disease 1
disease I-Disease 1
. O 0

Many O 0
of O 0
these O 0
patients O 0
are O 0
taking O 0
pentoxifylline B-Chemical 1
( O 0
Trental B-Chemical 1
) O 0
, O 0
a O 0
methylxanthine B-Chemical 1
derivative O 0
which O 0
may O 0
improve O 0
intermittent B-Disease 1
claudication I-Disease 1
. O 0

Whether O 0
pentoxifylline B-Chemical 1
inhibits O 0
dipyridamole B-Chemical 1
- O 0
induced O 0
coronary O 0
hyperemia B-Disease 1
like O 0
other O 0
methylxanthines B-Chemical 1
such O 0
as O 0
theophylline B-Chemical 1
and O 0
should O 0
be O 0
stopped O 0
prior O 0
to O 0
dipyridamole B-Chemical 1
- O 0
thallium B-Chemical 1
- O 0
201 O 0
imaging O 0
is O 0
unknown O 0
. O 0

Therefore O 0
, O 0
we O 0
studied O 0
the O 0
hyperemic O 0
response O 0
to O 0
dipyridamole B-Chemical 1
in O 0
seven O 0
open O 0
- O 0
chest O 0
anesthetized O 0
dogs O 0
after O 0
pretreatment O 0
with O 0
either O 0
pentoxifylline B-Chemical 1
( O 0
0 O 0
, O 0
7 O 0
. O 0
5 O 0
, O 0
or O 0
15 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
v O 0
. O 0
) O 0
or O 0
theophylline B-Chemical 1
( O 0
3 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
v O 0
. O 0
) O 0
. O 0

Baseline O 0
circumflex O 0
coronary O 0
blood O 0
flows O 0
did O 0
not O 0
differ O 0
significantly O 0
among O 0
treatment O 0
groups O 0
. O 0

Dipyridamole B-Chemical 1
significantly O 0
increased O 0
coronary O 0
blood O 0
flow O 0
before O 0
and O 0
after O 0
7 O 0
. O 0
5 O 0
or O 0
15 O 0
mm O 0
/ O 0
kg O 0
i O 0
. O 0
v O 0
. O 0
pentoxifylline B-Chemical 1
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
002 O 0
) O 0
. O 0

Neither O 0
dose O 0
of O 0
pentoxifylline B-Chemical 1
significantly O 0
decreased O 0
the O 0
dipyridamole B-Chemical 1
- O 0
induced O 0
hyperemia B-Disease 1
, O 0
while O 0
peak O 0
coronary O 0
blood O 0
flow O 0
was O 0
significantly O 0
lower O 0
after O 0
theophylline B-Chemical 1
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
01 O 0
) O 0
. O 0

We O 0
conclude O 0
that O 0
pentoxyifylline B-Chemical 1
does O 0
not O 0
inhibit O 0
dipyridamole B-Chemical 1
- O 0
induced O 0
coronary O 0
hyperemia B-Disease 1
even O 0
at O 0
high O 0
doses O 0
. O 0

Cause O 0
of O 0
death B-Disease 1
among O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
: O 0
a O 0
rare O 0
mortality O 0
due O 0
to O 0
cerebral B-Disease 1
haemorrhage I-Disease 1
. O 0

Causes O 0
of O 0
death B-Disease 1
, O 0
with O 0
special O 0
reference O 0
to O 0
cerebral B-Disease 1
haemorrhage I-Disease 1
, O 0
among O 0
240 O 0
patients O 0
with O 0
pathologically O 0
verified O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
were O 0
investigated O 0
using O 0
the O 0
Annuals O 0
of O 0
the O 0
Pathological O 0
Autopsy O 0
Cases O 0
in O 0
Japan O 0
from O 0
1981 O 0
to O 0
1985 O 0
. O 0

The O 0
leading O 0
causes O 0
of O 0
death B-Disease 1
were O 0
pneumonia B-Disease 1
and O 0
bronchitis B-Disease 1
( O 0
44 O 0
. O 0
1 O 0
% O 0
) O 0
, O 0
malignant O 0
neoplasms B-Disease 1
( O 0
11 O 0
. O 0
6 O 0
% O 0
) O 0
, O 0
heart B-Disease 1
diseases I-Disease 1
( O 0
4 O 0
. O 0
1 O 0
% O 0
) O 0
, O 0
cerebral B-Disease 1
infarction I-Disease 1
( O 0
3 O 0
. O 0
7 O 0
% O 0
) O 0
and O 0
septicaemia B-Disease 1
( O 0
3 O 0
. O 0
3 O 0
% O 0
) O 0
. O 0

Cerebral B-Disease 1
haemorrhage I-Disease 1
was O 0
the O 0
11th O 0
most O 0
frequent O 0
cause O 0
of O 0
death B-Disease 1
, O 0
accounting O 0
for O 0
only O 0
0 O 0
. O 0
8 O 0
% O 0
of O 0
deaths B-Disease 1
among O 0
the O 0
patients O 0
, O 0
whereas O 0
it O 0
was O 0
the O 0
5th O 0
most O 0
common O 0
cause O 0
of O 0
death B-Disease 1
among O 0
the O 0
Japanese O 0
general O 0
population O 0
in O 0
1985 O 0
. O 0

The O 0
low O 0
incidence O 0
of O 0
cerebral B-Disease 1
haemorrhage I-Disease 1
as O 0
a O 0
cause O 0
of O 0
death B-Disease 1
in O 0
patients O 0
with O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
may O 0
reflect O 0
the O 0
hypotensive B-Disease 1
effect O 0
of O 0
levodopa B-Chemical 1
and O 0
a O 0
hypotensive B-Disease 1
mechanism O 0
due O 0
to O 0
reduced O 0
noradrenaline B-Chemical 1
levels O 0
in O 0
the O 0
parkinsonian B-Disease 1
brain O 0
. O 0

Possible O 0
intramuscular O 0
midazolam B-Chemical 1
- O 0
associated O 0
cardiorespiratory B-Disease 1
arrest I-Disease 1
and O 0
death B-Disease 1
. O 0

Midazolam B-Chemical 1
hydrochloride I-Chemical 1
is O 0
commonly O 0
used O 0
for O 0
dental O 0
or O 0
endoscopic O 0
procedures O 0
. O 0

Although O 0
generally O 0
consisted O 0
safe O 0
when O 0
given O 0
intramuscularly O 0
, O 0
intravenous O 0
administration O 0
is O 0
known O 0
to O 0
cause O 0
respiratory B-Disease 1
and I-Disease 1
cardiovascular I-Disease 1
depression I-Disease 1
. O 0

This O 0
report O 0
describes O 0
the O 0
first O 0
published O 0
case O 0
of O 0
cardiorespiratory B-Disease 1
arrest I-Disease 1
and O 0
death B-Disease 1
associated O 0
with O 0
intramuscular O 0
administration O 0
of O 0
midazolam B-Chemical 1
. O 0

Information O 0
regarding O 0
midazolam B-Chemical 1
use O 0
is O 0
reviewed O 0
to O 0
provide O 0
recommendation O 0
for O 0
safe O 0
administration O 0
. O 0

Myasthenia B-Disease 1
gravis I-Disease 1
presenting O 0
as O 0
weakness O 0
after O 0
magnesium B-Chemical 1
administration O 0
. O 0

We O 0
studied O 0
a O 0
patient O 0
with O 0
no O 0
prior O 0
history O 0
of O 0
neuromuscular B-Disease 1
disease I-Disease 1
who O 0
became O 0
virtually O 0
quadriplegic B-Disease 1
after O 0
parenteral O 0
magnesium B-Chemical 1
administration O 0
for O 0
preeclampsia B-Disease 1
. O 0

The O 0
serum O 0
magnesium B-Chemical 1
concentration O 0
was O 0
3 O 0
. O 0
0 O 0
mEq O 0
/ O 0
L O 0
, O 0
which O 0
is O 0
usually O 0
well O 0
tolerated O 0
. O 0

The O 0
magnesium B-Chemical 1
was O 0
stopped O 0
and O 0
she O 0
recovered O 0
over O 0
a O 0
few O 0
days O 0
. O 0

While O 0
she O 0
was O 0
weak O 0
, O 0
2 O 0
- O 0
Hz O 0
repetitive O 0
stimulation O 0
revealed O 0
a O 0
decrement O 0
without O 0
significant O 0
facilitation O 0
at O 0
rapid O 0
rates O 0
or O 0
after O 0
exercise O 0
, O 0
suggesting O 0
postsynaptic B-Disease 1
neuromuscular I-Disease 1
blockade I-Disease 1
. O 0

After O 0
her O 0
strength O 0
returned O 0
, O 0
repetitive O 0
stimulation O 0
was O 0
normal O 0
, O 0
but O 0
single O 0
fiber O 0
EMG O 0
revealed O 0
increased O 0
jitter O 0
and O 0
blocking O 0
. O 0

Her O 0
acetylcholine B-Chemical 1
receptor O 0
antibody O 0
level O 0
was O 0
markedly O 0
elevated O 0
. O 0

Although O 0
paralysis B-Disease 1
after O 0
magnesium B-Chemical 1
administration O 0
has O 0
been O 0
described O 0
in O 0
patients O 0
with O 0
known O 0
myasthenia B-Disease 1
gravis I-Disease 1
, O 0
it O 0
has O 0
not O 0
previously O 0
been O 0
reported O 0
to O 0
be O 0
the O 0
initial O 0
or O 0
only O 0
manifestation O 0
of O 0
the O 0
disease O 0
. O 0

Patients O 0
who O 0
are O 0
unusually O 0
sensitive O 0
to O 0
the O 0
neuromuscular O 0
effects O 0
of O 0
magnesium B-Chemical 1
should O 0
be O 0
suspected O 0
of O 0
having O 0
an O 0
underlying O 0
disorder B-Disease 1
of I-Disease 1
neuromuscular I-Disease 1
transmission I-Disease 1
. O 0

No O 0
enhancement O 0
by O 0
phenobarbital B-Chemical 1
of O 0
the O 0
hepatocarcinogenicity O 0
of O 0
a O 0
choline B-Chemical 1
- O 0
devoid O 0
diet O 0
in O 0
the O 0
rat O 0
. O 0

An O 0
experiment O 0
was O 0
performed O 0
to O 0
test O 0
whether O 0
inclusion O 0
of O 0
phenobarbital B-Chemical 1
in O 0
a O 0
choline B-Chemical 1
- O 0
devoid O 0
diet O 0
would O 0
increase O 0
the O 0
hepatocarcinogenicity O 0
of O 0
the O 0
diet O 0
. O 0

Groups O 0
of O 0
5 O 0
- O 0
week O 0
old O 0
male O 0
Fischer O 0
- O 0
344 O 0
rats O 0
were O 0
fed O 0
for O 0
7 O 0
- O 0
25 O 0
months O 0
semipurified O 0
choline B-Chemical 1
- O 0
devoid O 0
or O 0
choline B-Chemical 1
- O 0
supplemented O 0
diets O 0
, O 0
containing O 0
or O 0
not O 0
0 O 0
. O 0
06 O 0
% O 0
phenobarbital B-Chemical 1
. O 0

No O 0
hepatic O 0
preneoplastic O 0
nodules O 0
or O 0
hepatocellular B-Disease 1
carcinomas I-Disease 1
developed O 0
in O 0
rats O 0
fed O 0
the O 0
plain O 0
choline B-Chemical 1
- O 0
supplemented O 0
diet O 0
, O 0
while O 0
one O 0
preneoplastic O 0
nodule O 0
and O 0
one O 0
hepatocellular B-Disease 1
carcinoma I-Disease 1
developed O 0
in O 0
two O 0
rats O 0
fed O 0
the O 0
same O 0
diet O 0
containing O 0
phenobarbital B-Chemical 1
. O 0

The O 0
incidence O 0
of O 0
preneoplastic O 0
nodules O 0
and O 0
of O 0
hepatocellular B-Disease 1
carcinomas I-Disease 1
was O 0
10 O 0
% O 0
and O 0
37 O 0
% O 0
, O 0
respectively O 0
, O 0
in O 0
rats O 0
fed O 0
the O 0
plain O 0
choline B-Chemical 1
- O 0
devoid O 0
diet O 0
, O 0
and O 0
17 O 0
% O 0
and O 0
30 O 0
% O 0
, O 0
in O 0
rats O 0
fed O 0
the O 0
phenobarbital B-Chemical 1
- O 0
containing O 0
choline B-Chemical 1
- O 0
devoid O 0
diet O 0
. O 0

The O 0
results O 0
evinced O 0
no O 0
enhancement O 0
of O 0
the O 0
hepatocarcinogenicity O 0
of O 0
the O 0
choline B-Chemical 1
- O 0
devoid O 0
diet O 0
by O 0
phenobarbital B-Chemical 1
. O 0

Sporadic O 0
neoplastic O 0
lesions O 0
were O 0
observed O 0
in O 0
organs O 0
other O 0
than O 0
the O 0
liver O 0
of O 0
some O 0
of O 0
the O 0
animals O 0
, O 0
irrespective O 0
of O 0
the O 0
diet O 0
fed O 0
. O 0

On O 0
two O 0
paradoxical O 0
side O 0
- O 0
effects O 0
of O 0
prednisolone B-Chemical 1
in O 0
rats O 0
, O 0
ribosomal O 0
RNA O 0
biosyntheses O 0
, O 0
and O 0
a O 0
mechanism O 0
of O 0
action O 0
. O 0

Liver B-Disease 1
enlargement I-Disease 1
and O 0
muscle B-Disease 1
wastage I-Disease 1
occurred O 0
in O 0
Wistar O 0
rats O 0
following O 0
the O 0
subcutaneous O 0
administration O 0
of O 0
prednisolone B-Chemical 1
. O 0

In O 0
the O 0
liver O 0
both O 0
the O 0
content O 0
of O 0
RNA O 0
and O 0
the O 0
biosynthesis O 0
of O 0
ribosomal O 0
RNA O 0
increased O 0
while O 0
both O 0
the O 0
RNA O 0
content O 0
and O 0
ribosomal O 0
RNA O 0
biosynthesis O 0
were O 0
reduced O 0
in O 0
the O 0
gastrocnemius O 0
muscle O 0
. O 0

It O 0
is O 0
suggested O 0
that O 0
the O 0
drug O 0
acted O 0
in O 0
a O 0
selective O 0
and O 0
tissue O 0
- O 0
specific O 0
manner O 0
to O 0
enhance O 0
ribosomal O 0
RNA O 0
synthesis O 0
in O 0
the O 0
liver O 0
and O 0
depress O 0
such O 0
synthesis O 0
in O 0
the O 0
muscle O 0
. O 0

This O 0
view O 0
supports O 0
the O 0
contention O 0
that O 0
the O 0
liver O 0
and O 0
muscle O 0
are O 0
independent O 0
sites O 0
of O 0
prednisolone B-Chemical 1
action O 0
. O 0

Differential O 0
effects O 0
of O 0
gamma B-Chemical 1
- I-Chemical 1
hexachlorocyclohexane I-Chemical 1
( O 0
lindane B-Chemical 1
) O 0
on O 0
pharmacologically O 0
- O 0
induced O 0
seizures B-Disease 1
. O 0

Gamma B-Chemical 1
- I-Chemical 1
hexachlorocyclohexane I-Chemical 1
( O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
) O 0
, O 0
the O 0
active O 0
ingredient O 0
of O 0
the O 0
insecticide O 0
lindane B-Chemical 1
, O 0
has O 0
been O 0
shown O 0
to O 0
decrease O 0
seizure B-Disease 1
threshold O 0
to O 0
pentylenetrazol O 0
( O 0
PTZ B-Chemical 1
) O 0
3 O 0
h O 0
after O 0
exposure O 0
to O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
and O 0
conversely O 0
increase O 0
threshold O 0
to O 0
PTZ B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
24 O 0
h O 0
after O 0
exposure O 0
to O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
( O 0
Vohland O 0
et O 0
al O 0
. O 0
1981 O 0
) O 0
. O 0

In O 0
this O 0
study O 0
, O 0
the O 0
severity O 0
of O 0
response O 0
to O 0
other O 0
seizure B-Disease 1
- O 0
inducing O 0
agents O 0
was O 0
tested O 0
in O 0
mice O 0
1 O 0
and O 0
24 O 0
h O 0
after O 0
intraperitoneal O 0
administration O 0
of O 0
80 O 0
mg O 0
/ O 0
kg O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
. O 0

One O 0
hour O 0
after O 0
the O 0
administration O 0
of O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
, O 0
the O 0
activity O 0
of O 0
seizure B-Disease 1
- O 0
inducing O 0
agents O 0
was O 0
increased O 0
, O 0
regardless O 0
of O 0
their O 0
mechanism O 0
, O 0
while O 0
24 O 0
h O 0
after O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
a O 0
differential O 0
response O 0
was O 0
observed O 0
. O 0

Seizure B-Disease 1
activity O 0
due O 0
to O 0
PTZ B-Chemical 1
and O 0
picrotoxin B-Chemical 1
( O 0
PTX B-Chemical 1
) O 0
was O 0
significantly O 0
decreased O 0
; O 0
however O 0
, O 0
seizure B-Disease 1
activity O 0
due O 0
to O 0
3 B-Chemical 1
- I-Chemical 1
mercaptopropionic I-Chemical 1
acid I-Chemical 1
( O 0
MPA B-Chemical 1
) O 0
, O 0
bicuculline B-Chemical 1
( O 0
BCC B-Chemical 1
) O 0
, O 0
methyl B-Chemical 1
6 I-Chemical 1
, I-Chemical 1
7 I-Chemical 1
- I-Chemical 1
dimethoxy I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
ethyl I-Chemical 1
- I-Chemical 1
B I-Chemical 1
- I-Chemical 1
carboline I-Chemical 1
- I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
carboxylate I-Chemical 1
( O 0
DMCM B-Chemical 1
) O 0
, O 0
or O 0
strychnine B-Chemical 1
( O 0
STR B-Chemical 1
) O 0
was O 0
not O 0
different O 0
from O 0
control O 0
. O 0

In O 0
vitro O 0
, O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
, O 0
pentylenetetrazol B-Chemical 1
and O 0
picrotoxin B-Chemical 1
were O 0
shown O 0
to O 0
inhibit O 0
3H B-Chemical 1
- I-Chemical 1
TBOB I-Chemical 1
binding O 0
in O 0
mouse O 0
whole O 0
brain O 0
, O 0
with O 0
IC50 O 0
values O 0
of O 0
4 O 0
. O 0
6 O 0
, O 0
404 O 0
and O 0
9 O 0
. O 0
4 O 0
microM O 0
, O 0
respectively O 0
. O 0

MPA B-Chemical 1
, O 0
BCC B-Chemical 1
, O 0
DMCM B-Chemical 1
, O 0
and O 0
STR B-Chemical 1
showed O 0
no O 0
inhibition O 0
of O 0
3H B-Chemical 1
- I-Chemical 1
TBOB I-Chemical 1
( O 0
t B-Chemical 1
- I-Chemical 1
butyl I-Chemical 1
bicyclo I-Chemical 1
- I-Chemical 1
orthobenzoate I-Chemical 1
) O 0
binding O 0
at O 0
concentrations O 0
of O 0
100 O 0
micron O 0
. O 0

The O 0
pharmacological O 0
challenge O 0
data O 0
suggest O 0
that O 0
tolerance O 0
may O 0
occur O 0
to O 0
seizure B-Disease 1
activity O 0
induced O 0
by O 0
PTZ B-Chemical 1
and O 0
PTX B-Chemical 1
24 O 0
h O 0
after O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
, O 0
since O 0
the O 0
response O 0
to O 0
only O 0
these O 0
two O 0
seizure B-Disease 1
- O 0
inducing O 0
agents O 0
is O 0
decreased O 0
. O 0

The O 0
in O 0
vitro O 0
data O 0
suggest O 0
that O 0
the O 0
site O 0
responsible O 0
for O 0
the O 0
decrease O 0
in O 0
seizure B-Disease 1
activity O 0
24 O 0
h O 0
after O 0
gamma B-Chemical 1
- I-Chemical 1
HCH I-Chemical 1
may O 0
be O 0
the O 0
GABA B-Chemical 1
- O 0
A O 0
receptor O 0
- O 0
linked O 0
chloride O 0
channel O 0
. O 0

Tolerance O 0
and O 0
antiviral O 0
effect O 0
of O 0
ribavirin B-Chemical 1
in O 0
patients O 0
with O 0
Argentine B-Disease 1
hemorrhagic I-Disease 1
fever I-Disease 1
. O 0

Tolerance O 0
and O 0
antiviral O 0
effect O 0
of O 0
ribavirin B-Chemical 1
was O 0
studied O 0
in O 0
6 O 0
patients O 0
with O 0
Argentine B-Disease 1
hemorrhagic I-Disease 1
fever I-Disease 1
( O 0
AHF B-Disease 1
) O 0
of O 0
more O 0
than O 0
8 O 0
days O 0
of O 0
evolution O 0
. O 0

Administration O 0
of O 0
ribavirin B-Chemical 1
resulted O 0
in O 0
a O 0
neutralization O 0
of O 0
viremia B-Disease 1
and O 0
a O 0
drop O 0
of O 0
endogenous O 0
interferon O 0
titers O 0
. O 0

The O 0
average O 0
time O 0
of O 0
death B-Disease 1
was O 0
delayed O 0
. O 0

A O 0
reversible O 0
anemia B-Disease 1
was O 0
the O 0
only O 0
adverse O 0
effect O 0
observed O 0
. O 0

From O 0
these O 0
results O 0
, O 0
we O 0
conclude O 0
that O 0
ribavirin B-Chemical 1
has O 0
an O 0
antiviral O 0
effect O 0
in O 0
advanced O 0
cases O 0
of O 0
AHF B-Disease 1
, O 0
and O 0
that O 0
anemia B-Disease 1
, O 0
the O 0
only O 0
secondary O 0
reaction O 0
observed O 0
, O 0
can O 0
be O 0
easily O 0
managed O 0
. O 0

The O 0
possible O 0
beneficial O 0
effect O 0
of O 0
ribavirin B-Chemical 1
during O 0
the O 0
initial O 0
days O 0
of O 0
AHF B-Disease 1
is O 0
discussed O 0
. O 0

Is O 0
the O 0
treatment O 0
of O 0
scabies B-Disease 1
hazardous O 0
? O 0

Treatment O 0
for O 0
scabies B-Disease 1
is O 0
usually O 0
initiated O 0
by O 0
general O 0
practitioners O 0
; O 0
most O 0
consider O 0
lindane B-Chemical 1
( O 0
gamma B-Chemical 1
benzene I-Chemical 1
hexachloride I-Chemical 1
) O 0
the O 0
treatment O 0
of O 0
choice O 0
. O 0

Lindane B-Chemical 1
is O 0
also O 0
widely O 0
used O 0
as O 0
an O 0
agricultural O 0
and O 0
industrial O 0
pesticide O 0
, O 0
and O 0
as O 0
a O 0
result O 0
the O 0
toxic O 0
profile O 0
of O 0
this O 0
insecticide O 0
is O 0
well O 0
understood O 0
. O 0

Evidence O 0
is O 0
accumulating O 0
that O 0
lindane B-Chemical 1
can O 0
be O 0
toxic B-Disease 1
to I-Disease 1
the I-Disease 1
central I-Disease 1
nervous I-Disease 1
system I-Disease 1
and O 0
may O 0
be O 0
associated O 0
with O 0
aplastic B-Disease 1
anaemia I-Disease 1
. O 0

Preparations O 0
containing O 0
lindane B-Chemical 1
continue O 0
to O 0
be O 0
sold O 0
over O 0
the O 0
counter O 0
and O 0
may O 0
represent O 0
a O 0
hazard O 0
to O 0
poorly O 0
informed O 0
patients O 0
. O 0

This O 0
literature O 0
review O 0
suggests O 0
that O 0
general O 0
practitioners O 0
should O 0
prescribe O 0
scabicides O 0
with O 0
increased O 0
caution O 0
for O 0
certain O 0
at O 0
- O 0
risk O 0
groups O 0
, O 0
and O 0
give O 0
adequate O 0
warnings O 0
regarding O 0
potential O 0
toxicity B-Disease 1
. O 0

Mouse O 0
strain O 0
- O 0
dependent O 0
effect O 0
of O 0
amantadine B-Chemical 1
on O 0
motility O 0
and O 0
brain O 0
biogenic O 0
amines B-Chemical 1
. O 0

The O 0
effect O 0
of O 0
amantadine B-Chemical 1
hydrochloride I-Chemical 1
, O 0
injected O 0
i O 0
. O 0
p O 0
. O 0
in O 0
6 O 0
increments O 0
of O 0
100 O 0
mg O 0
/ O 0
kg O 0
each O 0
over O 0
30 O 0
hr O 0
, O 0
on O 0
mouse O 0
motility O 0
and O 0
whole O 0
brain O 0
content O 0
of O 0
selected O 0
biogenic O 0
amines B-Chemical 1
and O 0
major O 0
metabolites O 0
was O 0
studied O 0
in O 0
4 O 0
strains O 0
of O 0
mice O 0
. O 0

These O 0
were O 0
the O 0
albino O 0
Sprague O 0
- O 0
Dawley O 0
ICR O 0
and O 0
BALB O 0
/ O 0
C O 0
, O 0
the O 0
black O 0
C57BL O 0
/ O 0
6 O 0
and O 0
the O 0
brown O 0
CDF O 0
- O 0
I O 0
mouse O 0
strains O 0
. O 0

Amantadine B-Chemical 1
treatment O 0
produced O 0
a O 0
biphasic O 0
effect O 0
on O 0
mouse O 0
motility O 0
. O 0

The O 0
initial O 0
dose O 0
of O 0
amantadine B-Chemical 1
depressed B-Disease 1
locomotor O 0
activity O 0
in O 0
all O 0
mouse O 0
strains O 0
studied O 0
with O 0
the O 0
BALB O 0
/ O 0
C O 0
mice O 0
being O 0
the O 0
most O 0
sensitive O 0
. O 0

Subsequent O 0
amantadine B-Chemical 1
treatments O 0
produced O 0
enhancement O 0
of O 0
motility O 0
from O 0
corresponding O 0
control O 0
in O 0
all O 0
mouse O 0
strains O 0
with O 0
the O 0
BALB O 0
/ O 0
C O 0
mice O 0
being O 0
the O 0
least O 0
sensitive O 0
. O 0

The O 0
locomotor O 0
activity O 0
was O 0
decreased O 0
from O 0
corresponding O 0
controls O 0
in O 0
all O 0
strains O 0
studied O 0
, O 0
except O 0
for O 0
the O 0
ICR O 0
mice O 0
, O 0
during O 0
an O 0
overnight O 0
drug O 0
- O 0
free O 0
period O 0
following O 0
the O 0
fourth O 0
amantadine B-Chemical 1
treatment O 0
. O 0

Readministration O 0
of O 0
amantadine B-Chemical 1
, O 0
after O 0
a O 0
drug O 0
- O 0
free O 0
overnight O 0
period O 0
, O 0
increased O 0
motility O 0
from O 0
respective O 0
saline O 0
control O 0
in O 0
all O 0
strains O 0
with O 0
exception O 0
of O 0
the O 0
BALB O 0
/ O 0
C O 0
mice O 0
where O 0
suppression B-Disease 1
of I-Disease 1
motility I-Disease 1
occurred O 0
. O 0

Treatment O 0
with O 0
amantadine B-Chemical 1
did O 0
not O 0
alter O 0
whole O 0
brain O 0
dopamine B-Chemical 1
levels O 0
but O 0
decreased O 0
the O 0
amounts O 0
of O 0
3 B-Chemical 1
, I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
dihydroxyphenylacetic I-Chemical 1
acid I-Chemical 1
in O 0
the O 0
BALB O 0
/ O 0
C O 0
mice O 0
compared O 0
to O 0
saline O 0
control O 0
. O 0

Conversely O 0
, O 0
brain O 0
normetanephrine B-Chemical 1
concentration O 0
was O 0
increased O 0
from O 0
saline O 0
control O 0
by O 0
amantadine B-Chemical 1
in O 0
the O 0
BALB O 0
/ O 0
C O 0
mice O 0
. O 0

The O 0
results O 0
suggest O 0
a O 0
strain O 0
- O 0
dependent O 0
effect O 0
of O 0
amantadine B-Chemical 1
on O 0
motility O 0
and O 0
indicate O 0
a O 0
differential O 0
response O 0
to O 0
the O 0
acute O 0
and O 0
multiple O 0
dose O 0
regimens O 0
used O 0
. O 0

The O 0
BALB O 0
/ O 0
C O 0
mouse O 0
was O 0
the O 0
most O 0
sensitive O 0
strain O 0
and O 0
could O 0
serve O 0
as O 0
the O 0
strain O 0
of O 0
choice O 0
for O 0
evaluating O 0
the O 0
side O 0
effects O 0
of O 0
amantadine B-Chemical 1
. O 0

The O 0
biochemical O 0
results O 0
of O 0
brain O 0
biogenic O 0
amines B-Chemical 1
of O 0
BALB O 0
/ O 0
C O 0
mouse O 0
strain O 0
suggest O 0
a O 0
probable O 0
decrease O 0
of O 0
catecholamine B-Chemical 1
turnover O 0
rate O 0
and O 0
/ O 0
or O 0
metabolism O 0
by O 0
monoamine O 0
oxidase O 0
and O 0
a O 0
resulting O 0
increase O 0
in O 0
O O 0
- O 0
methylation O 0
of O 0
norepinephrine B-Chemical 1
which O 0
may O 0
account O 0
for O 0
a O 0
behavioral B-Disease 1
depression I-Disease 1
caused O 0
by O 0
amantadine B-Chemical 1
in O 0
the O 0
BALB O 0
/ O 0
C O 0
mice O 0
. O 0

Chloroacetaldehyde B-Chemical 1
and O 0
its O 0
contribution O 0
to O 0
urotoxicity O 0
during O 0
treatment O 0
with O 0
cyclophosphamide B-Chemical 1
or O 0
ifosfamide B-Chemical 1
. O 0

An O 0
experimental O 0
study O 0
/ O 0
short O 0
communication O 0
. O 0

Based O 0
on O 0
clinical O 0
data O 0
, O 0
indicating O 0
that O 0
chloroacetaldehyde B-Chemical 1
( O 0
CAA B-Chemical 1
) O 0
is O 0
an O 0
important O 0
metabolite O 0
of O 0
oxazaphosphorine O 0
cytostatics O 0
, O 0
an O 0
experimental O 0
study O 0
was O 0
carried O 0
out O 0
in O 0
order O 0
to O 0
elucidate O 0
the O 0
role O 0
of O 0
CAA B-Chemical 1
in O 0
the O 0
development O 0
of O 0
hemorrhagic B-Disease 1
cystitis I-Disease 1
. O 0

The O 0
data O 0
demonstrate O 0
that O 0
CAA B-Chemical 1
after O 0
i O 0
. O 0
v O 0
. O 0
administration O 0
does O 0
not O 0
contribute O 0
to O 0
bladder B-Disease 1
damage I-Disease 1
. O 0

When O 0
instilled O 0
directly O 0
into O 0
the O 0
bladder O 0
, O 0
CAA B-Chemical 1
exerts O 0
urotoxic O 0
effects O 0
, O 0
it O 0
is O 0
, O 0
however O 0
, O 0
susceptible O 0
to O 0
detoxification O 0
with O 0
mesna B-Chemical 1
. O 0

Source O 0
of O 0
pain B-Disease 1
and O 0
primitive O 0
dysfunction O 0
in O 0
migraine B-Disease 1
: O 0
an O 0
identical O 0
site O 0
? O 0

Twenty O 0
common O 0
migraine B-Disease 1
patients O 0
received O 0
a O 0
one O 0
sided O 0
frontotemporal O 0
application O 0
of O 0
nitroglycerin B-Chemical 1
( O 0
10 O 0
patients O 0
) O 0
or O 0
placebo O 0
ointment O 0
( O 0
10 O 0
patients O 0
) O 0
in O 0
a O 0
double O 0
blind O 0
study O 0
. O 0

Early O 0
onset O 0
migraine B-Disease 1
attacks O 0
were O 0
induced O 0
by O 0
nitroglycerin B-Chemical 1
in O 0
seven O 0
out O 0
of O 0
10 O 0
patients O 0
versus O 0
no O 0
patient O 0
in O 0
the O 0
placebo O 0
group O 0
. O 0

Subsequently O 0
20 O 0
migraine B-Disease 1
patients O 0
, O 0
who O 0
developed O 0
an O 0
early O 0
onset O 0
attack O 0
with O 0
frontotemporal O 0
nitroglycerin B-Chemical 1
, O 0
received O 0
the O 0
drug O 0
in O 0
a O 0
second O 0
induction O 0
test O 0
at O 0
other O 0
body O 0
areas O 0
. O 0

No O 0
early O 0
onset O 0
migraine B-Disease 1
was O 0
observed O 0
. O 0

Thus O 0
the O 0
migraine B-Disease 1
- O 0
inducing O 0
effect O 0
of O 0
nitroglycerin B-Chemical 1
seems O 0
to O 0
depend O 0
on O 0
direct O 0
stimulation O 0
of O 0
the O 0
habitual O 0
site O 0
of O 0
pain B-Disease 1
, O 0
suggesting O 0
that O 0
the O 0
frontotemporal O 0
region O 0
is O 0
of O 0
crucial O 0
importance O 0
in O 0
the O 0
development O 0
of O 0
a O 0
migraine B-Disease 1
crisis O 0
. O 0

This O 0
is O 0
not O 0
consistent O 0
with O 0
a O 0
CNS O 0
origin O 0
of O 0
migraine B-Disease 1
attack O 0
. O 0

Hypersensitivity B-Disease 1
to O 0
carbamazepine B-Chemical 1
presenting O 0
with O 0
a O 0
leukemoid B-Disease 1
reaction I-Disease 1
, O 0
eosinophilia B-Disease 1
, O 0
erythroderma B-Disease 1
, O 0
and O 0
renal B-Disease 1
failure I-Disease 1
. O 0

We O 0
report O 0
a O 0
patient O 0
in O 0
whom O 0
hypersensitivity B-Disease 1
to O 0
carbamazepine B-Chemical 1
presented O 0
with O 0
generalized O 0
erythroderma B-Disease 1
, O 0
a O 0
severe O 0
leukemoid B-Disease 1
reaction I-Disease 1
, O 0
eosinophilia B-Disease 1
, O 0
hyponatremia B-Disease 1
, O 0
and O 0
renal B-Disease 1
failure I-Disease 1
. O 0

This O 0
is O 0
the O 0
first O 0
report O 0
of O 0
such O 0
an O 0
unusual O 0
reaction O 0
to O 0
carbamazepine B-Chemical 1
. O 0

Fluoxetine B-Chemical 1
- O 0
induced O 0
akathisia B-Disease 1
: O 0
clinical O 0
and O 0
theoretical O 0
implications O 0
. O 0

Five O 0
patients O 0
receiving O 0
fluoxetine B-Chemical 1
for O 0
the O 0
treatment O 0
of O 0
obsessive B-Disease 1
compulsive I-Disease 1
disorder I-Disease 1
or O 0
major B-Disease 1
depression I-Disease 1
developed O 0
akathisia B-Disease 1
. O 0

The O 0
typical O 0
fluoxetine B-Chemical 1
- O 0
induced O 0
symptoms O 0
of O 0
restlessness O 0
, O 0
constant O 0
pacing O 0
, O 0
purposeless O 0
movements O 0
of O 0
the O 0
feet O 0
and O 0
legs O 0
, O 0
and O 0
marked O 0
anxiety B-Disease 1
were O 0
indistinguishable O 0
from O 0
those O 0
of O 0
neuroleptic O 0
- O 0
induced O 0
akathisia B-Disease 1
. O 0

Three O 0
patients O 0
who O 0
had O 0
experienced O 0
neuroleptic O 0
- O 0
induced O 0
akathisia B-Disease 1
in O 0
the O 0
past O 0
reported O 0
that O 0
the O 0
symptoms O 0
of O 0
fluoxetine B-Chemical 1
- O 0
induced O 0
akathisia B-Disease 1
were O 0
identical O 0
, O 0
although O 0
somewhat O 0
milder O 0
. O 0

Akathisia B-Disease 1
appeared O 0
to O 0
be O 0
a O 0
common O 0
side O 0
effect O 0
of O 0
fluoxetine B-Chemical 1
and O 0
generally O 0
responded O 0
well O 0
to O 0
treatment O 0
with O 0
the O 0
beta O 0
- O 0
adrenergic O 0
antagonist O 0
propranolol B-Chemical 1
, O 0
dose O 0
reduction O 0
, O 0
or O 0
both O 0
. O 0

The O 0
authors O 0
suggest O 0
that O 0
fluoxetine B-Chemical 1
- O 0
induced O 0
akathisia B-Disease 1
may O 0
be O 0
caused O 0
by O 0
serotonergically O 0
mediated O 0
inhibition O 0
of O 0
dopaminergic O 0
neurotransmission O 0
and O 0
that O 0
the O 0
pathophysiology O 0
of O 0
fluoxetine B-Chemical 1
- O 0
induced O 0
akathisia B-Disease 1
and O 0
tricyclic O 0
antidepressant B-Chemical 1
- O 0
induced O 0
" O 0
jitteriness O 0
" O 0
may O 0
be O 0
identical O 0
. O 0

Effect O 0
of O 0
converting O 0
enzyme O 0
inhibition O 0
on O 0
the O 0
course O 0
of O 0
adriamycin B-Chemical 1
- O 0
induced O 0
nephropathy B-Disease 1
. O 0

The O 0
effect O 0
of O 0
the O 0
converting O 0
enzyme O 0
inhibitor O 0
( O 0
CEI O 0
) O 0
enalapril B-Chemical 1
was O 0
assessed O 0
in O 0
Munich O 0
- O 0
Wistar O 0
rats O 0
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adriamycin B-Chemical 1
nephrosis B-Disease 1
. O 0

Rats O 0
were O 0
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single O 0
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adriamycin B-Chemical 1
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divided O 0
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matched O 0
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albuminuria B-Disease 1
, O 0
blood O 0
pressure O 0
, O 0
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plasma O 0
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concentration O 0
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Groups O 0
1 O 0
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3 O 0
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groups O 0
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4 O 0
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enalapril B-Chemical 1
. O 0

Groups O 0
1 O 0
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underwent O 0
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10 O 0
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These O 0
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enalapril B-Chemical 1
reduced O 0
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pressure O 0
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101 O 0
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. O 0
124 O 0
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54 O 0
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61 O 0
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albuminuria B-Disease 1
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570 O 0
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1 O 0
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Groups O 0
3 O 0
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assess O 0
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in O 0
adriamycin B-Chemical 1
nephrosis B-Disease 1
. O 0

Chronic O 0
enalapril B-Chemical 1
treatment O 0
reduced O 0
blood O 0
pressure O 0
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albuminuria B-Disease 1
in O 0
group O 0
4 O 0
. O 0

Untreated O 0
group O 0
3 O 0
rats O 0
exhibited O 0
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progressive O 0
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GFR O 0
( O 0
0 O 0
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35 O 0
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0 O 0
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0 O 0
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27 O 0
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0 O 0
. O 0
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. O 0

Enalapril B-Chemical 1
treatment O 0
blunted O 0
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did O 0
not O 0
prevent O 0
reduction O 0
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GFR O 0
in O 0
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4 O 0
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0 O 0
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0 O 0
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3 O 0
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Reduction O 0
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ABSTRACT O 0
TRUNCATED O 0
AT O 0
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WORDS O 0
) O 0

Clotiazepam B-Chemical 1
- O 0
induced O 0
acute O 0
hepatitis B-Disease 1
. O 0

We O 0
report O 0
the O 0
case O 0
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hepatitis B-Disease 1
with O 0
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hepatocellular I-Disease 1
necrosis I-Disease 1
, O 0
7 O 0
months O 0
after O 0
the O 0
onset O 0
of O 0
administration O 0
of O 0
clotiazepam B-Chemical 1
, O 0
a O 0
thienodiazepine B-Chemical 1
derivative O 0
. O 0

Clotiazepam B-Chemical 1
withdrawal O 0
was O 0
followed O 0
by O 0
prompt O 0
recovery O 0
. O 0

The O 0
administration O 0
of O 0
several O 0
benzodiazepines B-Chemical 1
, O 0
chemically O 0
related O 0
to O 0
clotiazepam B-Chemical 1
, O 0
did O 0
not O 0
interfere O 0
with O 0
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did O 0
not O 0
induce O 0
any O 0
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hepatitis B-Disease 1
. O 0

This O 0
observation O 0
shows O 0
that O 0
clotiazepam B-Chemical 1
can O 0
induce O 0
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hepatitis B-Disease 1
and O 0
suggests O 0
that O 0
there O 0
is O 0
no O 0
cross O 0
hepatotoxicity B-Disease 1
between O 0
clotiazepam B-Chemical 1
and O 0
several O 0
benzodiazepines B-Chemical 1
. O 0

5 B-Chemical 1
- I-Chemical 1
azacytidine I-Chemical 1
potentiates O 0
initiation B-Disease 1
induced I-Disease 1
by I-Disease 1
carcinogens I-Disease 1
in O 0
rat O 0
liver O 0
. O 0

To O 0
test O 0
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role O 0
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initiation B-Disease 1
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, O 0
5 B-Chemical 1
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azacytidine I-Chemical 1
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5 B-Chemical 1
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AzC I-Chemical 1
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benzo B-Chemical 1
[ I-Chemical 1
a I-Chemical 1
] I-Chemical 1
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pyrene I-Chemical 1
( O 0
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mg O 0
/ O 0
kg O 0
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N B-Chemical 1
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methyl I-Chemical 1
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N I-Chemical 1
- I-Chemical 1
nitrosourea I-Chemical 1
( O 0
60 O 0
mg O 0
/ O 0
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1 B-Chemical 1
, I-Chemical 1
2 I-Chemical 1
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dimethylhydrazine I-Chemical 1
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1 B-Chemical 1
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2 I-Chemical 1
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DMH I-Chemical 1
) O 0
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The O 0
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2 B-Chemical 1
- I-Chemical 1
acetylaminofluorene I-Chemical 1
coupled O 0
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CCl4 B-Chemical 1
. O 0

The O 0
results O 0
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5 B-Chemical 1
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5 B-Chemical 1
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Administration O 0
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[ B-Chemical 1
3H I-Chemical 1
] I-Chemical 1
- I-Chemical 1
5 I-Chemical 1
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during O 0
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by O 0
1 B-Chemical 1
, I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
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further O 0
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0 O 0
. O 0
019 O 0
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cytosine B-Chemical 1
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DNA O 0
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5 B-Chemical 1
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In O 0
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5 B-Chemical 1
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given O 0
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The O 0
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se O 0
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. O 0

Perhaps O 0
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. O 0

Antihypertensive O 0
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and O 0
depression B-Disease 1
: O 0
a O 0
reappraisal O 0
. O 0

Eighty O 0
- O 0
nine O 0
new O 0
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out O 0
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46 O 0
new O 0
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non O 0
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hypertensive B-Disease 1
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physically O 0
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out O 0
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at O 0
regular O 0
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one O 0
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. O 0

The O 0
results O 0
showed O 0
a O 0
high O 0
prevalence O 0
of O 0
depression B-Disease 1
in O 0
both O 0
groups O 0
of O 0
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, O 0
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no O 0
preponderance O 0
in O 0
the O 0
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group O 0
. O 0

Hypertensive B-Disease 1
patients O 0
with O 0
psychiatric B-Disease 1
histories O 0
had O 0
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than O 0
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. O 0

This O 0
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number O 0
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occurring O 0
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methyl B-Chemical 1
dopa I-Chemical 1
treated O 0
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with O 0
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histories O 0
. O 0

Chronic B-Disease 1
active I-Disease 1
hepatitis I-Disease 1
associated O 0
with O 0
diclofenac B-Chemical 1
sodium I-Chemical 1
therapy O 0
. O 0

Diclofenac B-Chemical 1
sodium I-Chemical 1
( O 0
Voltarol B-Chemical 1
, O 0
Geigy O 0
Pharmaceuticals O 0
) O 0
is O 0
a O 0
non O 0
- O 0
steroidal O 0
anti O 0
- O 0
inflammatory O 0
derivative O 0
of O 0
phenylacetic B-Chemical 1
acid I-Chemical 1
. O 0

Although O 0
generally O 0
well O 0
- O 0
tolerated O 0
, O 0
asymptomatic O 0
abnormalities B-Disease 1
of I-Disease 1
liver I-Disease 1
function I-Disease 1
have O 0
been O 0
recorded O 0
and O 0
, O 0
less O 0
commonly O 0
, O 0
severe O 0
hepatitis B-Disease 1
induced O 0
by O 0
diclofenac B-Chemical 1
. O 0

The O 0
patient O 0
described O 0
developed O 0
chronic B-Disease 1
active I-Disease 1
hepatitis I-Disease 1
after O 0
six O 0
months O 0
therapy O 0
with O 0
diclofenac B-Chemical 1
sodium I-Chemical 1
which O 0
progressed O 0
despite O 0
the O 0
withdrawal O 0
of O 0
the O 0
drug O 0
, O 0
a O 0
finding O 0
not O 0
previously O 0
reported O 0
. O 0

Arterial O 0
hypertension B-Disease 1
as O 0
a O 0
complication O 0
of O 0
prolonged O 0
ketoconazole B-Chemical 1
treatment O 0
. O 0

Two O 0
of O 0
14 O 0
patients O 0
with O 0
Cushing B-Disease 1
' I-Disease 1
s I-Disease 1
syndrome I-Disease 1
treated O 0
on O 0
a O 0
long O 0
- O 0
term O 0
basis O 0
with O 0
ketoconazole B-Chemical 1
developed O 0
sustained O 0
hypertension B-Disease 1
. O 0

In O 0
both O 0
cases O 0
normal O 0
plasma O 0
and O 0
urinary O 0
free O 0
cortisol B-Chemical 1
levels O 0
had O 0
been O 0
achieved O 0
following O 0
ketoconazole B-Chemical 1
therapy O 0
, O 0
yet O 0
continuous O 0
blood O 0
pressure O 0
monitoring O 0
demonstrated O 0
hypertension B-Disease 1
31 O 0
( O 0
patient O 0
1 O 0
) O 0
and O 0
52 O 0
weeks O 0
( O 0
patient O 0
2 O 0
) O 0
after O 0
treatment O 0
. O 0

In O 0
patient O 0
1 O 0
, O 0
plasma O 0
levels O 0
of O 0
deoxycorticosterone B-Chemical 1
and O 0
11 B-Chemical 1
- I-Chemical 1
deoxycortisol I-Chemical 1
were O 0
elevated O 0
. O 0

In O 0
patient O 0
2 O 0
, O 0
in O 0
addition O 0
to O 0
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increase O 0
in O 0
both O 0
deoxycorticosterone B-Chemical 1
and O 0
11 B-Chemical 1
- I-Chemical 1
deoxycortisol I-Chemical 1
levels O 0
, O 0
plasma O 0
aldosterone B-Chemical 1
values O 0
were O 0
raised O 0
, O 0
with O 0
a O 0
concomitant O 0
suppression O 0
of O 0
renin O 0
levels O 0
. O 0

Our O 0
findings O 0
show O 0
that O 0
long O 0
- O 0
term O 0
treatment O 0
with O 0
high O 0
doses O 0
of O 0
ketoconazole B-Chemical 1
may O 0
induce O 0
enzyme O 0
blockade O 0
leading O 0
to O 0
mineralocorticoid O 0
- O 0
related O 0
hypertension B-Disease 1
. O 0

Effects O 0
of O 0
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of O 0
angiotensin B-Chemical 1
converting O 0
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( O 0
Captopril B-Chemical 1
) O 0
on O 0
pulmonary B-Disease 1
and I-Disease 1
renal I-Disease 1
insufficiency I-Disease 1
due O 0
to O 0
intravascular B-Disease 1
coagulation I-Disease 1
in O 0
the O 0
rat O 0
. O 0

Induction O 0
of O 0
intravascular B-Disease 1
coagulation I-Disease 1
and O 0
inhibition O 0
of O 0
fibrinolysis O 0
by O 0
injection O 0
of O 0
thrombin O 0
and O 0
tranexamic B-Chemical 1
acid I-Chemical 1
( O 0
AMCA B-Chemical 1
) O 0
in O 0
the O 0
rat O 0
gives O 0
rise O 0
to O 0
pulmonary B-Disease 1
and I-Disease 1
renal I-Disease 1
insufficiency I-Disease 1
resembling O 0
that O 0
occurring O 0
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or O 0
sepsis B-Disease 1
in O 0
man O 0
. O 0

Injection O 0
of O 0
Captopril B-Chemical 1
( O 0
1 O 0
mg O 0
/ O 0
kg O 0
) O 0
, O 0
an O 0
inhibitor O 0
of O 0
angiotensin B-Chemical 1
converting O 0
enzyme O 0
( O 0
ACE O 0
) O 0
, O 0
reduced O 0
both O 0
pulmonary B-Disease 1
and I-Disease 1
renal I-Disease 1
insufficiency I-Disease 1
in O 0
this O 0
rat O 0
model O 0
. O 0

The O 0
lung O 0
weights O 0
were O 0
lower O 0
and O 0
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was O 0
improved O 0
in O 0
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given O 0
this O 0
enzyme O 0
- O 0
blocking O 0
agent O 0
. O 0

The O 0
contents O 0
of O 0
albumin O 0
in O 0
the O 0
lungs O 0
were O 0
not O 0
changed O 0
, O 0
indicating O 0
that O 0
Captopril B-Chemical 1
did O 0
not O 0
influence O 0
the O 0
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of O 0
protein O 0
. O 0

Renal B-Disease 1
damage I-Disease 1
as O 0
reflected O 0
by O 0
an O 0
increase O 0
in O 0
serum O 0
urea B-Chemical 1
and O 0
in O 0
kidney O 0
weight O 0
was O 0
prevented O 0
by O 0
Captopril B-Chemical 1
. O 0

The O 0
amount O 0
of O 0
fibrin O 0
in O 0
the O 0
kidneys O 0
was O 0
also O 0
considerably O 0
lower O 0
than O 0
in O 0
animals O 0
which O 0
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and O 0
AMCA B-Chemical 1
alone O 0
. O 0

It O 0
is O 0
suggested O 0
that O 0
the O 0
effects O 0
of O 0
Captopril B-Chemical 1
on O 0
the O 0
lungs O 0
may O 0
be O 0
attributable O 0
to O 0
a O 0
vasodilatory O 0
effect O 0
due O 0
to O 0
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reduction O 0
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the O 0
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level O 0
of O 0
Angiotension B-Chemical 1
II I-Chemical 1
and O 0
an O 0
increase O 0
in O 0
prostacyclin B-Chemical 1
( O 0
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to O 0
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increase O 0
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bradykinin B-Chemical 1
) O 0
. O 0

Captopril B-Chemical 1
may O 0
, O 0
by O 0
the O 0
same O 0
mechanism O 0
, O 0
reduce O 0
the O 0
increase O 0
in O 0
glomerular O 0
filtration O 0
that O 0
is O 0
known O 0
to O 0
occur O 0
after O 0
an O 0
injection O 0
of O 0
thrombin O 0
, O 0
thereby O 0
diminishing O 0
the O 0
aggregation O 0
of O 0
fibrin O 0
monomers O 0
in O 0
the O 0
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, O 0
with O 0
the O 0
result O 0
that O 0
less O 0
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will O 0
be O 0
deposited O 0
and O 0
thus O 0
less O 0
kidney B-Disease 1
damage I-Disease 1
will O 0
be O 0
produced O 0
. O 0

Stroke B-Disease 1
associated O 0
with O 0
cocaine B-Chemical 1
use O 0
. O 0

We O 0
describe O 0
eight O 0
patients O 0
in O 0
whom O 0
cocaine B-Chemical 1
use O 0
was O 0
related O 0
to O 0
stroke B-Disease 1
and O 0
review O 0
39 O 0
cases O 0
from O 0
the O 0
literature O 0
. O 0

Among O 0
these O 0
47 O 0
patients O 0
the O 0
mean O 0
( O 0
+ O 0
/ O 0
- O 0
SD O 0
) O 0
age O 0
was O 0
32 O 0
. O 0
5 O 0
+ O 0
/ O 0
- O 0
12 O 0
. O 0
1 O 0
years O 0
; O 0
76 O 0
% O 0
( O 0
34 O 0
/ O 0
45 O 0
) O 0
were O 0
men O 0
. O 0

Stroke B-Disease 1
followed O 0
cocaine B-Chemical 1
use O 0
by O 0
inhalation O 0
, O 0
intranasal O 0
, O 0
intravenous O 0
, O 0
and O 0
intramuscular O 0
routes O 0
. O 0

Intracranial B-Disease 1
aneurysms I-Disease 1
or O 0
arteriovenous B-Disease 1
malformations I-Disease 1
were O 0
present O 0
in O 0
17 O 0
of O 0
32 O 0
patients O 0
studied O 0
angiographically O 0
or O 0
at O 0
autopsy O 0
; O 0
cerebral B-Disease 1
vasculitis I-Disease 1
was O 0
present O 0
in O 0
two O 0
patients O 0
. O 0

Cerebral B-Disease 1
infarction I-Disease 1
occurred O 0
in O 0
10 O 0
patients O 0
( O 0
22 O 0
% O 0
) O 0
, O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
in O 0
22 O 0
( O 0
49 O 0
% O 0
) O 0
, O 0
and O 0
subarachnoid B-Disease 1
hemorrhage I-Disease 1
in O 0
13 O 0
( O 0
29 O 0
% O 0
) O 0
. O 0

These O 0
data O 0
indicate O 0
that O 0
( O 0
1 O 0
) O 0
the O 0
apparent O 0
incidence O 0
of O 0
stroke B-Disease 1
related O 0
to O 0
cocaine B-Chemical 1
use O 0
is O 0
increasing O 0
; O 0
( O 0
2 O 0
) O 0
cocaine B-Chemical 1
- O 0
associated O 0
stroke B-Disease 1
occurs O 0
primarily O 0
in O 0
young O 0
adults O 0
; O 0
( O 0
3 O 0
) O 0
stroke B-Disease 1
may O 0
follow O 0
any O 0
route O 0
of O 0
cocaine B-Chemical 1
administration O 0
; O 0
( O 0
4 O 0
) O 0
stroke B-Disease 1
after O 0
cocaine B-Chemical 1
use O 0
is O 0
frequently O 0
associated O 0
with O 0
intracranial B-Disease 1
aneurysms I-Disease 1
and O 0
arteriovenous B-Disease 1
malformations I-Disease 1
; O 0
and O 0
( O 0
5 O 0
) O 0
in O 0
cocaine B-Chemical 1
- O 0
associated O 0
stroke B-Disease 1
, O 0
the O 0
frequency O 0
of O 0
intracranial B-Disease 1
hemorrhage I-Disease 1
exceeds O 0
that O 0
of O 0
cerebral B-Disease 1
infarction I-Disease 1
. O 0

A O 0
randomized O 0
comparison O 0
of O 0
labetalol B-Chemical 1
and O 0
nitroprusside B-Chemical 1
for O 0
induced O 0
hypotension B-Disease 1
. O 0

In O 0
a O 0
randomized O 0
study O 0
, O 0
labetalol B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
and O 0
nitroprusside B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
were O 0
compared O 0
in O 0
20 O 0
patients O 0
( O 0
10 O 0
in O 0
each O 0
group O 0
) O 0
scheduled O 0
for O 0
major O 0
orthopedic O 0
procedures O 0
. O 0

Each O 0
patient O 0
was O 0
subjected O 0
to O 0
an O 0
identical O 0
anesthetic O 0
protocol O 0
and O 0
similar O 0
drug O 0
- O 0
induced O 0
reductions B-Disease 1
in I-Disease 1
mean I-Disease 1
arterial I-Disease 1
blood I-Disease 1
pressure I-Disease 1
( O 0
BP O 0
) O 0
( O 0
50 O 0
to O 0
55 O 0
mmHg O 0
) O 0
. O 0

Nitroprusside O 0
infusion O 0
was O 0
associated O 0
with O 0
a O 0
significant O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
increase B-Disease 1
in I-Disease 1
heart I-Disease 1
rate I-Disease 1
and I-Disease 1
cardiac I-Disease 1
output I-Disease 1
; O 0
rebound O 0
hypertension B-Disease 1
was O 0
observed O 0
in O 0
three O 0
patients O 0
after O 0
discontinuation O 0
of O 0
nitroprusside B-Chemical 1
. O 0

Labetalol B-Chemical 1
administration O 0
was O 0
not O 0
associated O 0
with O 0
any O 0
of O 0
these O 0
findings O 0
. O 0

Arterial O 0
PO2 B-Chemical 1
decreased O 0
in O 0
both O 0
groups O 0
. O 0

It O 0
was O 0
concluded O 0
that O 0
labetalol B-Chemical 1
offers O 0
advantages O 0
over O 0
nitroprusside B-Chemical 1
. O 0

Sodium B-Chemical 1
status O 0
influences O 0
chronic O 0
amphotericin B-Chemical 1
B I-Chemical 1
nephrotoxicity B-Disease 1
in O 0
rats O 0
. O 0

The O 0
nephrotoxic B-Disease 1
potential O 0
of O 0
amphotericin B-Chemical 1
B I-Chemical 1
( O 0
5 O 0
mg O 0
/ O 0
kg O 0
per O 0
day O 0
intraperitoneally O 0
for O 0
3 O 0
weeks O 0
) O 0
has O 0
been O 0
investigated O 0
in O 0
salt O 0
- O 0
depleted O 0
, O 0
normal O 0
- O 0
salt O 0
, O 0
and O 0
salt O 0
- O 0
loaded O 0
rats O 0
. O 0

In O 0
salt O 0
- O 0
depleted O 0
rats O 0
, O 0
amphotericin B-Chemical 1
B I-Chemical 1
decreased O 0
creatinine B-Chemical 1
clearance O 0
linearly O 0
with O 0
time O 0
, O 0
with O 0
an O 0
85 O 0
% O 0
reduction O 0
by O 0
week O 0
3 O 0
. O 0

In O 0
contrast O 0
, O 0
in O 0
normal O 0
- O 0
salt O 0
rats O 0
creatinine B-Chemical 1
clearance O 0
was O 0
decreased O 0
but O 0
to O 0
a O 0
lesser O 0
extent O 0
at O 0
week O 0
2 O 0
and O 0
3 O 0
, O 0
and O 0
in O 0
salt O 0
- O 0
loaded O 0
rats O 0
creatinine B-Chemical 1
clearance O 0
did O 0
not O 0
change O 0
for O 0
2 O 0
weeks O 0
and O 0
was O 0
decreased O 0
by O 0
43 O 0
% O 0
at O 0
week O 0
3 O 0
. O 0

All O 0
rats O 0
in O 0
the O 0
sodium B-Chemical 1
- O 0
depleted O 0
group O 0
had O 0
histopathological O 0
evidence O 0
of O 0
patchy O 0
tubular O 0
cytoplasmic O 0
degeneration O 0
in O 0
tubules O 0
that O 0
was O 0
not O 0
observed O 0
in O 0
any O 0
normal O 0
- O 0
salt O 0
or O 0
salt O 0
- O 0
loaded O 0
rat O 0
. O 0

Concentrations O 0
of O 0
amphotericin B-Chemical 1
B I-Chemical 1
in O 0
plasma O 0
were O 0
not O 0
significantly O 0
different O 0
among O 0
the O 0
three O 0
groups O 0
at O 0
any O 0
time O 0
during O 0
the O 0
study O 0
. O 0

However O 0
, O 0
at O 0
the O 0
end O 0
of O 0
3 O 0
weeks O 0
, O 0
amphotericin B-Chemical 1
B I-Chemical 1
levels O 0
in O 0
the O 0
kidneys O 0
and O 0
liver O 0
were O 0
significantly O 0
higher O 0
in O 0
salt O 0
- O 0
depleted O 0
and O 0
normal O 0
- O 0
salt O 0
rats O 0
than O 0
those O 0
in O 0
salt O 0
- O 0
loaded O 0
rats O 0
, O 0
with O 0
plasma O 0
/ O 0
kidney O 0
ratios O 0
of O 0
21 O 0
, O 0
14 O 0
, O 0
and O 0
8 O 0
in O 0
salt O 0
- O 0
depleted O 0
, O 0
normal O 0
- O 0
salt O 0
, O 0
and O 0
salt O 0
- O 0
loaded O 0
rats O 0
, O 0
respectively O 0
. O 0

In O 0
conclusion O 0
, O 0
reductions O 0
in O 0
creatinine B-Chemical 1
clearance O 0
and O 0
renal O 0
amphotericin B-Chemical 1
B I-Chemical 1
accumulation O 0
after O 0
chronic O 0
amphotericin B-Chemical 1
B I-Chemical 1
administration O 0
were O 0
enhanced O 0
by O 0
salt O 0
depletion O 0
and O 0
attenuated O 0
by O 0
sodium B-Chemical 1
loading O 0
in O 0
rats O 0
. O 0

Flestolol B-Chemical 1
: O 0
an O 0
ultra O 0
- O 0
short O 0
- O 0
acting O 0
beta O 0
- O 0
adrenergic O 0
blocking O 0
agent O 0
. O 0

Flestolol B-Chemical 1
( O 0
ACC B-Chemical 1
- I-Chemical 1
9089 I-Chemical 1
) O 0
is O 0
a O 0
nonselective O 0
, O 0
competitive O 0
, O 0
ultra O 0
- O 0
short O 0
- O 0
acting O 0
beta O 0
- O 0
adrenergic O 0
blocking O 0
agent O 0
, O 0
without O 0
any O 0
intrinsic O 0
sympathomimetic O 0
activity O 0
. O 0

Flestolol B-Chemical 1
is O 0
metabolized O 0
by O 0
plasma O 0
esterases O 0
and O 0
has O 0
an O 0
elimination O 0
half O 0
- O 0
life O 0
of O 0
approximately O 0
6 O 0
. O 0
5 O 0
minutes O 0
. O 0

This O 0
agent O 0
was O 0
well O 0
tolerated O 0
in O 0
healthy O 0
volunteers O 0
at O 0
doses O 0
up O 0
to O 0
100 O 0
micrograms O 0
/ O 0
kg O 0
/ O 0
min O 0
. O 0

In O 0
long O 0
- O 0
term O 0
infusion O 0
studies O 0
, O 0
flestolol B-Chemical 1
was O 0
well O 0
tolerated O 0
at O 0
the O 0
effective O 0
beta O 0
- O 0
blocking O 0
dose O 0
( O 0
5 O 0
micrograms O 0
/ O 0
kg O 0
/ O 0
min O 0
) O 0
for O 0
up O 0
to O 0
seven O 0
days O 0
. O 0

Flestolol B-Chemical 1
blood O 0
concentrations O 0
increased O 0
linearly O 0
with O 0
increasing O 0
dose O 0
and O 0
good O 0
correlation O 0
exists O 0
between O 0
blood O 0
concentrations O 0
of O 0
flestolol B-Chemical 1
and O 0
beta O 0
- O 0
adrenergic O 0
blockade O 0
. O 0

Flestolol B-Chemical 1
produced O 0
a O 0
dose O 0
- O 0
dependent O 0
attenuation O 0
of O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
tachycardia B-Disease 1
. O 0

Electrophysiologic O 0
and O 0
hemodynamic O 0
effects O 0
of O 0
flestolol B-Chemical 1
are O 0
similar O 0
to O 0
those O 0
of O 0
other O 0
beta O 0
blockers O 0
. O 0

In O 0
contrast O 0
with O 0
other O 0
beta O 0
blockers O 0
, O 0
flestolol B-Chemical 1
- O 0
induced O 0
effects O 0
reverse O 0
rapidly O 0
( O 0
within O 0
30 O 0
minutes O 0
) O 0
following O 0
discontinuation O 0
because O 0
of O 0
its O 0
short O 0
half O 0
- O 0
life O 0
. O 0

Flestolol B-Chemical 1
effectively O 0
reduced O 0
heart O 0
rate O 0
in O 0
patients O 0
with O 0
supraventricular B-Disease 1
tachyarrhythmia I-Disease 1
. O 0

In O 0
patients O 0
with O 0
unstable B-Disease 1
angina I-Disease 1
, O 0
flestolol B-Chemical 1
infusion O 0
was O 0
found O 0
to O 0
be O 0
safe O 0
and O 0
effective O 0
in O 0
controlling O 0
chest B-Disease 1
pain I-Disease 1
. O 0

It O 0
is O 0
concluded O 0
that O 0
flestolol B-Chemical 1
is O 0
a O 0
potent O 0
, O 0
well O 0
- O 0
tolerated O 0
, O 0
ultra O 0
- O 0
short O 0
- O 0
acting O 0
beta O 0
- O 0
adrenergic O 0
blocking O 0
agent O 0
. O 0

Use O 0
of O 0
flestolol B-Chemical 1
in O 0
the O 0
critical O 0
care O 0
setting O 0
is O 0
currently O 0
undergoing O 0
investigation O 0
. O 0

Immunohistochemical O 0
, O 0
electron O 0
microscopic O 0
and O 0
morphometric O 0
studies O 0
of O 0
estrogen B-Chemical 1
- O 0
induced O 0
rat O 0
prolactinomas B-Disease 1
after O 0
bromocriptine B-Chemical 1
treatment O 0
. O 0

To O 0
clarify O 0
the O 0
effects O 0
of O 0
bromocriptine B-Chemical 1
on O 0
prolactinoma B-Disease 1
cells O 0
in O 0
vivo O 0
, O 0
immunohistochemical O 0
, O 0
ultrastructural O 0
and O 0
morphometrical O 0
analyses O 0
were O 0
applied O 0
to O 0
estrogen B-Chemical 1
- O 0
induced O 0
rat O 0
prolactinoma B-Disease 1
cells O 0
1 O 0
h O 0
and O 0
6 O 0
h O 0
after O 0
injection O 0
of O 0
bromocriptine B-Chemical 1
( O 0
3 O 0
mg O 0
/ O 0
kg O 0
of O 0
body O 0
weight O 0
) O 0
. O 0

One O 0
h O 0
after O 0
treatment O 0
, O 0
serum O 0
prolactin O 0
levels O 0
decreased O 0
markedly O 0
. O 0

Electron O 0
microscopy O 0
disclosed O 0
many O 0
secretory O 0
granules O 0
, O 0
slightly O 0
distorted O 0
rough O 0
endoplasmic O 0
reticulum O 0
, O 0
and O 0
partially O 0
dilated O 0
Golgi O 0
cisternae O 0
in O 0
the O 0
prolactinoma B-Disease 1
cells O 0
. O 0

Morphometric O 0
analysis O 0
revealed O 0
that O 0
the O 0
volume O 0
density O 0
of O 0
secretory O 0
granules O 0
increased O 0
, O 0
while O 0
the O 0
volume O 0
density O 0
of O 0
cytoplasmic O 0
microtubules O 0
decreased O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
lowered O 0
serum O 0
prolactin O 0
levels O 0
in O 0
the O 0
early O 0
phase O 0
of O 0
bromocriptine B-Chemical 1
treatment O 0
may O 0
result O 0
from O 0
an O 0
impaired O 0
secretion O 0
of O 0
prolactin O 0
due O 0
to O 0
decreasing O 0
numbers O 0
of O 0
cytoplasmic O 0
microtubules O 0
. O 0

At O 0
6 O 0
h O 0
after O 0
injection O 0
, O 0
serum O 0
prolactin O 0
levels O 0
were O 0
still O 0
considerably O 0
lower O 0
than O 0
in O 0
controls O 0
. O 0

The O 0
prolactinoma B-Disease 1
cells O 0
at O 0
this O 0
time O 0
were O 0
well O 0
granulated O 0
, O 0
with O 0
vesiculated O 0
rough O 0
endoplasmic O 0
reticulum O 0
and O 0
markedly O 0
dilated O 0
Golgi O 0
cisternae O 0
. O 0

Electron O 0
microscopical O 0
immunohistochemistry O 0
revealed O 0
positive O 0
reaction O 0
products O 0
noted O 0
on O 0
the O 0
secretory O 0
granules O 0
, O 0
Golgi O 0
cisternae O 0
, O 0
and O 0
endoplasmic O 0
reticulum O 0
of O 0
the O 0
untreated O 0
rat O 0
prolactinoma B-Disease 1
cells O 0
. O 0

However O 0
, O 0
only O 0
secretory O 0
granules O 0
showed O 0
the O 0
positive O 0
reaction O 0
products O 0
for O 0
prolactin O 0
6 O 0
h O 0
after O 0
bromocriptine B-Chemical 1
treatment O 0
of O 0
the O 0
adenoma B-Disease 1
cells O 0
. O 0

An O 0
increase O 0
in O 0
the O 0
volume O 0
density O 0
of O 0
secretory O 0
granules O 0
and O 0
a O 0
decrease O 0
in O 0
the O 0
volume O 0
densities O 0
of O 0
rough O 0
endoplasmic O 0
reticulum O 0
and O 0
microtubules O 0
was O 0
determined O 0
by O 0
morphometric O 0
analysis O 0
, O 0
suggesting O 0
that O 0
bromocriptine B-Chemical 1
inhibits O 0
protein O 0
synthesis O 0
as O 0
well O 0
as O 0
bringing O 0
about O 0
a O 0
disturbance O 0
of O 0
the O 0
prolactin O 0
secretion O 0
. O 0

Sulfasalazine B-Chemical 1
- O 0
induced O 0
lupus B-Disease 1
erythematosus I-Disease 1
. O 0

Pneumonitis B-Disease 1
, O 0
bilateral O 0
pleural B-Disease 1
effusions I-Disease 1
, O 0
echocardiographic O 0
evidence O 0
of O 0
cardiac B-Disease 1
tamponade I-Disease 1
, O 0
and O 0
positive O 0
autoantibodies O 0
developed O 0
in O 0
a O 0
43 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
, O 0
who O 0
was O 0
receiving O 0
long O 0
- O 0
term O 0
sulfasalazine B-Chemical 1
therapy O 0
for O 0
chronic O 0
ulcerative B-Disease 1
colitis I-Disease 1
. O 0

After O 0
cessation O 0
of O 0
the O 0
sulfasalazine B-Chemical 1
and O 0
completion O 0
of O 0
a O 0
six O 0
- O 0
week O 0
course O 0
of O 0
corticosteroids O 0
, O 0
these O 0
problems O 0
resolved O 0
over O 0
a O 0
period O 0
of O 0
four O 0
to O 0
six O 0
months O 0
. O 0

It O 0
is O 0
suggested O 0
that O 0
the O 0
patient O 0
had O 0
sulfasalazine B-Chemical 1
- O 0
induced O 0
lupus B-Disease 1
, O 0
which O 0
manifested O 0
with O 0
serositis B-Disease 1
and O 0
pulmonary O 0
parenchymal O 0
involvement O 0
in O 0
the O 0
absence O 0
of O 0
joint O 0
symptoms O 0
. O 0

Physicians O 0
who O 0
use O 0
sulfasalazine B-Chemical 1
to O 0
treat O 0
patients O 0
with O 0
inflammatory B-Disease 1
bowel I-Disease 1
disease I-Disease 1
should O 0
be O 0
aware O 0
of O 0
the O 0
signs O 0
of O 0
sulfasalazine B-Chemical 1
- O 0
induced O 0
lupus B-Disease 1
syndrome I-Disease 1
. O 0

Chronic O 0
carbamazepine B-Chemical 1
treatment O 0
in O 0
the O 0
rat O 0
: O 0
efficacy O 0
, O 0
toxicity B-Disease 1
, O 0
and O 0
effect O 0
on O 0
plasma O 0
and O 0
tissue O 0
folate B-Chemical 1
concentrations O 0
. O 0

Folate B-Chemical 1
depletion O 0
has O 0
often O 0
been O 0
a O 0
problem O 0
in O 0
chronic O 0
antiepileptic O 0
drug O 0
( O 0
AED O 0
) O 0
therapy O 0
. O 0

Carbamazepine B-Chemical 1
( O 0
CBZ B-Chemical 1
) O 0
, O 0
a O 0
commonly O 0
used O 0
AED O 0
, O 0
has O 0
been O 0
implicated O 0
in O 0
some O 0
clinical O 0
studies O 0
. O 0

A O 0
rat O 0
model O 0
was O 0
developed O 0
to O 0
examine O 0
the O 0
effects O 0
of O 0
chronic O 0
CBZ B-Chemical 1
treatment O 0
on O 0
folate B-Chemical 1
concentrations O 0
in O 0
the O 0
rat O 0
. O 0

In O 0
the O 0
course O 0
of O 0
developing O 0
this O 0
model O 0
, O 0
a O 0
common O 0
vehicle O 0
, O 0
propylene B-Chemical 1
glycol I-Chemical 1
, O 0
by O 0
itself O 0
in O 0
high O 0
doses O 0
, O 0
was O 0
found O 0
to O 0
exhibit O 0
protective O 0
properties O 0
against O 0
induced O 0
seizures B-Disease 1
and O 0
inhibited O 0
weight B-Disease 1
gain I-Disease 1
. O 0

Seizures B-Disease 1
induced O 0
by O 0
hexafluorodiethyl B-Chemical 1
ether I-Chemical 1
( O 0
HFDE B-Chemical 1
) O 0
were O 0
also O 0
found O 0
to O 0
be O 0
a O 0
more O 0
sensitive O 0
measure O 0
of O 0
protection O 0
by O 0
CBZ B-Chemical 1
than O 0
seizures B-Disease 1
induced O 0
by O 0
maximal O 0
electroshock O 0
( O 0
MES O 0
) O 0
. O 0

Oral O 0
administration O 0
of O 0
CBZ B-Chemical 1
as O 0
an O 0
aqueous O 0
suspension O 0
every O 0
8 O 0
h O 0
at O 0
a O 0
dose O 0
of O 0
250 O 0
mg O 0
/ O 0
kg O 0
was O 0
continuously O 0
protective O 0
against O 0
HFDE B-Chemical 1
- O 0
induced O 0
seizures B-Disease 1
and O 0
was O 0
minimally O 0
toxic O 0
as O 0
measured O 0
by O 0
weight B-Disease 1
gain I-Disease 1
over O 0
8 O 0
weeks O 0
of O 0
treatment O 0
. O 0

The O 0
CBZ B-Chemical 1
levels O 0
measured O 0
in O 0
plasma O 0
and O 0
brain O 0
of O 0
these O 0
animals O 0
, O 0
however O 0
, O 0
were O 0
below O 0
those O 0
normally O 0
considered O 0
protective O 0
. O 0

This O 0
treatment O 0
with O 0
CBZ B-Chemical 1
had O 0
no O 0
apparent O 0
adverse O 0
effect O 0
on O 0
folate B-Chemical 1
concentrations O 0
in O 0
the O 0
rat O 0
, O 0
and O 0
, O 0
indeed O 0
, O 0
the O 0
folate B-Chemical 1
concentration O 0
increased O 0
in O 0
liver O 0
after O 0
6 O 0
weeks O 0
of O 0
treatment O 0
and O 0
in O 0
plasma O 0
at O 0
8 O 0
weeks O 0
of O 0
treatment O 0
. O 0

Dipyridamole B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
ischemia I-Disease 1
. O 0

Angina B-Disease 1
and O 0
ischemic O 0
electrocardiographic O 0
changes O 0
occurred O 0
after O 0
administration O 0
of O 0
oral O 0
dipyridamole B-Chemical 1
in O 0
four O 0
patients O 0
awaiting O 0
urgent O 0
myocardial O 0
revascularization O 0
procedures O 0
. O 0

To O 0
our O 0
knowledge O 0
, O 0
this O 0
has O 0
not O 0
previously O 0
been O 0
reported O 0
as O 0
a O 0
side O 0
effect O 0
of O 0
preoperative O 0
dipyridamole B-Chemical 1
therapy O 0
, O 0
although O 0
dipyridamole B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
ischemia I-Disease 1
has O 0
been O 0
demonstrated O 0
to O 0
occur O 0
in O 0
animals O 0
and O 0
humans O 0
with O 0
coronary B-Disease 1
artery I-Disease 1
disease I-Disease 1
. O 0

Epicardial O 0
coronary O 0
collateral O 0
vessels O 0
were O 0
demonstrated O 0
in O 0
all O 0
four O 0
patients O 0
; O 0
a O 0
coronary O 0
" O 0
steal O 0
" O 0
phenomenon O 0
may O 0
be O 0
the O 0
mechanism O 0
of O 0
the O 0
dipyridamole B-Chemical 1
- O 0
induced O 0
ischemia B-Disease 1
observed O 0
. O 0

Inhibition O 0
of O 0
sympathoadrenal O 0
activity O 0
by O 0
atrial O 0
natriuretic O 0
factor O 0
in O 0
dogs O 0
. O 0

In O 0
six O 0
conscious O 0
, O 0
trained O 0
dogs O 0
, O 0
maintained O 0
on O 0
a O 0
normal O 0
sodium B-Chemical 1
intake O 0
of O 0
2 O 0
to O 0
4 O 0
mEq O 0
/ O 0
kg O 0
/ O 0
day O 0
, O 0
sympathetic O 0
activity O 0
was O 0
assessed O 0
as O 0
the O 0
release O 0
rate O 0
of O 0
norepinephrine B-Chemical 1
and O 0
epinephrine B-Chemical 1
during O 0
15 O 0
- O 0
minute O 0
i O 0
. O 0
v O 0
. O 0
infusions O 0
of O 0
human O 0
alpha O 0
- O 0
atrial O 0
natriuretic O 0
factor O 0
. O 0

Mean O 0
arterial O 0
pressure O 0
( O 0
as O 0
a O 0
percentage O 0
of O 0
control O 0
+ O 0
/ O 0
- O 0
SEM O 0
) O 0
during O 0
randomized O 0
infusions O 0
of O 0
0 O 0
. O 0
03 O 0
, O 0
0 O 0
. O 0
1 O 0
, O 0
0 O 0
. O 0
3 O 0
, O 0
or O 0
1 O 0
. O 0
0 O 0
microgram O 0
/ O 0
kg O 0
/ O 0
min O 0
was O 0
99 O 0
+ O 0
/ O 0
- O 0
1 O 0
, O 0
95 O 0
+ O 0
/ O 0
- O 0
1 O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
93 O 0
+ O 0
/ O 0
- O 0
1 O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
01 O 0
) O 0
, O 0
or O 0
79 O 0
+ O 0
/ O 0
- O 0
6 O 0
% O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
respectively O 0
, O 0
but O 0
no O 0
tachycardia B-Disease 1
and O 0
no O 0
augmentation O 0
of O 0
the O 0
norepinephrine B-Chemical 1
release O 0
rate O 0
( O 0
up O 0
to O 0
0 O 0
. O 0
3 O 0
microgram O 0
/ O 0
kg O 0
/ O 0
min O 0
) O 0
were O 0
observed O 0
, O 0
which O 0
is O 0
in O 0
contrast O 0
to O 0
comparable O 0
hypotension B-Disease 1
induced O 0
by O 0
hydralazine B-Chemical 1
or O 0
nitroglycerin B-Chemical 1
. O 0

The O 0
release O 0
rate O 0
of O 0
epinephrine B-Chemical 1
( O 0
control O 0
, O 0
6 O 0
. O 0
7 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
6 O 0
ng O 0
/ O 0
kg O 0
/ O 0
min O 0
) O 0
declined O 0
immediately O 0
during O 0
infusions O 0
of O 0
atrial O 0
natriuretic O 0
factor O 0
to O 0
a O 0
minimum O 0
of O 0
49 O 0
+ O 0
/ O 0
- O 0
5 O 0
% O 0
of O 0
control O 0
( O 0
p O 0
less O 0
than O 0
0 O 0
. O 0
001 O 0
) O 0
during O 0
0 O 0
. O 0
1 O 0
microgram O 0
/ O 0
kg O 0
/ O 0
min O 0
and O 0
to O 0
63 O 0
+ O 0
/ O 0
- O 0
5 O 0
% O 0
( O 0
0 O 0
. O 0
1 O 0
greater O 0
than O 0
p O 0
greater O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
or O 0
95 O 0
+ O 0
/ O 0
- O 0
13 O 0
% O 0
( O 0
not O 0
significant O 0
) O 0
during O 0
0 O 0
. O 0
3 O 0
or O 0
1 O 0
. O 0
0 O 0
microgram O 0
/ O 0
kg O 0
/ O 0
min O 0
. O 0

Steady O 0
state O 0
arterial O 0
plasma O 0
concentrations O 0
of O 0
atrial O 0
natriuretic O 0
factor O 0
were O 0
39 O 0
+ O 0
/ O 0
- O 0
10 O 0
pg O 0
/ O 0
ml O 0
( O 0
n O 0
= O 0
6 O 0
) O 0
during O 0
infusions O 0
of O 0
saline O 0
and O 0
284 O 0
+ O 0
/ O 0
- O 0
24 O 0
pg O 0
/ O 0
ml O 0
( O 0
n O 0
= O 0
6 O 0
) O 0
and O 0
1520 O 0
+ O 0
/ O 0
- O 0
300 O 0
pg O 0
/ O 0
ml O 0
( O 0
n O 0
= O 0
9 O 0
) O 0
during O 0
0 O 0
. O 0
03 O 0
and O 0
0 O 0
. O 0
1 O 0
microgram O 0
/ O 0
kg O 0
/ O 0
min O 0
infusions O 0
of O 0
the O 0
factor O 0
. O 0
( O 0
ABSTRACT O 0
TRUNCATED O 0
AT O 0
250 O 0
WORDS O 0
) O 0

Inhibition O 0
of O 0
immunoreactive O 0
corticotropin O 0
- O 0
releasing O 0
factor O 0
secretion O 0
into O 0
the O 0
hypophysial O 0
- O 0
portal O 0
circulation O 0
by O 0
delayed O 0
glucocorticoid O 0
feedback O 0
. O 0

Nitroprusside B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
evokes O 0
ACTH O 0
secretion O 0
which O 0
is O 0
primarily O 0
mediated O 0
by O 0
enhanced O 0
secretion O 0
of O 0
immunoreactive O 0
corticotropin O 0
- O 0
releasing O 0
factor O 0
( O 0
irCRF O 0
) O 0
into O 0
the O 0
hypophysial O 0
- O 0
portal O 0
circulation O 0
. O 0

Portal O 0
plasma O 0
concentrations O 0
of O 0
neither O 0
arginine B-Chemical 1
vasopressin I-Chemical 1
nor O 0
oxytocin B-Chemical 1
are O 0
significantly O 0
altered O 0
in O 0
this O 0
paradigm O 0
. O 0

Application O 0
of O 0
a O 0
delayed O 0
feedback O 0
signal O 0
, O 0
in O 0
the O 0
form O 0
of O 0
a O 0
2 O 0
- O 0
h O 0
systemic O 0
corticosterone B-Chemical 1
infusion O 0
in O 0
urethane B-Chemical 1
- O 0
anesthetized O 0
rats O 0
with O 0
pharmacological O 0
blockade O 0
of O 0
glucocorticoid O 0
synthesis O 0
, O 0
is O 0
without O 0
effect O 0
on O 0
the O 0
resting O 0
secretion O 0
of O 0
arginine B-Chemical 1
vasopressin I-Chemical 1
and O 0
oxytocin B-Chemical 1
at O 0
any O 0
corticosterone B-Chemical 1
feedback O 0
dose O 0
tested O 0
. O 0

Resting O 0
irCRF O 0
levels O 0
are O 0
suppressed O 0
only O 0
at O 0
the O 0
highest O 0
corticosterone B-Chemical 1
infusion O 0
rate O 0
, O 0
which O 0
resulted O 0
in O 0
systemic O 0
corticosterone B-Chemical 1
levels O 0
of O 0
40 O 0
micrograms O 0
/ O 0
dl O 0
. O 0

Suppression O 0
of O 0
irCRF O 0
secretion O 0
in O 0
response O 0
to O 0
nitroprusside B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
is O 0
observed O 0
and O 0
occurs O 0
at O 0
a O 0
plasma O 0
corticosterone B-Chemical 1
level O 0
between O 0
8 O 0
- O 0
12 O 0
micrograms O 0
/ O 0
dl O 0
. O 0

These O 0
studies O 0
provide O 0
further O 0
evidence O 0
for O 0
a O 0
strong O 0
central O 0
component O 0
of O 0
the O 0
delayed O 0
feedback O 0
process O 0
which O 0
is O 0
mediated O 0
by O 0
modulation O 0
of O 0
irCRF O 0
release O 0
. O 0

Noradrenergic O 0
involvement O 0
in O 0
catalepsy B-Disease 1
induced O 0
by O 0
delta B-Chemical 1
9 I-Chemical 1
- I-Chemical 1
tetrahydrocannabinol I-Chemical 1
. O 0

In O 0
order O 0
to O 0
elucidate O 0
the O 0
role O 0
of O 0
the O 0
catecholaminergic O 0
system O 0
in O 0
the O 0
cataleptogenic O 0
effect O 0
of O 0
delta B-Chemical 1
9 I-Chemical 1
- I-Chemical 1
tetrahydrocannabinol I-Chemical 1
( O 0
THC B-Chemical 1
) O 0
, O 0
the O 0
effect O 0
of O 0
pretreatment O 0
with O 0
6 B-Chemical 1
- I-Chemical 1
hydroxydopamine I-Chemical 1
( O 0
6 B-Chemical 1
- I-Chemical 1
OHDA I-Chemical 1
) O 0
or O 0
with O 0
desipramine B-Chemical 1
and O 0
6 B-Chemical 1
- I-Chemical 1
OHDA I-Chemical 1
and O 0
lesions O 0
of O 0
the O 0
locus O 0
coeruleus O 0
were O 0
investigated O 0
in O 0
rats O 0
. O 0

The O 0
cataleptogenic O 0
effect O 0
of O 0
THC B-Chemical 1
was O 0
significantly O 0
reduced O 0
in O 0
rats O 0
treated O 0
with O 0
6 B-Chemical 1
- I-Chemical 1
OHDA I-Chemical 1
and O 0
in O 0
rats O 0
with O 0
lesions O 0
of O 0
the O 0
locus O 0
coeruleus O 0
but O 0
not O 0
in O 0
rats O 0
treated O 0
with O 0
desipramine B-Chemical 1
and O 0
6 B-Chemical 1
- I-Chemical 1
OHDA I-Chemical 1
, O 0
as O 0
compared O 0
with O 0
control O 0
rats O 0
. O 0

On O 0
the O 0
contrary O 0
, O 0
the O 0
cataleptogenic O 0
effect O 0
of O 0
haloperidol B-Chemical 1
was O 0
significantly O 0
reduced O 0
in O 0
rats O 0
treated O 0
with O 0
desipramine B-Chemical 1
and O 0
6 B-Chemical 1
- I-Chemical 1
OHDA I-Chemical 1
but O 0
not O 0
in O 0
rats O 0
treated O 0
with O 0
6 B-Chemical 1
- I-Chemical 1
OHDA I-Chemical 1
or O 0
in O 0
rats O 0
with O 0
lesions O 0
of O 0
the O 0
locus O 0
coeruleus O 0
. O 0

These O 0
results O 0
indicate O 0
that O 0
noradrenergic O 0
neurons O 0
have O 0
an O 0
important O 0
role O 0
in O 0
the O 0
manifestation O 0
of O 0
catalepsy B-Disease 1
induced O 0
by O 0
THC B-Chemical 1
, O 0
whereas O 0
dopaminergic O 0
neurons O 0
are O 0
important O 0
in O 0
catalepsy B-Disease 1
induced O 0
by O 0
haloperidol B-Chemical 1
. O 0

Reversibility O 0
of O 0
captopril B-Chemical 1
- O 0
induced O 0
renal B-Disease 1
insufficiency I-Disease 1
after O 0
prolonged O 0
use O 0
in O 0
an O 0
unusual O 0
case O 0
of O 0
renovascular B-Disease 1
hypertension I-Disease 1
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
severe O 0
hypertension B-Disease 1
with O 0
an O 0
occluded O 0
renal O 0
artery O 0
to O 0
a O 0
solitary O 0
kidney O 0
, O 0
who O 0
developed O 0
sudden B-Disease 1
deterioration I-Disease 1
of I-Disease 1
renal I-Disease 1
function I-Disease 1
following O 0
treatment O 0
with O 0
captopril B-Chemical 1
. O 0

His O 0
renal O 0
function O 0
remained O 0
impaired O 0
but O 0
stable O 0
during O 0
2 O 0
years O 0
' O 0
treatment O 0
with O 0
captopril B-Chemical 1
but O 0
returned O 0
to O 0
pre O 0
- O 0
treatment O 0
levels O 0
soon O 0
after O 0
cessation O 0
of O 0
the O 0
drug O 0
. O 0

This O 0
indicates O 0
reversibility O 0
in O 0
captopril B-Chemical 1
- O 0
induced O 0
renal B-Disease 1
failure I-Disease 1
even O 0
after O 0
its O 0
prolonged O 0
use O 0
and O 0
suggests O 0
that O 0
no O 0
organic O 0
damage O 0
occurs O 0
to O 0
glomerular O 0
arterioles O 0
following O 0
chronic O 0
ACE O 0
inhibition O 0
. O 0

HMG O 0
CoA O 0
reductase O 0
inhibitors O 0
. O 0

Current O 0
clinical O 0
experience O 0
. O 0

Lovastatin B-Chemical 1
and O 0
simvastatin B-Chemical 1
are O 0
the O 0
2 O 0
best O 0
- O 0
known O 0
members O 0
of O 0
the O 0
class O 0
of O 0
hypolipidaemic O 0
agents O 0
known O 0
as O 0
HMG O 0
CoA O 0
reductase O 0
inhibitors O 0
. O 0

Clinical O 0
experience O 0
with O 0
lovastatin B-Chemical 1
includes O 0
over O 0
5000 O 0
patients O 0
, O 0
700 O 0
of O 0
whom O 0
have O 0
been O 0
treated O 0
for O 0
2 O 0
years O 0
or O 0
more O 0
, O 0
and O 0
experience O 0
with O 0
simvastatin B-Chemical 1
includes O 0
over O 0
3500 O 0
patients O 0
, O 0
of O 0
whom O 0
350 O 0
have O 0
been O 0
treated O 0
for O 0
18 O 0
months O 0
or O 0
more O 0
. O 0

Lovastatin B-Chemical 1
has O 0
been O 0
marketed O 0
in O 0
the O 0
United O 0
States O 0
for O 0
over O 0
6 O 0
months O 0
. O 0

Both O 0
agents O 0
show O 0
substantial O 0
clinical O 0
efficacy O 0
, O 0
with O 0
reductions O 0
in O 0
total O 0
cholesterol B-Chemical 1
of O 0
over O 0
30 O 0
% O 0
and O 0
in O 0
LDL O 0
- O 0
cholesterol B-Chemical 1
of O 0
40 O 0
% O 0
in O 0
clinical O 0
studies O 0
. O 0

Modest O 0
increases O 0
in O 0
HDL O 0
- O 0
cholesterol B-Chemical 1
levels O 0
of O 0
about O 0
10 O 0
% O 0
are O 0
also O 0
reported O 0
. O 0

Clinical O 0
tolerability O 0
of O 0
both O 0
agents O 0
has O 0
been O 0
good O 0
, O 0
with O 0
fewer O 0
than O 0
3 O 0
% O 0
of O 0
patients O 0
withdrawn O 0
from O 0
treatment O 0
because O 0
of O 0
clinical O 0
adverse O 0
experiences O 0
. O 0

Ophthalmological O 0
examinations O 0
in O 0
over O 0
1100 O 0
patients O 0
treated O 0
with O 0
one O 0
or O 0
the O 0
other O 0
agent O 0
have O 0
revealed O 0
no O 0
evidence O 0
of O 0
significant O 0
short O 0
term O 0
( O 0
up O 0
to O 0
2 O 0
years O 0
) O 0
cataractogenic O 0
potential O 0
. O 0

One O 0
to O 0
2 O 0
% O 0
of O 0
patients O 0
have O 0
elevations O 0
of O 0
serum O 0
transaminases O 0
to O 0
greater O 0
than O 0
3 O 0
times O 0
the O 0
upper O 0
limit O 0
of O 0
normal O 0
. O 0

These O 0
episodes O 0
are O 0
asymptomatic O 0
and O 0
reversible O 0
when O 0
therapy O 0
is O 0
discontinued O 0
. O 0

Minor O 0
elevations O 0
of O 0
creatine B-Chemical 1
kinase O 0
levels O 0
are O 0
reported O 0
in O 0
about O 0
5 O 0
% O 0
of O 0
patients O 0
. O 0

Myopathy B-Disease 1
, O 0
associated O 0
in O 0
some O 0
cases O 0
with O 0
myoglobinuria B-Disease 1
, O 0
and O 0
in O 0
2 O 0
cases O 0
with O 0
transient O 0
renal B-Disease 1
failure I-Disease 1
, O 0
has O 0
been O 0
rarely O 0
reported O 0
with O 0
lovastatin B-Chemical 1
, O 0
especially O 0
in O 0
patients O 0
concomitantly O 0
treated O 0
with O 0
cyclosporin B-Chemical 1
, O 0
gemfibrozil B-Chemical 1
or O 0
niacin B-Chemical 1
. O 0

Lovastatin B-Chemical 1
and O 0
simvastatin B-Chemical 1
are O 0
both O 0
effective O 0
and O 0
well O 0
- O 0
tolerated O 0
agents O 0
for O 0
lowering O 0
elevated O 0
levels O 0
of O 0
serum O 0
cholesterol B-Chemical 1
. O 0

As O 0
wider O 0
use O 0
confirms O 0
their O 0
safety O 0
profile O 0
, O 0
they O 0
will O 0
gain O 0
increasing O 0
importance O 0
in O 0
the O 0
therapeutic O 0
approach O 0
to O 0
hypercholesterolaemia B-Disease 1
and O 0
its O 0
consequences O 0
. O 0

Hepatic O 0
reactions O 0
associated O 0
with O 0
ketoconazole B-Chemical 1
in O 0
the O 0
United O 0
Kingdom O 0
. O 0

Ketoconazole B-Chemical 1
was O 0
introduced O 0
in O 0
the O 0
United O 0
Kingdom O 0
in O 0
1981 O 0
. O 0

By O 0
November O 0
1984 O 0
the O 0
Committee O 0
on O 0
Safety O 0
of O 0
Medicines O 0
had O 0
received O 0
82 O 0
reports O 0
of O 0
possible O 0
hepatotoxicity B-Disease 1
associated O 0
with O 0
the O 0
drug O 0
, O 0
including O 0
five O 0
deaths B-Disease 1
. O 0

An O 0
analysis O 0
of O 0
the O 0
75 O 0
cases O 0
that O 0
had O 0
been O 0
adequately O 0
followed O 0
up O 0
suggested O 0
that O 0
16 O 0
, O 0
including O 0
three O 0
deaths B-Disease 1
, O 0
were O 0
probably O 0
related O 0
to O 0
treatment O 0
with O 0
the O 0
drug O 0
. O 0

Of O 0
the O 0
remainder O 0
, O 0
48 O 0
were O 0
possibly O 0
related O 0
to O 0
treatment O 0
, O 0
five O 0
were O 0
unlikely O 0
to O 0
be O 0
so O 0
, O 0
and O 0
six O 0
were O 0
unclassifiable O 0
. O 0

The O 0
mean O 0
age O 0
of O 0
patients O 0
in O 0
the O 0
16 O 0
probable O 0
cases O 0
was O 0
57 O 0
. O 0
9 O 0
, O 0
with O 0
hepatotoxicity B-Disease 1
being O 0
more O 0
common O 0
in O 0
women O 0
. O 0

The O 0
average O 0
duration O 0
of O 0
treatment O 0
before O 0
the O 0
onset O 0
of O 0
jaundice B-Disease 1
was O 0
61 O 0
days O 0
. O 0

None O 0
of O 0
these O 0
well O 0
validated O 0
cases O 0
occurred O 0
within O 0
the O 0
first O 0
10 O 0
days O 0
after O 0
treatment O 0
. O 0

The O 0
results O 0
of O 0
serum O 0
liver O 0
function O 0
tests O 0
suggested O 0
hepatocellular B-Disease 1
injury I-Disease 1
in O 0
10 O 0
( O 0
63 O 0
% O 0
) O 0
; O 0
the O 0
rest O 0
showed O 0
a O 0
mixed O 0
pattern O 0
. O 0

In O 0
contrast O 0
, O 0
the O 0
results O 0
of O 0
histological O 0
examination O 0
of O 0
the O 0
liver O 0
often O 0
showed O 0
evidence O 0
of O 0
cholestasis B-Disease 1
. O 0

The O 0
characteristics O 0
of O 0
the O 0
48 O 0
patients O 0
in O 0
the O 0
possible O 0
cases O 0
were O 0
similar O 0
. O 0

Allergic O 0
manifestations O 0
such O 0
as O 0
rash B-Disease 1
and O 0
eosinophilia B-Disease 1
were O 0
rare O 0
. O 0

Hepatitis B-Disease 1
was O 0
usually O 0
reversible O 0
when O 0
treatment O 0
was O 0
stopped O 0
, O 0
with O 0
the O 0
results O 0
of O 0
liver O 0
function O 0
tests O 0
returning O 0
to O 0
normal O 0
after O 0
an O 0
average O 0
of O 0
3 O 0
. O 0
1 O 0
months O 0
. O 0

In O 0
two O 0
of O 0
the O 0
three O 0
deaths B-Disease 1
probably O 0
associated O 0
with O 0
ketoconazole B-Chemical 1
treatment O 0
the O 0
drug O 0
had O 0
been O 0
continued O 0
after O 0
the O 0
onset O 0
of O 0
jaundice B-Disease 1
and O 0
other O 0
symptoms O 0
of O 0
hepatitis B-Disease 1
. O 0

Clinical O 0
and O 0
biochemical O 0
monitoring O 0
at O 0
regular O 0
intervals O 0
for O 0
evidence O 0
of O 0
hepatitis B-Disease 1
is O 0
advised O 0
during O 0
long O 0
term O 0
treatment O 0
with O 0
ketoconazole B-Chemical 1
to O 0
prevent O 0
possible O 0
serious O 0
hepatic B-Disease 1
injury I-Disease 1
. O 0

Glyburide B-Chemical 1
- O 0
induced O 0
hepatitis B-Disease 1
. O 0

Drug O 0
- O 0
induced O 0
hepatotoxicity B-Disease 1
, O 0
although O 0
common O 0
, O 0
has O 0
been O 0
reported O 0
only O 0
infrequently O 0
with O 0
sulfonylureas B-Chemical 1
. O 0

For O 0
glyburide B-Chemical 1
, O 0
a O 0
second O 0
- O 0
generation O 0
sulfonylurea B-Chemical 1
, O 0
only O 0
two O 0
brief O 0
reports O 0
of O 0
hepatotoxicity B-Disease 1
exist O 0
. O 0

Two O 0
patients O 0
with O 0
type B-Disease 1
II I-Disease 1
diabetes I-Disease 1
mellitus I-Disease 1
developed O 0
an O 0
acute B-Disease 1
hepatitis I-Disease 1
- I-Disease 1
like I-Disease 1
syndrome I-Disease 1
soon O 0
after O 0
initiation O 0
of O 0
glyburide B-Chemical 1
therapy O 0
. O 0

There O 0
was O 0
no O 0
serologic O 0
evidence O 0
of O 0
viral B-Disease 1
infection I-Disease 1
, O 0
and O 0
a O 0
liver O 0
biopsy O 0
sample O 0
showed O 0
a O 0
histologic O 0
pattern O 0
consistent O 0
with O 0
drug B-Disease 1
- I-Disease 1
induced I-Disease 1
hepatitis I-Disease 1
. O 0

Both O 0
patients O 0
recovered O 0
quickly O 0
after O 0
stopping O 0
glyburide B-Chemical 1
therapy O 0
and O 0
have O 0
remained O 0
well O 0
for O 0
a O 0
follow O 0
- O 0
up O 0
period O 0
of O 0
1 O 0
year O 0
. O 0

Glyburide B-Chemical 1
can O 0
produce O 0
an O 0
acute B-Disease 1
hepatitis I-Disease 1
- I-Disease 1
like I-Disease 1
illness I-Disease 1
in O 0
some O 0
persons O 0
. O 0

Intracranial O 0
pressure O 0
increases O 0
during O 0
alfentanil B-Chemical 1
- O 0
induced O 0
rigidity B-Disease 1
. O 0

Intracranial O 0
pressure O 0
( O 0
ICP O 0
) O 0
was O 0
measured O 0
during O 0
alfentanil B-Chemical 1
- O 0
induced O 0
rigidity B-Disease 1
in O 0
rats O 0
. O 0

Ten O 0
rats O 0
had O 0
arterial O 0
, O 0
central O 0
venous O 0
( O 0
CVP O 0
) O 0
, O 0
and O 0
subdural O 0
cannulae O 0
inserted O 0
under O 0
halothane B-Chemical 1
anesthesia O 0
. O 0

The O 0
animals O 0
were O 0
mechanically O 0
ventilated O 0
to O 0
achieve O 0
normocarbia O 0
( O 0
PCO2 O 0
= O 0
42 O 0
+ O 0
/ O 0
- O 0
1 O 0
mmHg O 0
, O 0
mean O 0
+ O 0
/ O 0
- O 0
SE O 0
) O 0
. O 0

Following O 0
instrumentation O 0
, O 0
halothane B-Chemical 1
was O 0
discontinued O 0
and O 0
alfentanil B-Chemical 1
( O 0
125 O 0
mu O 0
/ O 0
kg O 0
) O 0
administered O 0
iv O 0
during O 0
emergence O 0
from O 0
halothane B-Chemical 1
anesthesia O 0
. O 0

In O 0
the O 0
five O 0
rats O 0
that O 0
developed O 0
somatic B-Disease 1
rigidity I-Disease 1
, O 0
ICP O 0
and O 0
CVP O 0
increased O 0
significantly O 0
above O 0
baseline O 0
( O 0
delta O 0
ICP O 0
7 O 0
. O 0
5 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
0 O 0
mmHg O 0
, O 0
delta O 0
CVP O 0
5 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
1 O 0
. O 0
3 O 0
mmHg O 0
) O 0
. O 0

These O 0
variables O 0
returned O 0
to O 0
baseline O 0
when O 0
rigidity B-Disease 1
was O 0
abolished O 0
with O 0
metocurine B-Chemical 1
. O 0

In O 0
five O 0
rats O 0
that O 0
did O 0
not O 0
become O 0
rigid O 0
, O 0
ICP O 0
and O 0
CVP O 0
did O 0
not O 0
change O 0
following O 0
alfentanil B-Chemical 1
. O 0

These O 0
observations O 0
suggest O 0
that O 0
rigidity B-Disease 1
should O 0
be O 0
prevented O 0
when O 0
alfentanil B-Chemical 1
, O 0
and O 0
, O 0
presumably O 0
, O 0
other O 0
opiates O 0
, O 0
are O 0
used O 0
in O 0
the O 0
anesthetic O 0
management O 0
of O 0
patients O 0
with O 0
ICP O 0
problems O 0
. O 0

Verapamil B-Chemical 1
withdrawal O 0
as O 0
a O 0
possible O 0
cause O 0
of O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
a O 0
hypertensive B-Disease 1
woman O 0
with O 0
a O 0
normal O 0
coronary O 0
angiogram O 0
. O 0

Verapamil B-Chemical 1
is O 0
an O 0
effective O 0
and O 0
relatively O 0
- O 0
safe O 0
antihypertensive O 0
drug O 0
. O 0

Serious O 0
adverse O 0
effects O 0
are O 0
uncommon O 0
and O 0
mainly O 0
have O 0
been O 0
related O 0
to O 0
the O 0
depression B-Disease 1
of O 0
cardiac O 0
contractility O 0
and O 0
conduction O 0
, O 0
especially O 0
when O 0
the O 0
drug O 0
is O 0
combined O 0
with O 0
beta O 0
- O 0
blocking O 0
agents O 0
. O 0

We O 0
report O 0
a O 0
case O 0
in O 0
which O 0
myocardial B-Disease 1
infarction I-Disease 1
coincided O 0
with O 0
the O 0
introduction O 0
of O 0
captopril B-Chemical 1
and O 0
the O 0
withdrawal O 0
of O 0
verapamil B-Chemical 1
in O 0
a O 0
previously O 0
asymptomatic O 0
woman O 0
with O 0
severe O 0
hypertension B-Disease 1
. O 0

Possible O 0
mechanisms O 0
that O 0
involve O 0
a O 0
verapamil B-Chemical 1
- O 0
related O 0
increase O 0
in O 0
platelet O 0
and O 0
/ O 0
or O 0
vascular O 0
alpha O 0
2 O 0
- O 0
adrenoreceptor O 0
affinity O 0
for O 0
catecholamines B-Chemical 1
are O 0
discussed O 0
. O 0

Haemolytic B-Disease 1
- I-Disease 1
uraemic I-Disease 1
syndrome I-Disease 1
after O 0
treatment O 0
with O 0
metronidazole B-Chemical 1
. O 0

This O 0
paper O 0
describes O 0
the O 0
clinical O 0
features O 0
of O 0
six O 0
children O 0
who O 0
developed O 0
the O 0
haemolytic B-Disease 1
- I-Disease 1
uraemic I-Disease 1
syndrome I-Disease 1
after O 0
treatment O 0
with O 0
metronidazole B-Chemical 1
. O 0

These O 0
children O 0
were O 0
older O 0
and O 0
were O 0
more O 0
likely O 0
to O 0
have O 0
undergone O 0
recent O 0
bowel O 0
surgery O 0
than O 0
are O 0
other O 0
children O 0
with O 0
this O 0
condition O 0
. O 0

While O 0
the O 0
involvement O 0
of O 0
metronidazole B-Chemical 1
in O 0
the O 0
aetiology O 0
of O 0
the O 0
haemolytic B-Disease 1
- I-Disease 1
uraemic I-Disease 1
syndrome I-Disease 1
is O 0
not O 0
established O 0
firmly O 0
, O 0
the O 0
action O 0
of O 0
this O 0
drug O 0
in O 0
sensitizing O 0
tissues O 0
to O 0
oxidation O 0
injury O 0
and O 0
the O 0
reported O 0
evidence O 0
of O 0
oxidation O 0
changes O 0
in O 0
the O 0
haemolytic B-Disease 1
- I-Disease 1
uraemic I-Disease 1
syndrome I-Disease 1
suggest O 0
a O 0
possible O 0
link O 0
between O 0
metronidazole B-Chemical 1
treatment O 0
and O 0
some O 0
cases O 0
of O 0
the O 0
haemolytic B-Disease 1
- I-Disease 1
uraemic I-Disease 1
syndrome I-Disease 1
. O 0

Adverse O 0
cardiac O 0
effects O 0
during O 0
induction O 0
chemotherapy O 0
treatment O 0
with O 0
cis B-Chemical 1
- I-Chemical 1
platin I-Chemical 1
and O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
. O 0

Survival O 0
for O 0
patients O 0
with O 0
advanced O 0
head B-Disease 1
and I-Disease 1
neck I-Disease 1
carcinoma I-Disease 1
and O 0
esophageal B-Disease 1
carcinoma I-Disease 1
is O 0
poor O 0
with O 0
radiotherapy O 0
and O 0
/ O 0
or O 0
surgery O 0
. O 0

Obviously O 0
, O 0
there O 0
is O 0
a O 0
need O 0
for O 0
effective O 0
chemotherapy O 0
. O 0

In O 0
the O 0
present O 0
study O 0
, O 0
cis B-Chemical 1
- I-Chemical 1
platin I-Chemical 1
( O 0
80 O 0
- O 0
120 O 0
mg O 0
/ O 0
m2BSA O 0
) O 0
and O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
( O 0
1000 O 0
mg O 0
/ O 0
m2BSA O 0
daily O 0
as O 0
a O 0
continuous O 0
infusion O 0
during O 0
5 O 0
days O 0
) O 0
were O 0
given O 0
to O 0
76 O 0
patients O 0
before O 0
radiotherapy O 0
and O 0
surgery O 0
. O 0

The O 0
aim O 0
of O 0
the O 0
study O 0
was O 0
to O 0
clarify O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
adverse O 0
cardiac O 0
effects O 0
to O 0
this O 0
treatment O 0
. O 0

Before O 0
treatment O 0
all O 0
patients O 0
had O 0
a O 0
cardiac O 0
evaluation O 0
and O 0
during O 0
treatment O 0
serial O 0
ECG O 0
recordings O 0
were O 0
performed O 0
. O 0

In O 0
the O 0
pre O 0
- O 0
treatment O 0
evaluation O 0
, O 0
signs O 0
of O 0
cardiovascular B-Disease 1
disease I-Disease 1
were O 0
found O 0
in O 0
33 O 0
patients O 0
( O 0
43 O 0
% O 0
) O 0
. O 0

During O 0
treatment O 0
, O 0
adverse O 0
cardiac O 0
effects O 0
were O 0
observed O 0
in O 0
14 O 0
patients O 0
( O 0
18 O 0
% O 0
) O 0
. O 0

The O 0
mean O 0
age O 0
of O 0
these O 0
patients O 0
was O 0
the O 0
same O 0
as O 0
for O 0
the O 0
entire O 0
group O 0
, O 0
64 O 0
years O 0
. O 0

The O 0
incidence O 0
of O 0
cardiotoxicity B-Disease 1
was O 0
not O 0
higher O 0
in O 0
patients O 0
with O 0
signs O 0
of O 0
cardiovascular B-Disease 1
disease I-Disease 1
than O 0
in O 0
those O 0
without O 0
in O 0
the O 0
pre O 0
- O 0
treatment O 0
evaluation O 0
. O 0

The O 0
most O 0
common O 0
signs O 0
of O 0
cardiotoxicity B-Disease 1
were O 0
chest B-Disease 1
pain I-Disease 1
, O 0
ST O 0
- O 0
T O 0
wave O 0
changes O 0
and O 0
atrial B-Disease 1
fibrillation I-Disease 1
. O 0

This O 0
was O 0
followed O 0
by O 0
ventricular B-Disease 1
fibrillation I-Disease 1
in O 0
one O 0
patient O 0
and O 0
sudden B-Disease 1
death I-Disease 1
in O 0
another O 0
. O 0

It O 0
is O 0
concluded O 0
that O 0
patients O 0
on O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
treatment O 0
should O 0
be O 0
under O 0
close O 0
supervision O 0
and O 0
that O 0
the O 0
treatment O 0
should O 0
be O 0
discontinued O 0
if O 0
chest B-Disease 1
pain I-Disease 1
or O 0
tachyarrhythmia B-Disease 1
is O 0
observed O 0
. O 0

Death B-Disease 1
from O 0
chemotherapy O 0
in O 0
gestational B-Disease 1
trophoblastic I-Disease 1
disease I-Disease 1
. O 0

Multiple O 0
cytotoxic O 0
drug O 0
administration O 0
is O 0
the O 0
generally O 0
accepted O 0
treatment O 0
of O 0
patients O 0
with O 0
a O 0
high O 0
- O 0
risk O 0
stage O 0
of O 0
choriocarcinoma B-Disease 1
. O 0

Based O 0
on O 0
this O 0
principle O 0
a O 0
27 O 0
- O 0
year O 0
old O 0
woman O 0
, O 0
classified O 0
as O 0
being O 0
in O 0
the O 0
high O 0
- O 0
risk O 0
group O 0
( O 0
Goldstein O 0
and O 0
Berkowitz O 0
score O 0
: O 0
11 O 0
) O 0
, O 0
was O 0
treated O 0
with O 0
multiple O 0
cytotoxic O 0
drugs O 0
. O 0

The O 0
multiple O 0
drug O 0
schema O 0
consisted O 0
of O 0
: O 0
Etoposide B-Chemical 1
16 O 0
. O 0
213 O 0
, O 0
Methotrexate B-Chemical 1
, O 0
Cyclophosphamide B-Chemical 1
, O 0
Actomycin B-Chemical 1
- I-Chemical 1
D I-Chemical 1
, O 0
and O 0
Cisplatin B-Chemical 1
. O 0

On O 0
the O 0
first O 0
day O 0
of O 0
the O 0
schedule O 0
, O 0
moderate O 0
high O 0
doses O 0
of O 0
Methotrexate B-Chemical 1
, O 0
Etoposide B-Chemical 1
and O 0
Cyclophosphamide B-Chemical 1
were O 0
administered O 0
. O 0

Within O 0
8 O 0
hours O 0
after O 0
initiation O 0
of O 0
therapy O 0
the O 0
patient O 0
died O 0
with O 0
a O 0
clinical O 0
picture O 0
resembling O 0
massive O 0
pulmonary B-Disease 1
obstruction I-Disease 1
due O 0
to O 0
choriocarcinomic O 0
tissue O 0
plugs O 0
, O 0
probably O 0
originating O 0
from O 0
the O 0
uterus O 0
. O 0

Formation O 0
of O 0
these O 0
plugs O 0
was O 0
probably O 0
due O 0
to O 0
extensive O 0
tumor B-Disease 1
necrosis B-Disease 1
at O 0
the O 0
level O 0
of O 0
the O 0
walls O 0
of O 0
the O 0
major O 0
uterine O 0
veins O 0
, O 0
which O 0
resulted O 0
in O 0
an O 0
open O 0
exchange O 0
of O 0
tumor B-Disease 1
plugs O 0
to O 0
the O 0
vascular O 0
spaces O 0
; O 0
decrease O 0
in O 0
tumor B-Disease 1
tissue O 0
coherence O 0
secondary O 0
to O 0
chemotherapy O 0
may O 0
have O 0
further O 0
contributed O 0
to O 0
the O 0
formation O 0
of O 0
tumor B-Disease 1
emboli O 0
. O 0

In O 0
view O 0
of O 0
the O 0
close O 0
time O 0
association O 0
between O 0
the O 0
start O 0
of O 0
chemotherapy O 0
and O 0
the O 0
acute O 0
onset O 0
of O 0
massive O 0
embolism B-Disease 1
other O 0
explanations O 0
, O 0
such O 0
as O 0
spontaneous O 0
necrosis B-Disease 1
, O 0
must O 0
be O 0
considered O 0
less O 0
likely O 0
. O 0

Patients O 0
with O 0
large O 0
pelvic B-Disease 1
tumor I-Disease 1
loads O 0
are O 0
, O 0
according O 0
to O 0
existing O 0
classifications O 0
, O 0
at O 0
high O 0
risk O 0
to O 0
die O 0
and O 0
to O 0
develop O 0
drug O 0
resistance O 0
. O 0

Notwithstanding O 0
these O 0
facts O 0
our O 0
findings O 0
suggest O 0
that O 0
these O 0
patients O 0
might O 0
benefit O 0
from O 0
relatively O 0
mild O 0
initial O 0
treatment O 0
, O 0
especially O 0
true O 0
for O 0
patients O 0
not O 0
previously O 0
exposed O 0
to O 0
this O 0
drug O 0
. O 0

Close O 0
observation O 0
of O 0
the O 0
response O 0
status O 0
both O 0
clinically O 0
and O 0
with O 0
beta O 0
- O 0
hCG O 0
values O 0
may O 0
indicate O 0
whether O 0
and O 0
when O 0
more O 0
agressive O 0
combination O 0
chemotherapy O 0
should O 0
be O 0
started O 0
. O 0
( O 0
ABSTRACT O 0
TRUNCATED O 0
AT O 0
250 O 0
WORDS O 0
) O 0

Pulmonary O 0
shunt O 0
and O 0
cardiovascular O 0
responses O 0
to O 0
CPAP O 0
during O 0
nitroprusside B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
. O 0

The O 0
effects O 0
of O 0
continuous O 0
positive O 0
airway O 0
pressure O 0
( O 0
CPAP O 0
) O 0
on O 0
cardiovascular O 0
dynamics O 0
and O 0
pulmonary O 0
shunt O 0
( O 0
QS O 0
/ O 0
QT O 0
) O 0
were O 0
investigated O 0
in O 0
12 O 0
dogs O 0
before O 0
and O 0
during O 0
sodium B-Chemical 1
nitroprusside I-Chemical 1
infusion O 0
that O 0
decreased O 0
mean O 0
arterial O 0
blood O 0
pressure O 0
40 O 0
- O 0
50 O 0
per O 0
cent O 0
. O 0

Before O 0
nitroprusside B-Chemical 1
infusion O 0
, O 0
5 O 0
cm O 0
H2O B-Chemical 1
CPAP O 0
significantly O 0
, O 0
P O 0
less O 0
than O 0
. O 0
05 O 0
, O 0
decreased O 0
arterial O 0
blood O 0
pressure O 0
, O 0
but O 0
did O 0
not O 0
significantly O 0
alter O 0
heart O 0
rate O 0
, O 0
cardiac O 0
output O 0
, O 0
systemic O 0
vascular O 0
resistance O 0
, O 0
or O 0
QS O 0
/ O 0
QT O 0
. O 0

Ten O 0
cm O 0
H2O B-Chemical 1
CPAP O 0
before O 0
nitroprusside B-Chemical 1
infusion O 0
produced O 0
a O 0
further O 0
decrease B-Disease 1
in I-Disease 1
arterial I-Disease 1
blood I-Disease 1
pressure I-Disease 1
and O 0
significantly O 0
increased O 0
heart O 0
rate O 0
and O 0
decreased B-Disease 1
cardiac I-Disease 1
output I-Disease 1
and O 0
QS O 0
/ O 0
QT O 0
. O 0

Nitroprusside B-Chemical 1
caused O 0
significant O 0
decreases B-Disease 1
in I-Disease 1
arterial I-Disease 1
blood I-Disease 1
pressure I-Disease 1
and O 0
systemic O 0
vascular O 0
resistance O 0
and O 0
increases O 0
in O 0
heart O 0
rate O 0
, O 0
but O 0
did O 0
not O 0
change O 0
cardiac O 0
output O 0
or O 0
QS O 0
/ O 0
QT O 0
. O 0

Five O 0
cm O 0
H2O B-Chemical 1
CPAP O 0
during O 0
nitroprusside B-Chemical 1
did O 0
not O 0
further O 0
alter O 0
any O 0
of O 0
the O 0
above O 0
- O 0
mentioned O 0
variables O 0
. O 0

However O 0
, O 0
10 O 0
cm O 0
H2O B-Chemical 1
CPAP O 0
decreased O 0
arterial O 0
blood O 0
pressure O 0
, O 0
cardiac O 0
output O 0
, O 0
and O 0
QS O 0
/ O 0
QT O 0
. O 0

These O 0
data O 0
indicate O 0
that O 0
nitroprusside B-Chemical 1
infusion O 0
rates O 0
that O 0
decrease O 0
mean O 0
arterial O 0
blood O 0
pressure O 0
by O 0
40 O 0
- O 0
50 O 0
per O 0
cent O 0
do O 0
not O 0
change O 0
cardiac O 0
output O 0
or O 0
QS O 0
/ O 0
QT O 0
. O 0

During O 0
nitroprusside B-Chemical 1
infusion O 0
low O 0
levels O 0
of O 0
CPAP O 0
do O 0
not O 0
markedly O 0
alter O 0
cardiovascular O 0
dynamics O 0
, O 0
but O 0
high O 0
levels O 0
of O 0
CPAP O 0
( O 0
10 O 0
cm O 0
H2O B-Chemical 1
) O 0
, O 0
while O 0
decreasing O 0
QS O 0
/ O 0
QT O 0
, O 0
produce O 0
marked O 0
decreases B-Disease 1
in I-Disease 1
arterial I-Disease 1
blood I-Disease 1
pressure I-Disease 1
and I-Disease 1
cardiac I-Disease 1
output I-Disease 1
. O 0

Systolic O 0
pressure O 0
variation O 0
is O 0
greater O 0
during O 0
hemorrhage B-Disease 1
than O 0
during O 0
sodium B-Chemical 1
nitroprusside I-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
in O 0
ventilated O 0
dogs O 0
. O 0

The O 0
systolic O 0
pressure O 0
variation O 0
( O 0
SPV O 0
) O 0
, O 0
which O 0
is O 0
the O 0
difference O 0
between O 0
the O 0
maximal O 0
and O 0
minimal O 0
values O 0
of O 0
the O 0
systolic O 0
blood O 0
pressure O 0
( O 0
SBP O 0
) O 0
after O 0
one O 0
positive O 0
- O 0
pressure O 0
breath O 0
, O 0
was O 0
studied O 0
in O 0
ventilated O 0
dogs O 0
subjected O 0
to O 0
hypotension B-Disease 1
. O 0

Mean O 0
arterial O 0
pressure O 0
was O 0
decreased O 0
to O 0
50 O 0
mm O 0
Hg O 0
for O 0
30 O 0
minutes O 0
either O 0
by O 0
hemorrhage B-Disease 1
( O 0
HEM B-Disease 1
, O 0
n O 0
= O 0
7 O 0
) O 0
or O 0
by O 0
continuous O 0
infusion O 0
of O 0
sodium B-Chemical 1
nitroprusside I-Chemical 1
( O 0
SNP B-Chemical 1
, O 0
n O 0
= O 0
7 O 0
) O 0
. O 0

During O 0
HEM B-Disease 1
- O 0
induced O 0
hypotension B-Disease 1
the O 0
cardiac O 0
output O 0
was O 0
significantly O 0
lower O 0
and O 0
systemic O 0
vascular O 0
resistance O 0
higher O 0
compared O 0
with O 0
that O 0
in O 0
the O 0
SNP B-Chemical 1
group O 0
. O 0

The O 0
systemic O 0
, O 0
central O 0
venous O 0
, O 0
pulmonary O 0
capillary O 0
wedge O 0
pressures O 0
, O 0
and O 0
heart O 0
rates O 0
, O 0
were O 0
similar O 0
in O 0
the O 0
two O 0
groups O 0
. O 0

Analysis O 0
of O 0
the O 0
respiratory O 0
changes O 0
in O 0
the O 0
arterial O 0
pressure O 0
waveform O 0
enabled O 0
differentiation O 0
between O 0
the O 0
two O 0
groups O 0
. O 0

The O 0
SPV O 0
during O 0
hypotension B-Disease 1
was O 0
15 O 0
. O 0
7 O 0
+ O 0
/ O 0
- O 0
6 O 0
. O 0
7 O 0
mm O 0
Hg O 0
in O 0
the O 0
HEM B-Disease 1
group O 0
, O 0
compared O 0
with O 0
9 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
0 O 0
mm O 0
Hg O 0
in O 0
the O 0
SNP B-Chemical 1
group O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
02 O 0
) O 0
. O 0

The O 0
delta O 0
down O 0
, O 0
which O 0
is O 0
the O 0
measure O 0
of O 0
decrease O 0
of O 0
SBP O 0
after O 0
a O 0
mechanical O 0
breath O 0
, O 0
was O 0
20 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
8 O 0
. O 0
4 O 0
and O 0
10 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
3 O 0
. O 0
8 O 0
mm O 0
Hg O 0
in O 0
the O 0
HEM B-Disease 1
and O 0
SNP B-Chemical 1
groups O 0
, O 0
respectively O 0
, O 0
during O 0
hypotension B-Disease 1
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
02 O 0
) O 0
. O 0

It O 0
is O 0
concluded O 0
that O 0
increases O 0
in O 0
the O 0
SPV O 0
and O 0
the O 0
delta O 0
down O 0
are O 0
characteristic O 0
of O 0
a O 0
hypotensive B-Disease 1
state O 0
due O 0
to O 0
a O 0
predominant O 0
decrease O 0
in O 0
preload O 0
. O 0

They O 0
are O 0
thus O 0
more O 0
important O 0
during O 0
absolute O 0
hypovolemia B-Disease 1
than O 0
during O 0
deliberate O 0
hypotension B-Disease 1
. O 0

Ventricular B-Disease 1
tachyarrhythmias I-Disease 1
during O 0
cesarean O 0
section O 0
after O 0
ritodrine B-Chemical 1
therapy O 0
: O 0
interaction O 0
with O 0
anesthetics O 0
. O 0

This O 0
case O 0
illustrates O 0
that O 0
patients O 0
receiving O 0
ritodrine B-Chemical 1
for O 0
preterm B-Disease 1
labor I-Disease 1
may O 0
risk O 0
interactions O 0
between O 0
the O 0
residual O 0
betamimetic O 0
effects O 0
of O 0
ritodrine B-Chemical 1
and O 0
the O 0
effects O 0
of O 0
anesthetics O 0
during O 0
cesarean O 0
section O 0
. O 0

Such O 0
interactions O 0
may O 0
result O 0
in O 0
serious O 0
cardiovascular B-Disease 1
complications I-Disease 1
even O 0
after O 0
cessation O 0
of O 0
an O 0
infusion O 0
of O 0
ritodrine B-Chemical 1
. O 0

Preoperative O 0
assessment O 0
should O 0
focus O 0
on O 0
cardiovascular O 0
status O 0
and O 0
serum O 0
potassium B-Chemical 1
level O 0
. O 0

Delaying O 0
induction O 0
of O 0
anesthesia O 0
should O 0
be O 0
considered O 0
whenever O 0
possible O 0
. O 0

Careful O 0
fluid O 0
administration O 0
and O 0
cautious O 0
use O 0
of O 0
titrated O 0
doses O 0
of O 0
ephedrine B-Chemical 1
are O 0
advised O 0
. O 0

After O 0
delivery O 0
of O 0
the O 0
infant O 0
, O 0
there O 0
should O 0
be O 0
no O 0
contraindication O 0
to O 0
the O 0
use O 0
of O 0
an O 0
alpha O 0
- O 0
adrenergic O 0
vasopressor O 0
such O 0
as O 0
phenylephrine B-Chemical 1
to O 0
treat O 0
hypotensive B-Disease 1
patients O 0
with O 0
tachycardia B-Disease 1
. O 0

Verapamil B-Chemical 1
- O 0
induced O 0
carbamazepine B-Chemical 1
neurotoxicity B-Disease 1
. O 0

A O 0
report O 0
of O 0
two O 0
cases O 0
. O 0

Two O 0
patients O 0
with O 0
signs O 0
of O 0
carbamazepine B-Chemical 1
neurotoxicity B-Disease 1
after O 0
combined O 0
treatment O 0
with O 0
verapamil B-Chemical 1
showed O 0
complete O 0
recovery O 0
after O 0
discontinuation O 0
of O 0
the O 0
calcium B-Chemical 1
entry O 0
blocker O 0
. O 0

Use O 0
of O 0
verapamil B-Chemical 1
in O 0
combination O 0
with O 0
carbamazepine B-Chemical 1
should O 0
either O 0
be O 0
avoided O 0
or O 0
prescribed O 0
only O 0
with O 0
appropriate O 0
adjustment O 0
of O 0
the O 0
carbamazepine B-Chemical 1
dose O 0
( O 0
usually O 0
reduction O 0
of O 0
the O 0
carbamazepine B-Chemical 1
dose O 0
by O 0
one O 0
half O 0
) O 0
. O 0

Paracetamol B-Chemical 1
- O 0
associated O 0
coma B-Disease 1
, O 0
metabolic B-Disease 1
acidosis I-Disease 1
, O 0
renal B-Disease 1
and I-Disease 1
hepatic I-Disease 1
failure I-Disease 1
. O 0

A O 0
case O 0
of O 0
metabolic B-Disease 1
acidosis I-Disease 1
, O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
and I-Disease 1
hepatic I-Disease 1
failure I-Disease 1
following O 0
paracetamol B-Chemical 1
ingestion O 0
is O 0
presented O 0
. O 0

The O 0
diagnostic O 0
difficulty O 0
at O 0
presentation O 0
is O 0
highlighted O 0
. O 0

Continuous O 0
arteriovenous O 0
haemofiltration O 0
proved O 0
a O 0
valuable O 0
means O 0
of O 0
maintaining O 0
fluid O 0
and O 0
electrolyte O 0
balance O 0
. O 0

The O 0
patient O 0
recovered O 0
. O 0

Sexual B-Disease 1
dysfunction I-Disease 1
among O 0
patients O 0
with O 0
arthritis B-Disease 1
. O 0

The O 0
relationship O 0
of O 0
arthritis B-Disease 1
and O 0
sexual B-Disease 1
dysfunction I-Disease 1
was O 0
investigated O 0
among O 0
169 O 0
patients O 0
with O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
, O 0
osteoarthritis B-Disease 1
and O 0
spondyloarthropathy B-Disease 1
, O 0
130 O 0
of O 0
whom O 0
were O 0
pair O 0
- O 0
matched O 0
to O 0
controls O 0
. O 0

Assessments O 0
of O 0
marital O 0
happiness O 0
and O 0
depressed B-Disease 1
mood I-Disease 1
were O 0
also O 0
made O 0
using O 0
the O 0
CES O 0
- O 0
D O 0
and O 0
the O 0
Azrin O 0
Marital O 0
Happiness O 0
Scale O 0
( O 0
AMHS O 0
) O 0
. O 0

Sexual B-Disease 1
dysfunctions I-Disease 1
were O 0
found O 0
to O 0
be O 0
common O 0
among O 0
patients O 0
and O 0
controls O 0
, O 0
the O 0
majority O 0
in O 0
both O 0
groups O 0
reporting O 0
one O 0
or O 0
more O 0
dysfunctions O 0
. O 0

Impotence B-Disease 1
was O 0
more O 0
common O 0
among O 0
male O 0
patients O 0
than O 0
controls O 0
and O 0
was O 0
found O 0
to O 0
be O 0
associated O 0
with O 0
co O 0
- O 0
morbidity O 0
and O 0
the O 0
taking O 0
of O 0
methotrexate B-Chemical 1
. O 0

Depressed B-Disease 1
mood I-Disease 1
was O 0
more O 0
common O 0
among O 0
patients O 0
and O 0
was O 0
associated O 0
with O 0
certain O 0
sexual O 0
difficulties O 0
, O 0
but O 0
not O 0
with O 0
impotence B-Disease 1
. O 0

Marital O 0
unhappiness O 0
, O 0
as O 0
indicated O 0
by O 0
AMHS O 0
scores O 0
, O 0
was O 0
not O 0
associated O 0
with O 0
arthritis B-Disease 1
but O 0
was O 0
associated O 0
with O 0
sexual B-Disease 1
dysfunction I-Disease 1
, O 0
sexual O 0
dissatisfaction O 0
and O 0
being O 0
female O 0
. O 0

Does O 0
paracetamol B-Chemical 1
cause O 0
urothelial B-Disease 1
cancer I-Disease 1
or O 0
renal B-Disease 1
papillary I-Disease 1
necrosis I-Disease 1
? O 0

The O 0
risk O 0
of O 0
developing O 0
renal B-Disease 1
papillary I-Disease 1
necrosis I-Disease 1
or O 0
cancer B-Disease 1
of I-Disease 1
the I-Disease 1
renal I-Disease 1
pelvis I-Disease 1
, I-Disease 1
ureter I-Disease 1
or I-Disease 1
bladder I-Disease 1
associated O 0
with O 0
consumption O 0
of O 0
either O 0
phenacetin B-Chemical 1
or O 0
paracetamol B-Chemical 1
was O 0
calculated O 0
from O 0
data O 0
acquired O 0
by O 0
questionnaire O 0
from O 0
381 O 0
cases O 0
and O 0
808 O 0
controls O 0
. O 0

The O 0
risk O 0
of O 0
renal B-Disease 1
papillary I-Disease 1
necrosis I-Disease 1
was O 0
increased O 0
nearly O 0
20 O 0
- O 0
fold O 0
by O 0
consumption O 0
of O 0
phenacetin B-Chemical 1
, O 0
which O 0
also O 0
increased O 0
the O 0
risk O 0
for O 0
cancer B-Disease 1
of I-Disease 1
the I-Disease 1
renal I-Disease 1
pelvis I-Disease 1
and I-Disease 1
bladder I-Disease 1
but O 0
not O 0
for O 0
ureteric B-Disease 1
cancer I-Disease 1
. O 0

By O 0
contrast O 0
, O 0
we O 0
were O 0
unable O 0
to O 0
substantiate O 0
an O 0
increased O 0
risk O 0
from O 0
paracetamol B-Chemical 1
consumption O 0
for O 0
renal B-Disease 1
papillary I-Disease 1
necrosis I-Disease 1
or O 0
any O 0
of O 0
these O 0
cancers B-Disease 1
although O 0
there O 0
was O 0
a O 0
suggestion O 0
of O 0
an O 0
association O 0
with O 0
cancer B-Disease 1
of I-Disease 1
the I-Disease 1
ureter I-Disease 1
. O 0

Dapsone B-Chemical 1
- O 0
associated O 0
Heinz O 0
body O 0
hemolytic B-Disease 1
anemia I-Disease 1
in O 0
a O 0
Cambodian O 0
woman O 0
with O 0
hemoglobin O 0
E O 0
trait O 0
. O 0

A O 0
Cambodian O 0
woman O 0
with O 0
hemoglobin O 0
E O 0
trait O 0
( O 0
AE O 0
) O 0
and O 0
leprosy B-Disease 1
developed O 0
a O 0
Heinz O 0
body O 0
hemolytic B-Disease 1
anemia I-Disease 1
while O 0
taking O 0
a O 0
dose O 0
of O 0
dapsone B-Chemical 1
( O 0
50 O 0
mg O 0
/ O 0
day O 0
) O 0
not O 0
usually O 0
associated O 0
with O 0
clinical O 0
hemolysis B-Disease 1
. O 0

Her O 0
red O 0
blood O 0
cells O 0
( O 0
RBCs O 0
) O 0
had O 0
increased O 0
incubated O 0
Heinz O 0
body O 0
formation O 0
, O 0
decreased O 0
reduced O 0
glutathione B-Chemical 1
( O 0
GSH B-Chemical 1
) O 0
, O 0
and O 0
decreased O 0
GSH B-Chemical 1
stability O 0
. O 0

The O 0
pentose B-Chemical 1
phosphate I-Chemical 1
shunt O 0
activity O 0
of O 0
the O 0
dapsone B-Chemical 1
- O 0
exposed O 0
AE O 0
RBCs O 0
was O 0
increased O 0
compared O 0
to O 0
normal O 0
RBCs O 0
. O 0

Although O 0
the O 0
AE O 0
RBCs O 0
from O 0
an O 0
individual O 0
not O 0
taking O 0
dapsone B-Chemical 1
had O 0
increased O 0
incubated O 0
Heinz O 0
body O 0
formation O 0
, O 0
the O 0
GSH B-Chemical 1
content O 0
and O 0
GSH B-Chemical 1
stability O 0
were O 0
normal O 0
. O 0

The O 0
pentose B-Chemical 1
phosphate I-Chemical 1
shunt O 0
activity O 0
of O 0
the O 0
non O 0
- O 0
dapsone B-Chemical 1
- O 0
exposed O 0
AE O 0
RBCs O 0
was O 0
decreased O 0
compared O 0
to O 0
normal O 0
RBCs O 0
. O 0

Thus O 0
, O 0
AE O 0
RBCs O 0
appear O 0
to O 0
have O 0
an O 0
increased O 0
sensitivity O 0
to O 0
oxidant O 0
stress O 0
both O 0
in O 0
vitro O 0
and O 0
in O 0
vivo O 0
, O 0
since O 0
dapsone B-Chemical 1
does O 0
not O 0
cause O 0
hemolytic B-Disease 1
anemia I-Disease 1
at O 0
this O 0
dose O 0
in O 0
hematologically O 0
normal O 0
individuals O 0
. O 0

Given O 0
the O 0
influx O 0
of O 0
Southeast O 0
Asians O 0
into O 0
the O 0
United O 0
States O 0
, O 0
oxidant O 0
medications O 0
should O 0
be O 0
used O 0
with O 0
caution O 0
, O 0
especially O 0
if O 0
an O 0
infection B-Disease 1
is O 0
present O 0
, O 0
in O 0
individuals O 0
of O 0
ethnic O 0
backgrounds O 0
that O 0
have O 0
an O 0
increased O 0
prevalence O 0
of O 0
hemoglobin O 0
E O 0
. O 0

Severe O 0
complications O 0
of O 0
antianginal O 0
drug O 0
therapy O 0
in O 0
a O 0
patient O 0
identified O 0
as O 0
a O 0
poor O 0
metabolizer O 0
of O 0
metoprolol B-Chemical 1
, O 0
propafenone B-Chemical 1
, O 0
diltiazem B-Chemical 1
, O 0
and O 0
sparteine B-Chemical 1
. O 0

A O 0
47 O 0
- O 0
year O 0
- O 0
old O 0
patient O 0
suffering O 0
from O 0
coronary B-Disease 1
artery I-Disease 1
disease I-Disease 1
was O 0
admitted O 0
to O 0
the O 0
CCU O 0
in O 0
shock B-Disease 1
with O 0
III O 0
. O 0

AV B-Disease 1
block I-Disease 1
, O 0
severe O 0
hypotension B-Disease 1
, O 0
and O 0
impairment B-Disease 1
of I-Disease 1
ventricular I-Disease 1
function I-Disease 1
. O 0

One O 0
week O 0
prior O 0
to O 0
admission O 0
a O 0
therapy O 0
with O 0
standard O 0
doses O 0
of O 0
metoprolol B-Chemical 1
( O 0
100 O 0
mg O 0
t O 0
. O 0
i O 0
. O 0
d O 0
. O 0
and O 0
then O 0
100 O 0
mg O 0
b O 0
. O 0
i O 0
. O 0
d O 0
. O 0
) O 0
had O 0
been O 0
initiated O 0
. O 0

Two O 0
days O 0
before O 0
admission O 0
diltiazem B-Chemical 1
( O 0
60 O 0
mg O 0
b O 0
. O 0
i O 0
. O 0
d O 0
. O 0
) O 0
was O 0
prescribed O 0
in O 0
addition O 0
. O 0

Analyses O 0
of O 0
a O 0
blood O 0
sample O 0
revealed O 0
unusually O 0
high O 0
plasma O 0
concentrations O 0
of O 0
metoprolol B-Chemical 1
( O 0
greater O 0
than O 0
3000 O 0
ng O 0
/ O 0
ml O 0
) O 0
and O 0
diltiazem B-Chemical 1
( O 0
526 O 0
ng O 0
/ O 0
ml O 0
) O 0
. O 0

The O 0
patient O 0
recovered O 0
within O 0
1 O 0
week O 0
following O 0
discontinuation O 0
of O 0
antianginal O 0
therapy O 0
. O 0

Three O 0
months O 0
later O 0
the O 0
patient O 0
was O 0
exposed O 0
to O 0
a O 0
single O 0
dose O 0
of O 0
metoprolol B-Chemical 1
, O 0
diltiazem B-Chemical 1
, O 0
propafenone B-Chemical 1
( O 0
since O 0
he O 0
had O 0
received O 0
this O 0
drug O 0
in O 0
the O 0
past O 0
) O 0
, O 0
and O 0
sparteine B-Chemical 1
( O 0
as O 0
a O 0
probe O 0
for O 0
the O 0
debrisoquine B-Chemical 1
/ O 0
sparteine B-Chemical 1
type O 0
polymorphism O 0
of O 0
oxidative O 0
drug O 0
metabolism O 0
) O 0
. O 0

It O 0
was O 0
found O 0
that O 0
he O 0
was O 0
a O 0
poor O 0
metabolizer O 0
of O 0
all O 0
four O 0
drugs O 0
, O 0
indicating O 0
that O 0
their O 0
metabolism O 0
is O 0
under O 0
the O 0
same O 0
genetic O 0
control O 0
. O 0

Therefore O 0
, O 0
patients O 0
belonging O 0
to O 0
the O 0
poor O 0
- O 0
metabolizer O 0
phenotype O 0
of O 0
sparteine B-Chemical 1
/ O 0
debrisoquine B-Chemical 1
polymorphism O 0
in O 0
drug O 0
metabolism O 0
, O 0
which O 0
constitutes O 0
6 O 0
. O 0
4 O 0
% O 0
of O 0
the O 0
German O 0
population O 0
, O 0
may O 0
experience O 0
adverse B-Disease 1
drug I-Disease 1
reactions I-Disease 1
when O 0
treated O 0
with O 0
standard O 0
doses O 0
of O 0
one O 0
of O 0
these O 0
drugs O 0
alone O 0
. O 0

Moreover O 0
, O 0
the O 0
coadministration O 0
of O 0
these O 0
frequently O 0
used O 0
drugs O 0
is O 0
expected O 0
to O 0
be O 0
especially O 0
harmful O 0
in O 0
this O 0
subgroup O 0
of O 0
patients O 0
. O 0

Clinical O 0
experiences O 0
in O 0
an O 0
open O 0
and O 0
a O 0
double O 0
- O 0
blind O 0
trial O 0
. O 0

A O 0
total O 0
of O 0
sixty O 0
patients O 0
were O 0
trated O 0
with O 0
bromperidol B-Chemical 1
first O 0
in O 0
open O 0
conditions O 0
( O 0
20 O 0
patients O 0
) O 0
, O 0
then O 0
on O 0
a O 0
double O 0
blind O 0
basis O 0
( O 0
40 O 0
patients O 0
) O 0
with O 0
haloperidol B-Chemical 1
as O 0
the O 0
reference O 0
substance O 0
. O 0

The O 0
open O 0
study O 0
lasted O 0
for O 0
four O 0
weeks O 0
; O 0
the O 0
drug O 0
was O 0
administrated O 0
in O 0
the O 0
form O 0
of O 0
1 O 0
mg O 0
tablets O 0
. O 0

The O 0
daily O 0
dose O 0
( O 0
initial O 0
dose O 0
: O 0
1 O 0
mg O 0
; O 0
mean O 0
dose O 0
at O 0
the O 0
end O 0
of O 0
the O 0
trial O 0
: O 0
4 O 0
. O 0
47 O 0
mg O 0
) O 0
was O 0
always O 0
administered O 0
in O 0
one O 0
single O 0
dose O 0
. O 0

Nineteen O 0
patients O 0
finished O 0
the O 0
trial O 0
, O 0
and O 0
in O 0
18 O 0
cases O 0
the O 0
therapeutic O 0
result O 0
was O 0
considered O 0
very O 0
good O 0
to O 0
good O 0
. O 0

These O 0
results O 0
were O 0
confirmed O 0
by O 0
statistical O 0
analysis O 0
. O 0

Nine O 0
patients O 0
exhibited O 0
mild O 0
to O 0
moderate O 0
extrapyramidal B-Disease 1
concomitant I-Disease 1
symptoms I-Disease 1
; O 0
no O 0
other O 0
side O 0
effects O 0
were O 0
observed O 0
. O 0

The O 0
results O 0
of O 0
detailed O 0
laboratory O 0
tests O 0
and O 0
evaluations O 0
of O 0
various O 0
quantitative O 0
and O 0
qualitative O 0
tolerability O 0
parameters O 0
were O 0
not O 0
indicative O 0
of O 0
toxic O 0
effects O 0
. O 0

In O 0
the O 0
double O 0
blind O 0
study O 0
with O 0
haloperidol B-Chemical 1
, O 0
both O 0
substances O 0
were O 0
found O 0
to O 0
be O 0
highly O 0
effective O 0
in O 0
the O 0
treatment O 0
of O 0
psychotic B-Disease 1
syndromes I-Disease 1
belonging I-Disease 1
predominantly I-Disease 1
to I-Disease 1
the I-Disease 1
schizophrenia I-Disease 1
group I-Disease 1
. O 0

Certain O 0
clues O 0
, O 0
including O 0
the O 0
onset O 0
of O 0
action O 0
, O 0
seem O 0
to O 0
be O 0
indicative O 0
of O 0
the O 0
superiority O 0
of O 0
bromperidol B-Chemical 1
. O 0

No O 0
differences O 0
were O 0
observed O 0
with O 0
respect O 0
to O 0
side O 0
effects O 0
and O 0
general O 0
tolerability O 0
. O 0

Prolonged O 0
cholestasis B-Disease 1
after O 0
troleandomycin B-Chemical 1
- O 0
induced O 0
acute O 0
hepatitis B-Disease 1
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
patient O 0
in O 0
whom O 0
troleandomycin B-Chemical 1
- O 0
induced O 0
hepatitis B-Disease 1
was O 0
followed O 0
by O 0
prolonged O 0
anicteric O 0
cholestasis B-Disease 1
. O 0

Jaundice B-Disease 1
occurred O 0
after O 0
administration O 0
of O 0
troleandomycin B-Chemical 1
for O 0
7 O 0
days O 0
and O 0
was O 0
associated O 0
with O 0
hypereosinophilia B-Disease 1
. O 0

Jaundice B-Disease 1
disappeared O 0
within O 0
3 O 0
months O 0
but O 0
was O 0
followed O 0
by O 0
prolonged O 0
anicteric O 0
cholestasis B-Disease 1
marked O 0
by O 0
pruritus B-Disease 1
and O 0
high O 0
levels O 0
of O 0
alkaline O 0
phosphatase O 0
and O 0
gammaglutamyltransferase O 0
activities O 0
. O 0

Finally O 0
, O 0
pruritus B-Disease 1
disappeared O 0
within O 0
19 O 0
months O 0
, O 0
and O 0
liver O 0
tests O 0
returned O 0
to O 0
normal O 0
27 O 0
months O 0
after O 0
the O 0
onset O 0
of O 0
hepatitis B-Disease 1
. O 0

This O 0
observation O 0
demonstrates O 0
that O 0
prolonged O 0
cholestasis B-Disease 1
can O 0
follow O 0
troleandomycin B-Chemical 1
- O 0
induced O 0
acute O 0
hepatitis B-Disease 1
. O 0

Serial O 0
studies O 0
of O 0
auditory B-Disease 1
neurotoxicity I-Disease 1
in O 0
patients O 0
receiving O 0
deferoxamine B-Chemical 1
therapy O 0
. O 0

Visual B-Disease 1
and I-Disease 1
auditory I-Disease 1
neurotoxicity I-Disease 1
was O 0
previously O 0
documented O 0
in O 0
42 O 0
of O 0
89 O 0
patients O 0
with O 0
transfusion O 0
- O 0
dependent O 0
anemia B-Disease 1
who O 0
were O 0
receiving O 0
iron B-Chemical 1
chelation O 0
therapy O 0
with O 0
daily O 0
subcutaneous O 0
deferoxamine B-Chemical 1
. O 0

Twenty O 0
- O 0
two O 0
patients O 0
in O 0
the O 0
affected O 0
group O 0
had O 0
abnormal B-Disease 1
audiograms I-Disease 1
with I-Disease 1
deficits I-Disease 1
mostly I-Disease 1
in I-Disease 1
the I-Disease 1
high I-Disease 1
frequency I-Disease 1
range I-Disease 1
of I-Disease 1
4 I-Disease 1
, I-Disease 1
000 I-Disease 1
to I-Disease 1
8 I-Disease 1
, I-Disease 1
000 I-Disease 1
Hz I-Disease 1
and O 0
in O 0
the O 0
hearing O 0
threshold O 0
levels O 0
of O 0
30 O 0
to O 0
100 O 0
decibels O 0
. O 0

When O 0
deferoxamine B-Chemical 1
therapy O 0
was O 0
discontinued O 0
and O 0
serial O 0
studies O 0
were O 0
performed O 0
, O 0
audiograms O 0
in O 0
seven O 0
cases O 0
reverted O 0
to O 0
normal O 0
or O 0
near O 0
normal O 0
within O 0
two O 0
to O 0
three O 0
weeks O 0
, O 0
and O 0
nine O 0
of O 0
13 O 0
patients O 0
with O 0
symptoms O 0
became O 0
asymptomatic O 0
. O 0

Audiograms O 0
from O 0
15 O 0
patients O 0
remained O 0
abnormal O 0
and O 0
four O 0
patients O 0
required O 0
hearing O 0
aids O 0
because O 0
of O 0
permanent B-Disease 1
disability I-Disease 1
. O 0

Since O 0
18 O 0
of O 0
the O 0
22 O 0
patients O 0
were O 0
initially O 0
receiving O 0
deferoxamine B-Chemical 1
doses O 0
in O 0
excess O 0
of O 0
the O 0
commonly O 0
recommended O 0
50 O 0
mg O 0
/ O 0
kg O 0
per O 0
dose O 0
, O 0
therapy O 0
was O 0
restarted O 0
with O 0
lower O 0
doses O 0
, O 0
usually O 0
50 O 0
mg O 0
/ O 0
kg O 0
per O 0
dose O 0
or O 0
less O 0
depending O 0
on O 0
the O 0
degree O 0
of O 0
auditory B-Disease 1
abnormality I-Disease 1
, O 0
and O 0
with O 0
the O 0
exception O 0
of O 0
two O 0
cases O 0
no O 0
further O 0
toxicity B-Disease 1
was O 0
demonstrated O 0
. O 0

Auditory O 0
deterioration O 0
and O 0
improvement O 0
, O 0
demonstrated O 0
serially O 0
in O 0
individual O 0
patients O 0
receiving O 0
and O 0
not O 0
receiving O 0
deferoxamine B-Chemical 1
, O 0
respectively O 0
, O 0
provided O 0
convincing O 0
evidence O 0
for O 0
a O 0
cause O 0
- O 0
and O 0
- O 0
effect O 0
relation O 0
between O 0
deferoxamine B-Chemical 1
administration O 0
and O 0
ototoxicity B-Disease 1
. O 0

Based O 0
on O 0
these O 0
data O 0
, O 0
a O 0
plan O 0
of O 0
management O 0
was O 0
developed O 0
that O 0
allows O 0
effective O 0
yet O 0
safe O 0
administration O 0
of O 0
deferoxamine B-Chemical 1
. O 0

A O 0
dose O 0
of O 0
50 O 0
mg O 0
/ O 0
kg O 0
is O 0
recommended O 0
in O 0
those O 0
without O 0
audiogram O 0
abnormalities O 0
. O 0

With O 0
mild O 0
toxicity B-Disease 1
, O 0
a O 0
reduction O 0
to O 0
30 O 0
or O 0
40 O 0
mg O 0
/ O 0
kg O 0
per O 0
dose O 0
should O 0
result O 0
in O 0
a O 0
reversal O 0
of O 0
the O 0
abnormal O 0
results O 0
to O 0
normal O 0
within O 0
four O 0
weeks O 0
. O 0

Moderate O 0
abnormalities O 0
require O 0
a O 0
reduction O 0
of O 0
deferoxamine B-Chemical 1
to O 0
25 O 0
mg O 0
/ O 0
kg O 0
per O 0
dose O 0
with O 0
careful O 0
monitoring O 0
. O 0

In O 0
those O 0
with O 0
symptoms O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
, O 0
the O 0
drug O 0
should O 0
be O 0
stopped O 0
for O 0
four O 0
weeks O 0
, O 0
and O 0
when O 0
the O 0
audiogram O 0
is O 0
stable O 0
or O 0
improved O 0
, O 0
therapy O 0
should O 0
be O 0
restarted O 0
at O 0
10 O 0
to O 0
25 O 0
mg O 0
/ O 0
kg O 0
per O 0
dose O 0
. O 0

Serial O 0
audiograms O 0
should O 0
be O 0
performed O 0
every O 0
six O 0
months O 0
in O 0
those O 0
without O 0
problems O 0
and O 0
more O 0
frequently O 0
in O 0
young O 0
patients O 0
with O 0
normal O 0
serum O 0
ferritin O 0
values O 0
and O 0
in O 0
those O 0
with O 0
auditory B-Disease 1
dysfunction I-Disease 1
. O 0

Lidocaine B-Chemical 1
- O 0
induced O 0
cardiac B-Disease 1
asystole I-Disease 1
. O 0

Intravenous O 0
administration O 0
of O 0
a O 0
single O 0
50 O 0
- O 0
mg O 0
bolus O 0
of O 0
lidocaine B-Chemical 1
in O 0
a O 0
67 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
resulted O 0
in O 0
profound O 0
depression B-Disease 1
of O 0
the O 0
activity O 0
of O 0
the O 0
sinoatrial O 0
and O 0
atrioventricular O 0
nodal O 0
pacemakers O 0
. O 0

The O 0
patient O 0
had O 0
no O 0
apparent O 0
associated O 0
conditions O 0
which O 0
might O 0
have O 0
predisposed O 0
him O 0
to O 0
the O 0
development O 0
of O 0
bradyarrhythmias B-Disease 1
; O 0
and O 0
, O 0
thus O 0
, O 0
this O 0
probably O 0
represented O 0
a O 0
true O 0
idiosyncrasy O 0
to O 0
lidocaine B-Chemical 1
. O 0

Flurbiprofen B-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
juvenile B-Disease 1
rheumatoid I-Disease 1
arthritis I-Disease 1
. O 0

Thirty O 0
- O 0
four O 0
patients O 0
with O 0
juvenile B-Disease 1
rheumatoid I-Disease 1
arthritis I-Disease 1
, O 0
who O 0
were O 0
treated O 0
with O 0
flurbiprofen B-Chemical 1
at O 0
a O 0
maximum O 0
dose O 0
of O 0
4 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
, O 0
had O 0
statistically O 0
significant O 0
decreases O 0
from O 0
baseline O 0
in O 0
6 O 0
arthritis B-Disease 1
indices O 0
after O 0
12 O 0
weeks O 0
of O 0
treatment O 0
. O 0

Improvements O 0
were O 0
seen O 0
in O 0
the O 0
number O 0
of O 0
tender B-Disease 1
joints I-Disease 1
, O 0
the O 0
severity O 0
of O 0
swelling B-Disease 1
and O 0
tenderness B-Disease 1
, O 0
the O 0
time O 0
of O 0
walk O 0
50 O 0
feet O 0
, O 0
the O 0
duration O 0
of O 0
morning B-Disease 1
stiffness I-Disease 1
and O 0
the O 0
circumference O 0
of O 0
the O 0
left O 0
knee O 0
. O 0

The O 0
most O 0
frequently O 0
observed O 0
side O 0
effect O 0
was O 0
fecal B-Disease 1
occult I-Disease 1
blood I-Disease 1
( O 0
25 O 0
% O 0
of O 0
patients O 0
) O 0
; O 0
however O 0
, O 0
there O 0
was O 0
no O 0
other O 0
evidence O 0
of O 0
gastrointestinal B-Disease 1
( I-Disease 1
GI I-Disease 1
) I-Disease 1
bleeding I-Disease 1
in O 0
these O 0
patients O 0
. O 0

One O 0
patient O 0
was O 0
prematurely O 0
discontinued O 0
from O 0
the O 0
study O 0
for O 0
severe O 0
headache B-Disease 1
and O 0
abdominal B-Disease 1
pain I-Disease 1
. O 0

Most O 0
side O 0
effects O 0
were O 0
mild O 0
and O 0
related O 0
to O 0
the O 0
GI O 0
tract O 0
. O 0

Hyperkalemia B-Disease 1
associated O 0
with O 0
sulindac B-Chemical 1
therapy O 0
. O 0

Hyperkalemia B-Disease 1
has O 0
recently O 0
been O 0
recognized O 0
as O 0
a O 0
complication O 0
of O 0
nonsteroidal O 0
antiinflammatory O 0
agents O 0
( O 0
NSAID O 0
) O 0
such O 0
as O 0
indomethacin B-Chemical 1
. O 0

Several O 0
recent O 0
studies O 0
have O 0
stressed O 0
the O 0
renal O 0
sparing O 0
features O 0
of O 0
sulindac B-Chemical 1
, O 0
owing O 0
to O 0
its O 0
lack O 0
of O 0
interference O 0
with O 0
renal O 0
prostacyclin B-Chemical 1
synthesis O 0
. O 0

We O 0
describe O 0
4 O 0
patients O 0
in O 0
whom O 0
hyperkalemia B-Disease 1
ranging O 0
from O 0
6 O 0
. O 0
1 O 0
to O 0
6 O 0
. O 0
9 O 0
mEq O 0
/ O 0
l O 0
developed O 0
within O 0
3 O 0
to O 0
8 O 0
days O 0
of O 0
sulindac B-Chemical 1
administration O 0
. O 0

In O 0
all O 0
of O 0
them O 0
normal O 0
serum O 0
potassium B-Chemical 1
levels O 0
reached O 0
within O 0
2 O 0
to O 0
4 O 0
days O 0
of O 0
stopping O 0
sulindac B-Chemical 1
. O 0

As O 0
no O 0
other O 0
medications O 0
known O 0
to O 0
effect O 0
serum O 0
potassium B-Chemical 1
had O 0
been O 0
given O 0
concomitantly O 0
, O 0
this O 0
course O 0
of O 0
events O 0
is O 0
suggestive O 0
of O 0
a O 0
cause O 0
- O 0
and O 0
- O 0
effect O 0
relationship O 0
between O 0
sulindac B-Chemical 1
and O 0
hyperkalemia B-Disease 1
. O 0

These O 0
observations O 0
indicate O 0
that O 0
initial O 0
hopes O 0
that O 0
sulindac B-Chemical 1
may O 0
not O 0
be O 0
associated O 0
with O 0
the O 0
adverse O 0
renal O 0
effects O 0
of O 0
other O 0
NSAID O 0
are O 0
probably O 0
not O 0
justified O 0
. O 0

Drug O 0
- O 0
induced O 0
arterial O 0
spasm B-Disease 1
relieved O 0
by O 0
lidocaine B-Chemical 1
. O 0

Case O 0
report O 0
. O 0

Following O 0
major O 0
intracranial O 0
surgery O 0
in O 0
a O 0
35 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
, O 0
sodium B-Chemical 1
pentothal I-Chemical 1
was O 0
intravenously O 0
infused O 0
to O 0
minimize O 0
cerebral B-Disease 1
ischaemia I-Disease 1
. O 0

Intense O 0
vasospasm B-Disease 1
with O 0
threatened O 0
gangrene B-Disease 1
arose O 0
in O 0
the O 0
arm O 0
used O 0
for O 0
the O 0
infusion O 0
. O 0

Since O 0
the O 0
cranial O 0
condition O 0
precluded O 0
use O 0
of O 0
more O 0
usual O 0
methods O 0
, O 0
lidocaine B-Chemical 1
was O 0
given O 0
intra O 0
- O 0
arterially O 0
, O 0
with O 0
careful O 0
cardiovascular O 0
monitoring O 0
, O 0
to O 0
counteract O 0
the O 0
vasospasm B-Disease 1
. O 0

The O 0
treatment O 0
was O 0
rapidly O 0
successful O 0
. O 0

Regional O 0
localization O 0
of O 0
the O 0
antagonism O 0
of O 0
amphetamine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
by O 0
intracerebral O 0
calcitonin B-Chemical 1
injections O 0
. O 0

Calcitonin B-Chemical 1
receptors O 0
are O 0
found O 0
in O 0
the O 0
brain O 0
, O 0
and O 0
intracerebral O 0
infusions O 0
of O 0
calcitonin B-Chemical 1
can O 0
produce O 0
behavioral O 0
effects O 0
. O 0

Among O 0
these O 0
behavioral O 0
effects O 0
are O 0
decreases O 0
in O 0
food O 0
intake O 0
and O 0
decreases O 0
in O 0
amphetamine B-Chemical 1
- O 0
induced O 0
locomotor O 0
activity O 0
. O 0

In O 0
previous O 0
experiments O 0
we O 0
found O 0
that O 0
decreases O 0
in O 0
food O 0
intake O 0
were O 0
induced O 0
by O 0
local O 0
administration O 0
of O 0
calcitonin B-Chemical 1
into O 0
several O 0
hypothalamic O 0
sites O 0
and O 0
into O 0
the O 0
nucleus O 0
accumbens O 0
. O 0

In O 0
the O 0
present O 0
experiment O 0
calcitonin B-Chemical 1
decreased O 0
locomotor O 0
activity O 0
when O 0
locally O 0
injected O 0
into O 0
the O 0
same O 0
sites O 0
where O 0
it O 0
decreases O 0
food O 0
intake O 0
. O 0

The O 0
areas O 0
where O 0
calcitonin B-Chemical 1
is O 0
most O 0
effective O 0
in O 0
decreasing O 0
locomotor O 0
activity O 0
are O 0
located O 0
in O 0
the O 0
hypothalamus O 0
and O 0
nucleus O 0
accumbens O 0
, O 0
suggesting O 0
that O 0
these O 0
areas O 0
are O 0
the O 0
major O 0
sites O 0
of O 0
action O 0
of O 0
calcitonin B-Chemical 1
in O 0
inhibiting O 0
amphetamine B-Chemical 1
- O 0
induced O 0
locomotor O 0
activity O 0
. O 0

The O 0
hematologic O 0
effects O 0
of O 0
cefonicid B-Chemical 1
and O 0
cefazedone B-Chemical 1
in O 0
the O 0
dog O 0
: O 0
a O 0
potential O 0
model O 0
of O 0
cephalosporin B-Chemical 1
hematotoxicity B-Disease 1
in O 0
man O 0
. O 0

Cephalosporin B-Chemical 1
antibiotics O 0
cause O 0
a O 0
variety O 0
of O 0
hematologic B-Disease 1
disturbances I-Disease 1
in O 0
man O 0
, O 0
the O 0
pathogeneses O 0
and O 0
hematopathology O 0
of O 0
which O 0
remain O 0
poorly O 0
characterized O 0
. O 0

There O 0
is O 0
a O 0
need O 0
for O 0
a O 0
well O 0
- O 0
defined O 0
animal O 0
model O 0
in O 0
which O 0
these O 0
blood B-Disease 1
dyscrasias I-Disease 1
can O 0
be O 0
studied O 0
. O 0

In O 0
four O 0
subacute O 0
toxicity B-Disease 1
studies O 0
, O 0
the O 0
intravenous O 0
administration O 0
of O 0
cefonicid B-Chemical 1
or O 0
cefazedone B-Chemical 1
to O 0
beagle O 0
dogs O 0
caused O 0
a O 0
dose O 0
- O 0
dependent O 0
incidence O 0
of O 0
anemia B-Disease 1
, O 0
neutropenia B-Disease 1
, O 0
and O 0
thrombocytopenia B-Disease 1
after O 0
1 O 0
- O 0
3 O 0
months O 0
of O 0
treatment O 0
. O 0

A O 0
nonregenerative O 0
anemia B-Disease 1
was O 0
the O 0
most O 0
compromising O 0
of O 0
the O 0
cytopenias B-Disease 1
and O 0
occurred O 0
in O 0
approximately O 0
50 O 0
% O 0
of O 0
dogs O 0
receiving O 0
400 O 0
- O 0
500 O 0
mg O 0
/ O 0
kg O 0
cefonicid B-Chemical 1
or O 0
540 O 0
- O 0
840 O 0
mg O 0
/ O 0
kg O 0
cefazedone B-Chemical 1
. O 0

All O 0
three O 0
cytopenias B-Disease 1
were O 0
completely O 0
reversible O 0
following O 0
cessation O 0
of O 0
treatment O 0
; O 0
the O 0
time O 0
required O 0
for O 0
recovery O 0
of O 0
the O 0
erythron O 0
( O 0
approximately O 0
1 O 0
month O 0
) O 0
was O 0
considerably O 0
longer O 0
than O 0
that O 0
of O 0
the O 0
granulocytes O 0
and O 0
platelets O 0
( O 0
hours O 0
to O 0
a O 0
few O 0
days O 0
) O 0
. O 0

Upon O 0
rechallenge O 0
with O 0
either O 0
cephalosporin B-Chemical 1
, O 0
the O 0
hematologic B-Disease 1
syndrome I-Disease 1
was O 0
reproduced O 0
in O 0
most O 0
dogs O 0
tested O 0
; O 0
cefonicid B-Chemical 1
( O 0
but O 0
not O 0
cefazedone B-Chemical 1
) O 0
- O 0
treated O 0
dogs O 0
showed O 0
a O 0
substantially O 0
reduced O 0
induction O 0
period O 0
( O 0
15 O 0
+ O 0
/ O 0
- O 0
5 O 0
days O 0
) O 0
compared O 0
to O 0
that O 0
of O 0
the O 0
first O 0
exposure O 0
to O 0
the O 0
drug O 0
( O 0
61 O 0
+ O 0
/ O 0
- O 0
24 O 0
days O 0
) O 0
. O 0

This O 0
observation O 0
, O 0
along O 0
with O 0
the O 0
rapid O 0
rate O 0
of O 0
decline O 0
in O 0
red O 0
cell O 0
mass O 0
parameters O 0
of O 0
affected O 0
dogs O 0
, O 0
suggests O 0
that O 0
a O 0
hemolytic B-Disease 1
component O 0
complicated O 0
the O 0
red O 0
cell O 0
production O 0
problem O 0
and O 0
that O 0
multiple O 0
toxicologic O 0
mechanisms O 0
contributed O 0
to O 0
the O 0
cytopenia B-Disease 1
. O 0

We O 0
conclude O 0
that O 0
the O 0
administration O 0
of O 0
high O 0
doses O 0
of O 0
cefonicid B-Chemical 1
or O 0
cefazedone B-Chemical 1
to O 0
dogs O 0
can O 0
induce O 0
hematotoxicity B-Disease 1
similar O 0
to O 0
the O 0
cephalosporin B-Chemical 1
- O 0
induced O 0
blood B-Disease 1
dyscrasias I-Disease 1
described O 0
in O 0
man O 0
and O 0
thus O 0
provides O 0
a O 0
useful O 0
model O 0
for O 0
studying O 0
the O 0
mechanisms O 0
of O 0
these O 0
disorders O 0
. O 0

Cerebral O 0
blood O 0
flow O 0
and O 0
metabolism O 0
during O 0
isoflurane B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
in O 0
patients O 0
subjected O 0
to O 0
surgery O 0
for O 0
cerebral B-Disease 1
aneurysms I-Disease 1
. O 0

Cerebral O 0
blood O 0
flow O 0
and O 0
cerebral O 0
metabolic O 0
rate O 0
for O 0
oxygen B-Chemical 1
were O 0
measured O 0
during O 0
isoflurane B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
in O 0
10 O 0
patients O 0
subjected O 0
to O 0
craniotomy O 0
for O 0
clipping O 0
of O 0
a O 0
cerebral B-Disease 1
aneurysm I-Disease 1
. O 0

Flow O 0
and O 0
metabolism O 0
were O 0
measured O 0
5 O 0
- O 0
13 O 0
days O 0
after O 0
the O 0
subarachnoid B-Disease 1
haemorrhage I-Disease 1
by O 0
a O 0
modification O 0
of O 0
the O 0
classical O 0
Kety O 0
- O 0
Schmidt O 0
technique O 0
using O 0
xenon B-Chemical 1
- O 0
133 O 0
i O 0
. O 0
v O 0
. O 0
Anaesthesia O 0
was O 0
maintained O 0
with O 0
an O 0
inspired O 0
isoflurane B-Chemical 1
concentration O 0
of O 0
0 O 0
. O 0
75 O 0
% O 0
( O 0
plus O 0
67 O 0
% O 0
nitrous B-Chemical 1
oxide I-Chemical 1
in O 0
oxygen B-Chemical 1
) O 0
, O 0
during O 0
which O 0
CBF O 0
and O 0
CMRO2 O 0
were O 0
34 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
1 O 0
ml O 0
/ O 0
100 O 0
g O 0
min O 0
- O 0
1 O 0
and O 0
2 O 0
. O 0
32 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
16 O 0
ml O 0
/ O 0
100 O 0
g O 0
min O 0
- O 0
1 O 0
at O 0
PaCO2 O 0
4 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
1 O 0
kPa O 0
( O 0
mean O 0
+ O 0
/ O 0
- O 0
SEM O 0
) O 0
. O 0

Controlled O 0
hypotension B-Disease 1
to O 0
an O 0
average O 0
MAP O 0
of O 0
50 O 0
- O 0
55 O 0
mm O 0
Hg B-Chemical 1
was O 0
induced O 0
by O 0
increasing O 0
the O 0
dose O 0
of O 0
isoflurane B-Chemical 1
, O 0
and O 0
maintained O 0
at O 0
an O 0
inspired O 0
concentration O 0
of O 0
2 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
2 O 0
% O 0
. O 0

This O 0
resulted O 0
in O 0
a O 0
significant O 0
decrease O 0
in O 0
CMRO2 O 0
( O 0
to O 0
1 O 0
. O 0
73 O 0
+ O 0
/ O 0
- O 0
0 O 0
. O 0
16 O 0
ml O 0
/ O 0
100 O 0
g O 0
min O 0
- O 0
1 O 0
) O 0
, O 0
while O 0
CBF O 0
was O 0
unchanged O 0
. O 0

After O 0
the O 0
clipping O 0
of O 0
the O 0
aneurysm B-Disease 1
the O 0
isoflurane B-Chemical 1
concentration O 0
was O 0
reduced O 0
to O 0
0 O 0
. O 0
75 O 0
% O 0
. O 0

There O 0
was O 0
a O 0
significant O 0
increase O 0
in O 0
CBF O 0
, O 0
although O 0
CMRO2 O 0
was O 0
unchanged O 0
, O 0
compared O 0
with O 0
pre O 0
- O 0
hypotensive B-Disease 1
values O 0
. O 0

These O 0
changes O 0
might O 0
offer O 0
protection O 0
to O 0
brain O 0
tissue O 0
during O 0
periods O 0
of O 0
induced O 0
hypotension B-Disease 1
. O 0

Triazolam B-Chemical 1
- O 0
induced O 0
brief O 0
episodes O 0
of O 0
secondary O 0
mania B-Disease 1
in O 0
a O 0
depressed B-Disease 1
patient O 0
. O 0

Large O 0
doses O 0
of O 0
triazolam B-Chemical 1
repeatedly O 0
induced O 0
brief O 0
episodes O 0
of O 0
mania B-Disease 1
in O 0
a O 0
depressed B-Disease 1
elderly O 0
woman O 0
. O 0

Features O 0
of O 0
organic B-Disease 1
mental I-Disease 1
disorder I-Disease 1
( O 0
delirium B-Disease 1
) O 0
were O 0
not O 0
present O 0
. O 0

Manic B-Disease 1
excitement O 0
was O 0
coincident O 0
with O 0
the O 0
duration O 0
of O 0
action O 0
of O 0
triazolam B-Chemical 1
. O 0

The O 0
possible O 0
contribution O 0
of O 0
the O 0
triazolo B-Chemical 1
group O 0
to O 0
changes O 0
in O 0
affective O 0
status O 0
is O 0
discussed O 0
. O 0

The O 0
correlation O 0
between O 0
neurotoxic B-Disease 1
esterase O 0
inhibition O 0
and O 0
mipafox B-Chemical 1
- O 0
induced O 0
neuropathic B-Disease 1
damage I-Disease 1
in O 0
rats O 0
. O 0

The O 0
correlation O 0
between O 0
neuropathic B-Disease 1
damage I-Disease 1
and O 0
inhibition O 0
of O 0
neurotoxic B-Disease 1
esterase O 0
or O 0
neuropathy B-Disease 1
target O 0
enzyme O 0
( O 0
NTE O 0
) O 0
was O 0
examined O 0
in O 0
rats O 0
acutely O 0
exposed O 0
to O 0
Mipafox B-Chemical 1
( O 0
N B-Chemical 1
, I-Chemical 1
N I-Chemical 1
' I-Chemical 1
- I-Chemical 1
diisopropylphosphorodiamidofluoridate I-Chemical 1
) O 0
, O 0
a O 0
neurotoxic B-Disease 1
organophosphate B-Chemical 1
. O 0

Brain O 0
and O 0
spinal O 0
cord O 0
NTE O 0
activities O 0
were O 0
measured O 0
in O 0
Long O 0
- O 0
Evans O 0
male O 0
rats O 0
1 O 0
hr O 0
post O 0
- O 0
exposure O 0
to O 0
various O 0
dosages O 0
of O 0
Mipafox B-Chemical 1
( O 0
ip O 0
, O 0
1 O 0
- O 0
15 O 0
mg O 0
/ O 0
kg O 0
) O 0
. O 0

These O 0
data O 0
were O 0
correlated O 0
with O 0
histologically O 0
scored O 0
cervical O 0
cord B-Disease 1
damage I-Disease 1
in O 0
a O 0
separate O 0
group O 0
of O 0
similarly O 0
dosed O 0
rats O 0
sampled O 0
14 O 0
- O 0
21 O 0
days O 0
post O 0
- O 0
exposure O 0
. O 0

Those O 0
dosages O 0
( O 0
greater O 0
than O 0
or O 0
equal O 0
to O 0
10 O 0
mg O 0
/ O 0
kg O 0
) O 0
that O 0
inhibited O 0
mean O 0
NTE O 0
activity O 0
in O 0
the O 0
spinal O 0
cord O 0
greater O 0
than O 0
or O 0
equal O 0
to O 0
73 O 0
% O 0
and O 0
brain O 0
greater O 0
than O 0
or O 0
equal O 0
to O 0
67 O 0
% O 0
of O 0
control O 0
values O 0
produced O 0
severe O 0
( O 0
greater O 0
than O 0
or O 0
equal O 0
to O 0
3 O 0
) O 0
cervical O 0
cord O 0
pathology O 0
in O 0
85 O 0
% O 0
of O 0
the O 0
rats O 0
. O 0

In O 0
contrast O 0
, O 0
dosages O 0
of O 0
Mipafox B-Chemical 1
( O 0
less O 0
than O 0
or O 0
equal O 0
to O 0
5 O 0
mg O 0
/ O 0
kg O 0
) O 0
which O 0
inhibited O 0
mean O 0
NTE O 0
activity O 0
in O 0
spinal O 0
cord O 0
less O 0
than O 0
or O 0
equal O 0
to O 0
61 O 0
% O 0
and O 0
brain O 0
less O 0
than O 0
or O 0
equal O 0
to O 0
60 O 0
% O 0
produced O 0
this O 0
degree O 0
of O 0
cord B-Disease 1
damage I-Disease 1
in O 0
only O 0
9 O 0
% O 0
of O 0
the O 0
animals O 0
. O 0

These O 0
data O 0
indicate O 0
that O 0
a O 0
critical O 0
percentage O 0
of O 0
NTE O 0
inhibition O 0
in O 0
brain O 0
and O 0
spinal O 0
cord O 0
sampled O 0
shortly O 0
after O 0
Mipafox B-Chemical 1
exposure O 0
can O 0
predict O 0
neuropathic B-Disease 1
damage I-Disease 1
in O 0
rats O 0
several O 0
weeks O 0
later O 0
. O 0

Allergic B-Disease 1
reaction I-Disease 1
to O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
infusion O 0
. O 0

An O 0
allergic B-Disease 1
reaction I-Disease 1
consisting O 0
of O 0
angioneurotic B-Disease 1
edema I-Disease 1
secondary O 0
to O 0
continuous O 0
infusion O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
occurred O 0
in O 0
a O 0
patient O 0
with O 0
recurrent O 0
carcinoma B-Disease 1
of I-Disease 1
the I-Disease 1
oral I-Disease 1
cavity I-Disease 1
, O 0
cirrhosis B-Disease 1
, O 0
and O 0
cisplatin B-Chemical 1
- O 0
induced O 0
impaired B-Disease 1
renal I-Disease 1
function I-Disease 1
. O 0

This O 0
reaction O 0
occurred O 0
during O 0
the O 0
sixth O 0
and O 0
seventh O 0
courses O 0
of O 0
infusional O 0
chemotherapy O 0
. O 0

Oral O 0
diphenhydramine B-Chemical 1
and O 0
prednisone B-Chemical 1
were O 0
ineffective O 0
in O 0
preventing O 0
the O 0
recurrence O 0
of O 0
the O 0
allergic B-Disease 1
reaction I-Disease 1
. O 0

Discontinuance O 0
of O 0
effective O 0
chemotherapy O 0
in O 0
this O 0
patient O 0
during O 0
partial O 0
remission O 0
resulted O 0
in O 0
fatal O 0
disease O 0
progression O 0
. O 0

Myasthenia B-Disease 1
gravis I-Disease 1
caused O 0
by O 0
penicillamine B-Chemical 1
and O 0
chloroquine B-Chemical 1
therapy O 0
for O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
. O 0

We O 0
have O 0
described O 0
a O 0
unique O 0
patient O 0
who O 0
had O 0
reversible O 0
and O 0
dose O 0
- O 0
related O 0
myasthenia B-Disease 1
gravis I-Disease 1
after O 0
penicillamine B-Chemical 1
and O 0
chloroquine B-Chemical 1
therapy O 0
for O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
. O 0

Although O 0
acetylcholine B-Chemical 1
receptor O 0
antibodies O 0
were O 0
not O 0
detectable O 0
, O 0
the O 0
time O 0
course O 0
was O 0
consistent O 0
with O 0
an O 0
autoimmune O 0
process O 0
. O 0

On O 0
the O 0
mechanisms O 0
of O 0
the O 0
development O 0
of O 0
tolerance O 0
to O 0
the O 0
muscular B-Disease 1
rigidity I-Disease 1
produced O 0
by O 0
morphine B-Chemical 1
in O 0
rats O 0
. O 0

The O 0
development O 0
of O 0
tolerance O 0
to O 0
the O 0
muscular B-Disease 1
rigidity I-Disease 1
produced O 0
by O 0
morphine B-Chemical 1
was O 0
studied O 0
in O 0
rats O 0
. O 0

Saline O 0
- O 0
pretreated O 0
controls O 0
given O 0
a O 0
test O 0
dose O 0
of O 0
morphine B-Chemical 1
( O 0
20 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
showed O 0
a O 0
pronounced O 0
rigidity B-Disease 1
recorded O 0
as O 0
tonic O 0
activity O 0
in O 0
the O 0
electromyogram O 0
. O 0

Rats O 0
treated O 0
for O 0
11 O 0
days O 0
with O 0
morphine B-Chemical 1
and O 0
withdrawn O 0
for O 0
36 O 0
- O 0
40 O 0
h O 0
showed O 0
differences O 0
in O 0
the O 0
development O 0
of O 0
tolerance O 0
: O 0
about O 0
half O 0
of O 0
the O 0
animals O 0
showed O 0
a O 0
rigidity B-Disease 1
after O 0
the O 0
test O 0
dose O 0
of O 0
morphine B-Chemical 1
that O 0
was O 0
not O 0
significantly O 0
less O 0
than O 0
in O 0
the O 0
controls O 0
and O 0
were O 0
akinetic B-Disease 1
( O 0
A O 0
group O 0
) O 0
. O 0

The O 0
other O 0
rats O 0
showed O 0
a O 0
strong O 0
decrease O 0
in O 0
the O 0
rigidity B-Disease 1
and O 0
the O 0
occurrence O 0
of O 0
stereotyped O 0
( O 0
S O 0
) O 0
licking O 0
and O 0
/ O 0
or O 0
gnawing O 0
in O 0
presence O 0
of O 0
akinetic B-Disease 1
or O 0
hyperkinetic B-Disease 1
( O 0
K O 0
) O 0
behaviour O 0
( O 0
AS O 0
/ O 0
KS O 0
group O 0
) O 0
, O 0
suggesting O 0
signs O 0
of O 0
dopaminergic O 0
activation O 0
. O 0

The O 0
rigidity B-Disease 1
was O 0
considerably O 0
decreased O 0
in O 0
both O 0
groups O 0
after O 0
20 O 0
days O 0
' O 0
treatment O 0
. O 0

In O 0
a O 0
further O 0
series O 0
of O 0
experiments O 0
, O 0
haloperidol B-Chemical 1
( O 0
0 O 0
. O 0
2 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
p O 0
. O 0
) O 0
was O 0
used O 0
in O 0
order O 0
to O 0
block O 0
the O 0
dopaminergic O 0
activation O 0
and O 0
to O 0
estimate O 0
the O 0
real O 0
degree O 0
of O 0
the O 0
tolerance O 0
to O 0
the O 0
rigidity B-Disease 1
without O 0
any O 0
dopaminergic O 0
interference O 0
. O 0

Haloperidol B-Chemical 1
enhanced O 0
the O 0
rigidity B-Disease 1
in O 0
the O 0
A O 0
group O 0
. O 0

However O 0
, O 0
the O 0
level O 0
in O 0
the O 0
AS O 0
/ O 0
KS O 0
group O 0
remained O 0
considerably O 0
lower O 0
than O 0
in O 0
the O 0
A O 0
group O 0
. O 0

The O 0
results O 0
suggest O 0
that O 0
rigidity B-Disease 1
, O 0
which O 0
is O 0
assumed O 0
to O 0
be O 0
due O 0
to O 0
an O 0
action O 0
of O 0
morphine B-Chemical 1
in O 0
the O 0
striatum O 0
, O 0
can O 0
be O 0
antagonized O 0
by O 0
another O 0
process O 0
leading O 0
to O 0
dopaminergic O 0
activation O 0
in O 0
the O 0
striatum O 0
. O 0

Nevertheless O 0
, O 0
there O 0
occurs O 0
some O 0
real O 0
tolerance O 0
to O 0
this O 0
effect O 0
. O 0

The O 0
rapid O 0
alternations O 0
of O 0
rigidity B-Disease 1
and O 0
the O 0
signs O 0
of O 0
dopaminergic O 0
activation O 0
observed O 0
in O 0
the O 0
animals O 0
of O 0
the O 0
AS O 0
/ O 0
KS O 0
group O 0
might O 0
be O 0
due O 0
to O 0
rapid O 0
shifts O 0
in O 0
the O 0
predominance O 0
of O 0
various O 0
DA O 0
- O 0
innervated O 0
structures O 0
. O 0

A O 0
case O 0
of O 0
massive O 0
rhabdomyolysis B-Disease 1
following O 0
molindone B-Chemical 1
administration O 0
. O 0

Rhabdomyolysis B-Disease 1
is O 0
a O 0
potentially O 0
lethal O 0
syndrome O 0
that O 0
psychiatric B-Disease 1
patients O 0
seem O 0
predisposed O 0
to O 0
develop O 0
. O 0

The O 0
clinical O 0
signs O 0
and O 0
symptoms O 0
, O 0
typical O 0
laboratory O 0
features O 0
, O 0
and O 0
complications O 0
of O 0
rhabdomyolysis B-Disease 1
are O 0
presented O 0
. O 0

The O 0
case O 0
of O 0
a O 0
schizophrenic B-Disease 1
patient O 0
is O 0
reported O 0
to O 0
illustrate O 0
massive O 0
rhabdomyolysis B-Disease 1
and O 0
subsequent O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
following O 0
molindone B-Chemical 1
administration O 0
. O 0

Physicians O 0
who O 0
prescribe O 0
molindone B-Chemical 1
should O 0
be O 0
aware O 0
of O 0
this O 0
reaction O 0
. O 0

Compression B-Disease 1
neuropathy I-Disease 1
of I-Disease 1
the I-Disease 1
radial I-Disease 1
nerve I-Disease 1
due O 0
to O 0
pentazocine B-Chemical 1
- O 0
induced O 0
fibrous B-Disease 1
myopathy I-Disease 1
. O 0

Fibrous B-Disease 1
myopathy I-Disease 1
is O 0
a O 0
common O 0
, O 0
well O 0
- O 0
known O 0
side O 0
effect O 0
of O 0
repeated O 0
pentazocine B-Chemical 1
injection O 0
. O 0

However O 0
, O 0
compression B-Disease 1
neuropathy I-Disease 1
due O 0
to O 0
fibrotic O 0
muscle O 0
affected O 0
by O 0
pentazocine B-Chemical 1
- O 0
induced O 0
myopathy B-Disease 1
has O 0
not O 0
previously O 0
been O 0
reported O 0
. O 0

In O 0
a O 0
37 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
with O 0
documented O 0
pentazocine B-Chemical 1
- O 0
induced O 0
fibrous B-Disease 1
myopathy I-Disease 1
of O 0
triceps O 0
and O 0
deltoid O 0
muscles O 0
bilaterally O 0
and O 0
a O 0
three O 0
- O 0
week O 0
history O 0
of O 0
right O 0
wrist O 0
drop O 0
, O 0
electrodiagnostic O 0
examination O 0
showed O 0
a O 0
severe O 0
but O 0
partial O 0
lesion O 0
of O 0
the O 0
right O 0
radial O 0
nerve O 0
distal O 0
to O 0
the O 0
branches O 0
to O 0
the O 0
triceps O 0
, O 0
in O 0
addition O 0
to O 0
the O 0
fibrous B-Disease 1
myopathy I-Disease 1
. O 0

Surgery O 0
revealed O 0
the O 0
right O 0
radial O 0
nerve O 0
to O 0
be O 0
severely O 0
compressed O 0
by O 0
the O 0
densely O 0
fibrotic O 0
lateral O 0
head O 0
of O 0
the O 0
triceps O 0
. O 0

Decompression O 0
and O 0
neurolysis O 0
were O 0
performed O 0
with O 0
good O 0
subsequent O 0
recovery O 0
of O 0
function O 0
. O 0

Recurrent O 0
reversible O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
from O 0
amphotericin B-Chemical 1
. O 0

A O 0
patient O 0
with O 0
cryptogenic O 0
cirrhosis B-Disease 1
and O 0
disseminated O 0
sporotrichosis B-Disease 1
developed O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
immediately O 0
following O 0
the O 0
administration O 0
of O 0
amphotericin B-Chemical 1
B I-Chemical 1
on O 0
four O 0
separate O 0
occasions O 0
. O 0

The O 0
abruptness O 0
of O 0
the O 0
renal B-Disease 1
failure I-Disease 1
and O 0
its O 0
reversibility O 0
within O 0
days O 0
suggests O 0
that O 0
there O 0
was O 0
a O 0
functional O 0
component O 0
to O 0
the O 0
renal B-Disease 1
dysfunction I-Disease 1
. O 0

We O 0
propose O 0
that O 0
amphotericin B-Chemical 1
, O 0
in O 0
the O 0
setting O 0
of O 0
reduced O 0
effective O 0
arterial O 0
volume O 0
, O 0
may O 0
activate O 0
tubuloglomerular O 0
feedback O 0
, O 0
thereby O 0
contributing O 0
to O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
. O 0

Cerebral B-Disease 1
infarction I-Disease 1
with O 0
a O 0
single O 0
oral O 0
dose O 0
of O 0
phenylpropanolamine B-Chemical 1
. O 0

Phenylpropanolamine B-Chemical 1
( O 0
PPA B-Chemical 1
) O 0
, O 0
a O 0
synthetic O 0
sympathomimetic O 0
that O 0
is O 0
structurally O 0
similar O 0
to O 0
amphetamine B-Chemical 1
, O 0
is O 0
available O 0
over O 0
the O 0
counter O 0
in O 0
anorectics O 0
, O 0
nasal O 0
congestants O 0
, O 0
and O 0
cold O 0
preparations O 0
. O 0

Its O 0
prolonged O 0
use O 0
or O 0
overuse O 0
has O 0
been O 0
associated O 0
with O 0
seizures B-Disease 1
, O 0
intracerebral B-Disease 1
hemorrhage I-Disease 1
, O 0
neuropsychiatric B-Disease 1
symptoms I-Disease 1
, O 0
and O 0
nonhemorrhagic O 0
cerebral B-Disease 1
infarction I-Disease 1
. O 0

We O 0
report O 0
the O 0
case O 0
of O 0
a O 0
young O 0
woman O 0
who O 0
suffered O 0
a O 0
cerebral B-Disease 1
infarction I-Disease 1
after O 0
taking O 0
a O 0
single O 0
oral O 0
dose O 0
of O 0
PPA B-Chemical 1
. O 0

Remission O 0
induction O 0
of O 0
meningeal B-Disease 1
leukemia I-Disease 1
with O 0
high O 0
- O 0
dose O 0
intravenous O 0
methotrexate B-Chemical 1
. O 0

Twenty O 0
children O 0
with O 0
acute B-Disease 1
lymphoblastic I-Disease 1
leukemia I-Disease 1
who O 0
developed O 0
meningeal B-Disease 1
disease I-Disease 1
were O 0
treated O 0
with O 0
a O 0
high O 0
- O 0
dose O 0
intravenous O 0
methotrexate B-Chemical 1
regimen O 0
that O 0
was O 0
designed O 0
to O 0
achieve O 0
and O 0
maintain O 0
CSF O 0
methotrexate B-Chemical 1
concentrations O 0
of O 0
10 O 0
( O 0
- O 0
5 O 0
) O 0
mol O 0
/ O 0
L O 0
without O 0
the O 0
need O 0
for O 0
concomitant O 0
intrathecal O 0
dosing O 0
. O 0

The O 0
methotrexate B-Chemical 1
was O 0
administered O 0
as O 0
a O 0
loading O 0
dose O 0
of O 0
6 O 0
, O 0
000 O 0
mg O 0
/ O 0
m2 O 0
for O 0
a O 0
period O 0
of O 0
one O 0
hour O 0
followed O 0
by O 0
an O 0
infusion O 0
of O 0
1 O 0
, O 0
200 O 0
mg O 0
/ O 0
m2 O 0
/ O 0
h O 0
for O 0
23 O 0
hours O 0
. O 0

Leucovorin B-Chemical 1
rescue O 0
was O 0
initiated O 0
12 O 0
hours O 0
after O 0
the O 0
end O 0
of O 0
the O 0
infusion O 0
with O 0
a O 0
loading O 0
dose O 0
of O 0
200 O 0
mg O 0
/ O 0
m2 O 0
followed O 0
by O 0
12 O 0
mg O 0
/ O 0
m2 O 0
every O 0
three O 0
hours O 0
for O 0
six O 0
doses O 0
and O 0
then O 0
every O 0
six O 0
hours O 0
until O 0
the O 0
plasma O 0
methotrexate B-Chemical 1
level O 0
decreased O 0
to O 0
less O 0
than O 0
1 O 0
X O 0
10 O 0
( O 0
- O 0
7 O 0
) O 0
mol O 0
/ O 0
L O 0
. O 0

The O 0
mean O 0
steady O 0
- O 0
state O 0
plasma O 0
and O 0
CSF O 0
methotrexate B-Chemical 1
concentrations O 0
achieved O 0
were O 0
1 O 0
. O 0
1 O 0
X O 0
10 O 0
( O 0
- O 0
3 O 0
) O 0
mol O 0
/ O 0
L O 0
and O 0
3 O 0
. O 0
6 O 0
X O 0
10 O 0
( O 0
- O 0
5 O 0
) O 0
mol O 0
/ O 0
L O 0
, O 0
respectively O 0
. O 0

All O 0
20 O 0
patients O 0
responded O 0
to O 0
this O 0
regimen O 0
, O 0
16 O 0
/ O 0
20 O 0
( O 0
80 O 0
% O 0
) O 0
achieved O 0
a O 0
complete O 0
remission O 0
, O 0
and O 0
20 O 0
% O 0
obtained O 0
a O 0
partial O 0
remission O 0
. O 0

The O 0
most O 0
common O 0
toxicities B-Disease 1
encountered O 0
were O 0
transient O 0
serum O 0
transaminase O 0
and O 0
bilirubin B-Chemical 1
elevations O 0
, O 0
neutropenia B-Disease 1
, O 0
and O 0
mucositis B-Disease 1
. O 0

One O 0
patient O 0
had O 0
focal O 0
seizures B-Disease 1
and O 0
transient B-Disease 1
hemiparesis I-Disease 1
but O 0
recovered O 0
completely O 0
. O 0

High O 0
- O 0
dose O 0
intravenous O 0
methotrexate B-Chemical 1
is O 0
an O 0
effective O 0
treatment O 0
for O 0
the O 0
induction O 0
of O 0
remission O 0
after O 0
meningeal O 0
relapse O 0
in O 0
acute B-Disease 1
lymphoblastic I-Disease 1
leukemia I-Disease 1
. O 0

Interaction O 0
of O 0
cyclosporin B-Chemical 1
A I-Chemical 1
with O 0
antineoplastic O 0
agents O 0
. O 0

A O 0
synergistic O 0
effect O 0
of O 0
etoposide B-Chemical 1
and O 0
cyclosporin B-Chemical 1
A I-Chemical 1
was O 0
observed O 0
in O 0
a O 0
patient O 0
with O 0
acute B-Disease 1
T I-Disease 1
- I-Disease 1
lymphocytic I-Disease 1
leukemia I-Disease 1
in O 0
relapse O 0
. O 0

The O 0
concomitant O 0
administration O 0
of O 0
etoposide B-Chemical 1
and O 0
cyclosporin B-Chemical 1
A I-Chemical 1
resulted O 0
in O 0
eradication O 0
of O 0
hitherto O 0
refractory O 0
leukemic B-Disease 1
infiltration I-Disease 1
of O 0
bone O 0
marrow O 0
. O 0

Severe O 0
side O 0
effects O 0
in O 0
terms O 0
of O 0
mental O 0
confusion B-Disease 1
and O 0
progressive O 0
hyperbilirubinemia B-Disease 1
, O 0
however O 0
, O 0
point O 0
to O 0
an O 0
enhancement O 0
not O 0
only O 0
of O 0
antineoplastic O 0
effects O 0
but O 0
also O 0
of O 0
toxicity B-Disease 1
in O 0
normal O 0
tissues O 0
. O 0

This O 0
report O 0
demonstrates O 0
for O 0
the O 0
first O 0
time O 0
that O 0
the O 0
pharmacodynamic O 0
properties O 0
of O 0
cyclosporin B-Chemical 1
A I-Chemical 1
may O 0
not O 0
be O 0
confined O 0
strictly O 0
to O 0
suppression O 0
of O 0
normal O 0
T O 0
- O 0
cell O 0
functions O 0
. O 0

Incidence O 0
of O 0
neoplasms B-Disease 1
in O 0
patients O 0
with O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
exposed O 0
to O 0
different O 0
treatment O 0
regimens O 0
. O 0

Immunosuppressive O 0
drugs O 0
have O 0
been O 0
used O 0
during O 0
the O 0
last O 0
30 O 0
years O 0
in O 0
treatment O 0
of O 0
patients O 0
with O 0
severe O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
. O 0

The O 0
drugs O 0
commonly O 0
used O 0
are O 0
cyclophosphamide B-Chemical 1
and O 0
chlorambucil B-Chemical 1
( O 0
alkylating B-Chemical 1
agents I-Chemical 1
) O 0
, O 0
azathioprine B-Chemical 1
( O 0
purine B-Chemical 1
analogue O 0
) O 0
, O 0
and O 0
methotrexate B-Chemical 1
( O 0
folic B-Chemical 1
acid I-Chemical 1
analogue O 0
) O 0
. O 0

There O 0
is O 0
evidence O 0
that O 0
all O 0
four O 0
immunosuppressive O 0
drugs O 0
can O 0
reduce O 0
synovitis B-Disease 1
, O 0
but O 0
disease O 0
activity O 0
almost O 0
always O 0
recurs O 0
after O 0
therapy O 0
is O 0
stopped O 0
. O 0

Since O 0
adverse O 0
reactions O 0
are O 0
frequent O 0
, O 0
less O 0
than O 0
50 O 0
percent O 0
of O 0
patients O 0
are O 0
able O 0
to O 0
continue O 0
a O 0
particular O 0
drug O 0
for O 0
more O 0
than O 0
one O 0
year O 0
. O 0

Since O 0
it O 0
takes O 0
three O 0
to O 0
12 O 0
months O 0
to O 0
achieve O 0
maximal O 0
effects O 0
, O 0
those O 0
patients O 0
who O 0
are O 0
unable O 0
to O 0
continue O 0
the O 0
drug O 0
receive O 0
little O 0
benefit O 0
from O 0
it O 0
. O 0

Patients O 0
treated O 0
with O 0
alkylating B-Chemical 1
agents I-Chemical 1
have O 0
an O 0
increased O 0
risk O 0
of O 0
development O 0
of O 0
acute B-Disease 1
nonlymphocytic I-Disease 1
leukemia I-Disease 1
, O 0
and O 0
both O 0
alkylating B-Chemical 1
agents I-Chemical 1
and O 0
azathioprine B-Chemical 1
are O 0
associated O 0
with O 0
the O 0
development O 0
of O 0
non B-Disease 1
- I-Disease 1
Hodgkin I-Disease 1
' I-Disease 1
s I-Disease 1
lymphoma I-Disease 1
. O 0

Cyclophosphamide B-Chemical 1
therapy O 0
increases O 0
the O 0
risk O 0
of O 0
carcinoma B-Disease 1
of I-Disease 1
the I-Disease 1
bladder I-Disease 1
. O 0

There O 0
have O 0
been O 0
several O 0
long O 0
- O 0
term O 0
studies O 0
of O 0
patients O 0
with O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
treated O 0
with O 0
azathioprine B-Chemical 1
and O 0
cyclophosphamide B-Chemical 1
and O 0
the O 0
incidence O 0
of O 0
most O 0
of O 0
the O 0
common O 0
cancers B-Disease 1
is O 0
not O 0
increased O 0
. O 0

Data O 0
on O 0
the O 0
possible O 0
increased O 0
risk O 0
of O 0
malignancy B-Disease 1
in O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
are O 0
still O 0
being O 0
collected O 0
, O 0
and O 0
until O 0
further O 0
information O 0
is O 0
available O 0
, O 0
the O 0
use O 0
of O 0
immunosuppressive O 0
drugs O 0
, O 0
particularly O 0
alkylating B-Chemical 1
agents I-Chemical 1
, O 0
in O 0
the O 0
treatment O 0
of O 0
rheumatoid B-Disease 1
arthritis I-Disease 1
should O 0
be O 0
reserved O 0
for O 0
patients O 0
with O 0
severe O 0
progressive O 0
disease O 0
or O 0
life O 0
- O 0
threatening O 0
complications O 0
. O 0

Warfarin B-Chemical 1
- O 0
induced O 0
iliopsoas O 0
hemorrhage B-Disease 1
with O 0
subsequent O 0
femoral B-Disease 1
nerve I-Disease 1
palsy I-Disease 1
. O 0

We O 0
present O 0
the O 0
case O 0
of O 0
a O 0
28 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
on O 0
chronic O 0
warfarin B-Chemical 1
therapy O 0
who O 0
sustained O 0
a O 0
minor O 0
muscle B-Disease 1
tear I-Disease 1
and O 0
developed O 0
increasing O 0
pain B-Disease 1
and O 0
a O 0
flexure O 0
contracture B-Disease 1
of O 0
the O 0
right O 0
hip O 0
. O 0

Surgical O 0
exploration O 0
revealed O 0
an O 0
iliopsoas O 0
hematoma B-Disease 1
and O 0
femoral O 0
nerve B-Disease 1
entrapment I-Disease 1
, O 0
resulting O 0
in O 0
a O 0
femoral B-Disease 1
nerve I-Disease 1
palsy I-Disease 1
and O 0
partial B-Disease 1
loss I-Disease 1
of I-Disease 1
quadriceps I-Disease 1
functions I-Disease 1
. O 0

Anticoagulant O 0
- O 0
induced O 0
femoral B-Disease 1
nerve I-Disease 1
palsy I-Disease 1
represents O 0
the O 0
most O 0
common O 0
form O 0
of O 0
warfarin B-Chemical 1
- O 0
induced O 0
peripheral B-Disease 1
neuropathy I-Disease 1
; O 0
it O 0
is O 0
characterized O 0
by O 0
severe O 0
pain B-Disease 1
in O 0
the O 0
inguinal O 0
region O 0
, O 0
varying O 0
degrees O 0
of O 0
motor B-Disease 1
and I-Disease 1
sensory I-Disease 1
impairment I-Disease 1
, O 0
and O 0
flexure O 0
contracture B-Disease 1
of O 0
the O 0
involved O 0
extremity O 0
. O 0

Pneumonitis O 0
with O 0
pleural B-Disease 1
and I-Disease 1
pericardial I-Disease 1
effusion I-Disease 1
and O 0
neuropathy B-Disease 1
during O 0
amiodarone B-Chemical 1
therapy O 0
. O 0

A O 0
patient O 0
with O 0
sinuatrial B-Disease 1
disease I-Disease 1
and O 0
implanted O 0
pacemaker O 0
was O 0
treated O 0
with O 0
amiodarone B-Chemical 1
( O 0
maximum O 0
dose O 0
1000 O 0
mg O 0
, O 0
maintenance O 0
dose O 0
800 O 0
mg O 0
daily O 0
) O 0
for O 0
10 O 0
months O 0
, O 0
for O 0
control O 0
of O 0
supraventricular B-Disease 1
tachyarrhythmias I-Disease 1
. O 0

He O 0
developed O 0
pneumonitis B-Disease 1
, O 0
pleural B-Disease 1
and I-Disease 1
pericardial I-Disease 1
effusions I-Disease 1
, O 0
and O 0
a O 0
predominantly O 0
proximal B-Disease 1
motor I-Disease 1
neuropathy I-Disease 1
. O 0

Immediate O 0
but O 0
gradual O 0
improvement O 0
followed O 0
withdrawal O 0
of O 0
amiodarone B-Chemical 1
and O 0
treatment O 0
with O 0
prednisolone B-Chemical 1
. O 0

Review O 0
of O 0
this O 0
and O 0
previously O 0
reported O 0
cases O 0
indicates O 0
the O 0
need O 0
for O 0
early O 0
diagnosis O 0
of O 0
amiodarone B-Chemical 1
pneumonitis B-Disease 1
, O 0
immediate O 0
withdrawal O 0
of O 0
amiodarone B-Chemical 1
, O 0
and O 0
prompt O 0
but O 0
continued O 0
steroid B-Chemical 1
therapy O 0
to O 0
ensure O 0
full O 0
recovery O 0
. O 0

Amiodarone B-Chemical 1
- O 0
induced O 0
sinoatrial B-Disease 1
block I-Disease 1
. O 0

We O 0
observed O 0
sinoatrial B-Disease 1
block I-Disease 1
due O 0
to O 0
chronic O 0
amiodarone B-Chemical 1
administration O 0
in O 0
a O 0
5 O 0
- O 0
year O 0
- O 0
old O 0
boy O 0
with O 0
primary B-Disease 1
cardiomyopathy I-Disease 1
, O 0
Wolff B-Disease 1
- I-Disease 1
Parkinson I-Disease 1
- I-Disease 1
White I-Disease 1
syndrome I-Disease 1
and O 0
supraventricular B-Disease 1
tachycardia I-Disease 1
. O 0

Reduction O 0
in O 0
the O 0
dosage O 0
of O 0
amiodarone B-Chemical 1
resulted O 0
in O 0
the O 0
disappearance O 0
of O 0
the O 0
sinoatrial B-Disease 1
block I-Disease 1
and O 0
the O 0
persistence O 0
of O 0
asymptomatic O 0
sinus B-Disease 1
bradycardia I-Disease 1
. O 0

Desipramine B-Chemical 1
- O 0
induced O 0
delirium B-Disease 1
at O 0
" O 0
subtherapeutic O 0
" O 0
concentrations O 0
: O 0
a O 0
case O 0
report O 0
. O 0

An O 0
elderly O 0
patient O 0
treated O 0
with O 0
low O 0
dose O 0
Desipramine B-Chemical 1
developed O 0
a O 0
delirium B-Disease 1
while O 0
her O 0
plasma O 0
level O 0
was O 0
in O 0
the O 0
" O 0
subtherapeutic O 0
" O 0
range O 0
. O 0

Delirium B-Disease 1
, O 0
which O 0
may O 0
be O 0
induced O 0
by O 0
tricyclic O 0
drug O 0
therapy O 0
in O 0
the O 0
elderly O 0
, O 0
can O 0
be O 0
caused O 0
by O 0
tricyclics O 0
with O 0
low O 0
anticholinergic O 0
potency O 0
. O 0

Therapeutic O 0
ranges O 0
for O 0
antidepressants B-Chemical 1
that O 0
have O 0
been O 0
derived O 0
from O 0
general O 0
adult O 0
population O 0
studies O 0
may O 0
not O 0
be O 0
appropriate O 0
for O 0
the O 0
elderly O 0
. O 0

Further O 0
studies O 0
of O 0
specifically O 0
elderly O 0
patients O 0
are O 0
now O 0
required O 0
to O 0
establish O 0
safer O 0
and O 0
more O 0
appropriate O 0
guidelines O 0
for O 0
drug O 0
therapy O 0
. O 0

Indomethacin B-Chemical 1
- O 0
induced O 0
renal B-Disease 1
insufficiency I-Disease 1
: O 0
recurrence O 0
on O 0
rechallenge O 0
. O 0

We O 0
have O 0
reported O 0
a O 0
case O 0
of O 0
acute O 0
oliguric O 0
renal B-Disease 1
failure I-Disease 1
with O 0
hyperkalemia B-Disease 1
in O 0
a O 0
patient O 0
with O 0
cirrhosis B-Disease 1
, O 0
ascites B-Disease 1
, O 0
and O 0
cor B-Disease 1
pulmonale I-Disease 1
after O 0
indomethacin B-Chemical 1
therapy O 0
. O 0

Prompt O 0
restoration O 0
of O 0
renal O 0
function O 0
followed O 0
drug O 0
withdrawal O 0
, O 0
while O 0
re O 0
- O 0
exposure O 0
to O 0
a O 0
single O 0
dose O 0
of O 0
indomethacin B-Chemical 1
caused O 0
recurrence O 0
of O 0
acute O 0
reversible O 0
oliguria B-Disease 1
. O 0

Our O 0
case O 0
supports O 0
the O 0
hypothesis O 0
that O 0
endogenous O 0
renal O 0
prostaglandins B-Chemical 1
play O 0
a O 0
role O 0
in O 0
the O 0
maintenance O 0
of O 0
renal O 0
blood O 0
flow O 0
when O 0
circulating O 0
plasma O 0
volume O 0
is O 0
diminished O 0
. O 0

Since O 0
nonsteroidal O 0
anti O 0
- O 0
inflammatory O 0
agents O 0
interfere O 0
with O 0
this O 0
compensatory O 0
mechanism O 0
and O 0
may O 0
cause O 0
acute B-Disease 1
renal I-Disease 1
failure I-Disease 1
, O 0
they O 0
should O 0
be O 0
used O 0
with O 0
caution O 0
in O 0
such O 0
patients O 0
. O 0

Patterns O 0
of O 0
hepatic B-Disease 1
injury I-Disease 1
induced O 0
by O 0
methyldopa B-Chemical 1
. O 0

Twelve O 0
patients O 0
with O 0
liver B-Disease 1
disease I-Disease 1
related O 0
to O 0
methyldopa B-Chemical 1
were O 0
seen O 0
between O 0
1967 O 0
and O 0
1977 O 0
. O 0

Illness O 0
occurred O 0
within O 0
1 O 0
- O 0
- O 0
9 O 0
weeks O 0
of O 0
commencement O 0
of O 0
therapy O 0
in O 0
9 O 0
patients O 0
, O 0
the O 0
remaining O 0
3 O 0
patients O 0
having O 0
received O 0
the O 0
drug O 0
for O 0
13 O 0
months O 0
, O 0
15 O 0
months O 0
and O 0
7 O 0
years O 0
before O 0
experiencing O 0
symptoms O 0
. O 0

Jaundice B-Disease 1
with O 0
tender O 0
hepatomegaly B-Disease 1
, O 0
usually O 0
preceded O 0
by O 0
symptoms O 0
of O 0
malaise O 0
, O 0
anorexia B-Disease 1
, O 0
nausea B-Disease 1
and O 0
vomiting B-Disease 1
, O 0
and O 0
associated O 0
with O 0
upper O 0
abdominal B-Disease 1
pain I-Disease 1
, O 0
was O 0
an O 0
invariable O 0
finding O 0
in O 0
all O 0
patients O 0
. O 0

Biochemical O 0
liver O 0
function O 0
tests O 0
indicated O 0
hepatocellular O 0
necrosis B-Disease 1
and O 0
correlated O 0
with O 0
histopathological O 0
evidence O 0
of O 0
hepatic B-Disease 1
injury I-Disease 1
, O 0
the O 0
spectrum O 0
of O 0
which O 0
ranged O 0
from O 0
fatty B-Disease 1
change I-Disease 1
and O 0
focal O 0
hepatocellular O 0
necrosis B-Disease 1
to O 0
massive B-Disease 1
hepatic I-Disease 1
necrosis I-Disease 1
. O 0

Most O 0
patients O 0
showed O 0
moderate O 0
to O 0
severe O 0
acute B-Disease 1
hepatitis I-Disease 1
or O 0
chronic B-Disease 1
active I-Disease 1
hepatitis I-Disease 1
with O 0
associated O 0
cholestasis B-Disease 1
. O 0

The O 0
drug O 0
was O 0
withdrawn O 0
on O 0
presentation O 0
to O 0
hospital O 0
in O 0
11 O 0
patients O 0
, O 0
with O 0
rapid O 0
clinical O 0
improvement O 0
in O 0
9 O 0
. O 0

One O 0
patient O 0
died O 0
, O 0
having O 0
presented O 0
in O 0
hepatic B-Disease 1
failure I-Disease 1
, O 0
and O 0
another O 0
, O 0
who O 0
had O 0
been O 0
taking O 0
methyldopa B-Chemical 1
for O 0
7 O 0
years O 0
, O 0
showed O 0
slower O 0
clinical O 0
and O 0
biochemical O 0
resolution O 0
over O 0
a O 0
period O 0
of O 0
several O 0
months O 0
. O 0

The O 0
remaining O 0
patient O 0
in O 0
the O 0
series O 0
developed O 0
fulminant B-Disease 1
hepatitis I-Disease 1
when O 0
the O 0
drug O 0
was O 0
accidentally O 0
recommenced O 0
1 O 0
year O 0
after O 0
a O 0
prior O 0
episode O 0
of O 0
methyldopa B-Chemical 1
- O 0
induced O 0
hepatitis B-Disease 1
. O 0

In O 0
this O 0
latter O 0
patient O 0
, O 0
and O 0
in O 0
2 O 0
others O 0
, O 0
the O 0
causal O 0
relationship O 0
between O 0
methyldopa B-Chemical 1
and O 0
hepatic B-Disease 1
dysfunction I-Disease 1
was O 0
proved O 0
with O 0
the O 0
recurrence O 0
of O 0
hepatitis B-Disease 1
within O 0
2 O 0
weeks O 0
of O 0
re O 0
- O 0
exposure O 0
to O 0
the O 0
drug O 0
. O 0

Suxamethonium B-Chemical 1
infusion O 0
rate O 0
and O 0
observed O 0
fasciculations B-Disease 1
. O 0

A O 0
dose O 0
- O 0
response O 0
study O 0
. O 0

Suxamethonium B-Chemical 1
chloride I-Chemical 1
( O 0
Sch B-Chemical 1
) O 0
was O 0
administered O 0
i O 0
. O 0
v O 0
. O 0
to O 0
36 O 0
adult O 0
males O 0
at O 0
six O 0
rates O 0
: O 0
0 O 0
. O 0
25 O 0
mg O 0
s O 0
- O 0
1 O 0
to O 0
20 O 0
mg O 0
s O 0
- O 0
1 O 0
. O 0

The O 0
infusion O 0
was O 0
discontinued O 0
either O 0
when O 0
there O 0
was O 0
no O 0
muscular O 0
response O 0
to O 0
tetanic B-Disease 1
stimulation O 0
of O 0
the O 0
ulnar O 0
nerve O 0
or O 0
when O 0
Sch B-Chemical 1
120 O 0
mg O 0
was O 0
exceeded O 0
. O 0

Six O 0
additional O 0
patients O 0
received O 0
a O 0
30 O 0
- O 0
mg O 0
i O 0
. O 0
v O 0
. O 0
bolus O 0
dose O 0
. O 0

Fasciculations B-Disease 1
in O 0
six O 0
areas O 0
of O 0
the O 0
body O 0
were O 0
scored O 0
from O 0
0 O 0
to O 0
3 O 0
and O 0
summated O 0
as O 0
a O 0
total O 0
fasciculation B-Disease 1
score O 0
. O 0

The O 0
times O 0
to O 0
first O 0
fasciculation B-Disease 1
, O 0
twitch B-Disease 1
suppression O 0
and O 0
tetanus B-Disease 1
suppression O 0
were O 0
inversely O 0
related O 0
to O 0
the O 0
infusion O 0
rates O 0
. O 0

Fasciculations B-Disease 1
in O 0
the O 0
six O 0
areas O 0
and O 0
the O 0
total O 0
fasciculation B-Disease 1
score O 0
were O 0
related O 0
directly O 0
to O 0
the O 0
rate O 0
of O 0
infusion O 0
. O 0

Total O 0
fasciculation B-Disease 1
scores O 0
in O 0
the O 0
30 O 0
- O 0
mg O 0
bolus O 0
group O 0
and O 0
the O 0
5 O 0
- O 0
mg O 0
s O 0
- O 0
1 O 0
and O 0
20 O 0
- O 0
mg O 0
s O 0
- O 0
1 O 0
infusion O 0
groups O 0
were O 0
not O 0
significantly O 0
different O 0
. O 0

Treatment O 0
of O 0
psoriasis B-Disease 1
with O 0
azathioprine B-Chemical 1
. O 0

Azathioprine B-Chemical 1
treatment O 0
benefited O 0
19 O 0
( O 0
66 O 0
% O 0
) O 0
out O 0
of O 0
29 O 0
patients O 0
suffering O 0
from O 0
severe O 0
psoriasis B-Disease 1
. O 0

Haematological O 0
complications O 0
were O 0
not O 0
troublesome O 0
and O 0
results O 0
of O 0
biochemical O 0
liver O 0
function O 0
tests O 0
remained O 0
normal O 0
. O 0

Minimal O 0
cholestasis B-Disease 1
was O 0
seen O 0
in O 0
two O 0
cases O 0
and O 0
portal O 0
fibrosis B-Disease 1
of O 0
a O 0
reversible O 0
degree O 0
in O 0
eight O 0
. O 0

Liver O 0
biopsies O 0
should O 0
be O 0
undertaken O 0
at O 0
regular O 0
intervals O 0
if O 0
azathioprine B-Chemical 1
therapy O 0
is O 0
continued O 0
so O 0
that O 0
structural O 0
liver B-Disease 1
damage I-Disease 1
may O 0
be O 0
detected O 0
at O 0
an O 0
early O 0
and O 0
reversible O 0
stage O 0
. O 0

Angiosarcoma B-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
associated O 0
with O 0
diethylstilbestrol B-Chemical 1
. O 0

Angiosarcoma B-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
occurred O 0
in O 0
a O 0
76 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
who O 0
had O 0
been O 0
treated O 0
for O 0
a O 0
well O 0
- O 0
differentiated O 0
adenocarcinoma B-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
with O 0
diethylstilbestrol B-Chemical 1
for O 0
13 O 0
years O 0
. O 0

Angiosarcoma B-Disease 1
was O 0
also O 0
present O 0
within O 0
pulmonary O 0
and O 0
renal O 0
arteries O 0
. O 0

The O 0
possibility O 0
that O 0
the O 0
intraarterial B-Disease 1
lesions I-Disease 1
might O 0
represent O 0
independent O 0
primary O 0
tumors B-Disease 1
is O 0
considered O 0
. O 0

Galanthamine B-Chemical 1
hydrobromide I-Chemical 1
, O 0
a O 0
longer O 0
acting O 0
anticholinesterase O 0
drug O 0
, O 0
in O 0
the O 0
treatment O 0
of O 0
the O 0
central O 0
effects O 0
of O 0
scopolamine B-Chemical 1
( O 0
Hyoscine B-Chemical 1
) O 0
. O 0

Galanthamine B-Chemical 1
hydrobromide I-Chemical 1
, O 0
an O 0
anticholinesterase O 0
drug O 0
capable O 0
of O 0
penetrating O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
, O 0
was O 0
used O 0
in O 0
a O 0
patient O 0
demonstrating O 0
central O 0
effects O 0
of O 0
scopolamine B-Chemical 1
( O 0
hyoscine B-Chemical 1
) O 0
overdosage B-Disease 1
. O 0

It O 0
is O 0
longer O 0
acting O 0
than O 0
physostigmine B-Chemical 1
and O 0
is O 0
used O 0
in O 0
anaesthesia O 0
to O 0
reverse O 0
the O 0
non O 0
- O 0
depolarizing O 0
neuromuscular O 0
block O 0
. O 0

However O 0
, O 0
studies O 0
into O 0
the O 0
dose O 0
necessary O 0
to O 0
combating O 0
scopolamine B-Chemical 1
intoxication O 0
are O 0
indicated O 0
. O 0

Comparison O 0
of O 0
the O 0
subjective O 0
effects O 0
and O 0
plasma O 0
concentrations O 0
following O 0
oral O 0
and O 0
i O 0
. O 0
m O 0
. O 0
administration O 0
of O 0
flunitrazepam B-Chemical 1
in O 0
volunteers O 0
. O 0

Flunitrazepam B-Chemical 1
0 O 0
. O 0
5 O 0
, O 0
1 O 0
. O 0
0 O 0
or O 0
2 O 0
. O 0
0 O 0
mg O 0
was O 0
given O 0
by O 0
the O 0
oral O 0
or O 0
i O 0
. O 0
m O 0
. O 0
routes O 0
to O 0
groups O 0
of O 0
volunteers O 0
and O 0
its O 0
effects O 0
compared O 0
. O 0

Plasma O 0
concentrations O 0
of O 0
the O 0
drug O 0
were O 0
estimated O 0
by O 0
gas O 0
- O 0
liquid O 0
chromatography O 0
, O 0
in O 0
a O 0
smaller O 0
number O 0
of O 0
the O 0
subjects O 0
. O 0

The O 0
most O 0
striking O 0
effect O 0
was O 0
sedation O 0
which O 0
increased O 0
with O 0
the O 0
dose O 0
, O 0
2 O 0
mg O 0
producing O 0
deep O 0
sleep O 0
although O 0
the O 0
subjects O 0
could O 0
still O 0
be O 0
aroused O 0
. O 0

The O 0
effects O 0
of O 0
i O 0
. O 0
m O 0
. O 0
administration O 0
were O 0
apparent O 0
earlier O 0
and O 0
sometimes O 0
lasted O 0
longer O 0
than O 0
those O 0
following O 0
oral O 0
administration O 0
. O 0

Dizziness B-Disease 1
was O 0
less O 0
marked O 0
than O 0
sedation O 0
, O 0
but O 0
increased O 0
with O 0
the O 0
dose O 0
. O 0

There O 0
was O 0
pain B-Disease 1
on O 0
i O 0
. O 0
m O 0
. O 0
injection O 0
of O 0
flunitrazepam B-Chemical 1
significantly O 0
more O 0
often O 0
than O 0
with O 0
isotonic O 0
saline O 0
. O 0

Plasma O 0
concentrations O 0
varied O 0
with O 0
dose O 0
and O 0
route O 0
and O 0
corresponded O 0
qualitatively O 0
with O 0
the O 0
subjective O 0
effects O 0
. O 0

The O 0
drug O 0
was O 0
still O 0
present O 0
in O 0
measurable O 0
quantities O 0
after O 0
24 O 0
h O 0
even O 0
with O 0
the O 0
smallest O 0
dose O 0
. O 0

Possible O 0
teratogenicity O 0
of O 0
sulphasalazine B-Chemical 1
. O 0

Three O 0
infants O 0
, O 0
born O 0
of O 0
two O 0
mothers O 0
with O 0
inflammatory B-Disease 1
bowel I-Disease 1
disease I-Disease 1
who O 0
received O 0
treatment O 0
with O 0
sulphasalazine B-Chemical 1
throughout O 0
pregnancy O 0
, O 0
were O 0
found O 0
to O 0
have O 0
major O 0
congenital B-Disease 1
anomalies I-Disease 1
. O 0

In O 0
the O 0
singleton O 0
pregnancy O 0
, O 0
the O 0
mother O 0
had O 0
ulcerative B-Disease 1
colitis I-Disease 1
, O 0
and O 0
the O 0
infant O 0
, O 0
a O 0
male O 0
, O 0
had O 0
coarctation B-Disease 1
of I-Disease 1
the I-Disease 1
aorta I-Disease 1
and O 0
a O 0
ventricular B-Disease 1
septal I-Disease 1
defect I-Disease 1
. O 0

In O 0
the O 0
twin O 0
pregnancy O 0
, O 0
the O 0
mother O 0
had O 0
Crohn B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

The O 0
first O 0
twin O 0
, O 0
a O 0
female O 0
, O 0
had O 0
a O 0
left O 0
Potter B-Disease 1
- I-Disease 1
type I-Disease 1
IIa I-Disease 1
polycystic I-Disease 1
kidney I-Disease 1
and O 0
a O 0
rudimentary B-Disease 1
left I-Disease 1
uterine I-Disease 1
cornu I-Disease 1
. O 0

The O 0
second O 0
twin O 0
, O 0
a O 0
male O 0
, O 0
had O 0
some O 0
features O 0
of O 0
Potter B-Disease 1
' I-Disease 1
s I-Disease 1
facies I-Disease 1
, O 0
hypoplastic B-Disease 1
lungs I-Disease 1
, O 0
absent B-Disease 1
kidneys I-Disease 1
and I-Disease 1
ureters I-Disease 1
, O 0
and O 0
talipes B-Disease 1
equinovarus I-Disease 1
. O 0

Despite O 0
reports O 0
to O 0
the O 0
contrary O 0
, O 0
it O 0
is O 0
suggested O 0
that O 0
sulphasalazine B-Chemical 1
may O 0
be O 0
teratogenic O 0
. O 0

Thrombotic B-Disease 1
microangiopathy I-Disease 1
and O 0
renal B-Disease 1
failure I-Disease 1
associated O 0
with O 0
antineoplastic O 0
chemotherapy O 0
. O 0

Five O 0
patients O 0
with O 0
carcinoma B-Disease 1
developed O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
( O 0
characterized O 0
by O 0
renal B-Disease 1
insufficiency I-Disease 1
, O 0
microangiopathic B-Disease 1
hemolytic I-Disease 1
anemia I-Disease 1
, O 0
and O 0
usually O 0
thrombocytopenia B-Disease 1
) O 0
after O 0
treatment O 0
with O 0
cisplatin B-Chemical 1
, O 0
bleomycin B-Chemical 1
, O 0
and O 0
a O 0
vinca B-Chemical 1
alkaloid I-Chemical 1
. O 0

One O 0
patient O 0
had O 0
thrombotic B-Disease 1
thrombocytopenic I-Disease 1
purpura I-Disease 1
, O 0
three O 0
the O 0
hemolytic B-Disease 1
- I-Disease 1
uremic I-Disease 1
syndrome I-Disease 1
, O 0
and O 0
one O 0
an O 0
apparent O 0
forme O 0
fruste O 0
of O 0
one O 0
of O 0
these O 0
disorders O 0
. O 0

Histologic O 0
examination O 0
of O 0
the O 0
renal O 0
tissue O 0
showed O 0
evidence O 0
of O 0
intravascular B-Disease 1
coagulation I-Disease 1
, O 0
primarily O 0
affecting O 0
the O 0
small O 0
arteries O 0
, O 0
arterioles O 0
, O 0
and O 0
glomeruli O 0
. O 0

Because O 0
each O 0
patient O 0
was O 0
tumor B-Disease 1
- O 0
free O 0
or O 0
had O 0
only O 0
a O 0
small O 0
tumor B-Disease 1
at O 0
the O 0
onset O 0
of O 0
this O 0
syndrome O 0
, O 0
the O 0
thrombotic B-Disease 1
microangiopathy I-Disease 1
may O 0
have O 0
been O 0
induced O 0
by O 0
chemotherapy O 0
. O 0

Diagnosis O 0
of O 0
this O 0
potentially O 0
fatal O 0
complication O 0
may O 0
be O 0
delayed O 0
or O 0
missed O 0
if O 0
renal O 0
tissue O 0
or O 0
the O 0
peripheral O 0
blood O 0
smear O 0
is O 0
not O 0
examined O 0
, O 0
because O 0
renal B-Disease 1
failure I-Disease 1
may O 0
be O 0
ascribed O 0
to O 0
cisplatin B-Chemical 1
nephrotoxicity B-Disease 1
and O 0
the O 0
anemia B-Disease 1
and O 0
thrombocytopenia B-Disease 1
to O 0
drug O 0
- O 0
induced O 0
bone B-Disease 1
marrow I-Disease 1
suppression I-Disease 1
. O 0

International O 0
mexiletine B-Chemical 1
and O 0
placebo O 0
antiarrhythmic O 0
coronary O 0
trial O 0
: O 0
I O 0
. O 0

Report O 0
on O 0
arrhythmia B-Disease 1
and O 0
other O 0
findings O 0
. O 0

Impact O 0
Research O 0
Group O 0
. O 0

The O 0
antiarrhythmic O 0
effects O 0
of O 0
the O 0
sustained O 0
release O 0
form O 0
of O 0
mexiletine B-Chemical 1
( O 0
Mexitil B-Chemical 1
- I-Chemical 1
Perlongets I-Chemical 1
) O 0
were O 0
evaluated O 0
in O 0
a O 0
double O 0
- O 0
blind O 0
placebo O 0
trial O 0
in O 0
630 O 0
patients O 0
with O 0
recent O 0
documented O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

The O 0
primary O 0
response O 0
variable O 0
was O 0
based O 0
on O 0
central O 0
reading O 0
of O 0
24 O 0
hour O 0
ambulatory O 0
electrocardiographic O 0
recordings O 0
and O 0
was O 0
defined O 0
as O 0
the O 0
occurrence O 0
of O 0
30 O 0
or O 0
more O 0
single O 0
premature O 0
ventricular O 0
complexes O 0
in O 0
any O 0
two O 0
consecutive O 0
30 O 0
minute O 0
blocks O 0
or O 0
one O 0
or O 0
more O 0
runs O 0
of O 0
two O 0
or O 0
more O 0
premature O 0
ventricular O 0
complexes O 0
in O 0
the O 0
entire O 0
24 O 0
hour O 0
electrocardiographic O 0
recording O 0
. O 0

Large O 0
differences O 0
, O 0
regarded O 0
as O 0
statistically O 0
significant O 0
, O 0
between O 0
the O 0
mexiletine B-Chemical 1
and O 0
placebo O 0
groups O 0
were O 0
noted O 0
in O 0
that O 0
end O 0
point O 0
at O 0
months O 0
1 O 0
and O 0
4 O 0
, O 0
but O 0
only O 0
trends O 0
were O 0
observed O 0
at O 0
month O 0
12 O 0
. O 0

These O 0
differences O 0
were O 0
observed O 0
even O 0
though O 0
the O 0
serum O 0
mexiletine B-Chemical 1
levels O 0
obtained O 0
in O 0
this O 0
study O 0
were O 0
generally O 0
lower O 0
than O 0
those O 0
observed O 0
in O 0
studies O 0
that O 0
have O 0
used O 0
the O 0
regular O 0
form O 0
of O 0
the O 0
drug O 0
. O 0

There O 0
were O 0
more O 0
deaths B-Disease 1
in O 0
the O 0
mexiletine B-Chemical 1
group O 0
( O 0
7 O 0
. O 0
6 O 0
% O 0
) O 0
than O 0
in O 0
the O 0
placebo O 0
group O 0
( O 0
4 O 0
. O 0
8 O 0
% O 0
) O 0
; O 0
the O 0
difference O 0
was O 0
not O 0
statistically O 0
significant O 0
. O 0

The O 0
incidence O 0
of O 0
coronary O 0
events O 0
was O 0
similar O 0
in O 0
both O 0
groups O 0
. O 0

Previously O 0
recognized O 0
side O 0
effects O 0
, O 0
particularly O 0
tremor B-Disease 1
and O 0
gastrointestinal B-Disease 1
problems I-Disease 1
, O 0
were O 0
more O 0
frequent O 0
in O 0
the O 0
mexiletine B-Chemical 1
group O 0
than O 0
in O 0
the O 0
placebo O 0
group O 0
. O 0

Changes O 0
in O 0
heart O 0
size O 0
during O 0
long O 0
- O 0
term O 0
timolol B-Chemical 1
treatment O 0
after O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

The O 0
effect O 0
of O 0
long O 0
- O 0
term O 0
timolol B-Chemical 1
treatment O 0
on O 0
heart O 0
size O 0
after O 0
myocardial B-Disease 1
infarction I-Disease 1
was O 0
evaluated O 0
by O 0
X O 0
- O 0
ray O 0
in O 0
a O 0
double O 0
- O 0
blind O 0
study O 0
including O 0
241 O 0
patients O 0
( O 0
placebo O 0
126 O 0
, O 0
timolol B-Chemical 1
115 O 0
) O 0
. O 0

The O 0
follow O 0
- O 0
up O 0
period O 0
was O 0
12 O 0
months O 0
. O 0

The O 0
timolol B-Chemical 1
- O 0
treated O 0
patients O 0
showed O 0
a O 0
small O 0
but O 0
significant O 0
increase O 0
in O 0
heart O 0
size O 0
from O 0
baseline O 0
in O 0
contrast O 0
to O 0
a O 0
decrease O 0
in O 0
the O 0
placebo O 0
group O 0
. O 0

These O 0
differences O 0
may O 0
be O 0
caused O 0
by O 0
timolol B-Chemical 1
- O 0
induced O 0
bradycardia B-Disease 1
and O 0
a O 0
compensatory O 0
increase O 0
in O 0
end O 0
- O 0
diastolic O 0
volume O 0
. O 0

The O 0
timolol B-Chemical 1
- O 0
related O 0
increase O 0
in O 0
heart O 0
size O 0
was O 0
observed O 0
only O 0
in O 0
patients O 0
with O 0
normal O 0
and O 0
borderline O 0
heart O 0
size O 0
. O 0

In O 0
patients O 0
with O 0
cardiomegaly B-Disease 1
, O 0
the O 0
increase O 0
in O 0
heart O 0
size O 0
was O 0
similar O 0
in O 0
both O 0
groups O 0
. O 0

After O 0
re O 0
- O 0
infarction B-Disease 1
, O 0
heart O 0
size O 0
increased O 0
in O 0
the O 0
placebo O 0
group O 0
and O 0
remained O 0
unchanged O 0
in O 0
the O 0
timolol B-Chemical 1
group O 0
. O 0

Vitamin B-Chemical 1
D3 I-Chemical 1
toxicity B-Disease 1
in O 0
dairy O 0
cows O 0
. O 0

Large O 0
parenteral O 0
doses O 0
of O 0
vitamin B-Chemical 1
D3 I-Chemical 1
( O 0
15 O 0
to O 0
17 O 0
. O 0
5 O 0
x O 0
10 O 0
( O 0
6 O 0
) O 0
IU O 0
vitamin B-Chemical 1
D3 I-Chemical 1
) O 0
were O 0
associated O 0
with O 0
prolonged O 0
hypercalcemia B-Disease 1
, O 0
hyperphosphatemia B-Disease 1
, O 0
and O 0
large O 0
increases O 0
of O 0
vitamin B-Chemical 1
D3 I-Chemical 1
and O 0
its O 0
metabolites O 0
in O 0
the O 0
blood O 0
plasma O 0
of O 0
nonlactating O 0
nonpregnant O 0
and O 0
pregnant O 0
Jersey O 0
cows O 0
. O 0

Calcium B-Chemical 1
concentrations O 0
1 O 0
day O 0
postpartum O 0
were O 0
higher O 0
in O 0
cows O 0
treated O 0
with O 0
vitamin B-Chemical 1
D3 I-Chemical 1
about O 0
32 O 0
days O 0
prepartum O 0
( O 0
8 O 0
. O 0
8 O 0
mg O 0
/ O 0
100 O 0
ml O 0
) O 0
than O 0
in O 0
control O 0
cows O 0
( O 0
5 O 0
. O 0
5 O 0
mg O 0
/ O 0
100 O 0
ml O 0
) O 0
. O 0

None O 0
of O 0
the O 0
cows O 0
treated O 0
with O 0
vitamin B-Chemical 1
D3 I-Chemical 1
showed O 0
signs O 0
of O 0
milk B-Disease 1
fever I-Disease 1
during O 0
the O 0
peripartal O 0
period O 0
; O 0
however O 0
, O 0
22 O 0
% O 0
of O 0
the O 0
control O 0
cows O 0
developed O 0
clinical O 0
signs O 0
of O 0
milk B-Disease 1
fever I-Disease 1
during O 0
this O 0
period O 0
. O 0

Signs O 0
of O 0
vitamin B-Chemical 1
D3 I-Chemical 1
toxicity B-Disease 1
were O 0
not O 0
observed O 0
in O 0
nonlactating O 0
nonpregnant O 0
cows O 0
; O 0
however O 0
, O 0
pregnant O 0
cows O 0
commonly O 0
developed O 0
severe O 0
signs O 0
of O 0
vitamin B-Chemical 1
D3 I-Chemical 1
toxicity B-Disease 1
and O 0
10 O 0
of O 0
17 O 0
cows O 0
died O 0
. O 0

There O 0
was O 0
widespread O 0
metastatic O 0
calcification O 0
in O 0
the O 0
cows O 0
that O 0
died O 0
. O 0

Because O 0
of O 0
the O 0
extreme O 0
toxicity B-Disease 1
of O 0
vitamin B-Chemical 1
D3 I-Chemical 1
in O 0
pregnant O 0
Jersey O 0
cows O 0
and O 0
the O 0
low O 0
margin O 0
of O 0
safety O 0
between O 0
doses O 0
of O 0
vitamin B-Chemical 1
D3 I-Chemical 1
that O 0
prevent O 0
milk B-Disease 1
fever I-Disease 1
and O 0
doses O 0
that O 0
induce O 0
milk B-Disease 1
fever I-Disease 1
, O 0
we O 0
concluded O 0
that O 0
vitamin B-Chemical 1
D3 I-Chemical 1
cannot O 0
be O 0
used O 0
practically O 0
to O 0
prevent O 0
milk B-Disease 1
fever I-Disease 1
when O 0
injected O 0
several O 0
weeks O 0
prepartum O 0
. O 0

Diseases B-Disease 1
of I-Disease 1
peripheral I-Disease 1
nerves I-Disease 1
as O 0
seen O 0
in O 0
the O 0
Nigerian O 0
African O 0
. O 0

The O 0
anatomical O 0
and O 0
aetiological O 0
diagnoses O 0
of O 0
peripheral B-Disease 1
nerve I-Disease 1
disease I-Disease 1
excluding O 0
its O 0
primary O 0
benign O 0
and O 0
malignant O 0
disorders O 0
, O 0
as O 0
seen O 0
in O 0
358 O 0
Nigerians O 0
are O 0
presented O 0
. O 0

There O 0
is O 0
a O 0
male O 0
preponderance O 0
and O 0
the O 0
peak O 0
incidence O 0
is O 0
in O 0
the O 0
fourth O 0
decade O 0
. O 0

Sensori B-Disease 1
- I-Disease 1
motor I-Disease 1
neuropathy I-Disease 1
was O 0
the O 0
commonest O 0
presentation O 0
( O 0
50 O 0
% O 0
) O 0
. O 0

Guillain B-Disease 1
- I-Disease 1
Barr I-Disease 1
syndrome I-Disease 1
was O 0
the O 0
commonest O 0
identifiable O 0
cause O 0
( O 0
15 O 0
. O 0
6 O 0
% O 0
) O 0
, O 0
accounting O 0
for O 0
half O 0
of O 0
the O 0
cases O 0
with O 0
motor B-Disease 1
neuropathy I-Disease 1
. O 0

Peripheral B-Disease 1
neuropathy I-Disease 1
due O 0
to O 0
nutritional B-Disease 1
deficiency I-Disease 1
of O 0
thiamine B-Chemical 1
and O 0
riboflavin B-Chemical 1
was O 0
common O 0
( O 0
10 O 0
. O 0
1 O 0
% O 0
) O 0
and O 0
presented O 0
mainly O 0
as O 0
sensory O 0
and O 0
sensori B-Disease 1
- I-Disease 1
motor I-Disease 1
neuropathy I-Disease 1
. O 0

Diabetes B-Disease 1
mellitus I-Disease 1
was O 0
the O 0
major O 0
cause O 0
of O 0
autonomic B-Disease 1
neuropathy I-Disease 1
. O 0

Isoniazid B-Chemical 1
was O 0
the O 0
most O 0
frequent O 0
agent O 0
in O 0
drug O 0
- O 0
induced O 0
neuropathy B-Disease 1
. O 0

Migraine B-Disease 1
( O 0
20 O 0
% O 0
) O 0
was O 0
not O 0
an O 0
uncommon O 0
cause O 0
of O 0
cranial B-Disease 1
neuropathy I-Disease 1
although O 0
malignancies B-Disease 1
arising O 0
from O 0
the O 0
reticuloendothelial O 0
system O 0
or O 0
related O 0
structures O 0
of O 0
the O 0
head O 0
and O 0
neck O 0
were O 0
more O 0
frequent O 0
( O 0
26 O 0
% O 0
) O 0
. O 0

In O 0
26 O 0
. O 0
5 O 0
% O 0
of O 0
all O 0
the O 0
cases O 0
, O 0
the O 0
aetiology O 0
of O 0
the O 0
neuropathy B-Disease 1
was O 0
undetermined O 0
. O 0

Heredofamilial O 0
and O 0
connective B-Disease 1
tissue I-Disease 1
disorders I-Disease 1
were O 0
rare O 0
. O 0

Some O 0
of O 0
the O 0
factors O 0
related O 0
to O 0
the O 0
clinical O 0
presentation O 0
and O 0
pathogenesis O 0
of O 0
the O 0
neuropathies B-Disease 1
are O 0
briefly O 0
discussed O 0
. O 0

Reduction O 0
in O 0
caffeine B-Chemical 1
toxicity B-Disease 1
by O 0
acetaminophen B-Chemical 1
. O 0

A O 0
patient O 0
who O 0
allegedly O 0
consumed O 0
100 O 0
tablets O 0
of O 0
an O 0
over O 0
- O 0
the O 0
- O 0
counter O 0
analgesic O 0
containing O 0
sodium B-Chemical 1
acetylsalicylate I-Chemical 1
, O 0
caffeine B-Chemical 1
, O 0
and O 0
acetaminophen B-Chemical 1
displayed O 0
no O 0
significant O 0
CNS O 0
stimulation O 0
despite O 0
the O 0
presence O 0
of O 0
175 O 0
micrograms O 0
of O 0
caffeine B-Chemical 1
per O 0
mL O 0
of O 0
serum O 0
. O 0

Because O 0
salicylates O 0
have O 0
been O 0
reported O 0
to O 0
augment O 0
the O 0
stimulatory O 0
effects O 0
of O 0
caffeine B-Chemical 1
on O 0
the O 0
CNS O 0
, O 0
attention O 0
was O 0
focused O 0
on O 0
the O 0
possibility O 0
that O 0
the O 0
presence O 0
of O 0
acetaminophen B-Chemical 1
( O 0
52 O 0
micrograms O 0
/ O 0
mL O 0
) O 0
reduced O 0
the O 0
CNS O 0
toxicity B-Disease 1
of O 0
caffeine B-Chemical 1
. O 0

Studies O 0
in O 0
DBA O 0
/ O 0
2J O 0
mice O 0
showed O 0
that O 0
: O 0
1 O 0
) O 0
pretreatment O 0
with O 0
acetaminophen B-Chemical 1
( O 0
100 O 0
mg O 0
/ O 0
kg O 0
) O 0
increased O 0
the O 0
interval O 0
between O 0
the O 0
administration O 0
of O 0
caffeine B-Chemical 1
( O 0
300 O 0
to O 0
450 O 0
mg O 0
/ O 0
kg O 0
IP O 0
) O 0
and O 0
the O 0
onset O 0
of O 0
fatal O 0
convulsions B-Disease 1
by O 0
a O 0
factor O 0
of O 0
about O 0
two O 0
; O 0
and O 0
2 O 0
) O 0
pretreatment O 0
with O 0
acetaminophen B-Chemical 1
( O 0
75 O 0
mg O 0
/ O 0
kg O 0
) O 0
reduced O 0
the O 0
incidence O 0
of O 0
audiogenic O 0
seizures B-Disease 1
produced O 0
in O 0
the O 0
presence O 0
of O 0
caffeine B-Chemical 1
( O 0
12 O 0
. O 0
5 O 0
to O 0
75 O 0
mg O 0
/ O 0
kg O 0
IP O 0
) O 0
. O 0

The O 0
frequency O 0
of O 0
sound O 0
- O 0
induced O 0
seizures B-Disease 1
after O 0
12 O 0
. O 0
5 O 0
or O 0
25 O 0
mg O 0
/ O 0
kg O 0
caffeine B-Chemical 1
was O 0
reduced O 0
from O 0
50 O 0
to O 0
5 O 0
% O 0
by O 0
acetaminophen B-Chemical 1
. O 0

In O 0
the O 0
absence O 0
of O 0
caffeine B-Chemical 1
, O 0
acetaminophen B-Chemical 1
( O 0
up O 0
to O 0
300 O 0
mg O 0
/ O 0
kg O 0
) O 0
did O 0
not O 0
modify O 0
the O 0
seizures B-Disease 1
induced O 0
by O 0
maximal O 0
electroshock O 0
and O 0
did O 0
not O 0
alter O 0
the O 0
convulsant O 0
dose O 0
of O 0
pentylenetetrezol B-Chemical 1
in O 0
mice O 0
( O 0
tests O 0
performed O 0
by O 0
the O 0
Anticonvulsant O 0
Screening O 0
Project O 0
of O 0
NINCDS O 0
) O 0
. O 0

Acetaminophen B-Chemical 1
( O 0
up O 0
to O 0
150 O 0
micrograms O 0
/ O 0
mL O 0
) O 0
did O 0
not O 0
retard O 0
the O 0
incorporation O 0
of O 0
radioactive O 0
adenosine B-Chemical 1
into O 0
ATP B-Chemical 1
in O 0
slices O 0
of O 0
rat O 0
cerebral O 0
cortex O 0
. O 0

Thus O 0
the O 0
mechanism O 0
by O 0
which O 0
acetaminophen B-Chemical 1
antagonizes O 0
the O 0
actions O 0
of O 0
caffeine B-Chemical 1
in O 0
the O 0
CNS O 0
remains O 0
unknown O 0
. O 0

A O 0
double O 0
- O 0
blind O 0
study O 0
of O 0
the O 0
efficacy O 0
and O 0
safety O 0
of O 0
dothiepin B-Chemical 1
hydrochloride I-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
major O 0
depressive B-Disease 1
disorder I-Disease 1
. O 0

In O 0
a O 0
6 O 0
- O 0
week O 0
double O 0
- O 0
blind O 0
parallel O 0
treatment O 0
study O 0
, O 0
dothiepin B-Chemical 1
and O 0
amitriptyline B-Chemical 1
were O 0
compared O 0
to O 0
placebo O 0
in O 0
the O 0
treatment O 0
of O 0
33 O 0
depressed B-Disease 1
outpatients O 0
. O 0

Dothiepin B-Chemical 1
and O 0
amitriptyline B-Chemical 1
were O 0
equally O 0
effective O 0
in O 0
alleviating O 0
the O 0
symptoms O 0
of O 0
depressive B-Disease 1
illness I-Disease 1
, O 0
and O 0
both O 0
were O 0
significantly O 0
superior O 0
to O 0
placebo O 0
. O 0

The O 0
overall O 0
incidence O 0
of O 0
side O 0
effects O 0
and O 0
the O 0
frequency O 0
and O 0
severity O 0
of O 0
blurred B-Disease 1
vision I-Disease 1
, O 0
dry B-Disease 1
mouth I-Disease 1
, O 0
and O 0
drowsiness O 0
were O 0
significantly O 0
less O 0
with O 0
dothiepin B-Chemical 1
than O 0
with O 0
amitriptyline B-Chemical 1
. O 0

Dothiepin B-Chemical 1
also O 0
produced O 0
fewer O 0
CNS O 0
and O 0
cardiovascular O 0
effects O 0
. O 0

There O 0
were O 0
no O 0
clinically O 0
important O 0
changes O 0
in O 0
laboratory O 0
parameters O 0
. O 0

Dothiepin B-Chemical 1
thus O 0
was O 0
found O 0
to O 0
be O 0
an O 0
effective O 0
antidepressant B-Chemical 1
drug O 0
associated O 0
with O 0
fewer O 0
side O 0
effects O 0
than O 0
amitriptyline B-Chemical 1
in O 0
the O 0
treatment O 0
of O 0
depressed B-Disease 1
outpatients O 0
. O 0

Behavioral O 0
effects O 0
of O 0
diazepam B-Chemical 1
and O 0
propranolol B-Chemical 1
in O 0
patients O 0
with O 0
panic B-Disease 1
disorder I-Disease 1
and O 0
agoraphobia B-Disease 1
. O 0

The O 0
effects O 0
of O 0
oral O 0
doses O 0
of O 0
diazepam B-Chemical 1
( O 0
single O 0
dose O 0
of O 0
10 O 0
mg O 0
and O 0
a O 0
median O 0
dose O 0
of O 0
30 O 0
mg O 0
/ O 0
day O 0
for O 0
2 O 0
weeks O 0
) O 0
and O 0
propranolol B-Chemical 1
( O 0
single O 0
dose O 0
of O 0
80 O 0
mg O 0
and O 0
a O 0
median O 0
dose O 0
of O 0
240 O 0
mg O 0
/ O 0
day O 0
for O 0
2 O 0
weeks O 0
) O 0
on O 0
psychological O 0
performance O 0
of O 0
patients O 0
with O 0
panic B-Disease 1
disorders I-Disease 1
and O 0
agoraphobia B-Disease 1
were O 0
investigated O 0
in O 0
a O 0
double O 0
- O 0
blind O 0
, O 0
randomized O 0
and O 0
crossover O 0
design O 0
. O 0

Both O 0
drugs O 0
impaired B-Disease 1
immediate I-Disease 1
free I-Disease 1
recall I-Disease 1
but O 0
the O 0
decrease O 0
was O 0
greater O 0
for O 0
diazepam B-Chemical 1
than O 0
propranolol B-Chemical 1
. O 0

Delayed B-Disease 1
free I-Disease 1
recall I-Disease 1
was I-Disease 1
also I-Disease 1
impaired I-Disease 1
but O 0
the O 0
two O 0
drugs O 0
did O 0
not O 0
differ O 0
. O 0

Patients O 0
tapped O 0
faster O 0
after O 0
propranolol B-Chemical 1
than O 0
diazepam B-Chemical 1
and O 0
they O 0
were O 0
more O 0
sedated O 0
after O 0
diazepam B-Chemical 1
than O 0
propranolol B-Chemical 1
. O 0

After O 0
2 O 0
weeks O 0
of O 0
treatment O 0
, O 0
patients O 0
tested O 0
5 O 0
- O 0
8 O 0
h O 0
after O 0
the O 0
last O 0
dose O 0
of O 0
medication O 0
did O 0
not O 0
show O 0
any O 0
decrement O 0
of O 0
performance O 0
. O 0

These O 0
results O 0
are O 0
similar O 0
to O 0
those O 0
previously O 0
found O 0
in O 0
healthy O 0
subjects O 0
. O 0

Accumulation O 0
of O 0
drugs O 0
was O 0
not O 0
reflected O 0
in O 0
prolonged O 0
behavioral B-Disease 1
impairment I-Disease 1
. O 0

Comparison O 0
of O 0
i O 0
. O 0
v O 0
. O 0
glycopyrrolate B-Chemical 1
and O 0
atropine B-Chemical 1
in O 0
the O 0
prevention O 0
of O 0
bradycardia B-Disease 1
and O 0
arrhythmias B-Disease 1
following O 0
repeated O 0
doses O 0
of O 0
suxamethonium B-Chemical 1
in O 0
children O 0
. O 0

The O 0
effectiveness O 0
of O 0
administration O 0
of O 0
glycopyrrolate B-Chemical 1
5 O 0
and O 0
10 O 0
micrograms O 0
kg O 0
- O 0
1 O 0
and O 0
atropine B-Chemical 1
10 O 0
and O 0
20 O 0
micrograms O 0
kg O 0
- O 0
1 O 0
i O 0
. O 0
v O 0
. O 0
immediately O 0
before O 0
the O 0
induction O 0
of O 0
anaesthesia O 0
, O 0
to O 0
prevent O 0
arrhythmia B-Disease 1
and O 0
bradycardia B-Disease 1
following O 0
repeated O 0
doses O 0
of O 0
suxamethonium B-Chemical 1
in O 0
children O 0
, O 0
was O 0
studied O 0
. O 0

A O 0
control O 0
group O 0
was O 0
included O 0
for O 0
comparison O 0
with O 0
the O 0
lower O 0
dose O 0
range O 0
of O 0
glycopyrrolate B-Chemical 1
and O 0
atropine B-Chemical 1
. O 0

A O 0
frequency O 0
of O 0
bradycardia B-Disease 1
of O 0
50 O 0
% O 0
was O 0
noted O 0
in O 0
the O 0
control O 0
group O 0
, O 0
but O 0
this O 0
was O 0
not O 0
significantly O 0
different O 0
from O 0
the O 0
frequency O 0
with O 0
the O 0
active O 0
drugs O 0
. O 0

Bradycardia B-Disease 1
( O 0
defined O 0
as O 0
a O 0
decrease O 0
in O 0
heart O 0
rate O 0
to O 0
less O 0
than O 0
50 O 0
beat O 0
min O 0
- O 0
1 O 0
) O 0
was O 0
prevented O 0
when O 0
the O 0
larger O 0
dose O 0
of O 0
either O 0
active O 0
drug O 0
was O 0
used O 0
. O 0

It O 0
is O 0
recommended O 0
that O 0
either O 0
glycopyrrolate B-Chemical 1
10 O 0
micrograms O 0
kg O 0
- O 0
1 O 0
or O 0
atropine B-Chemical 1
20 O 0
micrograms O 0
kg O 0
- O 0
1 O 0
i O 0
. O 0
v O 0
. O 0
should O 0
immediately O 0
precede O 0
induction O 0
of O 0
anaesthesia O 0
, O 0
in O 0
children O 0
, O 0
if O 0
the O 0
repeated O 0
administration O 0
of O 0
suxamethonium B-Chemical 1
is O 0
anticipated O 0
. O 0

Veno B-Disease 1
- I-Disease 1
occlusive I-Disease 1
liver I-Disease 1
disease I-Disease 1
after O 0
dacarbazine B-Chemical 1
therapy O 0
( O 0
DTIC B-Chemical 1
) O 0
for O 0
melanoma B-Disease 1
. O 0

A O 0
case O 0
of O 0
veno B-Disease 1
- I-Disease 1
occlusive I-Disease 1
disease I-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
with O 0
fatal O 0
outcome O 0
after O 0
dacarbazine B-Chemical 1
( O 0
DTIC B-Chemical 1
) O 0
therapy O 0
for O 0
melanoma B-Disease 1
is O 0
reported O 0
. O 0

There O 0
was O 0
a O 0
fulminant O 0
clinical O 0
course O 0
from O 0
start O 0
of O 0
symptoms O 0
until O 0
death B-Disease 1
. O 0

At O 0
autopsy O 0
the O 0
liver O 0
was O 0
enlarged O 0
and O 0
firm O 0
with O 0
signs O 0
of O 0
venous B-Disease 1
congestion I-Disease 1
. O 0

Small O 0
- O 0
and O 0
medium O 0
- O 0
sized O 0
hepatic O 0
veins O 0
were O 0
blocked O 0
by O 0
thrombosis B-Disease 1
. O 0

Eosinophilic O 0
infiltrations O 0
were O 0
found O 0
around O 0
the O 0
vessels O 0
. O 0

Published O 0
cases O 0
from O 0
the O 0
literature O 0
are O 0
reviewed O 0
and O 0
pertinent O 0
features O 0
discussed O 0
. O 0

Maternal O 0
lithium B-Chemical 1
and O 0
neonatal O 0
Ebstein B-Disease 1
' I-Disease 1
s I-Disease 1
anomaly I-Disease 1
: O 0
evaluation O 0
with O 0
cross O 0
- O 0
sectional O 0
echocardiography O 0
. O 0

Cross O 0
- O 0
sectional O 0
echocardiography O 0
was O 0
used O 0
to O 0
evaluate O 0
two O 0
neonates O 0
whose O 0
mothers O 0
ingested O 0
lithium B-Chemical 1
during O 0
pregnancy O 0
. O 0

In O 0
one O 0
infant O 0
, O 0
Ebstein B-Disease 1
' I-Disease 1
s I-Disease 1
anomaly I-Disease 1
of O 0
the O 0
tricuspid O 0
valve O 0
was O 0
identified O 0
. O 0

In O 0
the O 0
other O 0
infant O 0
cross O 0
- O 0
sectional O 0
echocardiography O 0
provided O 0
reassurance O 0
that O 0
the O 0
infant O 0
did O 0
not O 0
have O 0
Ebstein B-Disease 1
' I-Disease 1
s I-Disease 1
anomaly I-Disease 1
. O 0

Cross O 0
- O 0
sectional O 0
echocardiographic O 0
screening O 0
of O 0
newborns O 0
exposed O 0
to O 0
lithium B-Chemical 1
during O 0
gestation O 0
can O 0
provide O 0
highly O 0
accurate O 0
, O 0
noninvasive O 0
assessment O 0
of O 0
the O 0
presence O 0
or O 0
absence O 0
of O 0
lithium B-Chemical 1
- O 0
induced O 0
cardiac B-Disease 1
malformations I-Disease 1
. O 0

Effects O 0
of O 0
training O 0
on O 0
the O 0
extent O 0
of O 0
experimental O 0
myocardial B-Disease 1
infarction I-Disease 1
in O 0
aging O 0
rats O 0
. O 0

The O 0
effects O 0
of O 0
exercise O 0
on O 0
the O 0
severity O 0
of O 0
isoproterenol B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
infarction I-Disease 1
were O 0
studied O 0
in O 0
female O 0
albino O 0
rats O 0
of O 0
20 O 0
, O 0
40 O 0
, O 0
60 O 0
and O 0
80 O 0
weeks O 0
of O 0
age O 0
. O 0

The O 0
rats O 0
were O 0
trained O 0
to O 0
swim O 0
for O 0
a O 0
specific O 0
duration O 0
and O 0
for O 0
a O 0
particular O 0
period O 0
. O 0

The O 0
occurrence O 0
of O 0
infarcts B-Disease 1
were O 0
confirmed O 0
by O 0
histological O 0
methods O 0
. O 0

Elevations O 0
in O 0
the O 0
serum O 0
GOT O 0
and O 0
GPT O 0
were O 0
maximum O 0
in O 0
the O 0
sedentary O 0
- O 0
isoproterenols B-Chemical 1
and O 0
minimum O 0
in O 0
the O 0
exercise O 0
- O 0
controls O 0
. O 0

These O 0
changes O 0
in O 0
the O 0
serum O 0
transaminases O 0
were O 0
associated O 0
with O 0
corresponding O 0
depletions O 0
in O 0
the O 0
cardiac O 0
GOT O 0
and O 0
GPT O 0
. O 0

However O 0
, O 0
age O 0
was O 0
seen O 0
to O 0
interfere O 0
with O 0
the O 0
responses O 0
exhibited O 0
by O 0
the O 0
young O 0
and O 0
old O 0
rats O 0
. O 0

Studies O 0
dealing O 0
with O 0
myocardial B-Disease 1
infarction I-Disease 1
are O 0
more O 0
informative O 0
when O 0
dealt O 0
with O 0
age O 0
. O 0

Effect O 0
of O 0
polyethylene B-Chemical 1
glycol I-Chemical 1
400 I-Chemical 1
on O 0
adriamycin B-Chemical 1
toxicity B-Disease 1
in O 0
mice O 0
. O 0

The O 0
effect O 0
of O 0
a O 0
widely O 0
used O 0
organic O 0
solvent O 0
, O 0
polyethylene B-Chemical 1
glycol I-Chemical 1
400 I-Chemical 1
( O 0
PEG B-Chemical 1
400 I-Chemical 1
) O 0
, O 0
on O 0
the O 0
toxic O 0
action O 0
of O 0
an O 0
acute O 0
or O 0
chronic O 0
treatment O 0
with O 0
adriamycin B-Chemical 1
( O 0
ADR B-Chemical 1
) O 0
was O 0
evaluated O 0
in O 0
mice O 0
. O 0

PEG B-Chemical 1
400 I-Chemical 1
impressively O 0
decreased O 0
both O 0
acute O 0
high O 0
- O 0
dose O 0
and O 0
chronic O 0
low O 0
- O 0
dose O 0
- O 0
ADR B-Chemical 1
- O 0
associated O 0
lethality O 0
. O 0

Light O 0
microscopic O 0
analysis O 0
showed O 0
a O 0
significant O 0
protection O 0
against O 0
ADR B-Chemical 1
- O 0
induced O 0
cardiac B-Disease 1
morphological I-Disease 1
alterations I-Disease 1
. O 0

Such O 0
treatment O 0
did O 0
not O 0
diminish O 0
the O 0
ADR B-Chemical 1
antitumor O 0
activity O 0
in O 0
L1210 B-Disease 1
leukemia I-Disease 1
and O 0
in O 0
Ehrlich B-Disease 1
ascites I-Disease 1
tumor I-Disease 1
. O 0

Sublingual O 0
absorption O 0
of O 0
the O 0
quaternary B-Chemical 1
ammonium I-Chemical 1
antiarrhythmic O 0
agent O 0
, O 0
UM B-Chemical 1
- I-Chemical 1
272 I-Chemical 1
. O 0

UM B-Chemical 1
- I-Chemical 1
272 I-Chemical 1
( O 0
N B-Chemical 1
, I-Chemical 1
N I-Chemical 1
- I-Chemical 1
dimethylpropranolol I-Chemical 1
) O 0
, O 0
a O 0
quaternary O 0
antiarrhythmic O 0
agent O 0
, O 0
was O 0
administered O 0
sublingually O 0
to O 0
dogs O 0
with O 0
ouabain B-Chemical 1
- O 0
induced O 0
ventricular B-Disease 1
tachycardias I-Disease 1
. O 0

Both O 0
anti O 0
- O 0
arrhythmic O 0
efficacy O 0
and O 0
bioavailability O 0
were O 0
compared O 0
to O 0
oral O 0
drug O 0
. O 0

Sublingual O 0
UM B-Chemical 1
- I-Chemical 1
272 I-Chemical 1
converted O 0
ventricular B-Disease 1
tachycardia I-Disease 1
to O 0
sinus O 0
rhythm O 0
in O 0
all O 0
5 O 0
dogs O 0
. O 0

The O 0
area O 0
under O 0
the O 0
plasma O 0
concentration O 0
time O 0
curve O 0
at O 0
90 O 0
min O 0
was O 0
4 O 0
- O 0
12 O 0
times O 0
greater O 0
than O 0
for O 0
oral O 0
drug O 0
, O 0
suggesting O 0
the O 0
existence O 0
of O 0
an O 0
absorption O 0
- O 0
limiting O 0
process O 0
in O 0
the O 0
intestine O 0
, O 0
and O 0
providing O 0
an O 0
alternate O 0
form O 0
of O 0
administration O 0
for O 0
quaternary O 0
drugs O 0
. O 0

Early O 0
adjuvant O 0
adriamycin B-Chemical 1
in O 0
superficial O 0
bladder B-Disease 1
carcinoma I-Disease 1
. O 0

A O 0
multicenter O 0
study O 0
was O 0
performed O 0
in O 0
110 O 0
patients O 0
with O 0
superficial O 0
transitional O 0
cell O 0
carcinoma B-Disease 1
of I-Disease 1
the I-Disease 1
bladder I-Disease 1
. O 0

Adriamycin B-Chemical 1
( O 0
50 O 0
mg O 0
/ O 0
50 O 0
ml O 0
) O 0
was O 0
administered O 0
intravesically O 0
within O 0
24 O 0
h O 0
after O 0
transurethral O 0
resection O 0
of O 0
TA O 0
- O 0
T1 O 0
( O 0
O O 0
- O 0
A O 0
) O 0
bladder B-Disease 1
tumors I-Disease 1
. O 0

Instillation O 0
was O 0
repeated O 0
twice O 0
during O 0
the O 0
first O 0
week O 0
, O 0
then O 0
weekly O 0
during O 0
the O 0
first O 0
month O 0
and O 0
afterwards O 0
monthly O 0
for O 0
1 O 0
year O 0
. O 0

The O 0
tolerance O 0
was O 0
evaluated O 0
in O 0
these O 0
110 O 0
patients O 0
, O 0
and O 0
29 O 0
patients O 0
presented O 0
with O 0
local O 0
side O 0
- O 0
effects O 0
. O 0

In O 0
24 O 0
of O 0
these O 0
patients O 0
chemical O 0
cystitis B-Disease 1
was O 0
severe O 0
enough O 0
for O 0
them O 0
to O 0
drop O 0
out O 0
of O 0
the O 0
study O 0
. O 0

No O 0
systemic O 0
side O 0
- O 0
effects O 0
were O 0
observed O 0
. O 0

Recurrence O 0
was O 0
studied O 0
in O 0
82 O 0
evaluable O 0
patients O 0
after O 0
1 O 0
year O 0
of O 0
follow O 0
- O 0
up O 0
and O 0
in O 0
72 O 0
patients O 0
followed O 0
for O 0
2 O 0
- O 0
3 O 0
years O 0
( O 0
mean O 0
32 O 0
months O 0
) O 0
. O 0

Of O 0
the O 0
82 O 0
patients O 0
studied O 0
after O 0
1 O 0
year O 0
, O 0
23 O 0
had O 0
primary O 0
and O 0
59 O 0
recurrent O 0
disease O 0
. O 0

Of O 0
the O 0
82 O 0
evaluable O 0
patients O 0
, O 0
50 O 0
did O 0
not O 0
show O 0
any O 0
recurrence O 0
after O 0
1 O 0
year O 0
( O 0
61 O 0
% O 0
) O 0
, O 0
while O 0
32 O 0
presented O 0
with O 0
one O 0
or O 0
more O 0
recurrences O 0
( O 0
39 O 0
% O 0
) O 0
. O 0

Of O 0
these O 0
recurrences O 0
, O 0
27 O 0
were O 0
T1 O 0
tumors B-Disease 1
while O 0
five O 0
progressed O 0
to O 0
more O 0
highly O 0
invasive O 0
lesions O 0
. O 0

In O 0
patients O 0
that O 0
were O 0
free O 0
of O 0
recurrence O 0
during O 0
the O 0
first O 0
year O 0
, O 0
80 O 0
% O 0
remained O 0
tumor B-Disease 1
- O 0
free O 0
during O 0
the O 0
2 O 0
- O 0
to O 0
3 O 0
- O 0
year O 0
follow O 0
- O 0
up O 0
period O 0
. O 0

Of O 0
the O 0
patients O 0
developing O 0
one O 0
or O 0
more O 0
recurrences O 0
during O 0
the O 0
first O 0
year O 0
, O 0
only O 0
50 O 0
% O 0
presented O 0
with O 0
further O 0
recurrence O 0
once O 0
the O 0
instillations O 0
were O 0
stopped O 0
. O 0

The O 0
beneficial O 0
effect O 0
of O 0
Adriamycin B-Chemical 1
appears O 0
obvious O 0
and O 0
might O 0
be O 0
related O 0
to O 0
the O 0
drug O 0
itself O 0
, O 0
the O 0
early O 0
and O 0
repeated O 0
instillations O 0
after O 0
TUR O 0
, O 0
or O 0
both O 0
. O 0

D B-Chemical 1
- I-Chemical 1
penicillamine I-Chemical 1
- O 0
induced O 0
angiopathy B-Disease 1
in O 0
rats O 0
. O 0

The O 0
effect O 0
of O 0
high O 0
dose O 0
D B-Chemical 1
- I-Chemical 1
penicillamine I-Chemical 1
treatment O 0
on O 0
aortic O 0
permeability O 0
to O 0
albumin O 0
and O 0
on O 0
the O 0
ultrastructure O 0
of O 0
the O 0
vessel O 0
. O 0

Male O 0
Sprague O 0
- O 0
Dawley O 0
rats O 0
were O 0
treated O 0
with O 0
D B-Chemical 1
- I-Chemical 1
penicillamine I-Chemical 1
( O 0
D B-Chemical 1
- I-Chemical 1
pen I-Chemical 1
) O 0
500 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
for O 0
10 O 0
or O 0
42 O 0
days O 0
. O 0

Pair O 0
fed O 0
rats O 0
served O 0
as O 0
controls O 0
. O 0

Changes O 0
in O 0
aortic O 0
morphology O 0
were O 0
examined O 0
by O 0
light O 0
- O 0
and O 0
transmission O 0
- O 0
electron O 0
microscopy O 0
( O 0
TEM O 0
) O 0
. O 0

In O 0
addition O 0
, O 0
the O 0
endothelial O 0
permeability O 0
and O 0
the O 0
penetration O 0
through O 0
the O 0
aortic O 0
wall O 0
of O 0
albumin O 0
were O 0
studied O 0
10 O 0
minutes O 0
, O 0
24 O 0
and O 0
48 O 0
hours O 0
after O 0
i O 0
. O 0
v O 0
. O 0
injection O 0
of O 0
human O 0
serum O 0
131I O 0
- O 0
albumin O 0
( O 0
131I O 0
- O 0
HSA O 0
) O 0
. O 0

TEM O 0
revealed O 0
extensive O 0
elastolysis O 0
in O 0
the O 0
arterial O 0
wall O 0
of O 0
D B-Chemical 1
- I-Chemical 1
pen I-Chemical 1
- O 0
treated O 0
rats O 0
, O 0
consistent O 0
with O 0
an O 0
inhibitory O 0
effect O 0
on O 0
crosslink O 0
formation O 0
. O 0

In O 0
experimental O 0
animals O 0
excess O 0
deposition O 0
of O 0
collagen O 0
and O 0
glycoaminoglycans O 0
was O 0
observed O 0
in O 0
the O 0
subendothelial O 0
and O 0
medial O 0
layer O 0
of O 0
the O 0
aortic O 0
wall O 0
, O 0
together O 0
with O 0
prominent O 0
basal O 0
membrane O 0
substance O 0
around O 0
aortic O 0
smooth O 0
muscle O 0
cells O 0
. O 0

The O 0
aorta O 0
/ O 0
serum O 0
- O 0
ratio O 0
and O 0
the O 0
radioactive O 0
build O 0
- O 0
up O 0
24 O 0
and O 0
48 O 0
hours O 0
after O 0
injection O 0
of O 0
131I O 0
- O 0
HSA O 0
was O 0
reduced O 0
in O 0
animals O 0
treated O 0
with O 0
D B-Chemical 1
- I-Chemical 1
pen I-Chemical 1
for O 0
42 O 0
days O 0
, O 0
indicating O 0
an O 0
impeded O 0
transmural O 0
transport O 0
of O 0
tracer O 0
which O 0
may O 0
be O 0
caused O 0
by O 0
a O 0
steric O 0
exclusion O 0
effect O 0
of O 0
abundant O 0
hyaluronate B-Chemical 1
. O 0

The O 0
endothelial O 0
ultrastructure O 0
was O 0
unaffected O 0
by O 0
D B-Chemical 1
- I-Chemical 1
pen I-Chemical 1
, O 0
and O 0
no O 0
differences O 0
in O 0
aortic O 0
131I O 0
- O 0
HSA O 0
radioactivity O 0
or O 0
aorta O 0
/ O 0
serum O 0
- O 0
ratio O 0
were O 0
recorded O 0
between O 0
experimental O 0
and O 0
control O 0
groups O 0
10 O 0
minutes O 0
after O 0
tracer O 0
injection O 0
, O 0
indicating O 0
that O 0
the O 0
permeability O 0
of O 0
the O 0
endothelial O 0
barrier O 0
to O 0
albumin O 0
remained O 0
unaffected O 0
by O 0
D B-Chemical 1
- I-Chemical 1
pen I-Chemical 1
treatment O 0
. O 0

These O 0
observations O 0
support O 0
the O 0
hypothesis O 0
that O 0
treatment O 0
with O 0
high O 0
doses O 0
of O 0
D B-Chemical 1
- I-Chemical 1
pen I-Chemical 1
may O 0
induce O 0
a O 0
fibroproliferative O 0
response O 0
in O 0
rat O 0
aorta O 0
, O 0
possibly O 0
by O 0
an O 0
inhibitory O 0
effect O 0
on O 0
the O 0
cross O 0
- O 0
linking O 0
of O 0
collagen O 0
and O 0
elastin O 0
. O 0

Effect O 0
of O 0
aspirin B-Chemical 1
on O 0
N B-Chemical 1
- I-Chemical 1
[ I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
5 I-Chemical 1
- I-Chemical 1
nitro I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
furyl I-Chemical 1
) I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
thiazolyl I-Chemical 1
] I-Chemical 1
- I-Chemical 1
formamide I-Chemical 1
- O 0
induced O 0
epithelial O 0
proliferation O 0
in O 0
the O 0
urinary O 0
bladder O 0
and O 0
forestomach O 0
of O 0
the O 0
rat O 0
. O 0

The O 0
co O 0
- O 0
administration O 0
of O 0
aspirin B-Chemical 1
with O 0
N B-Chemical 1
- I-Chemical 1
[ I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
5 I-Chemical 1
- I-Chemical 1
nitro I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
furyl I-Chemical 1
) I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
thiazolyl I-Chemical 1
] I-Chemical 1
- I-Chemical 1
formamide I-Chemical 1
( O 0
FANFT B-Chemical 1
) O 0
to O 0
rats O 0
resulted O 0
in O 0
a O 0
reduced O 0
incidence O 0
of O 0
FANFT B-Chemical 1
- O 0
induced O 0
bladder B-Disease 1
carcinomas I-Disease 1
but O 0
a O 0
concomitant O 0
induction O 0
of O 0
forestomach B-Disease 1
tumors I-Disease 1
. O 0

An O 0
autoradiographic O 0
study O 0
was O 0
performed O 0
on O 0
male O 0
F O 0
- O 0
344 O 0
rats O 0
fed O 0
diet O 0
containing O 0
FANFT B-Chemical 1
at O 0
a O 0
level O 0
of O 0
0 O 0
. O 0
2 O 0
% O 0
and O 0
/ O 0
or O 0
aspirin B-Chemical 1
at O 0
a O 0
level O 0
of O 0
0 O 0
. O 0
5 O 0
% O 0
to O 0
evaluate O 0
the O 0
effect O 0
of O 0
aspirin B-Chemical 1
on O 0
the O 0
increased O 0
cell O 0
proliferation O 0
induced O 0
by O 0
FANFT B-Chemical 1
in O 0
the O 0
forestomach O 0
and O 0
bladder O 0
. O 0

FANFT B-Chemical 1
- O 0
induced O 0
cell O 0
proliferation O 0
in O 0
the O 0
bladder O 0
was O 0
significantly O 0
suppressed O 0
by O 0
aspirin B-Chemical 1
co O 0
- O 0
administration O 0
after O 0
4 O 0
weeks O 0
but O 0
not O 0
after O 0
12 O 0
weeks O 0
. O 0

In O 0
the O 0
forestomach O 0
, O 0
and O 0
also O 0
in O 0
the O 0
liver O 0
, O 0
aspirin B-Chemical 1
did O 0
not O 0
affect O 0
the O 0
FANFT B-Chemical 1
- O 0
induced O 0
increase O 0
in O 0
labeling O 0
index O 0
. O 0

The O 0
present O 0
results O 0
are O 0
consistent O 0
with O 0
the O 0
carcinogenicity O 0
experiment O 0
suggesting O 0
that O 0
different O 0
mechanisms O 0
are O 0
involved O 0
in O 0
FANFT B-Chemical 1
carcinogenesis B-Disease 1
in O 0
the O 0
bladder O 0
and O 0
forestomach O 0
, O 0
and O 0
that O 0
aspirin B-Chemical 1
' O 0
s O 0
effect O 0
on O 0
FANFT B-Chemical 1
in O 0
the O 0
forestomach O 0
is O 0
not O 0
due O 0
to O 0
an O 0
irritant O 0
effect O 0
associated O 0
with O 0
increased O 0
cell O 0
proliferation O 0
. O 0

Also O 0
, O 0
there O 0
appears O 0
to O 0
be O 0
an O 0
adaptation O 0
by O 0
the O 0
rats O 0
to O 0
the O 0
chronic O 0
ingestion O 0
of O 0
aspirin B-Chemical 1
. O 0

A O 0
case O 0
of O 0
tardive B-Disease 1
dyskinesia I-Disease 1
caused O 0
by O 0
metoclopramide B-Chemical 1
. O 0

Abnormal B-Disease 1
involuntary I-Disease 1
movements I-Disease 1
appeared O 0
in O 0
the O 0
mouth O 0
, O 0
tongue O 0
, O 0
neck O 0
and O 0
abdomen O 0
of O 0
a O 0
64 O 0
- O 0
year O 0
- O 0
old O 0
male O 0
patient O 0
after O 0
he O 0
took O 0
metoclopramide B-Chemical 1
for O 0
gastrointestinal B-Disease 1
disorder I-Disease 1
in O 0
a O 0
regimen O 0
of O 0
30 O 0
mg O 0
per O 0
day O 0
for O 0
a O 0
total O 0
of O 0
about O 0
260 O 0
days O 0
. O 0

The O 0
symptoms O 0
exacerbated O 0
to O 0
a O 0
maximum O 0
in O 0
a O 0
month O 0
. O 0

When O 0
the O 0
metoclopramide B-Chemical 1
administration O 0
was O 0
discontinued O 0
, O 0
the O 0
abnormal B-Disease 1
movements I-Disease 1
gradually O 0
improved O 0
to O 0
a O 0
considerable O 0
extent O 0
. O 0

Attention O 0
to O 0
the O 0
possible O 0
induction O 0
of O 0
specific O 0
tardive B-Disease 1
dyskinesia I-Disease 1
is O 0
called O 0
for O 0
in O 0
the O 0
use O 0
of O 0
this O 0
drug O 0
. O 0

Intra O 0
- O 0
arterial O 0
BCNU B-Chemical 1
chemotherapy O 0
for O 0
treatment O 0
of O 0
malignant B-Disease 1
gliomas I-Disease 1
of O 0
the O 0
central O 0
nervous O 0
system O 0
. O 0

Because O 0
of O 0
the O 0
rapid O 0
systemic O 0
clearance O 0
of O 0
BCNU B-Chemical 1
( O 0
1 B-Chemical 1
, I-Chemical 1
3 I-Chemical 1
- I-Chemical 1
bis I-Chemical 1
- I-Chemical 1
( I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
chloroethyl I-Chemical 1
) I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
nitrosourea I-Chemical 1
) O 0
, O 0
intra O 0
- O 0
arterial O 0
administration O 0
should O 0
provide O 0
a O 0
substantial O 0
advantage O 0
over O 0
intravenous O 0
administration O 0
for O 0
the O 0
treatment O 0
of O 0
malignant B-Disease 1
gliomas I-Disease 1
. O 0

Thirty O 0
- O 0
six O 0
patients O 0
were O 0
treated O 0
with O 0
BCNU B-Chemical 1
every O 0
6 O 0
to O 0
8 O 0
weeks O 0
, O 0
either O 0
by O 0
transfemoral O 0
catheterization O 0
of O 0
the O 0
internal O 0
carotid O 0
or O 0
vertebral O 0
artery O 0
or O 0
through O 0
a O 0
fully O 0
implantable O 0
intracarotid O 0
drug O 0
delivery O 0
system O 0
, O 0
beginning O 0
with O 0
a O 0
dose O 0
of O 0
200 O 0
mg O 0
/ O 0
sq O 0
m O 0
body O 0
surface O 0
area O 0
. O 0

Twelve O 0
patients O 0
with O 0
Grade O 0
III O 0
or O 0
IV O 0
astrocytomas B-Disease 1
were O 0
treated O 0
after O 0
partial O 0
resection O 0
of O 0
the O 0
tumor B-Disease 1
without O 0
prior O 0
radiation O 0
therapy O 0
. O 0

After O 0
two O 0
to O 0
seven O 0
cycles O 0
of O 0
chemotherapy O 0
, O 0
nine O 0
patients O 0
showed O 0
a O 0
decrease O 0
in O 0
tumor B-Disease 1
size O 0
and O 0
surrounding O 0
edema B-Disease 1
on O 0
contrast O 0
- O 0
enhanced O 0
computerized O 0
tomography O 0
scans O 0
. O 0

In O 0
the O 0
nine O 0
responders O 0
, O 0
median O 0
duration O 0
of O 0
chemotherapy O 0
response O 0
from O 0
the O 0
time O 0
of O 0
operation O 0
was O 0
25 O 0
weeks O 0
( O 0
range O 0
12 O 0
to O 0
more O 0
than O 0
91 O 0
weeks O 0
) O 0
. O 0

The O 0
median O 0
duration O 0
of O 0
survival O 0
in O 0
the O 0
12 O 0
patients O 0
was O 0
54 O 0
weeks O 0
( O 0
range O 0
21 O 0
to O 0
more O 0
than O 0
156 O 0
weeks O 0
) O 0
, O 0
with O 0
an O 0
18 O 0
- O 0
month O 0
survival O 0
rate O 0
of O 0
42 O 0
% O 0
. O 0

Twenty O 0
- O 0
four O 0
patients O 0
with O 0
recurrent O 0
Grade O 0
I O 0
to O 0
IV O 0
astrocytomas B-Disease 1
, O 0
whose O 0
resection O 0
and O 0
irradiation O 0
therapy O 0
had O 0
failed O 0
, O 0
received O 0
two O 0
to O 0
eight O 0
courses O 0
of O 0
intra O 0
- O 0
arterial O 0
BCNU B-Chemical 1
therapy O 0
. O 0

Seventeen O 0
of O 0
these O 0
had O 0
a O 0
response O 0
or O 0
were O 0
stable O 0
for O 0
a O 0
median O 0
of O 0
20 O 0
weeks O 0
( O 0
range O 0
6 O 0
to O 0
more O 0
than O 0
66 O 0
weeks O 0
) O 0
. O 0

The O 0
catheterization O 0
procedure O 0
is O 0
safe O 0
, O 0
with O 0
no O 0
immediate O 0
complication O 0
in O 0
111 O 0
infusions O 0
of O 0
BCNU B-Chemical 1
. O 0

A O 0
delayed O 0
complication O 0
in O 0
nine O 0
patients O 0
has O 0
been O 0
unilateral O 0
loss B-Disease 1
of I-Disease 1
vision I-Disease 1
secondary O 0
to O 0
a O 0
retinal B-Disease 1
vasculitis I-Disease 1
. O 0

The O 0
frequency O 0
of O 0
visual B-Disease 1
loss I-Disease 1
decreased O 0
after O 0
the O 0
concentration O 0
of O 0
the O 0
ethanol B-Chemical 1
diluent O 0
was O 0
lowered O 0
. O 0

Provocation O 0
of O 0
postural O 0
hypotension B-Disease 1
by O 0
nitroglycerin B-Chemical 1
in O 0
diabetic B-Disease 1
autonomic I-Disease 1
neuropathy I-Disease 1
? O 0

The O 0
effect O 0
of O 0
nitroglycerin B-Chemical 1
on O 0
heart O 0
rate O 0
and O 0
systolic O 0
blood O 0
pressure O 0
was O 0
compared O 0
in O 0
5 O 0
normal O 0
subjects O 0
, O 0
12 O 0
diabetic B-Disease 1
subjects O 0
without O 0
autonomic B-Disease 1
neuropathy I-Disease 1
, O 0
and O 0
5 O 0
diabetic B-Disease 1
subjects O 0
with O 0
autonomic B-Disease 1
neuropathy I-Disease 1
. O 0

The O 0
magnitude O 0
and O 0
time O 0
course O 0
of O 0
the O 0
increase O 0
in O 0
heart O 0
rate O 0
and O 0
the O 0
decrease O 0
in O 0
systolic O 0
blood O 0
pressure O 0
after O 0
nitroglycerin B-Chemical 1
were O 0
similar O 0
in O 0
the O 0
normal O 0
and O 0
diabetic B-Disease 1
subjects O 0
without O 0
autonomic B-Disease 1
neuropathy I-Disease 1
, O 0
whereas O 0
a O 0
lesser O 0
increase O 0
in O 0
heart O 0
rate O 0
and O 0
a O 0
greater O 0
decrease O 0
in O 0
systolic O 0
blood O 0
pressure O 0
occurred O 0
in O 0
the O 0
diabetic B-Disease 1
subjects O 0
with O 0
autonomic B-Disease 1
neuropathy I-Disease 1
. O 0

It O 0
is O 0
therefore O 0
suggested O 0
that O 0
caution O 0
should O 0
be O 0
exercised O 0
when O 0
prescribing O 0
vasodilator O 0
drugs O 0
in O 0
diabetic B-Disease 1
patients O 0
, O 0
particularly O 0
those O 0
with O 0
autonomic B-Disease 1
neuropathy I-Disease 1
. O 0

Blood O 0
pressure O 0
response O 0
to O 0
chronic O 0
low O 0
- O 0
dose O 0
intrarenal O 0
noradrenaline B-Chemical 1
infusion O 0
in O 0
conscious O 0
rats O 0
. O 0

Sodium B-Chemical 1
chloride I-Chemical 1
solution O 0
( O 0
0 O 0
. O 0
9 O 0
% O 0
) O 0
or O 0
noradrenaline B-Chemical 1
in O 0
doses O 0
of O 0
4 O 0
, O 0
12 O 0
and O 0
36 O 0
micrograms O 0
h O 0
- O 0
1 O 0
kg O 0
- O 0
1 O 0
was O 0
infused O 0
for O 0
five O 0
consecutive O 0
days O 0
, O 0
either O 0
intrarenally O 0
( O 0
by O 0
a O 0
new O 0
technique O 0
) O 0
or O 0
intravenously O 0
into O 0
rats O 0
with O 0
one O 0
kidney O 0
removed O 0
. O 0

Intrarenal O 0
infusion O 0
of O 0
noradrenaline B-Chemical 1
caused O 0
hypertension B-Disease 1
at O 0
doses O 0
which O 0
did O 0
not O 0
do O 0
so O 0
when O 0
infused O 0
intravenously O 0
. O 0

Intrarenal O 0
compared O 0
with O 0
intravenous O 0
infusion O 0
of O 0
noradrenaline B-Chemical 1
caused O 0
higher O 0
plasma O 0
noradrenaline B-Chemical 1
concentrations O 0
and O 0
a O 0
shift O 0
of O 0
the O 0
plasma O 0
noradrenaline B-Chemical 1
concentration O 0
- O 0
blood O 0
pressure O 0
effect O 0
curve O 0
towards O 0
lower O 0
plasma O 0
noradrenaline B-Chemical 1
levels O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
hypertension B-Disease 1
after O 0
chronic O 0
intrarenal O 0
noradrenaline B-Chemical 1
infusion O 0
is O 0
produced O 0
by O 0
relatively O 0
higher O 0
levels O 0
of O 0
circulating O 0
noradrenaline B-Chemical 1
and O 0
by O 0
triggering O 0
of O 0
an O 0
additional O 0
intrarenal O 0
pressor O 0
mechanism O 0
. O 0

Characterization O 0
of O 0
estrogen B-Chemical 1
- O 0
induced O 0
adenohypophyseal B-Disease 1
tumors I-Disease 1
in O 0
the O 0
Fischer O 0
344 O 0
rat O 0
. O 0

Pituitary B-Disease 1
tumors I-Disease 1
were O 0
induced O 0
in O 0
F344 O 0
female O 0
rats O 0
by O 0
chronic O 0
treatment O 0
with O 0
diethylstilbestrol B-Chemical 1
( O 0
DES B-Chemical 1
, O 0
8 O 0
- O 0
10 O 0
mg O 0
) O 0
implanted O 0
subcutaneously O 0
in O 0
silastic O 0
capsules O 0
. O 0

Over O 0
a O 0
range O 0
of O 0
1 O 0
- O 0
150 O 0
days O 0
of O 0
DES B-Chemical 1
treatment O 0
, O 0
pairs O 0
of O 0
control O 0
and O 0
DES B-Chemical 1
- O 0
treated O 0
rats O 0
were O 0
sacrificed O 0
, O 0
and O 0
their O 0
pituitaries O 0
dissociated O 0
enzymatically O 0
into O 0
single O 0
- O 0
cell O 0
preparations O 0
. O 0

The O 0
cell O 0
populations O 0
were O 0
examined O 0
regarding O 0
total O 0
cell O 0
recovery O 0
correlated O 0
with O 0
gland O 0
weight O 0
, O 0
intracellular O 0
prolactin O 0
( O 0
PRL O 0
) O 0
content O 0
and O 0
subsequent O 0
release O 0
in O 0
primary O 0
culture O 0
, O 0
immunocytochemical O 0
PRL O 0
staining O 0
, O 0
density O 0
and O 0
/ O 0
or O 0
size O 0
alterations O 0
via O 0
separation O 0
on O 0
Ficoll O 0
- O 0
Hypaque O 0
and O 0
by O 0
unit O 0
gravity O 0
sedimentation O 0
, O 0
and O 0
cell O 0
cycle O 0
analysis O 0
, O 0
after O 0
acriflavine B-Chemical 1
DNA O 0
staining O 0
, O 0
by O 0
laser O 0
flow O 0
cytometry O 0
. O 0

Total O 0
cell O 0
yields O 0
from O 0
DES B-Chemical 1
- O 0
treated O 0
pituitaries O 0
increased O 0
from O 0
1 O 0
. O 0
3 O 0
times O 0
control O 0
yields O 0
at O 0
8 O 0
days O 0
of O 0
treatment O 0
to O 0
58 O 0
. O 0
9 O 0
times O 0
control O 0
values O 0
by O 0
day O 0
150 O 0
. O 0

Intracellular O 0
PRL O 0
content O 0
ranged O 0
from O 0
1 O 0
. O 0
9 O 0
to O 0
9 O 0
. O 0
4 O 0
times O 0
control O 0
levels O 0
, O 0
and O 0
PRL O 0
release O 0
in O 0
vitro O 0
was O 0
significantly O 0
and O 0
consistently O 0
higher O 0
than O 0
controls O 0
, O 0
after O 0
at O 0
least O 0
8 O 0
days O 0
of O 0
DES B-Chemical 1
exposure O 0
. O 0

Beyond O 0
8 O 0
days O 0
of O 0
DES B-Chemical 1
exposure O 0
, O 0
the O 0
immunochemically O 0
PRL O 0
- O 0
positive O 0
proportion O 0
of O 0
cells O 0
increased O 0
to O 0
over O 0
50 O 0
% O 0
of O 0
the O 0
total O 0
population O 0
. O 0

Increased O 0
density O 0
and O 0
/ O 0
or O 0
size O 0
and O 0
PRL O 0
content O 0
were O 0
indicated O 0
for O 0
the O 0
majority O 0
of O 0
the O 0
PRL O 0
cell O 0
population O 0
in O 0
both O 0
types O 0
of O 0
separation O 0
protocols O 0
. O 0

All O 0
these O 0
effects O 0
of O 0
DES B-Chemical 1
were O 0
more O 0
pronounced O 0
among O 0
previously O 0
ovariectomized O 0
animals O 0
. O 0

The O 0
data O 0
extend O 0
the O 0
findings O 0
of O 0
other O 0
investigators O 0
, O 0
further O 0
establishing O 0
the O 0
DES B-Chemical 1
- O 0
induced O 0
tumor B-Disease 1
as O 0
a O 0
model O 0
for O 0
study O 0
of O 0
PRL O 0
cellular O 0
control O 0
mechanisms O 0
. O 0

Age O 0
and O 0
renal O 0
clearance O 0
of O 0
cimetidine B-Chemical 1
. O 0

In O 0
35 O 0
patients O 0
( O 0
ages O 0
20 O 0
to O 0
86 O 0
yr O 0
) O 0
receiving O 0
cimetidine B-Chemical 1
therapeutically O 0
two O 0
serum O 0
samples O 0
and O 0
all O 0
urine O 0
formed O 0
in O 0
the O 0
interim O 0
were O 0
collected O 0
for O 0
analysis O 0
of O 0
cimetidine B-Chemical 1
by O 0
high O 0
- O 0
pressure O 0
liquid O 0
chromatography O 0
and O 0
for O 0
creatinine B-Chemical 1
. O 0

Cimetidine B-Chemical 1
clearance O 0
decreased O 0
with O 0
age O 0
. O 0

The O 0
extrapolated O 0
6 O 0
- O 0
hr O 0
serum O 0
concentration O 0
of O 0
cimetidine B-Chemical 1
per O 0
unit O 0
dose O 0
, O 0
after O 0
intravenous O 0
cimetidine B-Chemical 1
, O 0
increased O 0
with O 0
age O 0
of O 0
the O 0
patients O 0
. O 0

The O 0
ratio O 0
of O 0
cimetidine B-Chemical 1
clearance O 0
to O 0
creatinine B-Chemical 1
clearance O 0
( O 0
Rc O 0
) O 0
averaged O 0
4 O 0
. O 0
8 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
0 O 0
, O 0
indicating O 0
net O 0
tubular O 0
secretion O 0
for O 0
cimetidine B-Chemical 1
. O 0

Rc O 0
seemed O 0
to O 0
be O 0
independent O 0
of O 0
age O 0
and O 0
decreased O 0
with O 0
increasing O 0
serum O 0
concentration O 0
of O 0
cimetidine B-Chemical 1
, O 0
suggesting O 0
that O 0
secretion O 0
of O 0
cimetidine B-Chemical 1
is O 0
a O 0
saturable O 0
process O 0
. O 0

There O 0
was O 0
only O 0
one O 0
case O 0
of O 0
dementia B-Disease 1
possibly O 0
due O 0
to O 0
cimetidine B-Chemical 1
( O 0
with O 0
a O 0
drug O 0
level O 0
of O 0
1 O 0
. O 0
9 O 0
microgram O 0
/ O 0
ml O 0
6 O 0
hr O 0
after O 0
a O 0
dose O 0
) O 0
in O 0
a O 0
group O 0
of O 0
13 O 0
patients O 0
without O 0
liver B-Disease 1
or I-Disease 1
kidney I-Disease 1
disease I-Disease 1
who O 0
had O 0
cimetidine B-Chemical 1
levels O 0
above O 0
1 O 0
. O 0
25 O 0
microgram O 0
/ O 0
ml O 0
. O 0

Thus O 0
, O 0
high O 0
cimetidine B-Chemical 1
levels O 0
alone O 0
do O 0
not O 0
always O 0
induce O 0
dementia B-Disease 1
. O 0

Further O 0
observations O 0
on O 0
the O 0
electrophysiologic O 0
effects O 0
of O 0
oral O 0
amiodarone B-Chemical 1
therapy O 0
. O 0

A O 0
case O 0
is O 0
presented O 0
of O 0
a O 0
reversible O 0
intra B-Disease 1
- I-Disease 1
Hisian I-Disease 1
block I-Disease 1
occurring O 0
under O 0
amiodarone B-Chemical 1
treatment O 0
for O 0
atrial B-Disease 1
tachycardia I-Disease 1
in O 0
a O 0
patient O 0
without O 0
clear O 0
intraventricular B-Disease 1
conduction I-Disease 1
abnormalities I-Disease 1
. O 0

His O 0
bundle O 0
recordings O 0
showed O 0
an O 0
atrial B-Disease 1
tachycardia I-Disease 1
with O 0
intermittent O 0
exit O 0
block O 0
and O 0
greatly O 0
prolonged O 0
BH O 0
and O 0
HV O 0
intervals O 0
( O 0
40 O 0
and O 0
100 O 0
msec O 0
, O 0
respectively O 0
) O 0
. O 0

Thirty O 0
days O 0
after O 0
amiodarone B-Chemical 1
discontinuation O 0
, O 0
His O 0
bundle O 0
electrograms O 0
showed O 0
atrial B-Disease 1
flutter I-Disease 1
without O 0
intra O 0
- O 0
Hisian O 0
or O 0
infra O 0
- O 0
Hisian O 0
delay O 0
. O 0

Amiodarone B-Chemical 1
should O 0
be O 0
used O 0
with O 0
caution O 0
during O 0
long O 0
- O 0
term O 0
oral O 0
therapy O 0
in O 0
patients O 0
with O 0
or O 0
without O 0
clear O 0
intraventricular O 0
conduction O 0
defects O 0
. O 0

Development O 0
of O 0
clear B-Disease 1
cell I-Disease 1
adenocarcinoma I-Disease 1
in O 0
DES B-Chemical 1
- O 0
exposed O 0
offspring O 0
under O 0
observation O 0
. O 0

Two O 0
cases O 0
of O 0
clear B-Disease 1
cell I-Disease 1
adenocarcinoma I-Disease 1
of I-Disease 1
the I-Disease 1
vagina I-Disease 1
detected O 0
at O 0
follow O 0
- O 0
up O 0
in O 0
young O 0
women O 0
exposed O 0
in O 0
utero O 0
to O 0
diethylstilbestrol B-Chemical 1
are O 0
reported O 0
. O 0

One O 0
patient O 0
, O 0
aged O 0
23 O 0
, O 0
had O 0
been O 0
followed O 0
for O 0
2 O 0
years O 0
before O 0
carcinoma B-Disease 1
was O 0
diagnosed O 0
; O 0
the O 0
second O 0
patient O 0
, O 0
aged O 0
22 O 0
, O 0
had O 0
been O 0
seen O 0
on O 0
a O 0
regular O 0
basis O 0
for O 0
5 O 0
years O 0
, O 0
8 O 0
months O 0
. O 0

In O 0
both O 0
instances O 0
, O 0
suspicion O 0
of O 0
the O 0
presence O 0
of O 0
carcinoma B-Disease 1
was O 0
aroused O 0
by O 0
the O 0
palpation O 0
of O 0
a O 0
small O 0
nodule O 0
in O 0
the O 0
vaginal O 0
fornix O 0
. O 0

Hysterosalpingography O 0
was O 0
performed O 0
on O 0
both O 0
patients O 0
and O 0
, O 0
in O 0
1 O 0
instance O 0
, O 0
an O 0
abnormal O 0
x O 0
- O 0
ray O 0
film O 0
was O 0
reflected O 0
by O 0
the O 0
gross O 0
appearance O 0
of O 0
the O 0
uterine O 0
cavity O 0
found O 0
in O 0
the O 0
surgical O 0
specimen O 0
. O 0

Neurologic O 0
effects O 0
of O 0
subarachnoid O 0
administration O 0
of O 0
2 B-Chemical 1
- I-Chemical 1
chloroprocaine I-Chemical 1
- I-Chemical 1
CE I-Chemical 1
, O 0
bupivacaine B-Chemical 1
, O 0
and O 0
low O 0
pH O 0
normal O 0
saline O 0
in O 0
dogs O 0
. O 0

The O 0
purpose O 0
of O 0
this O 0
study O 0
was O 0
to O 0
evaluate O 0
the O 0
neurologic O 0
consequences O 0
of O 0
deliberate O 0
subarachnoid O 0
injection O 0
of O 0
large O 0
volumes O 0
of O 0
2 B-Chemical 1
- I-Chemical 1
chloroprocaine I-Chemical 1
- I-Chemical 1
CE I-Chemical 1
in O 0
experimental O 0
animals O 0
. O 0

The O 0
possible O 0
role O 0
of O 0
low O 0
pH O 0
as O 0
well O 0
as O 0
total O 0
volume O 0
as O 0
potential O 0
factors O 0
in O 0
causing O 0
neurotoxicity B-Disease 1
was O 0
evaluated O 0
. O 0

The O 0
65 O 0
dogs O 0
in O 0
the O 0
study O 0
received O 0
injections O 0
in O 0
the O 0
subarachnoid O 0
space O 0
as O 0
follows O 0
: O 0
6 O 0
to O 0
8 O 0
ml O 0
of O 0
bupivacaine B-Chemical 1
( O 0
N O 0
= O 0
15 O 0
) O 0
, O 0
2 B-Chemical 1
- I-Chemical 1
chloroprocaine I-Chemical 1
- I-Chemical 1
CE I-Chemical 1
( O 0
N O 0
= O 0
20 O 0
) O 0
, O 0
low O 0
pH O 0
normal O 0
saline O 0
( O 0
pH O 0
3 O 0
. O 0
0 O 0
) O 0
( O 0
N O 0
= O 0
20 O 0
) O 0
, O 0
or O 0
normal O 0
saline O 0
( O 0
N O 0
= O 0
10 O 0
) O 0
. O 0

Of O 0
the O 0
20 O 0
animals O 0
that O 0
received O 0
subarachnoid O 0
injection O 0
of O 0
2 B-Chemical 1
- I-Chemical 1
chloroprocaine I-Chemical 1
- I-Chemical 1
CE I-Chemical 1
seven O 0
( O 0
35 O 0
% O 0
) O 0
developed O 0
hind O 0
- O 0
limb O 0
paralysis B-Disease 1
. O 0

None O 0
of O 0
the O 0
animals O 0
that O 0
received O 0
bupivacaine B-Chemical 1
, O 0
normal O 0
saline O 0
, O 0
or O 0
normal O 0
saline O 0
titrated O 0
to O 0
a O 0
pH O 0
3 O 0
. O 0
0 O 0
developed O 0
hind O 0
- O 0
limb O 0
paralysis B-Disease 1
. O 0

Of O 0
the O 0
15 O 0
spinal O 0
cords O 0
of O 0
the O 0
animals O 0
that O 0
received O 0
2 B-Chemical 1
- I-Chemical 1
chloroprocaine I-Chemical 1
- I-Chemical 1
CE I-Chemical 1
, O 0
13 O 0
showed O 0
subpial B-Disease 1
necrosis I-Disease 1
; O 0
the O 0
nerve O 0
roots O 0
and O 0
subarachnoid O 0
vessels O 0
were O 0
normal O 0
. O 0

The O 0
spinal O 0
cords O 0
of O 0
the O 0
animals O 0
that O 0
received O 0
bupivacaine B-Chemical 1
, O 0
low O 0
pH O 0
normal O 0
saline O 0
( O 0
pH O 0
3 O 0
. O 0
0 O 0
) O 0
, O 0
or O 0
normal O 0
saline O 0
did O 0
not O 0
show O 0
abnormal O 0
findings O 0
. O 0

Procainamide B-Chemical 1
- O 0
induced O 0
polymorphous O 0
ventricular B-Disease 1
tachycardia I-Disease 1
. O 0

Seven O 0
cases O 0
of O 0
procainamide B-Chemical 1
- O 0
induced O 0
polymorphous O 0
ventricular B-Disease 1
tachycardia I-Disease 1
are O 0
presented O 0
. O 0

In O 0
four O 0
patients O 0
, O 0
polymorphous O 0
ventricular B-Disease 1
tachycardia I-Disease 1
appeared O 0
after O 0
intravenous O 0
administration O 0
of O 0
200 O 0
to O 0
400 O 0
mg O 0
of O 0
procainamide B-Chemical 1
for O 0
the O 0
treatment O 0
of O 0
sustained O 0
ventricular B-Disease 1
tachycardia I-Disease 1
. O 0

In O 0
the O 0
remaining O 0
three O 0
patients O 0
, O 0
procainamide B-Chemical 1
was O 0
administered O 0
orally O 0
for O 0
treatment O 0
of O 0
chronic O 0
premature B-Disease 1
ventricular I-Disease 1
contractions I-Disease 1
or O 0
atrial B-Disease 1
flutter I-Disease 1
. O 0

These O 0
patients O 0
had O 0
Q B-Disease 1
- I-Disease 1
T I-Disease 1
prolongation I-Disease 1
and O 0
recurrent O 0
syncope B-Disease 1
due O 0
to O 0
polymorphous O 0
ventricular B-Disease 1
tachycardia I-Disease 1
. O 0

In O 0
four O 0
patients O 0
, O 0
the O 0
arrhythmia B-Disease 1
was O 0
rapidly O 0
diagnosed O 0
and O 0
treated O 0
with O 0
disappearance O 0
of O 0
further O 0
episodes O 0
of O 0
the O 0
arrhythmia B-Disease 1
. O 0

In O 0
two O 0
patients O 0
, O 0
the O 0
arrhythmia B-Disease 1
degenerated O 0
into O 0
irreversible O 0
ventricular B-Disease 1
fibrillation I-Disease 1
and O 0
both O 0
patients O 0
died O 0
. O 0

In O 0
the O 0
seventh O 0
patient O 0
, O 0
a O 0
permanent O 0
ventricular O 0
pacemaker O 0
was O 0
inserted O 0
and O 0
, O 0
despite O 0
continuation O 0
of O 0
procainamide B-Chemical 1
therapy O 0
, O 0
polymorphous O 0
ventricular B-Disease 1
tachycardia I-Disease 1
did O 0
not O 0
reoccur O 0
. O 0

These O 0
seven O 0
cases O 0
demonstrate O 0
that O 0
procainamide B-Chemical 1
can O 0
produce O 0
an O 0
acquired O 0
prolonged B-Disease 1
Q I-Disease 1
- I-Disease 1
T I-Disease 1
syndrome I-Disease 1
with O 0
polymorphous O 0
ventricular B-Disease 1
tachycardia I-Disease 1
. O 0

Phenobarbitone B-Chemical 1
- O 0
induced O 0
enlargement B-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
in O 0
the O 0
rat O 0
: O 0
its O 0
relationship O 0
to O 0
carbon B-Chemical 1
tetrachloride I-Chemical 1
- O 0
induced O 0
cirrhosis B-Disease 1
. O 0

The O 0
yield O 0
of O 0
severe O 0
cirrhosis B-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
( O 0
defined O 0
as O 0
a O 0
shrunken O 0
finely O 0
nodular O 0
liver O 0
with O 0
micronodular O 0
histology O 0
, O 0
ascites B-Disease 1
greater O 0
than O 0
30 O 0
ml O 0
, O 0
plasma O 0
albumin O 0
less O 0
than O 0
2 O 0
. O 0
2 O 0
g O 0
/ O 0
dl O 0
, O 0
splenomegaly B-Disease 1
2 O 0
- O 0
3 O 0
times O 0
normal O 0
, O 0
and O 0
testicular O 0
atrophy B-Disease 1
approximately O 0
half O 0
normal O 0
weight O 0
) O 0
after O 0
12 O 0
doses O 0
of O 0
carbon B-Chemical 1
tetrachloride I-Chemical 1
given O 0
intragastrically O 0
in O 0
the O 0
phenobarbitone B-Chemical 1
- O 0
primed O 0
rat O 0
was O 0
increased O 0
from O 0
25 O 0
% O 0
to O 0
56 O 0
% O 0
by O 0
giving O 0
the O 0
initial O 0
" O 0
calibrating O 0
" O 0
dose O 0
of O 0
carbon B-Chemical 1
tetrachloride I-Chemical 1
at O 0
the O 0
peak O 0
of O 0
the O 0
phenobarbitone B-Chemical 1
- O 0
induced O 0
enlargement B-Disease 1
of I-Disease 1
the I-Disease 1
liver I-Disease 1
. O 0

At O 0
this O 0
point O 0
it O 0
was O 0
assumed O 0
that O 0
the O 0
cytochrome O 0
P450 O 0
/ O 0
CCl4 B-Chemical 1
toxic O 0
state O 0
was O 0
both O 0
maximal O 0
and O 0
stable O 0
. O 0

The O 0
optimal O 0
rat O 0
size O 0
to O 0
begin O 0
phenobarbitone B-Chemical 1
was O 0
determined O 0
as O 0
100 O 0
g O 0
, O 0
and O 0
this O 0
size O 0
as O 0
a O 0
group O 0
had O 0
a O 0
mean O 0
maximum O 0
relative O 0
liver O 0
weight O 0
increase O 0
47 O 0
% O 0
greater O 0
than O 0
normal O 0
rats O 0
of O 0
the O 0
same O 0
body O 0
weight O 0
. O 0

The O 0
optimal O 0
time O 0
for O 0
the O 0
initial O 0
dose O 0
of O 0
carbon B-Chemical 1
tetrachloride I-Chemical 1
was O 0
after O 0
14 O 0
days O 0
on O 0
phenobarbitone B-Chemical 1
. O 0

Triamterene B-Chemical 1
nephrolithiasis B-Disease 1
complicating O 0
dyazide B-Chemical 1
therapy O 0
. O 0

A O 0
case O 0
of O 0
triamterene B-Chemical 1
nephrolithiasis B-Disease 1
is O 0
reported O 0
in O 0
a O 0
man O 0
after O 0
4 O 0
years O 0
of O 0
hydrochlorothiazide B-Chemical 1
- I-Chemical 1
triamterene I-Chemical 1
therapy O 0
for O 0
hypertension B-Disease 1
. O 0

The O 0
stone O 0
passed O 0
spontaneously O 0
and O 0
was O 0
found O 0
to O 0
contain O 0
a O 0
triamterene B-Chemical 1
metabolite O 0
admixed O 0
with O 0
uric B-Chemical 1
acid I-Chemical 1
salts I-Chemical 1
. O 0

Factors O 0
affecting O 0
triamterene B-Chemical 1
nephrolithiasis B-Disease 1
are O 0
discussed O 0
and O 0
2 O 0
previously O 0
reported O 0
cases O 0
are O 0
reviewed O 0
. O 0

Busulfan B-Chemical 1
- O 0
induced O 0
hemorrhagic B-Disease 1
cystitis I-Disease 1
. O 0

A O 0
case O 0
of O 0
a O 0
busulfan B-Chemical 1
- O 0
induced O 0
hemorrhage B-Disease 1
cystitis I-Disease 1
is O 0
reported O 0
. O 0

Spontaneous O 0
resolution O 0
occurred O 0
following O 0
cessation O 0
of O 0
the O 0
drug O 0
. O 0

The O 0
similarity O 0
between O 0
the O 0
histologic O 0
appearances O 0
of O 0
busulfan B-Chemical 1
cystitis B-Disease 1
and O 0
both O 0
radiation O 0
and O 0
cyclophosphamide B-Chemical 1
- O 0
induced O 0
cystitis B-Disease 1
is O 0
discussed O 0
and O 0
the O 0
world O 0
literature O 0
reviewed O 0
. O 0

In O 0
view O 0
of O 0
the O 0
known O 0
tendency O 0
of O 0
busulfan B-Chemical 1
to O 0
induce O 0
cellular O 0
atypia O 0
and O 0
carcinoma B-Disease 1
in O 0
other O 0
sites O 0
, O 0
periodic O 0
urinary O 0
cytology O 0
is O 0
suggested O 0
in O 0
patients O 0
on O 0
long O 0
- O 0
term O 0
therapy O 0
. O 0

Variant O 0
ventricular B-Disease 1
tachycardia I-Disease 1
in O 0
desipramine B-Chemical 1
toxicity B-Disease 1
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
variant O 0
ventricular B-Disease 1
tachycardia I-Disease 1
induced O 0
by O 0
desipramine B-Chemical 1
toxicity B-Disease 1
. O 0

Unusual O 0
features O 0
of O 0
the O 0
arrhythmia B-Disease 1
are O 0
repetitive O 0
group O 0
beating O 0
, O 0
progressive O 0
shortening O 0
of O 0
the O 0
R O 0
- O 0
R O 0
interval O 0
, O 0
progressive O 0
widening O 0
of O 0
the O 0
QRS O 0
complex O 0
with O 0
eventual O 0
failure O 0
of O 0
intraventricular O 0
conduction O 0
, O 0
and O 0
changes O 0
in O 0
direction O 0
of O 0
the O 0
QRS O 0
axis O 0
. O 0

Recognition O 0
of O 0
variant O 0
ventricular B-Disease 1
tachycardia I-Disease 1
is O 0
important O 0
because O 0
therapy O 0
differs O 0
from O 0
that O 0
of O 0
classic O 0
ventricular B-Disease 1
tachycardia I-Disease 1
. O 0

Rebound O 0
hypertensive B-Disease 1
after O 0
sodium B-Chemical 1
nitroprusside I-Chemical 1
prevented O 0
by O 0
saralasin B-Chemical 1
in O 0
rats O 0
. O 0

The O 0
role O 0
of O 0
the O 0
renin O 0
- O 0
- O 0
angiotensin B-Chemical 1
system O 0
in O 0
the O 0
maintenance O 0
of O 0
blood O 0
pressure O 0
during O 0
halothane B-Chemical 1
anesthesia O 0
and O 0
sodium B-Chemical 1
nitroprusside I-Chemical 1
( O 0
SNP B-Chemical 1
) O 0
- O 0
induced O 0
hypotension B-Disease 1
was O 0
evaluated O 0
. O 0

Control O 0
rats O 0
received O 0
halothane B-Chemical 1
anesthesia O 0
( O 0
1 O 0
MAC O 0
) O 0
for O 0
one O 0
hour O 0
, O 0
followed O 0
by O 0
SNP B-Chemical 1
infusion O 0
, O 0
40 O 0
microgram O 0
/ O 0
kg O 0
/ O 0
min O 0
, O 0
for O 0
30 O 0
min O 0
, O 0
followed O 0
by O 0
a O 0
30 O 0
- O 0
min O 0
recovery O 0
period O 0
. O 0

A O 0
second O 0
group O 0
of O 0
rats O 0
was O 0
treated O 0
identically O 0
and O 0
, O 0
in O 0
addition O 0
, O 0
received O 0
an O 0
infusion O 0
of O 0
saralasin B-Chemical 1
( O 0
a O 0
competitive O 0
inhibitor O 0
of O 0
angiotensin B-Chemical 1
II I-Chemical 1
) O 0
throughout O 0
the O 0
experimental O 0
period O 0
. O 0

In O 0
each O 0
group O 0
, O 0
SNP B-Chemical 1
infusion O 0
resulted O 0
in O 0
an O 0
initial O 0
decrease O 0
in O 0
blood O 0
pressure O 0
from O 0
86 O 0
torr O 0
and O 0
83 O 0
torr O 0
, O 0
respectively O 0
, O 0
to O 0
48 O 0
torr O 0
. O 0

During O 0
the O 0
SNP B-Chemical 1
infusion O 0
the O 0
control O 0
animals O 0
demonstrated O 0
a O 0
progressive O 0
increase B-Disease 1
in I-Disease 1
blood I-Disease 1
pressure I-Disease 1
to O 0
61 O 0
torr O 0
, O 0
whereas O 0
the O 0
saralasin B-Chemical 1
- O 0
treated O 0
animals O 0
showed O 0
no O 0
change O 0
. O 0

Following O 0
discontinuation O 0
of O 0
SNP B-Chemical 1
, O 0
blood O 0
pressure O 0
in O 0
the O 0
control O 0
animals O 0
rebounded O 0
to O 0
94 O 0
torr O 0
, O 0
as O 0
compared O 0
with O 0
78 O 0
torr O 0
in O 0
the O 0
saralasin B-Chemical 1
- O 0
treated O 0
rats O 0
. O 0

This O 0
study O 0
indicates O 0
that O 0
with O 0
stable O 0
halothane B-Chemical 1
anesthesia O 0
, O 0
the O 0
partial O 0
recovery O 0
of O 0
blood O 0
pressure O 0
during O 0
SNP B-Chemical 1
infusion O 0
and O 0
the O 0
post O 0
- O 0
SNP B-Chemical 1
rebound O 0
of O 0
blood O 0
pressure O 0
can O 0
be O 0
completely O 0
blocked O 0
by O 0
saralasin B-Chemical 1
. O 0

This O 0
demonstrates O 0
the O 0
participation O 0
of O 0
the O 0
renin O 0
- O 0
- O 0
angiotensin B-Chemical 1
system O 0
in O 0
antagonizing O 0
the O 0
combined O 0
hypotensive B-Disease 1
effects O 0
of O 0
halothane B-Chemical 1
and O 0
SNP B-Chemical 1
. O 0

Clinical O 0
nephrotoxicity B-Disease 1
of O 0
tobramycin B-Chemical 1
and O 0
gentamicin B-Chemical 1
. O 0

A O 0
prospective O 0
study O 0
. O 0

Nearly O 0
3 O 0
. O 0
2 O 0
million O 0
people O 0
in O 0
this O 0
country O 0
receive O 0
aminoglycoside B-Chemical 1
antibiotics O 0
annually O 0
. O 0

Gentamicin B-Chemical 1
sulfate I-Chemical 1
and O 0
tobramycin B-Chemical 1
sulfate I-Chemical 1
continue O 0
to O 0
demonstrate O 0
ototoxicity B-Disease 1
and O 0
nephrotoxicity B-Disease 1
in O 0
both O 0
animal O 0
and O 0
clinical O 0
studies O 0
. O 0

In O 0
this O 0
study O 0
, O 0
62 O 0
patients O 0
with O 0
confirmed O 0
initial O 0
normal O 0
renal O 0
function O 0
and O 0
treated O 0
with O 0
2 O 0
to O 0
5 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
of O 0
gentamicin B-Chemical 1
sulfate I-Chemical 1
or O 0
tobramycin B-Chemical 1
sulfate I-Chemical 1
for O 0
a O 0
minimum O 0
of O 0
seven O 0
days O 0
were O 0
followed O 0
up O 0
prospectively O 0
for O 0
the O 0
development O 0
of O 0
aminoglycoside B-Chemical 1
- O 0
related O 0
renal B-Disease 1
failure I-Disease 1
, O 0
defined O 0
as O 0
at O 0
least O 0
a O 0
one O 0
- O 0
third O 0
reduction O 0
in O 0
renal O 0
function O 0
. O 0

In O 0
these O 0
62 O 0
patients O 0
, O 0
no O 0
other O 0
causes O 0
for O 0
renal B-Disease 1
failure I-Disease 1
could O 0
be O 0
identified O 0
. O 0

Five O 0
of O 0
33 O 0
( O 0
15 O 0
% O 0
) O 0
of O 0
the O 0
tobramycin B-Chemical 1
- O 0
treated O 0
patients O 0
and O 0
16 O 0
of O 0
29 O 0
( O 0
55 O 0
. O 0
2 O 0
% O 0
) O 0
of O 0
the O 0
gentamicin B-Chemical 1
- O 0
treated O 0
patients O 0
had O 0
renal B-Disease 1
failure I-Disease 1
. O 0

Thus O 0
, O 0
gentamicin B-Chemical 1
was O 0
associated O 0
with O 0
renal B-Disease 1
failure I-Disease 1
more O 0
than O 0
three O 0
times O 0
as O 0
often O 0
as O 0
was O 0
tobramycin B-Chemical 1
. O 0

Metabolic O 0
involvement O 0
in O 0
adriamycin B-Chemical 1
cardiotoxicity B-Disease 1
. O 0

The O 0
cardiotoxic B-Disease 1
effects O 0
of O 0
adriamycin B-Chemical 1
were O 0
studied O 0
in O 0
mammalian O 0
myocardial O 0
cells O 0
in O 0
culture O 0
as O 0
a O 0
model O 0
system O 0
. O 0

Adriamycin B-Chemical 1
inhibited O 0
cell O 0
growth O 0
and O 0
the O 0
rhythmic O 0
contractions O 0
characteristic O 0
of O 0
myocardial O 0
cells O 0
in O 0
culture O 0
. O 0

A O 0
possible O 0
involvement O 0
of O 0
energy O 0
metabolism O 0
was O 0
suggested O 0
previously O 0
, O 0
and O 0
in O 0
this O 0
study O 0
the O 0
adenylate O 0
energy O 0
charge O 0
and O 0
phosphorylcreatine B-Chemical 1
mole O 0
fraction O 0
were O 0
determined O 0
in O 0
the O 0
adriamycin B-Chemical 1
- O 0
treated O 0
cells O 0
. O 0

The O 0
adenylate O 0
energy O 0
charge O 0
was O 0
found O 0
to O 0
be O 0
significantly O 0
decreased O 0
, O 0
while O 0
the O 0
phophorylcreatine B-Chemical 1
mole O 0
fraction O 0
was O 0
unchanged O 0
. O 0

Such O 0
disparity O 0
suggests O 0
an O 0
inhibition O 0
of O 0
creatine B-Chemical 1
phosphokinase O 0
. O 0

The O 0
addition O 0
of O 0
1 O 0
mM O 0
adenosine B-Chemical 1
to O 0
the O 0
myocardial O 0
cell O 0
cultures O 0
markedly O 0
increases O 0
the O 0
ATP B-Chemical 1
concentration O 0
through O 0
a O 0
pathway O 0
reportedly O 0
leading O 0
to O 0
a O 0
compartmentalized O 0
ATP B-Chemical 1
pool O 0
. O 0

In O 0
the O 0
adriamycin B-Chemical 1
- O 0
treated O 0
cells O 0
, O 0
the O 0
addition O 0
of O 0
adenosine B-Chemical 1
increased O 0
the O 0
adenylate O 0
charge O 0
and O 0
, O 0
concomitant O 0
with O 0
this O 0
inrcease O 0
, O 0
the O 0
cells O 0
' O 0
functional O 0
integrity O 0
, O 0
in O 0
terms O 0
of O 0
percentage O 0
of O 0
beating O 0
cells O 0
and O 0
rate O 0
of O 0
contractions O 0
, O 0
was O 0
maintained O 0
. O 0

Age O 0
- O 0
dependent O 0
sensitivity O 0
of O 0
the O 0
rat O 0
to O 0
neurotoxic B-Disease 1
effects O 0
of O 0
streptomycin B-Chemical 1
. O 0

Streptomycin B-Chemical 1
sulfate O 0
( O 0
300 O 0
mg O 0
/ O 0
kg O 0
s O 0
. O 0
c O 0
. O 0
) O 0
was O 0
injected O 0
for O 0
various O 0
periods O 0
into O 0
preweanling O 0
rats O 0
and O 0
for O 0
3 O 0
weeks O 0
into O 0
weanling O 0
rats O 0
. O 0

Beginning O 0
at O 0
8 O 0
days O 0
of O 0
age O 0
, O 0
body O 0
movement O 0
and O 0
hearing O 0
were O 0
examined O 0
for O 0
6 O 0
and O 0
up O 0
to O 0
17 O 0
weeks O 0
, O 0
respectively O 0
. O 0

Abnormal B-Disease 1
movements I-Disease 1
and O 0
deafness B-Disease 1
occurred O 0
only O 0
in O 0
rats O 0
treated O 0
during O 0
the O 0
preweaning O 0
period O 0
; O 0
within O 0
this O 0
period O 0
the O 0
greatest O 0
sensitivities O 0
for O 0
these O 0
abnormalities O 0
occurred O 0
from O 0
2 O 0
to O 0
11 O 0
- O 0
17 O 0
and O 0
5 O 0
to O 0
11 O 0
days O 0
of O 0
age O 0
, O 0
respectively O 0
, O 0
indicating O 0
that O 0
the O 0
cochlea O 0
is O 0
more O 0
sensitive O 0
to O 0
streptomycin B-Chemical 1
than O 0
the O 0
site O 0
( O 0
vestibular O 0
or O 0
central O 0
) O 0
responsible O 0
for O 0
the O 0
dyskinesias B-Disease 1
. O 0

Late O 0
, O 0
late O 0
doxorubicin B-Chemical 1
cardiotoxicity B-Disease 1
. O 0

Cardiac B-Disease 1
toxicity I-Disease 1
is O 0
a O 0
major O 0
complication O 0
which O 0
limits O 0
the O 0
use O 0
of O 0
adriamycin B-Chemical 1
as O 0
a O 0
chemotherapeutic O 0
agent O 0
. O 0

Cardiomyopathy B-Disease 1
is O 0
frequent O 0
when O 0
the O 0
total O 0
dose O 0
exceeds O 0
600 O 0
mg O 0
/ O 0
m2 O 0
and O 0
occurs O 0
within O 0
one O 0
to O 0
six O 0
months O 0
after O 0
cessation O 0
of O 0
therapy O 0
. O 0

A O 0
patient O 0
is O 0
reported O 0
who O 0
developed O 0
progressive O 0
cardiomyopathy B-Disease 1
two O 0
and O 0
one O 0
- O 0
half O 0
years O 0
after O 0
receiving O 0
580 O 0
mg O 0
/ O 0
m2 O 0
which O 0
apparently O 0
represents O 0
late O 0
, O 0
late O 0
cardiotoxicity B-Disease 1
. O 0

Attenuation O 0
of O 0
the O 0
lithium B-Chemical 1
- O 0
induced O 0
diabetes B-Disease 1
- I-Disease 1
insipidus I-Disease 1
- I-Disease 1
like I-Disease 1
syndrome I-Disease 1
by O 0
amiloride B-Chemical 1
in O 0
rats O 0
. O 0

The O 0
effect O 0
of O 0
amiloride B-Chemical 1
on O 0
lithium B-Chemical 1
- O 0
induced O 0
polydipsia B-Disease 1
and O 0
polyuria B-Disease 1
and O 0
on O 0
the O 0
lithium B-Chemical 1
concentration O 0
in O 0
the O 0
plasma O 0
, O 0
brain O 0
, O 0
kidney O 0
, O 0
thyroid O 0
and O 0
red O 0
blood O 0
cells O 0
was O 0
investigated O 0
in O 0
rats O 0
, O 0
chronically O 0
treated O 0
with O 0
LiCl B-Chemical 1
. O 0

Amiloride B-Chemical 1
reduced O 0
the O 0
drinking O 0
and O 0
urine O 0
volume O 0
of O 0
rats O 0
in O 0
an O 0
acute O 0
( O 0
6 O 0
or O 0
12 O 0
h O 0
) O 0
and O 0
a O 0
subacute O 0
( O 0
3 O 0
days O 0
) O 0
experiment O 0
. O 0

6 O 0
h O 0
after O 0
the O 0
administration O 0
of O 0
amiloride B-Chemical 1
, O 0
a O 0
reduction O 0
was O 0
observed O 0
in O 0
the O 0
lithium B-Chemical 1
content O 0
of O 0
the O 0
renal O 0
medulla O 0
but O 0
not O 0
in O 0
the O 0
other O 0
organs O 0
studied O 0
. O 0

At O 0
12 O 0
h O 0
, O 0
all O 0
the O 0
tissues O 0
showed O 0
a O 0
slight O 0
increase O 0
in O 0
lithium B-Chemical 1
levels O 0
. O 0

After O 0
3 O 0
days O 0
of O 0
combined O 0
treatment O 0
, O 0
a O 0
marked O 0
elevation O 0
in O 0
plasma O 0
and O 0
tissue O 0
lithium B-Chemical 1
levels O 0
accompanied O 0
a O 0
reduction O 0
in O 0
water O 0
intake O 0
. O 0

In O 0
all O 0
the O 0
experiments O 0
, O 0
the O 0
attenuation O 0
of O 0
the O 0
lithium B-Chemical 1
- O 0
induced O 0
diabetes B-Disease 1
- I-Disease 1
insipidus I-Disease 1
- I-Disease 1
like I-Disease 1
syndrome I-Disease 1
by O 0
amiloride B-Chemical 1
was O 0
accompanied O 0
by O 0
a O 0
reduction O 0
of O 0
the O 0
ratio O 0
between O 0
the O 0
lithium B-Chemical 1
concentration O 0
in O 0
the O 0
renal O 0
medulla O 0
and O 0
its O 0
levels O 0
in O 0
the O 0
blood O 0
and O 0
an O 0
elevation O 0
in O 0
the O 0
plasma O 0
potassium B-Chemical 1
level O 0
. O 0

It O 0
is O 0
concluded O 0
that O 0
acute O 0
amiloride B-Chemical 1
administration O 0
to O 0
lithium B-Chemical 1
- O 0
treated O 0
patients O 0
suffering O 0
from O 0
polydipsia B-Disease 1
and O 0
polyuria B-Disease 1
might O 0
relieve O 0
these O 0
patients O 0
but O 0
prolonged O 0
amiloride B-Chemical 1
supplementation O 0
would O 0
result O 0
in O 0
elevated O 0
lithium B-Chemical 1
levels O 0
and O 0
might O 0
be O 0
hazardous O 0
. O 0

Cardiovascular B-Disease 1
complications I-Disease 1
associated O 0
with O 0
terbutaline B-Chemical 1
treatment O 0
for O 0
preterm B-Disease 1
labor I-Disease 1
. O 0

Severe O 0
cardiovascular B-Disease 1
complications I-Disease 1
occurred O 0
in O 0
eight O 0
of O 0
160 O 0
patients O 0
treated O 0
with O 0
terbutaline B-Chemical 1
for O 0
preterm B-Disease 1
labor I-Disease 1
. O 0

Associated O 0
corticosteroid O 0
therapy O 0
and O 0
twin O 0
gestations O 0
appear O 0
to O 0
be O 0
predisposing O 0
factors O 0
. O 0

Potential O 0
mechanisms O 0
of O 0
the O 0
pathophysiology O 0
are O 0
briefly O 0
discussed O 0
. O 0

Toxic B-Disease 1
hepatitis I-Disease 1
induced O 0
by O 0
antithyroid O 0
drugs O 0
: O 0
four O 0
cases O 0
including O 0
one O 0
with O 0
cross O 0
- O 0
reactivity O 0
between O 0
carbimazole B-Chemical 1
and O 0
benzylthiouracil B-Chemical 1
. O 0

OBJECTIVE O 0
: O 0
This O 0
study O 0
was O 0
conducted O 0
to O 0
assess O 0
the O 0
occurrence O 0
of O 0
hepatic B-Disease 1
adverse I-Disease 1
effects I-Disease 1
encountered O 0
with O 0
antithyroid O 0
drugs O 0
. O 0

METHODS O 0
: O 0
Retrospective O 0
review O 0
of O 0
medical O 0
records O 0
of O 0
236 O 0
patients O 0
with O 0
hyperthyroidism B-Disease 1
admitted O 0
in O 0
our O 0
department O 0
( O 0
in O 0
- O 0
or O 0
out O 0
- O 0
patients O 0
) O 0
from O 0
1986 O 0
to O 0
1992 O 0
. O 0

RESULTS O 0
: O 0
Four O 0
patients O 0
( O 0
1 O 0
. O 0
7 O 0
% O 0
) O 0
were O 0
identified O 0
with O 0
toxic B-Disease 1
hepatitis I-Disease 1
which O 0
could O 0
reasonably O 0
be O 0
attributed O 0
to O 0
the O 0
use O 0
of O 0
antithyroid O 0
agent O 0
. O 0

Two O 0
patients O 0
had O 0
a O 0
cholestatic B-Disease 1
hepatitis I-Disease 1
induced O 0
by O 0
carbimazole B-Chemical 1
( O 0
N B-Chemical 1
omercazole I-Chemical 1
) O 0
. O 0

Two O 0
others O 0
had O 0
a O 0
mixed O 0
( O 0
cholestatic B-Disease 1
and O 0
cytolytic O 0
) O 0
hepatitis B-Disease 1
following O 0
carbimazole B-Chemical 1
. O 0

One O 0
of O 0
the O 0
latter O 0
two O 0
patients O 0
further O 0
experienced O 0
a O 0
cytolytic O 0
hepatitis B-Disease 1
which O 0
appeared O 0
after O 0
Benzylthiouracil B-Chemical 1
( O 0
Basd B-Chemical 1
ne I-Chemical 1
) O 0
had O 0
replaced O 0
carbimazole B-Chemical 1
. O 0

Biological O 0
features O 0
of O 0
hepatitis B-Disease 1
disappeared O 0
in O 0
all O 0
cases O 0
after O 0
cessation O 0
of O 0
the O 0
incriminated O 0
drug O 0
, O 0
while O 0
biliary O 0
, O 0
viral O 0
and O 0
immunological O 0
searches O 0
were O 0
negative O 0
. O 0

Only O 0
2 O 0
patients O 0
of O 0
our O 0
retrospective O 0
study O 0
experienced O 0
a O 0
mild O 0
or O 0
severe O 0
neutropenia B-Disease 1
. O 0

CONCLUSION O 0
: O 0
Toxic B-Disease 1
hepatitis I-Disease 1
is O 0
a O 0
potential O 0
adverse O 0
effect O 0
of O 0
antithyroid O 0
drugs O 0
which O 0
warrants O 0
, O 0
as O 0
for O 0
haematological O 0
disturbances O 0
, O 0
a O 0
pre O 0
- O 0
therapeutic O 0
determination O 0
and O 0
a O 0
careful O 0
follow O 0
- O 0
up O 0
of O 0
relevant O 0
biological O 0
markers O 0
. O 0

Moreover O 0
, O 0
hepatotoxicity B-Disease 1
may O 0
not O 0
be O 0
restricted O 0
to O 0
one O 0
class O 0
of O 0
antithyroid O 0
agents O 0
. O 0

Interactive O 0
effects O 0
of O 0
variations O 0
in O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
and O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
on O 0
rat O 0
atrial O 0
spontaneous O 0
frequency O 0
. O 0

The O 0
effects O 0
of O 0
varying O 0
the O 0
extracellular O 0
concentrations O 0
of O 0
Na B-Chemical 1
and O 0
Ca B-Chemical 1
( O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
and O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
) O 0
on O 0
both O 0
, O 0
the O 0
spontaneous O 0
beating O 0
and O 0
the O 0
negative O 0
chronotropic O 0
action O 0
of O 0
verapamil B-Chemical 1
, O 0
were O 0
studied O 0
in O 0
the O 0
isolated O 0
rat O 0
atria O 0
. O 0

Basal O 0
frequency O 0
( O 0
BF O 0
) O 0
evaluated O 0
by O 0
surface O 0
electrogram O 0
was O 0
223 O 0
+ O 0
/ O 0
- O 0
4 O 0
beats O 0
/ O 0
min O 0
. O 0
in O 0
control O 0
Krebs O 0
- O 0
Ringer O 0
containing O 0
137 O 0
mM O 0
Na B-Chemical 1
and O 0
1 O 0
. O 0
35 O 0
mM O 0
Ca B-Chemical 1
( O 0
N O 0
) O 0
. O 0

It O 0
decreased O 0
by O 0
16 O 0
+ O 0
/ O 0
- O 0
3 O 0
% O 0
by O 0
lowering O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
to O 0
78 O 0
mM O 0
( O 0
LNa O 0
) O 0
, O 0
23 O 0
+ O 0
/ O 0
- O 0
2 O 0
% O 0
by O 0
lowering O 0
simultaneously O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
to O 0
78 O 0
mM O 0
and O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
to O 0
0 O 0
. O 0
675 O 0
mM O 0
( O 0
LNa O 0
+ O 0
LCa O 0
) O 0
and O 0
31 O 0
+ O 0
/ O 0
- O 0
5 O 0
% O 0
by O 0
lowering O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
to O 0
78 O 0
mM O 0
plus O 0
increasing O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
to O 0
3 O 0
. O 0
6 O 0
mM O 0
( O 0
LNa O 0
+ O 0
HCa O 0
) O 0
. O 0

At O 0
normal O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
, O 0
decrease O 0
( O 0
0 O 0
. O 0
675 O 0
mM O 0
) O 0
or O 0
increase O 0
( O 0
3 O 0
. O 0
6 O 0
mM O 0
) O 0
of O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
did O 0
not O 0
modify O 0
BF O 0
; O 0
a O 0
reduction O 0
of O 0
ten O 0
times O 0
( O 0
0 O 0
. O 0
135 O 0
mM O 0
of O 0
normal O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
was O 0
effective O 0
to O 0
reduce O 0
BF O 0
by O 0
40 O 0
+ O 0
/ O 0
- O 0
13 O 0
% O 0
. O 0

All O 0
negative O 0
chronotropic O 0
effects O 0
were O 0
BF O 0
- O 0
dependent O 0
. O 0

Dose O 0
- O 0
dependent O 0
bradycardia B-Disease 1
induced O 0
by O 0
verapamil B-Chemical 1
was O 0
potentiated O 0
by O 0
LNa O 0
, O 0
LCa O 0
, O 0
and O 0
HCa O 0
. O 0

Independent O 0
but O 0
not O 0
additive O 0
effects O 0
of O 0
Na B-Chemical 1
and O 0
Ca B-Chemical 1
are O 0
shown O 0
by O 0
decreases O 0
in O 0
the O 0
values O 0
of O 0
[ O 0
verapamil B-Chemical 1
] O 0
o O 0
needed O 0
to O 0
reduce O 0
BF O 0
by O 0
30 O 0
% O 0
( O 0
IC30 O 0
) O 0
with O 0
the O 0
following O 0
order O 0
of O 0
inhibitory O 0
potency O 0
: O 0
LNa O 0
> O 0
LCa O 0
> O 0
HCa O 0
> O 0
N O 0
, O 0
resulting O 0
LNa O 0
+ O 0
HCa O 0
similar O 0
to O 0
LNa O 0
. O 0

The O 0
[ O 0
verapamil B-Chemical 1
] O 0
o O 0
that O 0
arrested O 0
atrial O 0
beating O 0
( O 0
AC O 0
) O 0
was O 0
also O 0
potentiated O 0
with O 0
the O 0
order O 0
LNa O 0
= O 0
LNa O 0
+ O 0
LCa O 0
= O 0
LNa O 0
+ O 0
HCa O 0
= O 0
LCa O 0
> O 0
HCa O 0
= O 0
N O 0
. O 0

The O 0
results O 0
indicate O 0
that O 0
rat O 0
atrial O 0
spontaneous O 0
beating O 0
is O 0
more O 0
dependent O 0
on O 0
[ O 0
Na B-Chemical 1
] O 0
o O 0
than O 0
on O 0
[ O 0
Ca B-Chemical 1
] O 0
o O 0
in O 0
a O 0
range O 0
of O 0
+ O 0
/ O 0
- O 0
50 O 0
% O 0
of O 0
their O 0
normal O 0
concentration O 0
. O 0

Also O 0
the O 0
enhancement O 0
of O 0
verapamil B-Chemical 1
effects O 0
on O 0
atrial O 0
beating O 0
was O 0
more O 0
pronounced O 0
at O 0
LNa O 0
than O 0
at O 0
LCa O 0
. O 0
( O 0
ABSTRACT O 0
TRUNCATED O 0
AT O 0
250 O 0
WORDS O 0
) O 0

Pseudo O 0
- O 0
allergic B-Disease 1
reactions I-Disease 1
to O 0
corticosteroids B-Chemical 1
: O 0
diagnosis O 0
and O 0
alternatives O 0
. O 0

Two O 0
patients O 0
treated O 0
with O 0
parenteral O 0
paramethasone B-Chemical 1
( O 0
Triniol O 0
) O 0
and O 0
dexamethasone B-Chemical 1
( O 0
Sedionbel O 0
) O 0
are O 0
described O 0
. O 0

A O 0
few O 0
minutes O 0
after O 0
administration O 0
of O 0
the O 0
drugs O 0
, O 0
they O 0
presented O 0
urticaria B-Disease 1
( O 0
patients O 0
1 O 0
and O 0
2 O 0
) O 0
and O 0
conjunctivitis B-Disease 1
( O 0
patient O 0
1 O 0
) O 0
. O 0

The O 0
purpose O 0
of O 0
our O 0
study O 0
was O 0
to O 0
determine O 0
the O 0
cause O 0
of O 0
the O 0
patients O 0
' O 0
reactions O 0
, O 0
the O 0
immunological O 0
mechanisms O 0
involved O 0
and O 0
whether O 0
these O 0
patients O 0
would O 0
be O 0
able O 0
to O 0
tolerate O 0
any O 0
kind O 0
of O 0
corticoid O 0
. O 0

Clinical O 0
examinations O 0
and O 0
skin O 0
, O 0
oral O 0
and O 0
parenteral O 0
challenges O 0
with O 0
different O 0
corticosteroids B-Chemical 1
and O 0
ELISA O 0
tests O 0
were O 0
performed O 0
. O 0

In O 0
the O 0
two O 0
patients O 0
, O 0
skin O 0
and O 0
ELISA O 0
tests O 0
with O 0
paramethasone B-Chemical 1
were O 0
negative O 0
, O 0
as O 0
was O 0
the O 0
prick O 0
test O 0
with O 0
each O 0
of O 0
its O 0
excipients O 0
. O 0

A O 0
single O 0
- O 0
blind O 0
parenteral O 0
challenge O 0
with O 0
Triniol O 0
was O 0
positive O 0
in O 0
both O 0
patients O 0
after O 0
the O 0
administration O 0
of O 0
1 O 0
ml O 0
of O 0
the O 0
drug O 0
, O 0
and O 0
negative O 0
with O 0
its O 0
excipients O 0
. O 0

We O 0
also O 0
carried O 0
out O 0
oral O 0
and O 0
parenteral O 0
challenges O 0
with O 0
other O 0
corticosteroids B-Chemical 1
and O 0
found O 0
intolerance O 0
to O 0
some O 0
of O 0
them O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
paramethasone B-Chemical 1
caused O 0
pseudoallergic O 0
reactions O 0
in O 0
our O 0
patients O 0
. O 0

Corticosteroids O 0
different O 0
from O 0
paramethasone B-Chemical 1
also O 0
produced O 0
hypersensitivity B-Disease 1
reactions O 0
in O 0
these O 0
patients O 0
; O 0
however O 0
, O 0
a O 0
few O 0
of O 0
them O 0
were O 0
tolerated O 0
. O 0

The O 0
basic O 0
mechanisms O 0
of O 0
those O 0
reactions O 0
are O 0
not O 0
yet O 0
fully O 0
understood O 0
. O 0

To O 0
our O 0
knowledge O 0
, O 0
this O 0
is O 0
the O 0
first O 0
report O 0
of O 0
a O 0
pseudo O 0
- O 0
allergy B-Disease 1
caused O 0
by O 0
paramethasone B-Chemical 1
. O 0

Study O 0
of O 0
the O 0
role O 0
of O 0
vitamin B-Chemical 1
B12 I-Chemical 1
and O 0
folinic B-Chemical 1
acid I-Chemical 1
supplementation O 0
in O 0
preventing O 0
hematologic O 0
toxicity B-Disease 1
of O 0
zidovudine B-Chemical 1
. O 0

A O 0
prospective O 0
, O 0
randomized O 0
study O 0
was O 0
conducted O 0
to O 0
evaluate O 0
the O 0
role O 0
of O 0
vitamin B-Chemical 1
B12 I-Chemical 1
and O 0
folinic B-Chemical 1
acid I-Chemical 1
supplementation O 0
in O 0
preventing O 0
zidovudine B-Chemical 1
( O 0
ZDV B-Chemical 1
) O 0
- O 0
induced O 0
bone B-Disease 1
marrow I-Disease 1
suppression I-Disease 1
. O 0

Seventy O 0
- O 0
five O 0
human B-Disease 1
immunodeficiency I-Disease 1
virus I-Disease 1
( I-Disease 1
HIV I-Disease 1
) I-Disease 1
- I-Disease 1
infected I-Disease 1
patients O 0
with O 0
CD4 O 0
+ O 0
cell O 0
counts O 0
< O 0
500 O 0
/ O 0
mm3 O 0
were O 0
randomized O 0
to O 0
receive O 0
either O 0
ZDV B-Chemical 1
( O 0
500 O 0
mg O 0
daily O 0
) O 0
alone O 0
( O 0
group O 0
I O 0
, O 0
n O 0
= O 0
38 O 0
) O 0
or O 0
in O 0
combination O 0
with O 0
folinic B-Chemical 1
acid I-Chemical 1
( O 0
15 O 0
mg O 0
daily O 0
) O 0
and O 0
intramascular O 0
vitamin B-Chemical 1
B12 I-Chemical 1
( O 0
1000 O 0
micrograms O 0
monthly O 0
) O 0
( O 0
group O 0
II O 0
, O 0
n O 0
= O 0
37 O 0
) O 0
. O 0

Finally O 0
, O 0
15 O 0
patients O 0
were O 0
excluded O 0
from O 0
the O 0
study O 0
( O 0
noncompliance O 0
14 O 0
, O 0
death B-Disease 1
1 O 0
) O 0
; O 0
thus O 0
, O 0
60 O 0
patients O 0
( O 0
31 O 0
in O 0
group O 0
I O 0
and O 0
29 O 0
in O 0
group O 0
II O 0
) O 0
were O 0
eligible O 0
for O 0
analysis O 0
. O 0

No O 0
significant O 0
differences O 0
between O 0
groups O 0
were O 0
found O 0
at O 0
enrollment O 0
. O 0

During O 0
the O 0
study O 0
, O 0
vitamin B-Chemical 1
B12 I-Chemical 1
and O 0
folate B-Chemical 1
levels O 0
were O 0
significantly O 0
higher O 0
in O 0
group O 0
II O 0
patients O 0
; O 0
however O 0
, O 0
no O 0
differences O 0
in O 0
hemoglobin O 0
, O 0
hematocrit O 0
, O 0
mean O 0
corpuscular O 0
volume O 0
, O 0
and O 0
white O 0
- O 0
cell O 0
, O 0
neutrophil O 0
and O 0
platelet O 0
counts O 0
were O 0
observed O 0
between O 0
groups O 0
at O 0
3 O 0
, O 0
6 O 0
, O 0
9 O 0
and O 0
12 O 0
months O 0
. O 0

Severe O 0
hematologic O 0
toxicity B-Disease 1
( O 0
neutrophil O 0
count O 0
< O 0
1000 O 0
/ O 0
mm3 O 0
and O 0
/ O 0
or O 0
hemoglobin O 0
< O 0
8 O 0
g O 0
/ O 0
dl O 0
) O 0
occurred O 0
in O 0
4 O 0
patients O 0
assigned O 0
to O 0
group O 0
I O 0
and O 0
7 O 0
assigned O 0
to O 0
group O 0
II O 0
. O 0

There O 0
was O 0
no O 0
correlation O 0
between O 0
vitamin B-Chemical 1
B12 I-Chemical 1
or O 0
folate B-Chemical 1
levels O 0
and O 0
development O 0
of O 0
myelosuppression B-Disease 1
. O 0

Vitamin B-Chemical 1
B12 I-Chemical 1
and O 0
folinic B-Chemical 1
acid I-Chemical 1
supplementation O 0
of O 0
ZDV B-Chemical 1
therapy O 0
does O 0
not O 0
seem O 0
useful O 0
in O 0
preventing O 0
or O 0
reducing O 0
ZDV B-Chemical 1
- O 0
induced O 0
myelotoxicity B-Disease 1
in O 0
the O 0
overall O 0
treated O 0
population O 0
, O 0
although O 0
a O 0
beneficial O 0
effect O 0
in O 0
certain O 0
subgroups O 0
of O 0
patients O 0
cannot O 0
be O 0
excluded O 0
. O 0

Safety O 0
and O 0
side O 0
- O 0
effects O 0
of O 0
alprazolam B-Chemical 1
. O 0

Controlled O 0
study O 0
in O 0
agoraphobia B-Disease 1
with O 0
panic B-Disease 1
disorder I-Disease 1
. O 0

BACKGROUND O 0
: O 0
The O 0
widespread O 0
use O 0
of O 0
benzodiazepines B-Chemical 1
has O 0
led O 0
to O 0
increasing O 0
recognition O 0
of O 0
their O 0
unwanted O 0
effects O 0
. O 0

The O 0
efficacy O 0
of O 0
alprazolam B-Chemical 1
and O 0
placebo O 0
in O 0
panic B-Disease 1
disorder I-Disease 1
with O 0
agoraphobia B-Disease 1
, O 0
and O 0
the O 0
side O 0
- O 0
effect O 0
and O 0
adverse O 0
effect O 0
profiles O 0
of O 0
both O 0
drug O 0
groups O 0
were O 0
measured O 0
. O 0

METHOD O 0
: O 0
In O 0
London O 0
and O 0
Toronto O 0
154 O 0
patients O 0
who O 0
met O 0
DSM O 0
- O 0
III O 0
criteria O 0
for O 0
panic B-Disease 1
disorder I-Disease 1
with O 0
agoraphobia B-Disease 1
were O 0
randomised O 0
to O 0
alprazolam B-Chemical 1
or O 0
placebo O 0
. O 0

Subjects O 0
in O 0
each O 0
drug O 0
group O 0
also O 0
received O 0
either O 0
exposure O 0
or O 0
relaxation O 0
. O 0

Treatment O 0
was O 0
from O 0
weeks O 0
0 O 0
to O 0
8 O 0
and O 0
was O 0
then O 0
tapered O 0
from O 0
weeks O 0
8 O 0
to O 0
16 O 0
. O 0

RESULTS O 0
: O 0
Mean O 0
alprazolam B-Chemical 1
dose O 0
was O 0
5 O 0
mg O 0
daily O 0
. O 0

Compared O 0
with O 0
placebo O 0
subjects O 0
, O 0
alprazolam B-Chemical 1
patients O 0
developed O 0
more O 0
adverse O 0
reactions O 0
( O 0
21 O 0
% O 0
v O 0
. O 0
0 O 0
% O 0
) O 0
of O 0
depression B-Disease 1
, O 0
enuresis B-Disease 1
, O 0
disinhibition O 0
and O 0
aggression B-Disease 1
; O 0
and O 0
more O 0
side O 0
- O 0
effects O 0
, O 0
particularly O 0
sedation O 0
, O 0
irritability B-Disease 1
, O 0
impaired B-Disease 1
memory I-Disease 1
, O 0
weight B-Disease 1
loss I-Disease 1
and O 0
ataxia B-Disease 1
. O 0

Side O 0
- O 0
effects O 0
tended O 0
to O 0
diminish O 0
during O 0
treatment O 0
but O 0
remained O 0
significant O 0
at O 0
week O 0
8 O 0
. O 0

Despite O 0
this O 0
, O 0
the O 0
drop O 0
- O 0
out O 0
rate O 0
was O 0
low O 0
. O 0

CONCLUSIONS O 0
: O 0
Alprazolam B-Chemical 1
caused O 0
side O 0
- O 0
effects O 0
and O 0
adverse O 0
effects O 0
during O 0
treatment O 0
but O 0
many O 0
patients O 0
were O 0
willing O 0
to O 0
accept O 0
these O 0
. O 0

Crescentic O 0
fibrillary O 0
glomerulonephritis B-Disease 1
associated O 0
with O 0
intermittent O 0
rifampin B-Chemical 1
therapy O 0
for O 0
pulmonary B-Disease 1
tuberculosis I-Disease 1
. O 0

This O 0
case O 0
study O 0
reveals O 0
an O 0
unusual O 0
finding O 0
of O 0
rapidly O 0
proliferative O 0
crescentic O 0
glomerulonephritis B-Disease 1
in O 0
a O 0
patient O 0
treated O 0
with O 0
rifampin B-Chemical 1
who O 0
had O 0
no O 0
other O 0
identifiable O 0
causes O 0
for O 0
developing O 0
this O 0
disease O 0
. O 0

This O 0
patient O 0
underwent O 0
a O 0
10 O 0
- O 0
month O 0
regimen O 0
of O 0
rifampin B-Chemical 1
and O 0
isoniazid B-Chemical 1
for O 0
pulmonary B-Disease 1
tuberculosis I-Disease 1
and O 0
was O 0
discovered O 0
to O 0
have O 0
developed O 0
signs O 0
of O 0
severe O 0
renal B-Disease 1
failure I-Disease 1
five O 0
weeks O 0
after O 0
completion O 0
of O 0
therapy O 0
. O 0

Renal O 0
biopsy O 0
revealed O 0
severe O 0
glomerulonephritis B-Disease 1
with O 0
crescents O 0
, O 0
electron O 0
dense O 0
fibrillar O 0
deposits O 0
and O 0
moderate O 0
lymphocytic O 0
interstitial O 0
infiltrate O 0
. O 0

Other O 0
possible O 0
causes O 0
of O 0
rapidly O 0
progressive O 0
glomerulonephritis B-Disease 1
were O 0
investigated O 0
and O 0
ruled O 0
out O 0
. O 0

This O 0
report O 0
documents O 0
the O 0
unusual O 0
occurrence O 0
of O 0
rapidly O 0
progressive O 0
glomerulonephritis B-Disease 1
with O 0
crescents O 0
and O 0
fibrillar O 0
glomerulonephritis B-Disease 1
in O 0
a O 0
patient O 0
treated O 0
with O 0
rifampin B-Chemical 1
. O 0

Acute O 0
confusion B-Disease 1
induced O 0
by O 0
a O 0
high O 0
- O 0
dose O 0
infusion O 0
of O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
and O 0
folinic B-Chemical 1
acid I-Chemical 1
. O 0

A O 0
61 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
was O 0
treated O 0
with O 0
combination O 0
chemotherapy O 0
incorporating O 0
cisplatinum B-Chemical 1
, O 0
etoposide B-Chemical 1
, O 0
high O 0
- O 0
dose O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
( O 0
2 O 0
, O 0
250 O 0
mg O 0
/ O 0
m2 O 0
/ O 0
24 O 0
hours O 0
) O 0
and O 0
folinic B-Chemical 1
acid I-Chemical 1
for O 0
an O 0
inoperable O 0
gastric B-Disease 1
adenocarcinoma I-Disease 1
. O 0

He O 0
developed O 0
acute O 0
neurologic O 0
symptoms O 0
of O 0
mental O 0
confusion B-Disease 1
, O 0
disorientation B-Disease 1
and O 0
irritability B-Disease 1
, O 0
and O 0
then O 0
lapsed O 0
into O 0
a O 0
deep O 0
coma B-Disease 1
, O 0
lasting O 0
for O 0
approximately O 0
40 O 0
hours O 0
during O 0
the O 0
first O 0
dose O 0
( O 0
day O 0
2 O 0
) O 0
of O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
and O 0
folinic B-Chemical 1
acid I-Chemical 1
infusion O 0
. O 0

This O 0
complication O 0
reappeared O 0
on O 0
day O 0
25 O 0
during O 0
the O 0
second O 0
dose O 0
of O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
and O 0
folinic B-Chemical 1
acid I-Chemical 1
, O 0
which O 0
were O 0
then O 0
the O 0
only O 0
drugs O 0
given O 0
. O 0

Because O 0
folinic B-Chemical 1
acid I-Chemical 1
was O 0
unlikely O 0
to O 0
be O 0
associated O 0
with O 0
this O 0
condition O 0
, O 0
neurotoxicity B-Disease 1
due O 0
to O 0
high O 0
- O 0
dose O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
was O 0
highly O 0
suspected O 0
. O 0

The O 0
pathogenesis O 0
of O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
neurotoxicity B-Disease 1
may O 0
be O 0
due O 0
to O 0
a O 0
Krebs O 0
cycle O 0
blockade O 0
by O 0
fluoroacetate B-Chemical 1
and O 0
fluorocitrate B-Chemical 1
, O 0
thiamine B-Chemical 1
deficiency O 0
, O 0
or O 0
dihydrouracil B-Chemical 1
dehydrogenase O 0
deficiency O 0
. O 0

High O 0
- O 0
dose O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
/ O 0
folinic B-Chemical 1
acid I-Chemical 1
infusion O 0
therapy O 0
has O 0
recently O 0
become O 0
a O 0
popular O 0
regimen O 0
for O 0
various O 0
cancers B-Disease 1
. O 0

It O 0
is O 0
necessary O 0
that O 0
both O 0
oncologists O 0
and O 0
neurologists O 0
be O 0
fully O 0
aware O 0
of O 0
this O 0
unusual O 0
complication O 0
. O 0

Effect O 0
of O 0
switching O 0
carbamazepine B-Chemical 1
to O 0
oxcarbazepine B-Chemical 1
on O 0
the O 0
plasma O 0
levels O 0
of O 0
neuroleptics O 0
. O 0

A O 0
case O 0
report O 0
. O 0

Carbamazepine B-Chemical 1
was O 0
switched O 0
to O 0
its O 0
10 O 0
- O 0
keto O 0
analogue O 0
oxcarbazepine B-Chemical 1
among O 0
six O 0
difficult O 0
- O 0
to O 0
- O 0
treat O 0
schizophrenic B-Disease 1
or O 0
organic B-Disease 1
psychotic I-Disease 1
patients O 0
using O 0
concomitantly O 0
haloperidol B-Chemical 1
, O 0
chlorpromazine B-Chemical 1
or O 0
clozapine B-Chemical 1
. O 0

This O 0
change O 0
resulted O 0
within O 0
2 O 0
- O 0
4 O 0
weeks O 0
in O 0
the O 0
50 O 0
- O 0
200 O 0
% O 0
increase O 0
in O 0
the O 0
plasma O 0
levels O 0
of O 0
these O 0
neuroleptics O 0
and O 0
the O 0
appearance O 0
of O 0
extrapyramidal B-Disease 1
symptoms I-Disease 1
. O 0

None O 0
of O 0
the O 0
patients O 0
showed O 0
any O 0
clinical O 0
deteriotation O 0
during O 0
the O 0
following O 0
3 O 0
- O 0
6 O 0
months O 0
. O 0

The O 0
results O 0
of O 0
this O 0
case O 0
report O 0
support O 0
the O 0
idea O 0
that O 0
in O 0
contrast O 0
with O 0
carbamazepine B-Chemical 1
oxcarbazepine B-Chemical 1
does O 0
not O 0
induce O 0
the O 0
hepatic O 0
microsomal O 0
enzyme O 0
systems O 0
regulating O 0
the O 0
inactivation O 0
of O 0
antipsychotic O 0
drugs O 0
. O 0

Time O 0
course O 0
of O 0
lipid O 0
peroxidation O 0
in O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
- O 0
induced O 0
nephropathy B-Disease 1
. O 0

Reactive O 0
oxygen B-Chemical 1
species O 0
have O 0
been O 0
implicated O 0
in O 0
the O 0
pathogenesis O 0
of O 0
acute O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
( O 0
PAN B-Chemical 1
) O 0
- O 0
induced O 0
nephropathy B-Disease 1
, O 0
with O 0
antioxidants O 0
significantly O 0
reducing O 0
the O 0
proteinuria B-Disease 1
. O 0

The O 0
temporal O 0
relationship O 0
between O 0
lipid O 0
peroxidation O 0
in O 0
the O 0
kidney O 0
and O 0
proteinuria B-Disease 1
was O 0
examined O 0
in O 0
this O 0
study O 0
. O 0

Rats O 0
were O 0
treated O 0
with O 0
a O 0
single O 0
IV O 0
injection O 0
of O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
, O 0
( O 0
PAN B-Chemical 1
, O 0
7 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
) O 0
and O 0
24 O 0
hour O 0
urine O 0
samples O 0
were O 0
obtained O 0
prior O 0
to O 0
sacrifice O 0
on O 0
days O 0
3 O 0
, O 0
5 O 0
, O 0
7 O 0
, O 0
10 O 0
, O 0
17 O 0
, O 0
27 O 0
, O 0
41 O 0
( O 0
N O 0
= O 0
5 O 0
- O 0
10 O 0
per O 0
group O 0
) O 0
. O 0

The O 0
kidneys O 0
were O 0
removed O 0
, O 0
flushed O 0
with O 0
ice O 0
cold O 0
TRIS O 0
buffer O 0
. O 0

Kidney O 0
cortices O 0
from O 0
each O 0
animal O 0
were O 0
used O 0
to O 0
prepare O 0
homogenates O 0
. O 0

Tissue O 0
lipid O 0
peroxidation O 0
was O 0
measured O 0
in O 0
whole O 0
homogenates O 0
as O 0
well O 0
as O 0
in O 0
lipid O 0
extracts O 0
from O 0
homogenates O 0
as O 0
thiobarbituric B-Chemical 1
acid I-Chemical 1
reactive O 0
substances O 0
. O 0

Proteinuria B-Disease 1
was O 0
evident O 0
at O 0
day O 0
5 O 0
, O 0
peaked O 0
at O 0
day O 0
7 O 0
and O 0
persisted O 0
to O 0
day O 0
27 O 0
. O 0

Lipid O 0
peroxidation O 0
in O 0
homogenates O 0
was O 0
maximal O 0
at O 0
day O 0
3 O 0
and O 0
declined O 0
rapidly O 0
to O 0
control O 0
levels O 0
by O 0
day O 0
17 O 0
. O 0

This O 0
study O 0
supports O 0
the O 0
role O 0
of O 0
lipid O 0
peroxidation O 0
in O 0
mediating O 0
the O 0
proteinuric B-Disease 1
injury I-Disease 1
in O 0
PAN B-Chemical 1
nephropathy B-Disease 1
. O 0

Composition O 0
of O 0
gall B-Disease 1
bladder I-Disease 1
stones I-Disease 1
associated O 0
with O 0
octreotide B-Chemical 1
: O 0
response O 0
to O 0
oral O 0
ursodeoxycholic B-Chemical 1
acid I-Chemical 1
. O 0

Octreotide B-Chemical 1
, O 0
an O 0
effective O 0
treatment O 0
for O 0
acromegaly B-Disease 1
, O 0
induces O 0
gall B-Disease 1
bladder I-Disease 1
stones I-Disease 1
in O 0
13 O 0
- O 0
60 O 0
% O 0
of O 0
patients O 0
. O 0

Because O 0
knowledge O 0
of O 0
stone O 0
composition O 0
is O 0
essential O 0
for O 0
studies O 0
of O 0
their O 0
pathogenesis O 0
, O 0
treatment O 0
, O 0
and O 0
prevention O 0
, O 0
this O 0
was O 0
investigated O 0
by O 0
direct O 0
and O 0
indirect O 0
methods O 0
in O 0
14 O 0
octreotide B-Chemical 1
treated O 0
acromegalic B-Disease 1
patients O 0
with O 0
gall B-Disease 1
stones I-Disease 1
. O 0

Chemical O 0
analysis O 0
of O 0
gall B-Disease 1
stones I-Disease 1
retrieved O 0
at O 0
cholecystectomy O 0
from O 0
two O 0
patients O 0
, O 0
showed O 0
that O 0
they O 0
contained O 0
71 O 0
% O 0
and O 0
87 O 0
% O 0
cholesterol B-Chemical 1
by O 0
weight O 0
. O 0

In O 0
the O 0
remaining O 0
12 O 0
patients O 0
, O 0
localised O 0
computed O 0
tomography O 0
of O 0
the O 0
gall O 0
bladder O 0
showed O 0
that O 0
eight O 0
had O 0
stones O 0
with O 0
maximum O 0
attenuation O 0
scores O 0
of O 0
< O 0
100 O 0
Hounsfield O 0
units O 0
( O 0
values O 0
of O 0
< O 0
100 O 0
HU O 0
predict O 0
cholesterol B-Chemical 1
rich O 0
, O 0
dissolvable O 0
stones O 0
) O 0
. O 0

Gall O 0
bladder O 0
bile O 0
was O 0
obtained O 0
by O 0
ultrasound O 0
guided O 0
, O 0
fine O 0
needle O 0
puncture O 0
from O 0
six O 0
patients O 0
. O 0

All O 0
six O 0
patients O 0
had O 0
supersaturated O 0
bile O 0
( O 0
mean O 0
( O 0
SEM O 0
) O 0
cholesterol B-Chemical 1
saturation O 0
index O 0
of O 0
1 O 0
. O 0
19 O 0
( O 0
0 O 0
. O 0
08 O 0
) O 0
( O 0
range O 0
1 O 0
. O 0
01 O 0
- O 0
1 O 0
. O 0
53 O 0
) O 0
) O 0
and O 0
all O 0
had O 0
abnormally O 0
rapid O 0
cholesterol B-Chemical 1
microcrystal O 0
nucleation O 0
times O 0
( O 0
< O 0
4 O 0
days O 0
( O 0
range O 0
1 O 0
- O 0
4 O 0
) O 0
) O 0
, O 0
whilst O 0
in O 0
four O 0
, O 0
the O 0
bile O 0
contained O 0
cholesterol B-Chemical 1
microcrystals O 0
immediately O 0
after O 0
sampling O 0
. O 0

Of O 0
the O 0
12 O 0
patients O 0
considered O 0
for O 0
oral O 0
ursodeoxycholic B-Chemical 1
acid I-Chemical 1
( O 0
UDCA B-Chemical 1
) O 0
treatment O 0
, O 0
two O 0
had O 0
a O 0
blocked O 0
cystic O 0
duct O 0
and O 0
were O 0
not O 0
started O 0
on O 0
UDCA B-Chemical 1
while O 0
one O 0
was O 0
lost O 0
to O 0
follow O 0
up O 0
. O 0

After O 0
one O 0
year O 0
of O 0
treatment O 0
, O 0
five O 0
of O 0
the O 0
remaining O 0
nine O 0
patients O 0
showed O 0
either O 0
partial O 0
( O 0
n O 0
= O 0
3 O 0
) O 0
or O 0
complete O 0
( O 0
n O 0
= O 0
2 O 0
) O 0
gall B-Disease 1
stone I-Disease 1
dissolution O 0
, O 0
suggesting O 0
that O 0
their O 0
stones O 0
were O 0
cholesterol B-Chemical 1
rich O 0
. O 0

This O 0
corresponds O 0
, O 0
by O 0
actuarial O 0
( O 0
life O 0
table O 0
) O 0
analysis O 0
, O 0
to O 0
a O 0
combined O 0
gall B-Disease 1
stone I-Disease 1
dissolution O 0
rate O 0
of O 0
58 O 0
. O 0
3 O 0
( O 0
15 O 0
. O 0
9 O 0
% O 0
) O 0
. O 0

In O 0
conclusion O 0
, O 0
octreotide B-Chemical 1
induced O 0
gall B-Disease 1
stones I-Disease 1
are O 0
generally O 0
small O 0
, O 0
multiple O 0
, O 0
and O 0
cholesterol B-Chemical 1
rich O 0
although O 0
, O 0
in O 0
common O 0
with O 0
spontaneous O 0
gall B-Disease 1
stone I-Disease 1
disease I-Disease 1
, O 0
at O 0
presentation O 0
some O 0
patients O 0
will O 0
have O 0
a O 0
blocked O 0
cystic O 0
duct O 0
and O 0
some O 0
gall B-Disease 1
stones I-Disease 1
containing O 0
calcium B-Chemical 1
. O 0

Erythema B-Disease 1
multiforme I-Disease 1
and O 0
hypersensitivity B-Disease 1
myocarditis I-Disease 1
caused O 0
by O 0
ampicillin B-Chemical 1
. O 0

OBJECTIVE O 0
: O 0
To O 0
report O 0
a O 0
case O 0
of O 0
erythema B-Disease 1
multiforme I-Disease 1
and O 0
hypersensitivity B-Disease 1
myocarditis I-Disease 1
caused O 0
by O 0
ampicillin B-Chemical 1
. O 0

CASE O 0
SUMMARY O 0
: O 0
A O 0
13 O 0
- O 0
year O 0
- O 0
old O 0
boy O 0
was O 0
treated O 0
with O 0
ampicillin B-Chemical 1
and O 0
gentamicin B-Chemical 1
because O 0
of O 0
suspected O 0
septicemia B-Disease 1
. O 0

Medications O 0
were O 0
discontinued O 0
when O 0
erythema B-Disease 1
multiforme I-Disease 1
and O 0
congestive B-Disease 1
heart I-Disease 1
failure I-Disease 1
caused O 0
by O 0
myocarditis B-Disease 1
occurred O 0
. O 0

The O 0
patient O 0
was O 0
treated O 0
with O 0
methylprednisolone B-Chemical 1
and O 0
gradually O 0
improved O 0
. O 0

Macrophage O 0
- O 0
migration O 0
inhibition O 0
( O 0
MIF O 0
) O 0
test O 0
with O 0
ampicillin B-Chemical 1
was O 0
positive O 0
. O 0

DISCUSSION O 0
: O 0
After O 0
most O 0
infections B-Disease 1
causing O 0
erythema B-Disease 1
multiforme I-Disease 1
and O 0
myocarditis B-Disease 1
were O 0
ruled O 0
out O 0
, O 0
a O 0
drug B-Disease 1
- I-Disease 1
induced I-Disease 1
allergic I-Disease 1
reaction I-Disease 1
was O 0
suspected O 0
. O 0

Positive O 0
MIF O 0
test O 0
for O 0
ampicillin B-Chemical 1
showed O 0
sensitization O 0
of O 0
the O 0
patient O 0
' O 0
s O 0
lymphocytes O 0
to O 0
ampicillin B-Chemical 1
. O 0

CONCLUSIONS O 0
: O 0
Hypersensitivity B-Disease 1
myocarditis I-Disease 1
is O 0
a O 0
rare O 0
and O 0
dangerous O 0
manifestation O 0
of O 0
allergy B-Disease 1
to O 0
penicillins B-Chemical 1
. O 0

Clomipramine B-Chemical 1
- O 0
induced O 0
sleep B-Disease 1
disturbance I-Disease 1
does O 0
not O 0
impair O 0
its O 0
prolactin O 0
- O 0
releasing O 0
action O 0
. O 0

The O 0
present O 0
study O 0
was O 0
undertaken O 0
to O 0
examine O 0
the O 0
role O 0
of O 0
sleep B-Disease 1
disturbance I-Disease 1
, O 0
induced O 0
by O 0
clomipramine B-Chemical 1
administration O 0
, O 0
on O 0
the O 0
secretory O 0
rate O 0
of O 0
prolactin O 0
( O 0
PRL O 0
) O 0
in O 0
addition O 0
to O 0
the O 0
direct O 0
drug O 0
effect O 0
. O 0

Two O 0
groups O 0
of O 0
supine O 0
subjects O 0
were O 0
studied O 0
under O 0
placebo O 0
- O 0
controlled O 0
conditions O 0
, O 0
one O 0
during O 0
the O 0
night O 0
, O 0
when O 0
sleeping O 0
( O 0
n O 0
= O 0
7 O 0
) O 0
and O 0
the O 0
other O 0
at O 0
daytime O 0
, O 0
when O 0
awake O 0
( O 0
n O 0
= O 0
6 O 0
) O 0
. O 0

Each O 0
subject O 0
received O 0
a O 0
single O 0
50 O 0
mg O 0
dose O 0
of O 0
clomipramine B-Chemical 1
given O 0
orally O 0
2 O 0
hours O 0
before O 0
blood O 0
collection O 0
. O 0

Plasma O 0
PRL O 0
concentrations O 0
were O 0
analysed O 0
at O 0
10 O 0
min O 0
intervals O 0
and O 0
underlying O 0
secretory O 0
rates O 0
calculated O 0
by O 0
a O 0
deconvolution O 0
procedure O 0
. O 0

For O 0
both O 0
experiments O 0
the O 0
drug O 0
intake O 0
led O 0
to O 0
significant O 0
increases O 0
in O 0
PRL O 0
secretion O 0
, O 0
acting O 0
preferentially O 0
on O 0
tonic O 0
secretion O 0
as O 0
pulse O 0
amplitude O 0
and O 0
frequency O 0
did O 0
not O 0
differ O 0
significantly O 0
from O 0
corresponding O 0
control O 0
values O 0
. O 0

During O 0
the O 0
night O 0
clomipramine B-Chemical 1
ingestion O 0
altered O 0
the O 0
complete O 0
sleep O 0
architecture O 0
in O 0
that O 0
it O 0
suppressed O 0
REM O 0
sleep O 0
and O 0
the O 0
sleep O 0
cycles O 0
and O 0
induced O 0
increased O 0
wakefulness O 0
. O 0

As O 0
the O 0
relative O 0
increase O 0
in O 0
PRL O 0
secretion O 0
expressed O 0
as O 0
a O 0
percentage O 0
of O 0
the O 0
mean O 0
did O 0
not O 0
significantly O 0
differ O 0
between O 0
the O 0
night O 0
and O 0
day O 0
time O 0
studies O 0
( O 0
46 O 0
+ O 0
/ O 0
- O 0
19 O 0
% O 0
vs O 0
34 O 0
+ O 0
/ O 0
- O 0
10 O 0
% O 0
) O 0
, O 0
it O 0
can O 0
be O 0
concluded O 0
that O 0
the O 0
observed O 0
sleep B-Disease 1
disturbance I-Disease 1
did O 0
not O 0
interfere O 0
with O 0
the O 0
drug O 0
action O 0
per O 0
se O 0
. O 0

The O 0
presence O 0
of O 0
REM O 0
sleep O 0
was O 0
shown O 0
not O 0
to O 0
be O 0
a O 0
determining O 0
factor O 0
either O 0
for O 0
secretory O 0
pulse O 0
amplitude O 0
and O 0
frequency O 0
, O 0
as O 0
, O 0
for O 0
both O 0
, O 0
mean O 0
nocturnal O 0
values O 0
were O 0
similar O 0
with O 0
and O 0
without O 0
prior O 0
clomipramine B-Chemical 1
ingestion O 0
. O 0

Survey O 0
of O 0
complications O 0
of O 0
indocyanine B-Chemical 1
green I-Chemical 1
angiography O 0
in O 0
Japan O 0
. O 0

PURPOSE O 0
: O 0
We O 0
evaluated O 0
the O 0
safety O 0
of O 0
indocyanine B-Chemical 1
green I-Chemical 1
for O 0
use O 0
in O 0
fundus O 0
angiography O 0
. O 0

METHODS O 0
: O 0
We O 0
sent O 0
a O 0
questionnaire O 0
concerning O 0
complications O 0
of O 0
indocyanine B-Chemical 1
green I-Chemical 1
to O 0
32 O 0
institutions O 0
in O 0
Japan O 0
, O 0
which O 0
were O 0
selected O 0
on O 0
the O 0
basis O 0
of O 0
the O 0
client O 0
list O 0
from O 0
the O 0
Topcon O 0
Company O 0
, O 0
which O 0
manufactures O 0
the O 0
indocyanine B-Chemical 1
green I-Chemical 1
fundus O 0
camera O 0
. O 0

RESULTS O 0
: O 0
Ophthalmologists O 0
at O 0
15 O 0
institutions O 0
responded O 0
, O 0
reporting O 0
a O 0
total O 0
of O 0
3 O 0
, O 0
774 O 0
indocyanine B-Chemical 1
green I-Chemical 1
angiograms O 0
performed O 0
on O 0
2 O 0
, O 0
820 O 0
patients O 0
between O 0
June O 0
1984 O 0
and O 0
September O 0
1992 O 0
. O 0

Before O 0
angiography O 0
, O 0
intradermal O 0
or O 0
intravenous O 0
indocyanine B-Chemical 1
green I-Chemical 1
testing O 0
, O 0
or O 0
both O 0
was O 0
performed O 0
at O 0
13 O 0
of O 0
15 O 0
institutions O 0
. O 0

For O 0
three O 0
patients O 0
, O 0
the O 0
decision O 0
was O 0
made O 0
not O 0
to O 0
proceed O 0
with O 0
angiography O 0
after O 0
positive O 0
preangiographic O 0
testing O 0
. O 0

The O 0
dosage O 0
of O 0
indocyanine B-Chemical 1
green I-Chemical 1
used O 0
for O 0
angiography O 0
varied O 0
from O 0
25 O 0
to O 0
75 O 0
mg O 0
, O 0
depending O 0
upon O 0
the O 0
institution O 0
. O 0

There O 0
were O 0
13 O 0
cases O 0
of O 0
adverse O 0
reactions O 0
( O 0
0 O 0
. O 0
34 O 0
% O 0
) O 0
, O 0
ten O 0
of O 0
which O 0
were O 0
mild O 0
reactions O 0
such O 0
as O 0
nausea B-Disease 1
, O 0
exanthema B-Disease 1
, O 0
urtication B-Disease 1
, O 0
itchiness B-Disease 1
, O 0
and O 0
urgency O 0
to O 0
defecate O 0
, O 0
and O 0
did O 0
not O 0
require O 0
treatment O 0
. O 0

Also O 0
recorded O 0
were O 0
one O 0
case O 0
of O 0
pain B-Disease 1
of O 0
the O 0
vein O 0
, O 0
which O 0
required O 0
treatment O 0
, O 0
and O 0
two O 0
cases O 0
of O 0
hypotension B-Disease 1
. O 0

The O 0
two O 0
hypotensive B-Disease 1
patients O 0
required O 0
treatment O 0
for O 0
shock B-Disease 1
. O 0

CONCLUSIONS O 0
: O 0
A O 0
comparison O 0
of O 0
frequency O 0
of O 0
adverse O 0
reactions O 0
to O 0
indocyanine B-Chemical 1
green I-Chemical 1
with O 0
the O 0
previously O 0
reported O 0
frequency O 0
of O 0
such O 0
reactions O 0
to O 0
fluorescein B-Chemical 1
sodium I-Chemical 1
indicated O 0
that O 0
indocyanine B-Chemical 1
green I-Chemical 1
is O 0
a O 0
safe O 0
as O 0
fluorescein B-Chemical 1
for O 0
use O 0
in O 0
angiography O 0
. O 0

Angioedema B-Disease 1
following O 0
the O 0
intravenous O 0
administration O 0
of O 0
metoprolol B-Chemical 1
. O 0

A O 0
72 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
was O 0
admitted O 0
to O 0
the O 0
hospital O 0
with O 0
" O 0
flash O 0
" O 0
pulmonary B-Disease 1
edema I-Disease 1
, O 0
preceded O 0
by O 0
chest B-Disease 1
pain I-Disease 1
, O 0
requiring O 0
intubation O 0
. O 0

Her O 0
medical O 0
history O 0
included O 0
coronary B-Disease 1
artery I-Disease 1
disease I-Disease 1
with O 0
previous O 0
myocardial B-Disease 1
infarctions I-Disease 1
, O 0
hypertension B-Disease 1
, O 0
and O 0
diabetes B-Disease 1
mellitus I-Disease 1
. O 0

A O 0
history O 0
of O 0
angioedema B-Disease 1
secondary O 0
to O 0
lisinopril B-Chemical 1
therapy O 0
was O 0
elicited O 0
. O 0

Current O 0
medications O 0
did O 0
not O 0
include O 0
angiotensin B-Chemical 1
- O 0
converting O 0
enzyme O 0
inhibitors O 0
or O 0
beta O 0
- O 0
blockers O 0
. O 0

She O 0
had O 0
no O 0
previous O 0
beta O 0
- O 0
blocking O 0
drug O 0
exposure O 0
. O 0

During O 0
the O 0
first O 0
day O 0
of O 0
hospitalization O 0
( O 0
while O 0
intubated O 0
) O 0
, O 0
intravenous O 0
metoprolol B-Chemical 1
was O 0
given O 0
, O 0
resulting O 0
in O 0
severe O 0
angioedema B-Disease 1
. O 0

The O 0
angioedema B-Disease 1
resolved O 0
after O 0
therapy O 0
with O 0
intravenous O 0
steroids B-Chemical 1
and O 0
diphenhydramine B-Chemical 1
hydrochloride O 0
. O 0

Effect O 0
of O 0
coniine B-Chemical 1
on O 0
the O 0
developing O 0
chick O 0
embryo O 0
. O 0

Coniine B-Chemical 1
, O 0
an O 0
alkaloid O 0
from O 0
Conium O 0
maculatum O 0
( O 0
poison O 0
hemlock O 0
) O 0
, O 0
has O 0
been O 0
shown O 0
to O 0
be O 0
teratogenic O 0
in O 0
livestock O 0
. O 0

The O 0
major O 0
teratogenic O 0
outcome O 0
is O 0
arthrogryposis B-Disease 1
, O 0
presumably O 0
due O 0
to O 0
nicotinic O 0
receptor O 0
blockade O 0
. O 0

However O 0
, O 0
coniine B-Chemical 1
has O 0
failed O 0
to O 0
produce O 0
arthrogryposis B-Disease 1
in O 0
rats O 0
or O 0
mice O 0
and O 0
is O 0
only O 0
weakly O 0
teratogenic O 0
in O 0
rabbits O 0
. O 0

The O 0
purpose O 0
of O 0
this O 0
study O 0
was O 0
to O 0
evaluate O 0
and O 0
compare O 0
the O 0
effects O 0
of O 0
coniine B-Chemical 1
and O 0
nicotine B-Chemical 1
in O 0
the O 0
developing O 0
chick O 0
. O 0

Concentrations O 0
of O 0
coniine B-Chemical 1
and O 0
nicotine B-Chemical 1
sulfate O 0
were O 0
0 O 0
. O 0
015 O 0
% O 0
, O 0
0 O 0
. O 0
03 O 0
% O 0
, O 0
0 O 0
. O 0
075 O 0
% O 0
, O 0
0 O 0
. O 0
15 O 0
% O 0
, O 0
0 O 0
. O 0
75 O 0
% O 0
, O 0
1 O 0
. O 0
5 O 0
% O 0
, O 0
3 O 0
% O 0
, O 0
and O 0
6 O 0
% O 0
and O 0
1 O 0
% O 0
, O 0
5 O 0
% O 0
, O 0
and O 0
10 O 0
% O 0
, O 0
respectively O 0
. O 0

Both O 0
compounds O 0
caused O 0
deformations B-Disease 1
and O 0
lethality O 0
in O 0
a O 0
dose O 0
- O 0
dependent O 0
manner O 0
. O 0

All O 0
concentrations O 0
of O 0
nicotine B-Chemical 1
sulfate O 0
caused O 0
some O 0
lethality O 0
but O 0
a O 0
no O 0
effect O 0
level O 0
for O 0
coniine B-Chemical 1
lethality O 0
was O 0
0 O 0
. O 0
75 O 0
% O 0
. O 0

The O 0
deformations B-Disease 1
caused O 0
by O 0
both O 0
coniine B-Chemical 1
and O 0
nicotine B-Chemical 1
sulfate O 0
were O 0
excessive B-Disease 1
flexion I-Disease 1
or I-Disease 1
extension I-Disease 1
of I-Disease 1
one I-Disease 1
or I-Disease 1
more I-Disease 1
toes I-Disease 1
. O 0

No O 0
histopathological O 0
alterations O 0
or O 0
differences O 0
in O 0
bone O 0
formation O 0
were O 0
seen O 0
in O 0
the O 0
limbs O 0
or O 0
toes O 0
of O 0
any O 0
chicks O 0
from O 0
any O 0
group O 0
; O 0
however O 0
, O 0
extensive O 0
cranial B-Disease 1
hemorrhage I-Disease 1
occurred O 0
in O 0
all O 0
nicotine B-Chemical 1
sulfate O 0
- O 0
treated O 0
chicks O 0
. O 0

There O 0
was O 0
a O 0
statistically O 0
significant O 0
( O 0
P O 0
< O 0
or O 0
= O 0
0 O 0
. O 0
01 O 0
) O 0
decrease O 0
in O 0
movement O 0
in O 0
coniine B-Chemical 1
and O 0
nicotine B-Chemical 1
sulfate O 0
treated O 0
chicks O 0
as O 0
determined O 0
by O 0
ultrasound O 0
. O 0

Control O 0
chicks O 0
were O 0
in O 0
motion O 0
an O 0
average O 0
of O 0
33 O 0
. O 0
67 O 0
% O 0
of O 0
the O 0
time O 0
, O 0
while O 0
coniine B-Chemical 1
- O 0
treated O 0
chicks O 0
were O 0
only O 0
moving O 0
8 O 0
. O 0
95 O 0
% O 0
of O 0
a O 0
5 O 0
- O 0
min O 0
interval O 0
, O 0
and O 0
no O 0
movement O 0
was O 0
observed O 0
for O 0
nicotine B-Chemical 1
sulfate O 0
treated O 0
chicks O 0
. O 0

In O 0
summary O 0
, O 0
the O 0
chick O 0
embryo O 0
provides O 0
a O 0
reliable O 0
and O 0
simple O 0
experimental O 0
animal O 0
model O 0
of O 0
coniine B-Chemical 1
- O 0
induced O 0
arthrogryposis B-Disease 1
. O 0

Data O 0
from O 0
this O 0
model O 0
support O 0
a O 0
mechanism O 0
involving O 0
nicotinic O 0
receptor O 0
blockade O 0
with O 0
subsequent O 0
decreased O 0
fetal O 0
movement O 0
. O 0

Immediate O 0
allergic B-Disease 1
reactions I-Disease 1
to O 0
amoxicillin B-Chemical 1
. O 0

A O 0
large O 0
group O 0
of O 0
patients O 0
with O 0
suspected O 0
allergic B-Disease 1
reactions I-Disease 1
to O 0
beta B-Chemical 1
- I-Chemical 1
lactam I-Chemical 1
antibiotics O 0
was O 0
evaluated O 0
. O 0

A O 0
detailed O 0
clinical O 0
history O 0
, O 0
together O 0
with O 0
skin O 0
tests O 0
, O 0
RAST O 0
( O 0
radioallergosorbent O 0
test O 0
) O 0
, O 0
and O 0
controlled O 0
challenge O 0
tests O 0
, O 0
was O 0
used O 0
to O 0
establish O 0
whether O 0
patients O 0
allergic B-Disease 1
to O 0
beta B-Chemical 1
- I-Chemical 1
lactam I-Chemical 1
antibiotics O 0
had O 0
selective O 0
immediate O 0
allergic B-Disease 1
responses O 0
to O 0
amoxicillin B-Chemical 1
( O 0
AX B-Chemical 1
) O 0
or O 0
were O 0
cross O 0
- O 0
reacting O 0
with O 0
other O 0
penicillin B-Chemical 1
derivatives O 0
. O 0

Skin O 0
tests O 0
were O 0
performed O 0
with O 0
benzylpenicilloyl B-Chemical 1
- I-Chemical 1
poly I-Chemical 1
- I-Chemical 1
L I-Chemical 1
- I-Chemical 1
lysine I-Chemical 1
( O 0
BPO B-Chemical 1
- I-Chemical 1
PLL I-Chemical 1
) O 0
, O 0
benzylpenicilloate B-Chemical 1
, O 0
benzylpenicillin B-Chemical 1
( O 0
PG B-Chemical 1
) O 0
, O 0
ampicillin B-Chemical 1
( O 0
AMP B-Chemical 1
) O 0
, O 0
and O 0
AX B-Chemical 1
. O 0

RAST O 0
for O 0
BPO B-Chemical 1
- I-Chemical 1
PLL I-Chemical 1
and O 0
AX B-Chemical 1
- O 0
PLL O 0
was O 0
done O 0
. O 0

When O 0
both O 0
skin O 0
test O 0
and O 0
RAST O 0
for O 0
BPO B-Chemical 1
were O 0
negative O 0
, O 0
single O 0
- O 0
blind O 0
, O 0
placebo O 0
- O 0
controlled O 0
challenge O 0
tests O 0
were O 0
done O 0
to O 0
ensure O 0
tolerance O 0
of O 0
PG B-Chemical 1
or O 0
sensitivity O 0
to O 0
AX B-Chemical 1
. O 0

A O 0
total O 0
of O 0
177 O 0
patients O 0
were O 0
diagnosed O 0
as O 0
allergic B-Disease 1
to O 0
beta B-Chemical 1
- I-Chemical 1
lactam I-Chemical 1
antibiotics O 0
. O 0

We O 0
selected O 0
the O 0
54 O 0
( O 0
30 O 0
. O 0
5 O 0
% O 0
) O 0
cases O 0
of O 0
immediate O 0
AX B-Chemical 1
allergy B-Disease 1
with O 0
good O 0
tolerance O 0
of O 0
PG B-Chemical 1
. O 0

Anaphylaxis B-Disease 1
was O 0
seen O 0
in O 0
37 O 0
patients O 0
( O 0
69 O 0
% O 0
) O 0
, O 0
the O 0
other O 0
17 O 0
( O 0
31 O 0
% O 0
) O 0
having O 0
urticaria B-Disease 1
and O 0
/ O 0
or O 0
angioedema B-Disease 1
. O 0

All O 0
the O 0
patients O 0
were O 0
skin O 0
test O 0
negative O 0
to O 0
BPO B-Chemical 1
; O 0
49 O 0
of O 0
51 O 0
( O 0
96 O 0
% O 0
) O 0
were O 0
also O 0
negative O 0
to O 0
MDM B-Disease 1
, O 0
and O 0
44 O 0
of O 0
46 O 0
( O 0
96 O 0
% O 0
) O 0
to O 0
PG B-Chemical 1
. O 0

Skin O 0
tests O 0
with O 0
AX B-Chemical 1
were O 0
positive O 0
in O 0
34 O 0
( O 0
63 O 0
% O 0
) O 0
patients O 0
. O 0

RAST O 0
was O 0
positive O 0
for O 0
AX B-Chemical 1
in O 0
22 O 0
patients O 0
( O 0
41 O 0
% O 0
) O 0
and O 0
to O 0
BPO B-Chemical 1
in O 0
just O 0
5 O 0
( O 0
9 O 0
% O 0
) O 0
. O 0

None O 0
of O 0
the O 0
sera O 0
with O 0
negative O 0
RAST O 0
for O 0
AX B-Chemical 1
were O 0
positive O 0
to O 0
BPO B-Chemical 1
. O 0

Challenge O 0
tests O 0
with O 0
AX B-Chemical 1
were O 0
performed O 0
in O 0
23 O 0
subjects O 0
( O 0
43 O 0
% O 0
) O 0
to O 0
establish O 0
the O 0
diagnosis O 0
of O 0
immediate O 0
allergic B-Disease 1
reaction I-Disease 1
to O 0
AX B-Chemical 1
, O 0
and O 0
in O 0
15 O 0
cases O 0
( O 0
28 O 0
% O 0
) O 0
both O 0
skin O 0
test O 0
and O 0
RAST O 0
for O 0
AX B-Chemical 1
were O 0
negative O 0
. O 0

PG B-Chemical 1
was O 0
well O 0
tolerated O 0
by O 0
all O 0
54 O 0
patients O 0
. O 0

We O 0
describe O 0
the O 0
largest O 0
group O 0
of O 0
AX B-Chemical 1
- O 0
allergic B-Disease 1
patients O 0
who O 0
have O 0
tolerated O 0
PG B-Chemical 1
reported O 0
so O 0
far O 0
. O 0

Diagnosis O 0
of O 0
these O 0
patients O 0
can O 0
be O 0
achieved O 0
only O 0
if O 0
specific O 0
AX B-Chemical 1
- O 0
related O 0
reagents O 0
are O 0
employed O 0
. O 0

Further O 0
studies O 0
are O 0
necessary O 0
to O 0
determine O 0
the O 0
exact O 0
extent O 0
of O 0
this O 0
problem O 0
and O 0
to O 0
improve O 0
the O 0
efficacy O 0
of O 0
diagnostic O 0
methods O 0
. O 0

Reversal O 0
by O 0
phenylephrine B-Chemical 1
of O 0
the O 0
beneficial O 0
effects O 0
of O 0
intravenous O 0
nitroglycerin B-Chemical 1
in O 0
patients O 0
with O 0
acute B-Disease 1
myocardial I-Disease 1
infarction I-Disease 1
. O 0

Nitroglycerin B-Chemical 1
has O 0
been O 0
shown O 0
to O 0
reduce O 0
ST O 0
- O 0
segment O 0
elevation O 0
during O 0
acute B-Disease 1
myocardial I-Disease 1
infarction I-Disease 1
, O 0
an O 0
effect O 0
potentiated O 0
in O 0
the O 0
dog O 0
by O 0
agents O 0
that O 0
reverse O 0
nitroglycerin B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
. O 0

Our O 0
study O 0
was O 0
designed O 0
to O 0
determine O 0
the O 0
effects O 0
of O 0
combined O 0
nitroglycerin B-Chemical 1
and O 0
phenylephrine B-Chemical 1
therapy O 0
. O 0

Ten O 0
patients O 0
with O 0
acute O 0
transmural O 0
myocardial B-Disease 1
infarctions I-Disease 1
received O 0
intravenous O 0
nitroglycerin B-Chemical 1
, O 0
sufficient O 0
to O 0
reduce O 0
mean O 0
arterial O 0
pressure O 0
from O 0
107 O 0
+ O 0
/ O 0
- O 0
6 O 0
to O 0
85 O 0
+ O 0
/ O 0
- O 0
6 O 0
mm O 0
Hg O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
001 O 0
) O 0
, O 0
for O 0
60 O 0
minutes O 0
. O 0

Left O 0
ventricular O 0
filling O 0
pressure O 0
decreased O 0
from O 0
19 O 0
+ O 0
/ O 0
- O 0
2 O 0
to O 0
11 O 0
+ O 0
/ O 0
- O 0
2 O 0
mm O 0
Hg O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

SigmaST O 0
, O 0
the O 0
sum O 0
of O 0
ST O 0
- O 0
segment O 0
elevations O 0
in O 0
16 O 0
precordial O 0
leads O 0
, O 0
decreased O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
02 O 0
) O 0
with O 0
intravenous O 0
nitroglycerin B-Chemical 1
. O 0

Subsequent O 0
addition O 0
of O 0
phenylephrine B-Chemical 1
infusion O 0
, O 0
sufficient O 0
to O 0
re O 0
- O 0
elevate O 0
mean O 0
arterial O 0
pressure O 0
to O 0
106 O 0
+ O 0
/ O 0
- O 0
4 O 0
mm O 0
Hg O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
001 O 0
) O 0
for O 0
30 O 0
minutes O 0
, O 0
increased O 0
left O 0
ventricular O 0
filling O 0
pressure O 0
to O 0
17 O 0
+ O 0
/ O 0
- O 0
2 O 0
mm O 0
Hg O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
and O 0
also O 0
significantly O 0
increased O 0
sigmaST O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

Our O 0
results O 0
suggest O 0
that O 0
addition O 0
of O 0
phenylephrine B-Chemical 1
to O 0
nitroglycerin B-Chemical 1
is O 0
not O 0
beneficial O 0
in O 0
the O 0
treatment O 0
of O 0
patients O 0
with O 0
acute B-Disease 1
myocardial I-Disease 1
infarction I-Disease 1
. O 0

Acetazolamide B-Chemical 1
- O 0
induced O 0
nephrolithiasis B-Disease 1
: O 0
implications O 0
for O 0
treatment O 0
of O 0
neuromuscular B-Disease 1
disorders I-Disease 1
. O 0

Carbonic O 0
anhydrase O 0
inhibitors O 0
can O 0
cause O 0
nephrolithiasis B-Disease 1
. O 0

We O 0
studied O 0
20 O 0
patients O 0
receiving O 0
long O 0
- O 0
term O 0
carbonic O 0
anhydrase O 0
inhibitor O 0
treatment O 0
for O 0
periodic O 0
paralysis B-Disease 1
and O 0
myotonia B-Disease 1
. O 0

Three O 0
patients O 0
on O 0
acetazolamide B-Chemical 1
( O 0
15 O 0
% O 0
) O 0
developed O 0
renal B-Disease 1
calculi I-Disease 1
. O 0

Extracorporeal O 0
lithotripsy O 0
successfully O 0
removed O 0
a O 0
renal B-Disease 1
calculus I-Disease 1
in O 0
one O 0
patient O 0
and O 0
surgery O 0
removed O 0
a O 0
staghorn O 0
calculus B-Disease 1
in O 0
another O 0
, O 0
permitting O 0
continued O 0
treatment O 0
. O 0

Renal O 0
function O 0
remained O 0
normal O 0
in O 0
all O 0
patients O 0
. O 0

Nephrolithiasis B-Disease 1
is O 0
a O 0
complication O 0
of O 0
acetazolamide B-Chemical 1
but O 0
does O 0
not O 0
preclude O 0
its O 0
use O 0
. O 0

Effects O 0
of O 0
calcium B-Chemical 1
channel O 0
blockers O 0
on O 0
bupivacaine B-Chemical 1
- O 0
induced O 0
toxicity B-Disease 1
. O 0

The O 0
purpose O 0
of O 0
this O 0
study O 0
was O 0
to O 0
investigate O 0
the O 0
influence O 0
of O 0
calcium B-Chemical 1
channel O 0
blockers O 0
on O 0
bupivacaine B-Chemical 1
- O 0
induced O 0
acute O 0
toxicity B-Disease 1
. O 0

For O 0
each O 0
of O 0
the O 0
three O 0
tested O 0
calcium B-Chemical 1
channel O 0
blockers O 0
( O 0
diltiazem B-Chemical 1
, O 0
verapamil B-Chemical 1
and O 0
bepridil B-Chemical 1
) O 0
6 O 0
groups O 0
of O 0
mice O 0
were O 0
treated O 0
by O 0
two O 0
different O 0
doses O 0
, O 0
i O 0
. O 0
e O 0
. O 0
2 O 0
and O 0
10 O 0
mg O 0
/ O 0
kg O 0
/ O 0
i O 0
. O 0
p O 0
. O 0
, O 0
or O 0
an O 0
equal O 0
volume O 0
of O 0
saline O 0
for O 0
the O 0
control O 0
group O 0
( O 0
n O 0
= O 0
20 O 0
) O 0
; O 0
15 O 0
minutes O 0
later O 0
, O 0
all O 0
the O 0
animals O 0
were O 0
injected O 0
with O 0
a O 0
single O 0
50 O 0
mg O 0
/ O 0
kg O 0
/ O 0
i O 0
. O 0
p O 0
. O 0
dose O 0
of O 0
bupivacaine B-Chemical 1
. O 0

The O 0
convulsant O 0
activity O 0
, O 0
the O 0
time O 0
of O 0
latency O 0
to O 0
convulse O 0
and O 0
the O 0
mortality O 0
rate O 0
were O 0
assessed O 0
in O 0
each O 0
group O 0
. O 0

The O 0
local O 0
anesthetic O 0
- O 0
induced O 0
mortality O 0
was O 0
significantly O 0
increased O 0
by O 0
the O 0
three O 0
different O 0
calcium B-Chemical 1
channel O 0
blockers O 0
. O 0

The O 0
convulsant O 0
activity O 0
of O 0
bupivacaine B-Chemical 1
was O 0
not O 0
significantly O 0
modified O 0
but O 0
calcium B-Chemical 1
channel O 0
blockers O 0
decreased O 0
the O 0
time O 0
of O 0
latency O 0
to O 0
obtain O 0
bupivacaine B-Chemical 1
- O 0
induced O 0
convulsions B-Disease 1
; O 0
this O 0
effect O 0
was O 0
less O 0
pronounced O 0
with O 0
bepridil B-Chemical 1
. O 0

Epidural O 0
blood O 0
flow O 0
during O 0
prostaglandin B-Chemical 1
E1 I-Chemical 1
or O 0
trimethaphan B-Chemical 1
induced O 0
hypotension B-Disease 1
. O 0

To O 0
evaluate O 0
the O 0
effect O 0
of O 0
prostaglandin B-Chemical 1
E1 I-Chemical 1
( O 0
PGE1 B-Chemical 1
) O 0
or O 0
trimethaphan B-Chemical 1
( O 0
TMP B-Chemical 1
) O 0
induced O 0
hypotension B-Disease 1
on O 0
epidural O 0
blood O 0
flow O 0
( O 0
EBF O 0
) O 0
during O 0
spinal O 0
surgery O 0
, O 0
EBF O 0
was O 0
measured O 0
using O 0
the O 0
heat O 0
clearance O 0
method O 0
in O 0
30 O 0
patients O 0
who O 0
underwent O 0
postero O 0
- O 0
lateral O 0
interbody O 0
fusion O 0
under O 0
isoflurane B-Chemical 1
anaesthesia O 0
. O 0

An O 0
initial O 0
dose O 0
of O 0
0 O 0
. O 0
1 O 0
microgram O 0
. O 0
kg O 0
- O 0
1 O 0
. O 0
min O 0
- O 0
1 O 0
of O 0
PGE1 B-Chemical 1
( O 0
15 O 0
patients O 0
) O 0
, O 0
or O 0
10 O 0
micrograms O 0
. O 0
kg O 0
- O 0
1 O 0
. O 0
min O 0
- O 0
1 O 0
of O 0
TMP B-Chemical 1
( O 0
15 O 0
patients O 0
) O 0
was O 0
administered O 0
intravenously O 0
after O 0
the O 0
dural O 0
opening O 0
and O 0
the O 0
dose O 0
was O 0
adjusted O 0
to O 0
maintain O 0
the O 0
mean O 0
arterial O 0
blood O 0
pressure O 0
( O 0
MAP O 0
) O 0
at O 0
about O 0
60 O 0
mmHg O 0
. O 0

The O 0
hypotensive B-Disease 1
drug O 0
was O 0
discontinued O 0
at O 0
the O 0
completion O 0
of O 0
the O 0
operative O 0
procedure O 0
. O 0

After O 0
starting O 0
PGE1 B-Chemical 1
or O 0
TMP B-Chemical 1
, O 0
MAP O 0
and O 0
rate O 0
pressure O 0
product O 0
( O 0
RPP O 0
) O 0
decreased O 0
significantly O 0
compared O 0
with O 0
preinfusion O 0
values O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
01 O 0
) O 0
, O 0
and O 0
the O 0
degree O 0
of O 0
hypotension B-Disease 1
due O 0
to O 0
PGE1 B-Chemical 1
remained O 0
constant O 0
until O 0
60 O 0
min O 0
after O 0
its O 0
discontinuation O 0
. O 0

Heart O 0
rate O 0
( O 0
HR O 0
) O 0
did O 0
not O 0
change O 0
in O 0
either O 0
group O 0
. O 0

EBFF O 0
did O 0
not O 0
change O 0
during O 0
PGE1 B-Chemical 1
infusion O 0
whereas O 0
in O 0
the O 0
TMP B-Chemical 1
group O 0
, O 0
EBF O 0
decreased O 0
significantly O 0
at O 0
30 O 0
and O 0
60 O 0
min O 0
after O 0
the O 0
start O 0
of O 0
TMP B-Chemical 1
( O 0
preinfusion O 0
: O 0
45 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
13 O 0
. O 0
9 O 0
ml O 0
/ O 0
100g O 0
/ O 0
min O 0
. O 0
30 O 0
min O 0
: O 0
32 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
9 O 0
. O 0
9 O 0
ml O 0
/ O 0
100 O 0
g O 0
/ O 0
min O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0
60 O 0
min O 0
: O 0
30 O 0
+ O 0
/ O 0
- O 0
7 O 0
. O 0
5 O 0
ml O 0
/ O 0
100 O 0
g O 0
/ O 0
min O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
) O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
PGE1 B-Chemical 1
may O 0
be O 0
preferable O 0
to O 0
TMP B-Chemical 1
for O 0
hypotensive B-Disease 1
anaesthesia O 0
in O 0
spinal O 0
surgery O 0
because O 0
TMP B-Chemical 1
decreased O 0
EBF O 0
. O 0

Dup B-Chemical 1
753 I-Chemical 1
prevents O 0
the O 0
development O 0
of O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
- O 0
induced O 0
nephrosis B-Disease 1
. O 0

The O 0
appearance O 0
of O 0
nephrotic B-Disease 1
syndromes I-Disease 1
such O 0
as O 0
proteinuria B-Disease 1
, O 0
hypoalbuminemia B-Disease 1
, O 0
hypercholesterolemia B-Disease 1
and O 0
increase O 0
in O 0
blood B-Chemical 1
nitrogen I-Chemical 1
urea I-Chemical 1
, O 0
induced O 0
in O 0
rats O 0
by O 0
injection O 0
of O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
was O 0
markedly O 0
inhibited O 0
by O 0
oral O 0
administration O 0
of O 0
Dup B-Chemical 1
753 I-Chemical 1
( O 0
losartan B-Chemical 1
) O 0
, O 0
a O 0
novel O 0
angiotensin B-Chemical 1
II I-Chemical 1
receptor O 0
antagonist O 0
, O 0
at O 0
a O 0
dose O 0
of O 0
1 O 0
or O 0
2 O 0
mg O 0
/ O 0
kg O 0
per O 0
day O 0
. O 0

The O 0
results O 0
suggest O 0
a O 0
possible O 0
involvement O 0
of O 0
the O 0
renin O 0
- O 0
angiotensin B-Chemical 1
system O 0
in O 0
the O 0
development O 0
of O 0
puromycin B-Chemical 1
aminonucleoside I-Chemical 1
- O 0
induced O 0
nephrosis B-Disease 1
. O 0

Neuroplasticity O 0
of O 0
the O 0
adult O 0
primate O 0
auditory O 0
cortex O 0
following O 0
cochlear O 0
hearing B-Disease 1
loss I-Disease 1
. O 0

Tonotopic O 0
organization O 0
is O 0
an O 0
essential O 0
feature O 0
of O 0
the O 0
primary O 0
auditory O 0
area O 0
( O 0
A1 O 0
) O 0
of O 0
primate O 0
cortex O 0
. O 0

In O 0
A1 O 0
of O 0
macaque O 0
monkeys O 0
, O 0
low O 0
frequencies O 0
are O 0
represented O 0
rostrolaterally O 0
and O 0
high O 0
frequencies O 0
are O 0
represented O 0
caudomedially O 0
. O 0

The O 0
purpose O 0
of O 0
this O 0
study O 0
was O 0
to O 0
determine O 0
if O 0
changes O 0
occur O 0
in O 0
this O 0
tonotopic O 0
organization O 0
following O 0
cochlear O 0
hearing B-Disease 1
loss I-Disease 1
. O 0

Under O 0
anesthesia O 0
, O 0
the O 0
superior O 0
temporal O 0
gyrus O 0
of O 0
adult O 0
macaque O 0
monkeys O 0
was O 0
exposed O 0
, O 0
and O 0
the O 0
tonotopic O 0
organization O 0
of O 0
A1 O 0
was O 0
mapped O 0
using O 0
conventional O 0
microelectrode O 0
recording O 0
techniques O 0
. O 0

Following O 0
recovery O 0
, O 0
the O 0
monkeys O 0
were O 0
selectively O 0
deafened O 0
for O 0
high O 0
frequencies O 0
using O 0
kanamycin B-Chemical 1
and O 0
furosemide B-Chemical 1
. O 0

The O 0
actual O 0
frequencies O 0
deafened O 0
were O 0
determined O 0
by O 0
the O 0
loss O 0
of O 0
tone O 0
- O 0
burst O 0
elicited O 0
auditory O 0
brainstem O 0
responses O 0
. O 0

Three O 0
months O 0
after O 0
deafening O 0
, O 0
A1 O 0
was O 0
remapped O 0
. O 0

Postmortem O 0
cytoarchitectural O 0
features O 0
identifying O 0
A1 O 0
were O 0
correlated O 0
with O 0
the O 0
electrophysiologic O 0
data O 0
. O 0

The O 0
results O 0
indicate O 0
that O 0
the O 0
deprived O 0
area O 0
of O 0
A1 O 0
undergoes O 0
extensive O 0
reorganization O 0
and O 0
becomes O 0
responsive O 0
to O 0
intact O 0
cochlear O 0
frequencies O 0
. O 0

The O 0
region O 0
of O 0
cortex O 0
that O 0
represents O 0
the O 0
low O 0
frequencies O 0
was O 0
not O 0
obviously O 0
affected O 0
by O 0
the O 0
cochlear O 0
hearing B-Disease 1
loss I-Disease 1
. O 0

Sodium B-Chemical 1
bicarbonate I-Chemical 1
alleviates O 0
penile B-Disease 1
pain I-Disease 1
induced O 0
by O 0
intracavernous O 0
injections O 0
for O 0
erectile B-Disease 1
dysfunction I-Disease 1
. O 0

In O 0
an O 0
attempt O 0
to O 0
determine O 0
whether O 0
penile B-Disease 1
pain I-Disease 1
associated O 0
with O 0
intracorporeal O 0
injections O 0
could O 0
be O 0
due O 0
to O 0
the O 0
acidity O 0
of O 0
the O 0
medication O 0
, O 0
we O 0
performed O 0
a O 0
randomized O 0
study O 0
comparing O 0
the O 0
incidence O 0
of O 0
penile B-Disease 1
pain I-Disease 1
following O 0
intracorporeal O 0
injections O 0
with O 0
or O 0
without O 0
the O 0
addition O 0
of O 0
sodium B-Chemical 1
bicarbonate I-Chemical 1
to O 0
the O 0
intracorporeal O 0
medications O 0
. O 0

A O 0
total O 0
of O 0
38 O 0
consecutive O 0
patients O 0
who O 0
presented O 0
to O 0
our O 0
clinic O 0
with O 0
impotence B-Disease 1
received O 0
0 O 0
. O 0
2 O 0
ml O 0
. O 0
of O 0
a O 0
combination O 0
of O 0
3 O 0
drugs O 0
: O 0
6 O 0
mg O 0
. O 0
papaverine B-Chemical 1
, O 0
100 O 0
micrograms O 0
. O 0
phentolamine B-Chemical 1
and O 0
10 O 0
micrograms O 0
. O 0
prostaglandin B-Chemical 1
E1 I-Chemical 1
with O 0
( O 0
pH O 0
7 O 0
. O 0
05 O 0
) O 0
or O 0
without O 0
( O 0
pH O 0
4 O 0
. O 0
17 O 0
) O 0
the O 0
addition O 0
of O 0
sodium B-Chemical 1
bicarbonate I-Chemical 1
( O 0
0 O 0
. O 0
03 O 0
mEq O 0
. O 0
) O 0
. O 0

Of O 0
the O 0
19 O 0
patients O 0
without O 0
sodium B-Chemical 1
bicarbonate I-Chemical 1
added O 0
to O 0
the O 0
medication O 0
11 O 0
( O 0
58 O 0
% O 0
) O 0
complained O 0
of O 0
penile B-Disease 1
pain I-Disease 1
due O 0
to O 0
the O 0
medication O 0
, O 0
while O 0
only O 0
1 O 0
of O 0
the O 0
19 O 0
men O 0
( O 0
5 O 0
% O 0
) O 0
who O 0
received O 0
sodium B-Chemical 1
bicarbonate I-Chemical 1
complained O 0
of O 0
penile B-Disease 1
pain I-Disease 1
. O 0

From O 0
these O 0
data O 0
we O 0
conclude O 0
that O 0
the O 0
penile B-Disease 1
pain I-Disease 1
following O 0
intracorporeal O 0
injections O 0
is O 0
most O 0
likely O 0
due O 0
to O 0
the O 0
acidity O 0
of O 0
the O 0
medication O 0
, O 0
which O 0
can O 0
be O 0
overcome O 0
by O 0
elevating O 0
the O 0
pH O 0
to O 0
a O 0
neutral O 0
level O 0
. O 0

The O 0
use O 0
and O 0
toxicity B-Disease 1
of O 0
didanosine B-Chemical 1
( O 0
ddI B-Chemical 1
) O 0
in O 0
HIV B-Disease 1
antibody I-Disease 1
- I-Disease 1
positive I-Disease 1
individuals O 0
intolerant O 0
to O 0
zidovudine B-Chemical 1
( O 0
AZT B-Chemical 1
) O 0

One O 0
hundred O 0
and O 0
fifty O 0
- O 0
one O 0
patients O 0
intolerant O 0
to O 0
zidovudine B-Chemical 1
( O 0
AZT B-Chemical 1
) O 0
received O 0
didanosine B-Chemical 1
( O 0
ddI B-Chemical 1
) O 0
to O 0
a O 0
maximum O 0
dose O 0
of O 0
12 O 0
. O 0
5 O 0
mg O 0
/ O 0
kg O 0
/ O 0
day O 0
. O 0

Patient O 0
response O 0
was O 0
assessed O 0
using O 0
changes O 0
in O 0
CD4 O 0
+ O 0
lymphocyte O 0
subset O 0
count O 0
, O 0
HIV O 0
p24 O 0
antigen O 0
, O 0
weight O 0
, O 0
and O 0
quality O 0
of O 0
life O 0
. O 0

Seventy O 0
patients O 0
developed O 0
major O 0
opportunistic B-Disease 1
infections I-Disease 1
whilst O 0
on O 0
therapy O 0
; O 0
this O 0
was O 0
the O 0
first O 0
AIDS B-Disease 1
diagnosis O 0
in O 0
17 O 0
. O 0

Only O 0
minor O 0
changes O 0
in O 0
CD4 O 0
+ O 0
lymphocyte O 0
subset O 0
count O 0
were O 0
observed O 0
in O 0
AIDS B-Disease 1
patients O 0
, O 0
although O 0
a O 0
more O 0
significant O 0
rise O 0
occurred O 0
in O 0
those O 0
with O 0
earlier O 0
stages O 0
of O 0
disease O 0
. O 0

Of O 0
those O 0
positive O 0
for O 0
p24 O 0
antigen O 0
at O 0
the O 0
commencement O 0
of O 0
the O 0
study O 0
67 O 0
% O 0
showed O 0
a O 0
positive O 0
response O 0
, O 0
and O 0
this O 0
was O 0
most O 0
likely O 0
in O 0
those O 0
with O 0
CD4 O 0
+ O 0
lymphocyte O 0
subset O 0
counts O 0
above O 0
100 O 0
mm3 O 0
. O 0

A O 0
positive O 0
weight O 0
response O 0
was O 0
seen O 0
in O 0
16 O 0
% O 0
of O 0
patients O 0
. O 0

Most O 0
patients O 0
showed O 0
improvement O 0
in O 0
individual O 0
parameters O 0
and O 0
global O 0
score O 0
of O 0
quality O 0
of O 0
life O 0
. O 0

Adverse O 0
reactions O 0
possibly O 0
attributable O 0
to O 0
didanosine B-Chemical 1
were O 0
common O 0
. O 0

The O 0
most O 0
common O 0
side O 0
- O 0
effect O 0
was O 0
diarrhoea B-Disease 1
, O 0
which O 0
resulted O 0
in O 0
cessation O 0
of O 0
therapy O 0
in O 0
19 O 0
individuals O 0
. O 0

Peripheral B-Disease 1
neuropathy I-Disease 1
occurred O 0
in O 0
12 O 0
patients O 0
and O 0
pancreatitis B-Disease 1
in O 0
six O 0
. O 0

Thirteen O 0
patients O 0
developed O 0
a O 0
raised O 0
serum O 0
amylase O 0
without O 0
abdominal B-Disease 1
pain I-Disease 1
. O 0

Seven O 0
patients O 0
developed O 0
glucose B-Disease 1
tolerance I-Disease 1
curves I-Disease 1
characteristic O 0
of O 0
diabetes B-Disease 1
but O 0
these O 0
were O 0
mild O 0
, O 0
did O 0
not O 0
require O 0
treatment O 0
and O 0
returned O 0
to O 0
normal O 0
on O 0
ceasing O 0
didanosine B-Chemical 1
. O 0

Immunohistochemical O 0
studies O 0
with O 0
antibodies O 0
to O 0
neurofilament O 0
proteins O 0
on O 0
axonal B-Disease 1
damage I-Disease 1
in O 0
experimental O 0
focal O 0
lesions O 0
in O 0
rat O 0
. O 0

Immunohistochemistry O 0
with O 0
monoclonal O 0
antibodies O 0
against O 0
neurofilament O 0
( O 0
NF O 0
) O 0
proteins O 0
of O 0
middle O 0
and O 0
high O 0
molecular O 0
weight O 0
class O 0
, O 0
NF O 0
- O 0
M O 0
and O 0
NF O 0
- O 0
H O 0
, O 0
was O 0
used O 0
to O 0
study O 0
axonal B-Disease 1
injury I-Disease 1
in O 0
the O 0
borderzone O 0
of O 0
focal O 0
lesions O 0
in O 0
rats O 0
. O 0

Focal O 0
injury B-Disease 1
in I-Disease 1
the I-Disease 1
cortex I-Disease 1
was O 0
produced O 0
by O 0
infusion O 0
of O 0
lactate B-Chemical 1
at O 0
acid O 0
pH O 0
or O 0
by O 0
stab O 0
caused O 0
by O 0
needle O 0
insertion O 0
. O 0

Infarcts B-Disease 1
in I-Disease 1
substantia I-Disease 1
nigra I-Disease 1
pars I-Disease 1
reticulata I-Disease 1
were O 0
evoked O 0
by O 0
prolonged O 0
pilocarpine B-Chemical 1
- O 0
induced O 0
status B-Disease 1
epilepticus I-Disease 1
. O 0

Immunohistochemical O 0
staining O 0
for O 0
NFs O 0
showed O 0
characteristic O 0
terminal O 0
clubs O 0
of O 0
axons O 0
in O 0
the O 0
borderzone O 0
of O 0
lesions O 0
. O 0

Differences O 0
in O 0
the O 0
labelling O 0
pattern O 0
occurred O 0
with O 0
different O 0
antibodies O 0
which O 0
apparently O 0
depended O 0
on O 0
molecular O 0
weight O 0
class O 0
of O 0
NFs O 0
and O 0
phosphorylation O 0
state O 0
. O 0

These O 0
immunohistochemical O 0
changes O 0
of O 0
NFs O 0
can O 0
serve O 0
as O 0
a O 0
marker O 0
for O 0
axonal B-Disease 1
damage I-Disease 1
in O 0
various O 0
experimental O 0
traumatic B-Disease 1
or O 0
ischemic O 0
lesions O 0
. O 0

Pharmacokinetic O 0
and O 0
clinical O 0
studies O 0
in O 0
patients O 0
with O 0
cimetidine B-Chemical 1
- O 0
associated O 0
mental O 0
confusion B-Disease 1
. O 0

15 O 0
cases O 0
of O 0
cimetidine B-Chemical 1
- O 0
associated O 0
mental O 0
confusion B-Disease 1
have O 0
been O 0
reported O 0
. O 0

In O 0
order O 0
that O 0
this O 0
syndrome O 0
might O 0
be O 0
investigated O 0
changes O 0
in O 0
mental O 0
status O 0
( O 0
M O 0
. O 0
S O 0
. O 0
) O 0
were O 0
correlated O 0
with O 0
serum O 0
concentrations O 0
and O 0
renal O 0
and O 0
hepatic O 0
function O 0
in O 0
36 O 0
patients O 0
, O 0
30 O 0
patients O 0
had O 0
no O 0
M O 0
. O 0
S O 0
. O 0
change O 0
on O 0
cimetidine B-Chemical 1
and O 0
6 O 0
had O 0
moderate O 0
to O 0
severe O 0
changes O 0
. O 0

These O 0
6 O 0
patients O 0
had O 0
both O 0
renal B-Disease 1
and I-Disease 1
liver I-Disease 1
dysfunction I-Disease 1
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
, O 0
as O 0
well O 0
as O 0
cimetidine B-Chemical 1
trough O 0
- O 0
concentrations O 0
of O 0
more O 0
than O 0
1 O 0
. O 0
25 O 0
microgram O 0
/ O 0
ml O 0
( O 0
P O 0
less O 0
than O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

The O 0
severity O 0
of O 0
M O 0
. O 0
S O 0
. O 0
changes O 0
increased O 0
as O 0
trough O 0
- O 0
concentrations O 0
rose O 0
, O 0
5 O 0
patients O 0
had O 0
lumbar O 0
puncture O 0
. O 0

The O 0
cerebrospinal O 0
fluid O 0
: O 0
serum O 0
ratio O 0
of O 0
cimetidine B-Chemical 1
concentrations O 0
was O 0
0 O 0
. O 0
24 O 0
: O 0
1 O 0
and O 0
indicates O 0
that O 0
cimetidine B-Chemical 1
passes O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
; O 0
it O 0
also O 0
raises O 0
the O 0
possibility O 0
that O 0
M O 0
. O 0
S O 0
. O 0
changes O 0
are O 0
due O 0
to O 0
blockade O 0
of O 0
histamine B-Chemical 1
H2 O 0
- O 0
receptors O 0
in O 0
the O 0
central O 0
nervous O 0
system O 0
. O 0

Patients O 0
likely O 0
to O 0
have O 0
both O 0
raised O 0
trough O 0
- O 0
concentrations O 0
and O 0
mental O 0
confusion B-Disease 1
are O 0
those O 0
with O 0
both O 0
severe O 0
renal B-Disease 1
and I-Disease 1
hepatic I-Disease 1
dysfunction I-Disease 1
. O 0

They O 0
should O 0
be O 0
closely O 0
observed O 0
and O 0
should O 0
be O 0
given O 0
reduced O 0
doses O 0
of O 0
cimetidine B-Chemical 1
. O 0

Prospective O 0
study O 0
of O 0
the O 0
long O 0
- O 0
term O 0
effects O 0
of O 0
somatostatin O 0
analog O 0
( O 0
octreotide B-Chemical 1
) O 0
on O 0
gallbladder O 0
function O 0
and O 0
gallstone B-Disease 1
formation O 0
in O 0
Chinese O 0
acromegalic B-Disease 1
patients O 0
. O 0

This O 0
article O 0
reports O 0
the O 0
changes O 0
in O 0
gallbladder O 0
function O 0
examined O 0
by O 0
ultrasonography O 0
in O 0
20 O 0
Chinese O 0
patients O 0
with O 0
active O 0
acromegaly B-Disease 1
treated O 0
with O 0
sc O 0
injection O 0
of O 0
the O 0
somatostatin O 0
analog O 0
octreotide B-Chemical 1
in O 0
dosages O 0
of O 0
300 O 0
- O 0
1500 O 0
micrograms O 0
/ O 0
day O 0
for O 0
a O 0
mean O 0
of O 0
24 O 0
. O 0
2 O 0
+ O 0
/ O 0
- O 0
13 O 0
. O 0
9 O 0
months O 0
. O 0

During O 0
treatment O 0
with O 0
octreotide B-Chemical 1
, O 0
17 O 0
patients O 0
developed O 0
sludge O 0
, O 0
10 O 0
had O 0
gallstones B-Disease 1
, O 0
and O 0
1 O 0
developed O 0
acute B-Disease 1
cholecystitis I-Disease 1
requiring O 0
surgery O 0
. O 0

In O 0
all O 0
of O 0
7 O 0
patients O 0
examined O 0
acutely O 0
, O 0
gallbladder O 0
contractility O 0
was O 0
inhibited O 0
after O 0
a O 0
single O 0
100 O 0
- O 0
micrograms O 0
injection O 0
. O 0

In O 0
8 O 0
patients O 0
followed O 0
for O 0
24 O 0
weeks O 0
, O 0
gallbladder O 0
contractility O 0
remained O 0
depressed B-Disease 1
throughout O 0
therapy O 0
. O 0

After O 0
withdrawal O 0
of O 0
octreotide B-Chemical 1
in O 0
10 O 0
patients O 0
without O 0
gallstones B-Disease 1
, O 0
8 O 0
patients O 0
assessed O 0
had O 0
return O 0
of O 0
normal O 0
gallbladder O 0
contractility O 0
within O 0
1 O 0
month O 0
. O 0

In O 0
8 O 0
of O 0
the O 0
remaining O 0
10 O 0
patients O 0
who O 0
developed O 0
gallstones B-Disease 1
during O 0
treatment O 0
, O 0
gallbladder O 0
contractility O 0
normalized O 0
in O 0
5 O 0
patients O 0
( O 0
3 O 0
of O 0
whom O 0
has O 0
disappearance O 0
of O 0
their O 0
stones O 0
within O 0
3 O 0
weeks O 0
) O 0
, O 0
and O 0
remained O 0
depressed B-Disease 1
in O 0
3 O 0
( O 0
2 O 0
of O 0
whom O 0
had O 0
stones O 0
present O 0
at O 0
6 O 0
months O 0
) O 0
. O 0

Our O 0
results O 0
suggest O 0
that O 0
the O 0
suppression O 0
of O 0
gallbladder O 0
contractility O 0
is O 0
the O 0
cause O 0
of O 0
the O 0
successive O 0
formation O 0
of O 0
bile O 0
sludge O 0
, O 0
gallstones B-Disease 1
, O 0
and O 0
cholecystitis B-Disease 1
during O 0
octreotide B-Chemical 1
therapy O 0
in O 0
Chinese O 0
acromegalic B-Disease 1
patients O 0
. O 0

It O 0
is O 0
therefore O 0
very O 0
important O 0
to O 0
follow O 0
the O 0
changes O 0
of O 0
gallbladder O 0
function O 0
during O 0
long O 0
- O 0
term O 0
octreotide B-Chemical 1
therapy O 0
of O 0
acromegalic B-Disease 1
patients O 0
. O 0

Increase O 0
of O 0
Parkinson B-Disease 1
disability I-Disease 1
after O 0
fluoxetine B-Chemical 1
medication O 0
. O 0

Depression B-Disease 1
is O 0
a O 0
major O 0
clinical O 0
feature O 0
of O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

We O 0
report O 0
the O 0
increased O 0
amount O 0
of O 0
motor B-Disease 1
disability I-Disease 1
in O 0
four O 0
patients O 0
with O 0
idiopathic B-Disease 1
Parkinson I-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
after O 0
exposure O 0
to O 0
the O 0
antidepressant B-Chemical 1
fluoxetine B-Chemical 1
. O 0

The O 0
possibility O 0
of O 0
a O 0
clinically O 0
relevant O 0
dopamine B-Chemical 1
- O 0
antagonistic O 0
capacity O 0
of O 0
fluoxetine B-Chemical 1
in O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
patients O 0
must O 0
be O 0
considered O 0
. O 0

Sinus B-Disease 1
arrest I-Disease 1
associated O 0
with O 0
continuous O 0
- O 0
infusion O 0
cimetidine B-Chemical 1
. O 0

The O 0
administration O 0
of O 0
intermittent O 0
intravenous O 0
infusions O 0
of O 0
cimetidine B-Chemical 1
is O 0
infrequently O 0
associated O 0
with O 0
the O 0
development O 0
of O 0
bradyarrhythmias B-Disease 1
. O 0

A O 0
40 O 0
- O 0
year O 0
- O 0
old O 0
man O 0
with O 0
leukemia B-Disease 1
and O 0
no O 0
history O 0
of O 0
cardiac B-Disease 1
disease I-Disease 1
developed O 0
recurrent O 0
, O 0
brief O 0
episodes O 0
of O 0
apparent O 0
sinus B-Disease 1
arrest I-Disease 1
while O 0
receiving O 0
continuous O 0
- O 0
infusion O 0
cimetidine B-Chemical 1
50 O 0
mg O 0
/ O 0
hour O 0
. O 0

The O 0
arrhythmias B-Disease 1
were O 0
temporally O 0
related O 0
to O 0
cimetidine B-Chemical 1
administration O 0
, O 0
disappeared O 0
after O 0
dechallenge O 0
, O 0
and O 0
did O 0
not O 0
recur O 0
during O 0
ranitidine B-Chemical 1
treatment O 0
. O 0

This O 0
is O 0
the O 0
first O 0
reported O 0
case O 0
of O 0
sinus B-Disease 1
arrest I-Disease 1
associated O 0
with O 0
continuous O 0
- O 0
infusion O 0
cimetidine B-Chemical 1
. O 0

Phase O 0
II O 0
trial O 0
of O 0
vinorelbine B-Chemical 1
in O 0
metastatic O 0
squamous B-Disease 1
cell I-Disease 1
esophageal I-Disease 1
carcinoma I-Disease 1
. O 0

European O 0
Organization O 0
for O 0
Research O 0
and O 0
Treatment O 0
of O 0
Cancer B-Disease 1
Gastrointestinal O 0
Treat O 0
Cancer B-Disease 1
Cooperative O 0
Group O 0
. O 0

PURPOSE O 0
: O 0
To O 0
evaluate O 0
the O 0
response O 0
rate O 0
and O 0
toxic O 0
effects O 0
of O 0
vinorelbine B-Chemical 1
( O 0
VNB B-Chemical 1
) O 0
administered O 0
as O 0
a O 0
single O 0
agent O 0
in O 0
metastatic O 0
squamous B-Disease 1
cell I-Disease 1
esophageal I-Disease 1
carcinoma I-Disease 1
. O 0

PATIENTS O 0
AND O 0
METHODS O 0
: O 0
Forty O 0
- O 0
six O 0
eligible O 0
patients O 0
with O 0
measurable O 0
lesions O 0
were O 0
included O 0
and O 0
were O 0
stratified O 0
according O 0
to O 0
previous O 0
chemotherapy O 0
. O 0

Thirty O 0
patients O 0
without O 0
prior O 0
chemotherapy O 0
and O 0
16 O 0
pretreated O 0
with O 0
cisplatin B-Chemical 1
- O 0
based O 0
chemotherapy O 0
were O 0
assessable O 0
for O 0
toxicity B-Disease 1
and O 0
response O 0
. O 0

VNB B-Chemical 1
was O 0
administered O 0
weekly O 0
as O 0
a O 0
25 O 0
- O 0
mg O 0
/ O 0
m2 O 0
short O 0
intravenous O 0
( O 0
i O 0
. O 0
v O 0
. O 0
) O 0
infusion O 0
. O 0

RESULTS O 0
: O 0
Six O 0
of O 0
30 O 0
patients O 0
( O 0
20 O 0
% O 0
) O 0
without O 0
prior O 0
chemotherapy O 0
achieved O 0
a O 0
partial O 0
response O 0
( O 0
PR O 0
) O 0
( O 0
95 O 0
% O 0
confidence O 0
interval O 0
[ O 0
CI O 0
] O 0
, O 0
8 O 0
% O 0
to O 0
39 O 0
% O 0
) O 0
. O 0

The O 0
median O 0
duration O 0
of O 0
response O 0
was O 0
21 O 0
weeks O 0
( O 0
range O 0
, O 0
17 O 0
to O 0
28 O 0
) O 0
. O 0

One O 0
of O 0
16 O 0
patients O 0
( O 0
6 O 0
% O 0
) O 0
with O 0
prior O 0
chemotherapy O 0
had O 0
a O 0
complete O 0
response O 0
( O 0
CR O 0
) O 0
of O 0
31 O 0
weeks O 0
' O 0
duration O 0
( O 0
95 O 0
% O 0
CI O 0
, O 0
0 O 0
% O 0
to O 0
30 O 0
% O 0
) O 0
. O 0

The O 0
overall O 0
response O 0
rate O 0
( O 0
World O 0
Health O 0
Organization O 0
[ O 0
WHO O 0
] O 0
criteria O 0
) O 0
was O 0
15 O 0
% O 0
( O 0
CR O 0
, O 0
2 O 0
% O 0
; O 0
PR O 0
13 O 0
% O 0
; O 0
95 O 0
% O 0
CI O 0
, O 0
6 O 0
% O 0
to O 0
29 O 0
% O 0
) O 0
. O 0

The O 0
median O 0
dose O 0
- O 0
intensity O 0
( O 0
DI O 0
) O 0
was O 0
20 O 0
mg O 0
/ O 0
m2 O 0
/ O 0
wk O 0
. O 0

VNB B-Chemical 1
was O 0
well O 0
tolerated O 0
and O 0
zero O 0
instances O 0
of O 0
WHO O 0
grade O 0
4 O 0
nonhematologic O 0
toxicity B-Disease 1
occurred O 0
. O 0

At O 0
least O 0
one O 0
episode O 0
of O 0
grade O 0
3 O 0
or O 0
4 O 0
granulocytopenia B-Disease 1
was O 0
seen O 0
in O 0
59 O 0
% O 0
of O 0
patients O 0
. O 0

A O 0
grade O 0
2 O 0
or O 0
3 O 0
infection B-Disease 1
occurred O 0
in O 0
16 O 0
% O 0
of O 0
patients O 0
, O 0
but O 0
no O 0
toxic O 0
deaths B-Disease 1
occurred O 0
. O 0

Other O 0
side O 0
effects O 0
were O 0
rare O 0
, O 0
and O 0
peripheral B-Disease 1
neurotoxicity I-Disease 1
has O 0
been O 0
minor O 0
( O 0
26 O 0
% O 0
grade O 0
1 O 0
) O 0
. O 0

CONCLUSION O 0
: O 0
These O 0
data O 0
indicate O 0
that O 0
VNB B-Chemical 1
is O 0
an O 0
active O 0
agent O 0
in O 0
metastatic O 0
esophageal B-Disease 1
squamous I-Disease 1
cell I-Disease 1
carcinoma I-Disease 1
. O 0

Given O 0
its O 0
excellent O 0
tolerance O 0
profile O 0
and O 0
low O 0
toxicity B-Disease 1
, O 0
further O 0
evaluation O 0
of O 0
VNB B-Chemical 1
in O 0
combination O 0
therapy O 0
is O 0
warranted O 0
. O 0

Evaluation O 0
of O 0
adverse O 0
reactions O 0
of O 0
aponidine B-Chemical 1
hydrochloride I-Chemical 1
ophthalmic O 0
solution O 0
. O 0

We O 0
prospectively O 0
evaluated O 0
the O 0
adverse O 0
reactions O 0
of O 0
apraclonidine B-Chemical 1
in O 0
20 O 0
normal O 0
volunteers O 0
by O 0
instilling O 0
a O 0
single O 0
drop O 0
of O 0
1 O 0
% O 0
apraclonidine B-Chemical 1
in O 0
their O 0
right O 0
eyes O 0
. O 0

Examinations O 0
, O 0
including O 0
blood O 0
pressure O 0
, O 0
pulse O 0
rate O 0
, O 0
conjunctiva O 0
and O 0
cornea O 0
, O 0
intraocular O 0
pressure O 0
( O 0
IOP O 0
) O 0
, O 0
pupil O 0
diameter O 0
, O 0
basal O 0
tear O 0
secretion O 0
and O 0
margin O 0
reflex O 0
distance O 0
of O 0
both O 0
upper O 0
and O 0
lower O 0
eyelids O 0
, O 0
were O 0
performed O 0
prior O 0
to O 0
entry O 0
and O 0
at O 0
1 O 0
, O 0
3 O 0
, O 0
5 O 0
and O 0
7 O 0
hours O 0
after O 0
instillation O 0
. O 0

The O 0
ocular B-Disease 1
hypotensive I-Disease 1
effects O 0
were O 0
statistically O 0
significant O 0
for O 0
apraclonidine B-Chemical 1
- O 0
treated O 0
eyes O 0
throughout O 0
the O 0
study O 0
and O 0
also O 0
statistically O 0
significant O 0
for O 0
contralateral O 0
eyes O 0
from O 0
three O 0
hours O 0
after O 0
topical O 0
administration O 0
of O 0
1 O 0
% O 0
apraclonidine B-Chemical 1
. O 0

Decreases B-Disease 1
in I-Disease 1
systolic I-Disease 1
blood I-Disease 1
pressure I-Disease 1
were O 0
statistically O 0
, O 0
but O 0
not O 0
clinically O 0
, O 0
significant O 0
. O 0

No O 0
significant O 0
changes O 0
in O 0
diastolic O 0
blood O 0
pressure O 0
, O 0
pulse O 0
rate O 0
and O 0
basal O 0
tear O 0
secretion O 0
were O 0
noted O 0
. O 0

Conjunctival B-Disease 1
blanching I-Disease 1
and O 0
mydriasis B-Disease 1
were O 0
commonly O 0
found O 0
. O 0

Upper O 0
lid O 0
retraction O 0
was O 0
frequently O 0
noted O 0
. O 0

While O 0
the O 0
elevations O 0
of O 0
the O 0
upper O 0
lid O 0
margin O 0
in O 0
most O 0
subjects O 0
were O 0
not O 0
more O 0
than O 0
2 O 0
mm O 0
and O 0
did O 0
not O 0
cause O 0
noticeable O 0
change O 0
in O 0
appearance O 0
, O 0
one O 0
subject O 0
suffered O 0
from O 0
mechanical O 0
entropion B-Disease 1
and O 0
marked O 0
corneal B-Disease 1
abrasion I-Disease 1
3 O 0
hours O 0
after O 0
instillation O 0
of O 0
the O 0
medication O 0
. O 0

This O 0
may O 0
well O 0
be O 0
a O 0
particularly O 0
notable O 0
finding O 0
in O 0
Asian O 0
people O 0
. O 0

Thiopentone B-Chemical 1
pretreatment O 0
for O 0
propofol B-Chemical 1
injection O 0
pain B-Disease 1
in O 0
ambulatory O 0
patients O 0
. O 0

This O 0
study O 0
investigated O 0
propofol B-Chemical 1
injection O 0
pain B-Disease 1
in O 0
patients O 0
undergoing O 0
ambulatory O 0
anaesthesia O 0
. O 0

In O 0
a O 0
randomized O 0
, O 0
double O 0
- O 0
blind O 0
trial O 0
, O 0
90 O 0
women O 0
were O 0
allocated O 0
to O 0
receive O 0
one O 0
of O 0
three O 0
treatments O 0
prior O 0
to O 0
induction O 0
of O 0
anaesthesia O 0
with O 0
propofol B-Chemical 1
. O 0

Patients O 0
in O 0
Group O 0
C O 0
received O 0
2 O 0
ml O 0
normal O 0
saline O 0
, O 0
Group O 0
L O 0
, O 0
2 O 0
ml O 0
, O 0
lidocaine B-Chemical 1
2 O 0
% O 0
( O 0
40 O 0
mg O 0
) O 0
and O 0
Group O 0
T O 0
, O 0
2 O 0
ml O 0
thiopentone B-Chemical 1
2 O 0
. O 0
5 O 0
% O 0
( O 0
50 O 0
mg O 0
) O 0
. O 0

Venous O 0
discomfort O 0
was O 0
assessed O 0
with O 0
a O 0
visual O 0
analogue O 0
scale O 0
( O 0
VAS O 0
) O 0
5 O 0
- O 0
15 O 0
sec O 0
after O 0
commencing O 0
propofol B-Chemical 1
administration O 0
using O 0
an O 0
infusion O 0
pump O 0
( O 0
rate O 0
1000 O 0
micrograms O 0
. O 0
kg O 0
- O 0
1 O 0
. O 0
min O 0
- O 0
1 O 0
) O 0
. O 0

Loss B-Disease 1
of I-Disease 1
consciousness I-Disease 1
occurred O 0
in O 0
60 O 0
- O 0
90 O 0
sec O 0
. O 0

Visual O 0
analogue O 0
scores O 0
( O 0
mean O 0
+ O 0
/ O 0
- O 0
SD O 0
) O 0
during O 0
induction O 0
were O 0
lower O 0
in O 0
Groups O 0
L O 0
( O 0
3 O 0
. O 0
3 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
5 O 0
) O 0
and O 0
T O 0
( O 0
4 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
7 O 0
) O 0
than O 0
in O 0
Group O 0
C O 0
( O 0
5 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
2 O 0
. O 0
3 O 0
) O 0
; O 0
P O 0
= O 0
0 O 0
. O 0
0031 O 0
. O 0

The O 0
incidence O 0
of O 0
venous O 0
discomfort O 0
was O 0
lower O 0
in O 0
Group O 0
L O 0
( O 0
76 O 0
. O 0
6 O 0
% O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
than O 0
in O 0
Group O 0
C O 0
( O 0
100 O 0
% O 0
) O 0
but O 0
not O 0
different O 0
from O 0
Group O 0
T O 0
( O 0
90 O 0
% O 0
) O 0
. O 0

The O 0
VAS O 0
scores O 0
for O 0
recall O 0
of O 0
pain B-Disease 1
in O 0
the O 0
recovery O 0
room O 0
were O 0
correlated O 0
with O 0
the O 0
VAS O 0
scores O 0
during O 0
induction O 0
( O 0
r O 0
= O 0
0 O 0
. O 0
7045 O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
0001 O 0
) O 0
. O 0

Recovery O 0
room O 0
discharge O 0
times O 0
were O 0
similar O 0
: O 0
C O 0
( O 0
75 O 0
. O 0
9 O 0
+ O 0
/ O 0
- O 0
19 O 0
. O 0
4 O 0
min O 0
) O 0
; O 0
L O 0
73 O 0
. O 0
6 O 0
+ O 0
/ O 0
- O 0
21 O 0
. O 0
6 O 0
min O 0
) O 0
; O 0
T O 0
( O 0
77 O 0
. O 0
1 O 0
+ O 0
/ O 0
- O 0
18 O 0
. O 0
9 O 0
min O 0
) O 0
. O 0

Assessing O 0
their O 0
overall O 0
satisfaction O 0
, O 0
89 O 0
. O 0
7 O 0
% O 0
would O 0
choose O 0
propofol B-Chemical 1
anaesthesia O 0
again O 0
. O 0

We O 0
conclude O 0
that O 0
lidocaine B-Chemical 1
reduces O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
propofol B-Chemical 1
injection O 0
pain B-Disease 1
in O 0
ambulatory O 0
patients O 0
whereas O 0
thiopentone B-Chemical 1
only O 0
reduces O 0
its O 0
severity O 0
. O 0

Persistent O 0
paralysis B-Disease 1
after O 0
prolonged O 0
use O 0
of O 0
atracurium B-Chemical 1
in O 0
the O 0
absence O 0
of O 0
corticosteroids O 0
. O 0

Neuromuscular O 0
blocking O 0
agents O 0
( O 0
NMBAs O 0
) O 0
are O 0
often O 0
used O 0
for O 0
patients O 0
requiring O 0
prolonged O 0
mechanical O 0
ventilation O 0
. O 0

Reports O 0
of O 0
persistent O 0
paralysis B-Disease 1
after O 0
the O 0
discontinuance O 0
of O 0
these O 0
drugs O 0
have O 0
most O 0
often O 0
involved O 0
aminosteroid O 0
- O 0
based O 0
NMBAs O 0
such O 0
as O 0
vecuronium B-Chemical 1
bromide I-Chemical 1
, O 0
especially O 0
when O 0
used O 0
in O 0
conjunction O 0
with O 0
corticosteroids O 0
. O 0

Atracurium B-Chemical 1
besylate I-Chemical 1
, O 0
a O 0
short O 0
- O 0
acting O 0
benzylisoquinolinium B-Chemical 1
NMBA O 0
that O 0
is O 0
eliminated O 0
independently O 0
of O 0
renal O 0
or O 0
hepatic O 0
function O 0
, O 0
has O 0
also O 0
been O 0
associated O 0
with O 0
persistent O 0
paralysis B-Disease 1
, O 0
but O 0
only O 0
when O 0
used O 0
with O 0
corticosteroids O 0
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
atracurium B-Chemical 1
- O 0
related O 0
paralysis B-Disease 1
persisting O 0
for O 0
approximately O 0
50 O 0
hours O 0
in O 0
a O 0
patient O 0
who O 0
was O 0
not O 0
treated O 0
with O 0
corticosteroids O 0
. O 0

A O 0
phase O 0
I O 0
/ O 0
II O 0
study O 0
of O 0
paclitaxel B-Chemical 1
plus O 0
cisplatin B-Chemical 1
as O 0
first O 0
- O 0
line O 0
therapy O 0
for O 0
head B-Disease 1
and I-Disease 1
neck I-Disease 1
cancers I-Disease 1
: O 0
preliminary O 0
results O 0
. O 0

Improved O 0
outcomes O 0
among O 0
patients O 0
with O 0
head B-Disease 1
and I-Disease 1
neck I-Disease 1
carcinomas I-Disease 1
require O 0
investigations O 0
of O 0
new O 0
drugs O 0
for O 0
induction O 0
therapy O 0
. O 0

Preliminary O 0
results O 0
of O 0
an O 0
Eastern O 0
Cooperative O 0
Oncology O 0
Group O 0
study O 0
of O 0
single O 0
- O 0
agent O 0
paclitaxel B-Chemical 1
( O 0
Taxol B-Chemical 1
; O 0
Bristol O 0
- O 0
Myers O 0
Squibb O 0
Company O 0
, O 0
Princeton O 0
, O 0
NJ O 0
) O 0
reported O 0
a O 0
37 O 0
% O 0
response O 0
rate O 0
in O 0
patients O 0
with O 0
head B-Disease 1
and I-Disease 1
neck I-Disease 1
cancer I-Disease 1
, O 0
and O 0
the O 0
paclitaxel B-Chemical 1
/ O 0
cisplatin B-Chemical 1
combination O 0
has O 0
been O 0
used O 0
successfully O 0
and O 0
has O 0
significantly O 0
improved O 0
median O 0
response O 0
duration O 0
in O 0
ovarian B-Disease 1
cancer I-Disease 1
patients O 0
. O 0

We O 0
initiated O 0
a O 0
phase O 0
I O 0
/ O 0
II O 0
trial O 0
to O 0
determine O 0
the O 0
response O 0
and O 0
toxicity B-Disease 1
of O 0
escalating O 0
paclitaxel B-Chemical 1
doses O 0
combined O 0
with O 0
fixed O 0
- O 0
dose O 0
cisplatin B-Chemical 1
with O 0
granulocyte O 0
colony O 0
- O 0
stimulating O 0
factor O 0
support O 0
in O 0
patients O 0
with O 0
untreated O 0
locally O 0
advanced O 0
inoperable O 0
head B-Disease 1
and I-Disease 1
neck I-Disease 1
carcinoma I-Disease 1
. O 0

To O 0
date O 0
, O 0
23 O 0
men O 0
with O 0
a O 0
median O 0
age O 0
of O 0
50 O 0
years O 0
and O 0
good O 0
performance O 0
status O 0
have O 0
entered O 0
the O 0
trial O 0
. O 0

Primary O 0
tumor B-Disease 1
sites O 0
were O 0
oropharynx O 0
, O 0
10 O 0
patients O 0
; O 0
hypopharynx O 0
, O 0
four O 0
; O 0
larynx O 0
, O 0
two O 0
; O 0
oral O 0
cavity O 0
, O 0
three O 0
; O 0
unknown O 0
primary O 0
, O 0
two O 0
; O 0
and O 0
nasal O 0
cavity O 0
and O 0
parotid O 0
gland O 0
, O 0
one O 0
each O 0
. O 0

Of O 0
20 O 0
patients O 0
evaluable O 0
for O 0
toxicity B-Disease 1
, O 0
four O 0
had O 0
stage O 0
III O 0
and O 0
16 O 0
had O 0
stage O 0
IV O 0
disease O 0
. O 0

Treatment O 0
, O 0
given O 0
every O 0
21 O 0
days O 0
for O 0
a O 0
maximum O 0
of O 0
three O 0
cycles O 0
, O 0
consisted O 0
of O 0
paclitaxel B-Chemical 1
by O 0
3 O 0
- O 0
hour O 0
infusion O 0
followed O 0
the O 0
next O 0
day O 0
by O 0
a O 0
fixed O 0
dose O 0
of O 0
cisplatin B-Chemical 1
( O 0
75 O 0
mg O 0
/ O 0
m2 O 0
) O 0
. O 0

The O 0
dose O 0
levels O 0
incorporate O 0
escalating O 0
paclitaxel B-Chemical 1
doses O 0
, O 0
and O 0
intrapatient O 0
escalations O 0
within O 0
a O 0
given O 0
dose O 0
level O 0
are O 0
permitted O 0
if O 0
toxicity B-Disease 1
permits O 0
. O 0

At O 0
the O 0
time O 0
of O 0
this O 0
writing O 0
, O 0
dose O 0
level O 0
4 O 0
( O 0
260 O 0
, O 0
270 O 0
, O 0
and O 0
280 O 0
mg O 0
/ O 0
m2 O 0
) O 0
is O 0
being O 0
evaluated O 0
; O 0
three O 0
patients O 0
from O 0
this O 0
level O 0
are O 0
evaluable O 0
. O 0

With O 0
paclitaxel B-Chemical 1
doses O 0
of O 0
200 O 0
mg O 0
/ O 0
m2 O 0
and O 0
higher O 0
, O 0
granulocyte O 0
colony O 0
- O 0
stimulating O 0
factor O 0
5 O 0
micrograms O 0
/ O 0
kg O 0
/ O 0
d O 0
is O 0
given O 0
( O 0
days O 0
4 O 0
through O 0
12 O 0
) O 0
. O 0

Of O 0
18 O 0
patients O 0
evaluable O 0
for O 0
response O 0
, O 0
seven O 0
( O 0
39 O 0
% O 0
) O 0
achieved O 0
a O 0
complete O 0
response O 0
and O 0
six O 0
( O 0
33 O 0
% O 0
) O 0
achieved O 0
a O 0
partial O 0
response O 0
. O 0

Three O 0
patients O 0
had O 0
no O 0
change O 0
and O 0
disease O 0
progressed O 0
in O 0
two O 0
. O 0

The O 0
overall O 0
response O 0
rate O 0
is O 0
72 O 0
% O 0
. O 0

Eleven O 0
responding O 0
patients O 0
had O 0
subsequent O 0
surgery O 0
/ O 0
radiotherapy O 0
or O 0
radical O 0
radiotherapy O 0
. O 0

Two O 0
pathologic O 0
complete O 0
responses O 0
were O 0
observed O 0
in O 0
patients O 0
who O 0
had O 0
achieved O 0
clinical O 0
complete O 0
responses O 0
. O 0

Alopecia B-Disease 1
, O 0
paresthesias B-Disease 1
, O 0
and O 0
arthralgias B-Disease 1
/ O 0
myalgias B-Disease 1
have O 0
occurred O 0
frequently O 0
, O 0
but O 0
with O 0
one O 0
exception O 0
( O 0
a O 0
grade O 0
3 O 0
myalgia B-Disease 1
) O 0
they O 0
have O 0
been O 0
grade O 0
1 O 0
or O 0
2 O 0
. O 0

No O 0
dose O 0
- O 0
limiting O 0
hematologic O 0
toxicity B-Disease 1
has O 0
been O 0
seen O 0
. O 0

Paclitaxel B-Chemical 1
/ O 0
cisplatin B-Chemical 1
is O 0
an O 0
effective O 0
first O 0
- O 0
line O 0
regimen O 0
for O 0
locoregionally O 0
advanced O 0
head B-Disease 1
and I-Disease 1
neck I-Disease 1
cancer I-Disease 1
and O 0
continued O 0
study O 0
is O 0
warranted O 0
. O 0

Results O 0
thus O 0
far O 0
suggest O 0
no O 0
dose O 0
- O 0
response O 0
effect O 0
for O 0
paclitaxel B-Chemical 1
doses O 0
above O 0
200 O 0
mg O 0
/ O 0
m2 O 0
. O 0

Improvement O 0
of O 0
levodopa B-Chemical 1
- O 0
induced O 0
dyskinesia B-Disease 1
by O 0
propranolol B-Chemical 1
in O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

Seven O 0
patients O 0
suffering O 0
from O 0
Parkinson B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
( O 0
PD B-Disease 1
) O 0
with O 0
severely O 0
disabling O 0
dyskinesia B-Disease 1
received O 0
low O 0
- O 0
dose O 0
propranolol B-Chemical 1
as O 0
an O 0
adjunct O 0
to O 0
the O 0
currently O 0
used O 0
medical O 0
treatment O 0
. O 0

There O 0
was O 0
a O 0
significant O 0
40 O 0
% O 0
improvement O 0
in O 0
the O 0
dyskinesia B-Disease 1
score O 0
without O 0
increase O 0
of O 0
parkinsonian B-Disease 1
motor B-Disease 1
disability I-Disease 1
. O 0

Ballistic O 0
and O 0
choreic O 0
dyskinesia B-Disease 1
were O 0
markedly O 0
ameliorated O 0
, O 0
whereas O 0
dystonia B-Disease 1
was O 0
not O 0
. O 0

This O 0
study O 0
suggests O 0
that O 0
administration O 0
of O 0
low O 0
doses O 0
of O 0
beta O 0
- O 0
blockers O 0
may O 0
improve O 0
levodopa B-Chemical 1
- O 0
induced O 0
ballistic O 0
and O 0
choreic O 0
dyskinesia B-Disease 1
in O 0
PD B-Disease 1
. O 0

Habitual O 0
use O 0
of O 0
acetaminophen B-Chemical 1
as O 0
a O 0
risk O 0
factor O 0
for O 0
chronic B-Disease 1
renal I-Disease 1
failure I-Disease 1
: O 0
a O 0
comparison O 0
with O 0
phenacetin B-Chemical 1
. O 0

Six O 0
epidemiologic O 0
studies O 0
in O 0
the O 0
United O 0
States O 0
and O 0
Europe O 0
indicate O 0
that O 0
habitual O 0
use O 0
of O 0
phenacetin B-Chemical 1
is O 0
associated O 0
with O 0
the O 0
development O 0
of O 0
chronic B-Disease 1
renal I-Disease 1
failure I-Disease 1
and O 0
end B-Disease 1
- I-Disease 1
stage I-Disease 1
renal I-Disease 1
disease I-Disease 1
( O 0
ESRD B-Disease 1
) O 0
, O 0
with O 0
a O 0
relative O 0
risk O 0
in O 0
the O 0
range O 0
of O 0
4 O 0
to O 0
19 O 0
. O 0

As O 0
a O 0
result O 0
of O 0
these O 0
and O 0
other O 0
studies O 0
, O 0
phenacetin B-Chemical 1
has O 0
now O 0
been O 0
withdrawn O 0
from O 0
the O 0
market O 0
in O 0
most O 0
countries O 0
. O 0

However O 0
, O 0
three O 0
case O 0
control O 0
studies O 0
, O 0
one O 0
each O 0
in O 0
North O 0
Carolina O 0
, O 0
northern O 0
Maryland O 0
, O 0
and O 0
West O 0
Berlin O 0
, O 0
Germany O 0
, O 0
showed O 0
that O 0
habitual O 0
use O 0
of O 0
acetaminophen B-Chemical 1
is O 0
also O 0
associated O 0
with O 0
chronic B-Disease 1
renal I-Disease 1
failure I-Disease 1
and O 0
ESRD B-Disease 1
, O 0
with O 0
a O 0
relative O 0
risk O 0
in O 0
the O 0
range O 0
of O 0
2 O 0
to O 0
4 O 0
. O 0

These O 0
studies O 0
suggest O 0
that O 0
both O 0
phenacetin B-Chemical 1
and O 0
acetaminophen B-Chemical 1
may O 0
contribute O 0
to O 0
the O 0
burden O 0
of O 0
ESRD B-Disease 1
, O 0
with O 0
the O 0
risk O 0
of O 0
the O 0
latter O 0
being O 0
somewhat O 0
less O 0
than O 0
that O 0
of O 0
the O 0
former O 0
. O 0

This O 0
apparent O 0
difference O 0
in O 0
risk O 0
may O 0
not O 0
be O 0
due O 0
to O 0
differences O 0
in O 0
nephrotoxic B-Disease 1
potential O 0
of O 0
the O 0
drugs O 0
themselves O 0
. O 0

A O 0
lower O 0
relative O 0
risk O 0
would O 0
be O 0
expected O 0
for O 0
acetaminophen B-Chemical 1
if O 0
the O 0
risk O 0
of O 0
both O 0
drugs O 0
in O 0
combination O 0
with O 0
other O 0
analgesics O 0
was O 0
higher O 0
than O 0
the O 0
risk O 0
of O 0
either O 0
agent O 0
alone O 0
. O 0

Thus O 0
, O 0
acetaminophen B-Chemical 1
has O 0
been O 0
used O 0
both O 0
as O 0
a O 0
single O 0
agent O 0
and O 0
in O 0
combination O 0
with O 0
other O 0
analgesics O 0
, O 0
whereas O 0
phenacetin B-Chemical 1
was O 0
available O 0
only O 0
in O 0
combinations O 0
. O 0

The O 0
possibility O 0
that O 0
habitual O 0
use O 0
of O 0
acetaminophen B-Chemical 1
alone O 0
increases O 0
the O 0
risk O 0
of O 0
ESRD B-Disease 1
has O 0
not O 0
been O 0
clearly O 0
demonstrated O 0
, O 0
but O 0
cannot O 0
be O 0
dismissed O 0
. O 0

Acetaminophen B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
. O 0

Through O 0
30 O 0
years O 0
of O 0
widespread O 0
use O 0
, O 0
acetaminophen B-Chemical 1
has O 0
been O 0
shown O 0
to O 0
be O 0
a O 0
remarkably O 0
safe O 0
medication O 0
in O 0
therapeutic O 0
dosages O 0
. O 0

The O 0
potential O 0
for O 0
acetaminophen B-Chemical 1
to O 0
produce O 0
cardiovascular B-Disease 1
toxicities I-Disease 1
is O 0
very O 0
low O 0
. O 0

However O 0
, O 0
acetaminophen B-Chemical 1
has O 0
been O 0
demonstrated O 0
to O 0
produce O 0
symptoms O 0
of O 0
anaphylaxis B-Disease 1
, O 0
including O 0
hypotension B-Disease 1
, O 0
in O 0
sensitive O 0
individuals O 0
. O 0

This O 0
article O 0
describes O 0
two O 0
critically B-Disease 1
ill I-Disease 1
patients O 0
in O 0
whom O 0
transient O 0
episodes O 0
of O 0
hypotension B-Disease 1
reproducibly O 0
developed O 0
after O 0
administration O 0
of O 0
acetaminophen B-Chemical 1
. O 0

Other O 0
symptoms O 0
of O 0
allergic B-Disease 1
reactions I-Disease 1
were O 0
not O 0
clinically O 0
detectable O 0
. O 0

The O 0
hypotensive B-Disease 1
episodes O 0
were O 0
severe O 0
enough O 0
to O 0
require O 0
vasopressor O 0
administration O 0
. O 0

The O 0
reports O 0
illustrate O 0
the O 0
need O 0
for O 0
clinicians O 0
to O 0
consider O 0
acetaminophen B-Chemical 1
in O 0
patients O 0
with O 0
hypotension B-Disease 1
of O 0
unknown O 0
origin O 0
. O 0

Reduction O 0
of O 0
heparan B-Chemical 1
sulphate I-Chemical 1
- O 0
associated O 0
anionic O 0
sites O 0
in O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
of O 0
rats O 0
with O 0
streptozotocin B-Chemical 1
- O 0
induced O 0
diabetic B-Disease 1
nephropathy I-Disease 1
. O 0

Heparan B-Chemical 1
sulphate I-Chemical 1
- O 0
associated O 0
anionic O 0
sites O 0
in O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
were O 0
studied O 0
in O 0
rats O 0
8 O 0
months O 0
after O 0
induction O 0
of O 0
diabetes B-Disease 1
by O 0
streptozotocin B-Chemical 1
and O 0
in O 0
age O 0
- O 0
adn O 0
sex O 0
- O 0
matched O 0
control O 0
rats O 0
, O 0
employing O 0
the O 0
cationic O 0
dye O 0
cuprolinic B-Chemical 1
blue I-Chemical 1
. O 0

Morphometric O 0
analysis O 0
at O 0
the O 0
ultrastructural O 0
level O 0
was O 0
performed O 0
using O 0
a O 0
computerized O 0
image O 0
processor O 0
. O 0

The O 0
heparan B-Chemical 1
sulphate I-Chemical 1
specificity O 0
of O 0
the O 0
cuprolinic B-Chemical 1
blue I-Chemical 1
staining O 0
was O 0
demonstrated O 0
by O 0
glycosaminoglycan B-Chemical 1
- O 0
degrading O 0
enzymes O 0
, O 0
showing O 0
that O 0
pretreatment O 0
of O 0
the O 0
sections O 0
with O 0
heparitinase O 0
abolished O 0
all O 0
staining O 0
, O 0
whereas O 0
chondroitinase O 0
ABC O 0
had O 0
no O 0
effect O 0
. O 0

The O 0
majority O 0
of O 0
anionic O 0
sites O 0
( O 0
74 O 0
% O 0
in O 0
diabetic B-Disease 1
and O 0
81 O 0
% O 0
in O 0
control O 0
rats O 0
) O 0
were O 0
found O 0
within O 0
the O 0
lamina O 0
rara O 0
externa O 0
of O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
. O 0

A O 0
minority O 0
of O 0
anionic O 0
sites O 0
were O 0
scattered O 0
throughout O 0
the O 0
lamina O 0
densa O 0
and O 0
lamina O 0
rara O 0
interna O 0
, O 0
and O 0
were O 0
significantly O 0
smaller O 0
than O 0
those O 0
in O 0
the O 0
lamina O 0
rara O 0
externa O 0
of O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
001 O 0
and O 0
p O 0
< O 0
0 O 0
. O 0
01 O 0
for O 0
diabetic B-Disease 1
and O 0
control O 0
rats O 0
, O 0
respectively O 0
) O 0
. O 0

Diabetic B-Disease 1
rats O 0
progressively O 0
developed O 0
albuminuria B-Disease 1
reaching O 0
40 O 0
. O 0
3 O 0
( O 0
32 O 0
. O 0
2 O 0
- O 0
62 O 0
. O 0
0 O 0
) O 0
mg O 0
/ O 0
24 O 0
h O 0
after O 0
8 O 0
months O 0
in O 0
contrast O 0
to O 0
the O 0
control O 0
animals O 0
( O 0
0 O 0
. O 0
8 O 0
( O 0
0 O 0
. O 0
2 O 0
- O 0
0 O 0
. O 0
9 O 0
) O 0
mg O 0
/ O 0
24 O 0
h O 0
, O 0
p O 0
< O 0
0 O 0
. O 0
002 O 0
) O 0
. O 0

At O 0
the O 0
same O 0
time O 0
, O 0
the O 0
number O 0
of O 0
heparan B-Chemical 1
sulphate I-Chemical 1
anionic O 0
sites O 0
and O 0
the O 0
total O 0
anionic O 0
site O 0
surface O 0
( O 0
number O 0
of O 0
anionic O 0
sites O 0
x O 0
mean O 0
anionic O 0
site O 0
surface O 0
) O 0
in O 0
the O 0
lamina O 0
rara O 0
externa O 0
of O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
was O 0
reduced O 0
by O 0
19 O 0
% O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
021 O 0
) O 0
and O 0
by O 0
26 O 0
% O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
02 O 0
) O 0
, O 0
respectively O 0
. O 0

Number O 0
and O 0
total O 0
anionic O 0
site O 0
surface O 0
in O 0
the O 0
remaining O 0
part O 0
of O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
( O 0
lamina O 0
densa O 0
and O 0
lamina O 0
rara O 0
interna O 0
) O 0
were O 0
not O 0
significantly O 0
changed O 0
. O 0

We O 0
conclude O 0
that O 0
in O 0
streptozotocin B-Chemical 1
- O 0
diabetic B-Disease 1
rats O 0
with O 0
an O 0
increased O 0
urinary O 0
albumin O 0
excretion O 0
, O 0
a O 0
reduced O 0
heparan B-Chemical 1
sulphate I-Chemical 1
charge O 0
barrier O 0
/ O 0
density O 0
is O 0
found O 0
at O 0
the O 0
lamina O 0
rara O 0
externa O 0
of O 0
the O 0
glomerular O 0
basement O 0
membrane O 0
. O 0

Mediation O 0
of O 0
enhanced O 0
reflex O 0
vagal O 0
bradycardia B-Disease 1
by O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
via O 0
central O 0
dopamine B-Chemical 1
formation O 0
in O 0
dogs O 0
. O 0

L B-Chemical 1
- I-Chemical 1
Dopa I-Chemical 1
( O 0
5 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
v O 0
. O 0
) O 0
decreased O 0
blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
after O 0
extracerebral O 0
decarboxylase O 0
inhibition O 0
with O 0
MK B-Chemical 1
- I-Chemical 1
486 I-Chemical 1
( O 0
25 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
v O 0
. O 0
) O 0
in O 0
anesthetize O 0
MAO B-Chemical 1
- O 0
inhibited O 0
dogs O 0
. O 0

In O 0
addition O 0
, O 0
reflex O 0
bradycardia B-Disease 1
caused O 0
by O 0
injected O 0
norepinephrine B-Chemical 1
was O 0
significantly O 0
enhanced O 0
by O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
, O 0
DL B-Chemical 1
- I-Chemical 1
Threo I-Chemical 1
- I-Chemical 1
dihydroxyphenylserine I-Chemical 1
had O 0
no O 0
effect O 0
on O 0
blood O 0
pressure O 0
, O 0
heart O 0
rate O 0
or O 0
reflex O 0
responses O 0
to O 0
norepinephrine B-Chemical 1
. O 0

FLA B-Chemical 1
- I-Chemical 1
63 I-Chemical 1
, O 0
a O 0
dopamine B-Chemical 1
- O 0
beta O 0
- O 0
oxidase O 0
inhibitor O 0
, O 0
did O 0
not O 0
have O 0
any O 0
effect O 0
on O 0
the O 0
hypotension B-Disease 1
, O 0
bradycardia B-Disease 1
or O 0
reflex O 0
- O 0
enhancing O 0
effect O 0
of O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
. O 0

Pimozide B-Chemical 1
did O 0
not O 0
affect O 0
the O 0
actions O 0
of O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
on O 0
blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
but O 0
completely O 0
blocked O 0
the O 0
enhancement O 0
of O 0
reflexes O 0
. O 0

Removal O 0
of O 0
the O 0
carotid O 0
sinuses O 0
caused O 0
an O 0
elevation O 0
blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
and O 0
abolished O 0
the O 0
negative O 0
chronotropic O 0
effect O 0
of O 0
norepinephrine B-Chemical 1
. O 0

However O 0
, O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
restored O 0
the O 0
bradycardia B-Disease 1
caused O 0
by O 0
norepinephrine B-Chemical 1
in O 0
addition O 0
to O 0
decreasing O 0
blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
. O 0

5 B-Chemical 1
- I-Chemical 1
HTP I-Chemical 1
( O 0
5 O 0
mg O 0
/ O 0
kg O 0
i O 0
. O 0
v O 0
. O 0
) O 0
decreased O 0
blood O 0
pressure O 0
and O 0
heart O 0
rate O 0
and O 0
decreased O 0
the O 0
reflex O 0
bradycardia B-Disease 1
to O 0
norepinephrine B-Chemical 1
. O 0

It O 0
is O 0
concluded O 0
that O 0
L B-Chemical 1
- I-Chemical 1
dopa I-Chemical 1
enhances O 0
reflex O 0
bradycardia B-Disease 1
through O 0
central O 0
alpha O 0
- O 0
receptor O 0
stimulation O 0
. O 0

Furthermore O 0
, O 0
the O 0
effects O 0
are O 0
mediated O 0
through O 0
dopamine B-Chemical 1
rather O 0
than O 0
norepinephrine B-Chemical 1
and O 0
do O 0
not O 0
require O 0
the O 0
carotid O 0
sinus O 0
baroreceptors O 0
. O 0

Microangiopathic B-Disease 1
hemolytic I-Disease 1
anemia I-Disease 1
complicating O 0
FK506 B-Chemical 1
( O 0
tacrolimus B-Chemical 1
) O 0
therapy O 0
. O 0

We O 0
describe O 0
3 O 0
episodes O 0
of O 0
microangiopathic B-Disease 1
hemolytic I-Disease 1
anemia I-Disease 1
( O 0
MAHA B-Disease 1
) O 0
in O 0
2 O 0
solid O 0
organ O 0
recipients O 0
under O 0
FK506 B-Chemical 1
( O 0
tacrolimus B-Chemical 1
) O 0
therapy O 0
. O 0

In O 0
both O 0
cases O 0
, O 0
discontinuation O 0
of O 0
FK506 B-Chemical 1
and O 0
treatment O 0
with O 0
plasma O 0
exchange O 0
, O 0
fresh O 0
frozen O 0
plasma O 0
replacement O 0
, O 0
corticosteroids B-Chemical 1
, O 0
aspirin B-Chemical 1
, O 0
and O 0
dipyridamole B-Chemical 1
led O 0
to O 0
resolution O 0
of O 0
MAHA B-Disease 1
. O 0

In O 0
one O 0
patient O 0
, O 0
reintroduction O 0
of O 0
FK506 B-Chemical 1
led O 0
to O 0
rapid O 0
recurrence O 0
of O 0
MAHA B-Disease 1
. O 0

FK506 B-Chemical 1
- O 0
associated O 0
MAHA B-Disease 1
is O 0
probably O 0
rare O 0
but O 0
physicians O 0
must O 0
be O 0
aware O 0
of O 0
this O 0
severe O 0
complication O 0
. O 0

In O 0
our O 0
experience O 0
and O 0
according O 0
to O 0
the O 0
literature O 0
, O 0
FK506 B-Chemical 1
does O 0
not O 0
seem O 0
to O 0
cross O 0
- O 0
react O 0
with O 0
cyclosporin B-Chemical 1
A I-Chemical 1
( O 0
CyA B-Chemical 1
) O 0
, O 0
an O 0
immuno O 0
- O 0
suppressive O 0
drug O 0
already O 0
known O 0
to O 0
induce O 0
MAHA B-Disease 1
. O 0

Effect O 0
of O 0
some O 0
anticancer O 0
drugs O 0
and O 0
combined O 0
chemotherapy O 0
on O 0
renal B-Disease 1
toxicity I-Disease 1
. O 0

The O 0
nephrotoxic B-Disease 1
action O 0
of O 0
anticancer O 0
drugs O 0
such O 0
as O 0
nitrogranulogen B-Chemical 1
( O 0
NG B-Chemical 1
) O 0
, O 0
methotrexate B-Chemical 1
( O 0
MTX B-Chemical 1
) O 0
, O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
( O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
) O 0
and O 0
cyclophosphamide B-Chemical 1
( O 0
CY B-Chemical 1
) O 0
administered O 0
alone O 0
or O 0
in O 0
combination O 0
[ O 0
MTX B-Chemical 1
+ O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
+ O 0
CY B-Chemical 1
( O 0
CMF O 0
) O 0
] O 0
was O 0
evaluated O 0
in O 0
experiments O 0
on O 0
Wistar O 0
rats O 0
. O 0

After O 0
drug O 0
administration O 0
, O 0
creatinine B-Chemical 1
concentrations O 0
in O 0
the O 0
plasma O 0
and O 0
in O 0
the O 0
urine O 0
of O 0
the O 0
rats O 0
were O 0
determined O 0
, O 0
as O 0
well O 0
as O 0
creatinine B-Chemical 1
clearance O 0
. O 0

Histopathologic O 0
evaluation O 0
of O 0
the O 0
kidneys O 0
was O 0
also O 0
performed O 0
. O 0

After O 0
MTX B-Chemical 1
administration O 0
a O 0
significant O 0
increase O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
0228 O 0
) O 0
in O 0
the O 0
plasma O 0
creatinine B-Chemical 1
concentration O 0
and O 0
a O 0
significant O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
0001 O 0
) O 0
decrease O 0
in O 0
creatinine B-Chemical 1
clearance O 0
was O 0
noted O 0
compared O 0
to O 0
controls O 0
. O 0

After O 0
the O 0
administration O 0
of O 0
NG B-Chemical 1
, O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
and O 0
CY B-Chemical 1
neither O 0
a O 0
statistically O 0
significant O 0
increase O 0
in O 0
creatinine B-Chemical 1
concentration O 0
nor O 0
an O 0
increase O 0
in O 0
creatinine B-Chemical 1
clearance O 0
was O 0
observed O 0
compared O 0
to O 0
the O 0
group O 0
receiving O 0
no O 0
cytostatics O 0
. O 0

Following O 0
polytherapy O 0
according O 0
to O 0
the O 0
CMF O 0
regimen O 0
, O 0
a O 0
statistically O 0
significant O 0
decrease O 0
( O 0
p O 0
= O 0
0 O 0
. O 0
0343 O 0
) O 0
in O 0
creatinine B-Chemical 1
clearance O 0
was O 0
found O 0
, O 0
but O 0
creatinine B-Chemical 1
concentration O 0
did O 0
not O 0
increase O 0
significantly O 0
compared O 0
to O 0
controls O 0
. O 0

CY B-Chemical 1
caused O 0
hemorrhagic B-Disease 1
cystitis I-Disease 1
in O 0
40 O 0
% O 0
of O 0
rats O 0
, O 0
but O 0
it O 0
did O 0
not O 0
cause O 0
this O 0
complication O 0
when O 0
combined O 0
with O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
and O 0
MTX B-Chemical 1
. O 0

Histologic O 0
changes O 0
were O 0
found O 0
in O 0
rat O 0
kidneys O 0
after O 0
administration O 0
of O 0
MTX B-Chemical 1
, O 0
CY B-Chemical 1
and O 0
NG B-Chemical 1
, O 0
while O 0
no O 0
such O 0
change O 0
was O 0
observed O 0
after O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
and O 0
joint O 0
administration O 0
of O 0
MTX B-Chemical 1
+ O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
+ O 0
CY B-Chemical 1
compared O 0
to O 0
controls O 0
. O 0

Our O 0
studies O 0
indicate O 0
that O 0
nephrotoxicity B-Disease 1
of O 0
MTX B-Chemical 1
+ O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
+ O 0
CY B-Chemical 1
administered O 0
jointly O 0
is O 0
lower O 0
than O 0
in O 0
monotherapy O 0
. O 0

The O 0
interpeduncular O 0
nucleus O 0
regulates O 0
nicotine B-Chemical 1
' O 0
s O 0
effects O 0
on O 0
free O 0
- O 0
field O 0
activity O 0
. O 0

Partial O 0
lesions O 0
were O 0
made O 0
with O 0
kainic B-Chemical 1
acid I-Chemical 1
in O 0
the O 0
interpeduncular O 0
nucleus O 0
of O 0
the O 0
ventral O 0
midbrain O 0
of O 0
the O 0
rat O 0
. O 0

Compared O 0
with O 0
sham O 0
- O 0
operated O 0
controls O 0
, O 0
lesions O 0
significantly O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
25 O 0
) O 0
blunted O 0
the O 0
early O 0
( O 0
< O 0
60 O 0
min O 0
) O 0
free O 0
- O 0
field O 0
locomotor B-Disease 1
hypoactivity I-Disease 1
caused O 0
by O 0
nicotine B-Chemical 1
( O 0
0 O 0
. O 0
5 O 0
mg O 0
kg O 0
( O 0
- O 0
1 O 0
) O 0
, O 0
i O 0
. O 0
m O 0
. O 0
) O 0
, O 0
enhanced O 0
the O 0
later O 0
( O 0
60 O 0
- O 0
120 O 0
min O 0
) O 0
nicotine B-Chemical 1
- O 0
induced O 0
hyperactivity B-Disease 1
, O 0
and O 0
raised O 0
spontaneous O 0
nocturnal O 0
activity O 0
. O 0

Lesions O 0
reduced O 0
the O 0
extent O 0
of O 0
immunohistological O 0
staining O 0
for O 0
choline B-Chemical 1
acetyltransferase O 0
in O 0
the O 0
interpeduncular O 0
nucleus O 0
( O 0
p O 0
< O 0
0 O 0
. O 0
025 O 0
) O 0
, O 0
but O 0
not O 0
for O 0
tyrosine B-Chemical 1
hydroxylase O 0
in O 0
the O 0
surrounding O 0
catecholaminergic O 0
A10 O 0
region O 0
. O 0

We O 0
conclude O 0
that O 0
the O 0
interpeduncular O 0
nucleus O 0
mediates O 0
nicotinic O 0
depression B-Disease 1
of O 0
locomotor O 0
activity O 0
and O 0
dampens O 0
nicotinic O 0
arousal O 0
mechanisms O 0
located O 0
elsewhere O 0
in O 0
the O 0
brain O 0
. O 0

Lithium B-Chemical 1
- O 0
associated O 0
cognitive B-Disease 1
and I-Disease 1
functional I-Disease 1
deficits I-Disease 1
reduced O 0
by O 0
a O 0
switch O 0
to O 0
divalproex B-Chemical 1
sodium I-Chemical 1
: O 0
a O 0
case O 0
series O 0
. O 0

BACKGROUND O 0
: O 0
Lithium B-Chemical 1
remains O 0
a O 0
first O 0
- O 0
line O 0
treatment O 0
for O 0
the O 0
acute O 0
and O 0
maintenance O 0
treatment O 0
of O 0
bipolar B-Disease 1
disorder I-Disease 1
. O 0

Although O 0
much O 0
has O 0
been O 0
written O 0
about O 0
the O 0
management O 0
of O 0
the O 0
more O 0
common O 0
adverse O 0
effects O 0
of O 0
lithium B-Chemical 1
, O 0
such O 0
as O 0
polyuria B-Disease 1
and O 0
tremor B-Disease 1
, O 0
more O 0
subtle O 0
lithium B-Chemical 1
side O 0
effects O 0
such O 0
as O 0
cognitive B-Disease 1
deficits I-Disease 1
, O 0
loss B-Disease 1
of I-Disease 1
creativity I-Disease 1
, O 0
and O 0
functional B-Disease 1
impairments I-Disease 1
remain O 0
understudied O 0
. O 0

This O 0
report O 0
summarizes O 0
our O 0
experience O 0
in O 0
switching O 0
bipolar B-Disease 1
patients O 0
from O 0
lithium B-Chemical 1
to O 0
divalproex B-Chemical 1
sodium I-Chemical 1
to O 0
alleviate O 0
such O 0
cognitive B-Disease 1
and I-Disease 1
functional I-Disease 1
impairments I-Disease 1
. O 0

METHOD O 0
: O 0
Open O 0
, O 0
case O 0
series O 0
design O 0
. O 0

RESULTS O 0
: O 0
We O 0
report O 0
seven O 0
cases O 0
where O 0
substitution O 0
of O 0
lithium B-Chemical 1
, O 0
either O 0
fully O 0
or O 0
partially O 0
, O 0
with O 0
divalproex B-Chemical 1
sodium I-Chemical 1
was O 0
extremely O 0
helpful O 0
in O 0
reducing O 0
the O 0
cognitive B-Disease 1
, I-Disease 1
motivational I-Disease 1
, I-Disease 1
or I-Disease 1
creative I-Disease 1
deficits I-Disease 1
attributed O 0
to O 0
lithium B-Chemical 1
in O 0
our O 0
bipolar B-Disease 1
patients O 0
. O 0

CONCLUSION O 0
: O 0
In O 0
this O 0
preliminary O 0
report O 0
, O 0
divalproex B-Chemical 1
sodium I-Chemical 1
was O 0
a O 0
superior O 0
alternative O 0
to O 0
lithium B-Chemical 1
in O 0
bipolar B-Disease 1
patients O 0
experiencing O 0
cognitive B-Disease 1
deficits I-Disease 1
, O 0
loss B-Disease 1
of I-Disease 1
creativity I-Disease 1
, O 0
and O 0
functional B-Disease 1
impairments I-Disease 1
. O 0

Effect O 0
of O 0
nifedipine B-Chemical 1
on O 0
renal O 0
function O 0
in O 0
liver O 0
transplant O 0
recipients O 0
receiving O 0
tacrolimus B-Chemical 1
. O 0

The O 0
effect O 0
of O 0
nifedipine B-Chemical 1
on O 0
renal O 0
function O 0
in O 0
liver O 0
transplant O 0
recipients O 0
who O 0
were O 0
receiving O 0
tacrolimus B-Chemical 1
was O 0
evaluated O 0
between O 0
January O 0
1992 O 0
and O 0
January O 0
1996 O 0
. O 0

Two O 0
groups O 0
of O 0
patients O 0
receiving O 0
tacrolimus B-Chemical 1
were O 0
compared O 0
over O 0
a O 0
period O 0
of O 0
1 O 0
year O 0
, O 0
one O 0
group O 0
comprising O 0
hypertensive B-Disease 1
patients O 0
who O 0
were O 0
receiving O 0
nifedipine B-Chemical 1
, O 0
and O 0
the O 0
other O 0
comprising O 0
nonhypertensive O 0
patients O 0
not O 0
receiving O 0
nifedipine B-Chemical 1
. O 0

The O 0
time O 0
from O 0
transplant O 0
to O 0
baseline O 0
was O 0
similar O 0
in O 0
all O 0
patients O 0
. O 0

Nifedipine B-Chemical 1
significantly O 0
improved O 0
kidney O 0
function O 0
as O 0
indicated O 0
by O 0
a O 0
significant O 0
lowering O 0
of O 0
serum O 0
creatinine B-Chemical 1
levels O 0
at O 0
6 O 0
and O 0
12 O 0
months O 0
. O 0

The O 0
observed O 0
positive O 0
impact O 0
of O 0
nifedipine B-Chemical 1
on O 0
reducing O 0
the O 0
nephrotoxicity B-Disease 1
associated O 0
with O 0
tacrolimus B-Chemical 1
in O 0
liver O 0
transplant O 0
recipients O 0
should O 0
be O 0
an O 0
important O 0
factor O 0
in O 0
selecting O 0
an O 0
agent O 0
to O 0
treat O 0
hypertension B-Disease 1
in O 0
this O 0
population O 0
. O 0

Alpha O 0
and O 0
beta O 0
coma B-Disease 1
in O 0
drug O 0
intoxication O 0
uncomplicated O 0
by O 0
cerebral B-Disease 1
hypoxia I-Disease 1
. O 0

Four O 0
patients O 0
who O 0
were O 0
rendered O 0
comatose B-Disease 1
or O 0
stuporous B-Disease 1
by O 0
drug O 0
intoxication O 0
, O 0
but O 0
who O 0
were O 0
not O 0
hypoxic O 0
, O 0
are O 0
described O 0
. O 0

Three O 0
patients O 0
received O 0
high O 0
doses O 0
of O 0
chlormethiazole B-Chemical 1
for O 0
alcohol B-Chemical 1
withdrawal B-Disease 1
symptoms I-Disease 1
, O 0
and O 0
one O 0
took O 0
a O 0
suicidal O 0
overdose B-Disease 1
of O 0
nitrazepam B-Chemical 1
. O 0

The O 0
patient O 0
with O 0
nitrazepam B-Chemical 1
overdose B-Disease 1
and O 0
two O 0
of O 0
those O 0
with O 0
chlormethiazole B-Chemical 1
intoxication O 0
conformed O 0
to O 0
the O 0
criteria O 0
of O 0
' O 0
alpha O 0
coma B-Disease 1
' O 0
, O 0
showing O 0
non O 0
- O 0
reactive O 0
generalized O 0
or O 0
frontally O 0
predominant O 0
alpha O 0
activity O 0
in O 0
the O 0
EEG O 0
. O 0

The O 0
fourth O 0
patient O 0
who O 0
was O 0
unconscious O 0
after O 0
chlormethiazole B-Chemical 1
administration O 0
exhibite O 0
generalized O 0
non O 0
- O 0
reactive O 0
activity O 0
in O 0
the O 0
slow O 0
beta O 0
range O 0
. O 0

All O 0
four O 0
recovered O 0
completely O 0
without O 0
neurological B-Disease 1
sequelae I-Disease 1
following O 0
the O 0
withdrawal O 0
of O 0
the O 0
offending O 0
agents O 0
. O 0

The O 0
similarities O 0
between O 0
the O 0
effects O 0
of O 0
structural O 0
lesions O 0
and O 0
pharmacological O 0
depression B-Disease 1
of O 0
the O 0
brain O 0
stem O 0
reticular O 0
formation O 0
are O 0
discussed O 0
. O 0

It O 0
is O 0
suggested O 0
that O 0
in O 0
both O 0
situations O 0
disturbed O 0
reticulo O 0
- O 0
thalamic O 0
interactions O 0
are O 0
important O 0
in O 0
the O 0
pathogenesis O 0
of O 0
alpha O 0
coma B-Disease 1
. O 0

It O 0
is O 0
concluded O 0
that O 0
when O 0
this O 0
electroencephalographic O 0
and O 0
behavioural O 0
picture O 0
is O 0
seen O 0
in O 0
drug O 0
intoxication O 0
, O 0
in O 0
the O 0
absence O 0
of O 0
significant O 0
hypoxaemia B-Disease 1
, O 0
a O 0
favourable O 0
outcome O 0
may O 0
be O 0
anticipated O 0
. O 0

Magnetic O 0
resonance O 0
volumetry O 0
of O 0
the O 0
cerebellum O 0
in O 0
epileptic B-Disease 1
patients O 0
after O 0
phenytoin B-Chemical 1
overdosages B-Disease 1
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
evaluate O 0
the O 0
relationship O 0
between O 0
phenytoin B-Chemical 1
medication O 0
and O 0
cerebellar B-Disease 1
atrophy I-Disease 1
in O 0
patients O 0
who O 0
had O 0
experienced O 0
clinical O 0
intoxication O 0
. O 0

Five O 0
females O 0
and O 0
6 O 0
males O 0
, O 0
21 O 0
- O 0
59 O 0
years O 0
of O 0
age O 0
, O 0
were O 0
examined O 0
with O 0
a O 0
1 O 0
. O 0
5 O 0
- O 0
T O 0
whole O 0
- O 0
body O 0
system O 0
using O 0
a O 0
circular O 0
polarized O 0
head O 0
coil O 0
. O 0

Conventional O 0
spin O 0
echo O 0
images O 0
were O 0
acquired O 0
in O 0
the O 0
sagittal O 0
and O 0
transverse O 0
orientation O 0
. O 0

In O 0
addition O 0
, O 0
we O 0
performed O 0
a O 0
high O 0
- O 0
resolution O 0
3D O 0
gradient O 0
echo O 0
, O 0
T1 O 0
- O 0
weighted O 0
sequences O 0
at O 0
a O 0
1 O 0
- O 0
mm O 0
slice O 0
thickness O 0
. O 0

The O 0
images O 0
were O 0
subsequently O 0
processed O 0
to O 0
obtain O 0
volumetric O 0
data O 0
for O 0
the O 0
cerebellum O 0
. O 0

Cerebellar O 0
volume O 0
for O 0
the O 0
patient O 0
group O 0
ranged O 0
between O 0
67 O 0
. O 0
66 O 0
and O 0
131 O 0
. O 0
08 O 0
ml O 0
( O 0
mean O 0
108 O 0
. O 0
9 O 0
ml O 0
) O 0
. O 0

In O 0
addition O 0
3D O 0
gradient O 0
echo O 0
data O 0
sets O 0
from O 0
10 O 0
healthy O 0
male O 0
and O 0
10 O 0
healthy O 0
female O 0
age O 0
- O 0
matched O 0
volunteers O 0
were O 0
used O 0
to O 0
compare O 0
cerebellar O 0
volumes O 0
. O 0

Using O 0
linear O 0
regression O 0
we O 0
found O 0
that O 0
no O 0
correlation O 0
exists O 0
between O 0
seizure B-Disease 1
duration O 0
, O 0
elevation O 0
of O 0
phenytoin B-Chemical 1
serum O 0
levels O 0
and O 0
cerebellar O 0
volume O 0
. O 0

However O 0
, O 0
multiple O 0
regression O 0
for O 0
the O 0
daily O 0
dosage O 0
, O 0
duration O 0
of O 0
phenytoin B-Chemical 1
treatment O 0
and O 0
cerebellar O 0
volume O 0
revealed O 0
a O 0
correlation O 0
of O 0
these O 0
parameters O 0
. O 0

We O 0
conclude O 0
that O 0
phenytoin B-Chemical 1
overdosage B-Disease 1
does O 0
not O 0
necessarily O 0
result O 0
in O 0
cerebellar B-Disease 1
atrophy I-Disease 1
and O 0
it O 0
is O 0
unlikely O 0
that O 0
phenytoin B-Chemical 1
medication O 0
was O 0
the O 0
only O 0
cause O 0
of O 0
cerebellar B-Disease 1
atrophy I-Disease 1
in O 0
the O 0
remaining O 0
patients O 0
. O 0

Quantitative O 0
morphometric O 0
studies O 0
of O 0
the O 0
cerebellum O 0
provide O 0
valuable O 0
insights O 0
into O 0
the O 0
pathogenesis O 0
of O 0
cerebellar B-Disease 1
disorders I-Disease 1
. O 0

Late O 0
recovery O 0
of O 0
renal O 0
function O 0
in O 0
a O 0
woman O 0
with O 0
the O 0
hemolytic B-Disease 1
uremic I-Disease 1
syndrome I-Disease 1
. O 0

A O 0
case O 0
is O 0
reported O 0
of O 0
the O 0
hemolytic B-Disease 1
uremic I-Disease 1
syndrome I-Disease 1
( O 0
HUS B-Disease 1
) O 0
in O 0
a O 0
woman O 0
taking O 0
oral B-Chemical 1
contraceptives I-Chemical 1
. O 0

She O 0
was O 0
treated O 0
with O 0
heparin B-Chemical 1
, O 0
dipyridamole B-Chemical 1
and O 0
hemodialysis O 0
; O 0
and O 0
after O 0
more O 0
than O 0
three O 0
months O 0
, O 0
her O 0
urinary O 0
output O 0
rose O 0
above O 0
500 O 0
ml O 0
; O 0
and O 0
six O 0
months O 0
after O 0
the O 0
onset O 0
of O 0
anuria B-Disease 1
, O 0
dialysis O 0
treatment O 0
was O 0
stopped O 0
. O 0

This O 0
case O 0
emphasizes O 0
the O 0
possibility O 0
that O 0
HUS B-Disease 1
in O 0
adults O 0
is O 0
not O 0
invariably O 0
irreversible O 0
and O 0
that O 0
, O 0
despite O 0
prolonged O 0
oliguria B-Disease 1
, O 0
recovery O 0
of O 0
renal O 0
function O 0
can O 0
be O 0
obtained O 0
. O 0

Therefore O 0
, O 0
in O 0
adult O 0
patients O 0
affected O 0
by O 0
HUS B-Disease 1
, O 0
dialysis O 0
should O 0
not O 0
be O 0
discontinued O 0
prematurely O 0
; O 0
moreover O 0
, O 0
bilateral O 0
nephrectomy O 0
, O 0
for O 0
treatment O 0
of O 0
severe O 0
hypertension B-Disease 1
and O 0
microangiopathic B-Disease 1
hemolytic I-Disease 1
anemia I-Disease 1
, O 0
should O 0
be O 0
performed O 0
with O 0
caution O 0
. O 0

Morphological O 0
features O 0
of O 0
encephalopathy B-Disease 1
after O 0
chronic O 0
administration O 0
of O 0
the O 0
antiepileptic O 0
drug O 0
valproate B-Chemical 1
to O 0
rats O 0
. O 0

A O 0
transmission O 0
electron O 0
microscopic O 0
study O 0
of O 0
capillaries O 0
in O 0
the O 0
cerebellar O 0
cortex O 0
. O 0

Long O 0
- O 0
term O 0
intragastric O 0
application O 0
of O 0
the O 0
antiepileptic O 0
drug O 0
sodium B-Chemical 1
valproate I-Chemical 1
( O 0
Vupral O 0
" O 0
Polfa O 0
" O 0
) O 0
at O 0
the O 0
effective O 0
dose O 0
of O 0
200 O 0
mg O 0
/ O 0
kg O 0
b O 0
. O 0

w O 0
. O 0
once O 0
daily O 0
to O 0
rats O 0
for O 0
1 O 0
, O 0
3 O 0
, O 0
6 O 0
, O 0
9 O 0
and O 0
12 O 0
months O 0
revealed O 0
neurological B-Disease 1
disorders I-Disease 1
indicating O 0
cerebellum B-Disease 1
damage I-Disease 1
( O 0
" O 0
valproate B-Chemical 1
encephalopathy B-Disease 1
" O 0
) O 0
. O 0

The O 0
first O 0
ultrastructural O 0
changes O 0
in O 0
structural O 0
elements O 0
of O 0
the O 0
blood O 0
- O 0
brain O 0
- O 0
barrier O 0
( O 0
BBB O 0
) O 0
in O 0
the O 0
cerebellar O 0
cortex O 0
were O 0
detectable O 0
after O 0
3 O 0
months O 0
of O 0
the O 0
experiment O 0
. O 0

They O 0
became O 0
more O 0
severe O 0
in O 0
the O 0
later O 0
months O 0
of O 0
the O 0
experiment O 0
, O 0
and O 0
were O 0
most O 0
severe O 0
after O 0
12 O 0
months O 0
, O 0
located O 0
mainly O 0
in O 0
the O 0
molecular O 0
layer O 0
of O 0
the O 0
cerebellar O 0
cortex O 0
. O 0

Lesions O 0
of O 0
the O 0
capillary O 0
included O 0
necrosis B-Disease 1
of O 0
endothelial O 0
cells O 0
. O 0

Organelles O 0
of O 0
these O 0
cells O 0
, O 0
in O 0
particular O 0
the O 0
mitochondria O 0
( O 0
increased O 0
number O 0
and O 0
size O 0
, O 0
distinct O 0
degeneration O 0
of O 0
their O 0
matrix O 0
and O 0
cristae O 0
) O 0
and O 0
Golgi O 0
apparatus O 0
were O 0
altered O 0
. O 0

Reduced O 0
size O 0
of O 0
capillary O 0
lumen O 0
and O 0
occlusion O 0
were O 0
caused O 0
by O 0
swollen O 0
endothelial O 0
cells O 0
which O 0
had O 0
luminal B-Chemical 1
protrusions O 0
and O 0
swollen O 0
microvilli O 0
. O 0

Pressure O 0
on O 0
the O 0
vessel O 0
wall O 0
was O 0
produced O 0
by O 0
enlarged O 0
perivascular O 0
astrocytic O 0
processes O 0
. O 0

Fragments O 0
of O 0
necrotic B-Disease 1
endothelial O 0
cells O 0
were O 0
in O 0
the O 0
vascular O 0
lumens O 0
and O 0
in O 0
these O 0
there O 0
was O 0
loosening O 0
and O 0
breaking O 0
of O 0
tight O 0
cellular O 0
junctions O 0
. O 0

Damage O 0
to O 0
the O 0
vascular O 0
basement O 0
lamina O 0
was O 0
also O 0
observed O 0
. O 0

Damage O 0
to O 0
the O 0
capillary O 0
was O 0
accompanied O 0
by O 0
marked O 0
damage O 0
to O 0
neuroglial O 0
cells O 0
, O 0
mainly O 0
to O 0
perivascular O 0
processes O 0
of O 0
astrocytes O 0
. O 0

The O 0
proliferation O 0
of O 0
astrocytes O 0
( O 0
Bergmann O 0
' O 0
s O 0
in O 0
particular O 0
) O 0
and O 0
occasionally O 0
of O 0
oligodendrocytes O 0
was O 0
found O 0
. O 0

Alterations O 0
in O 0
the O 0
structural O 0
elements O 0
of O 0
the O 0
BBB O 0
coexisted O 0
with O 0
marked O 0
lesions O 0
of O 0
neurons O 0
of O 0
the O 0
cerebellum O 0
( O 0
Purkinje O 0
cells O 0
are O 0
earliest O 0
) O 0
. O 0

In O 0
electron O 0
micrographs O 0
both O 0
luminal B-Chemical 1
and O 0
antiluminal O 0
sides O 0
of O 0
the O 0
BBB O 0
of O 0
the O 0
cerebellar O 0
cortex O 0
had O 0
similar O 0
lesions O 0
. O 0

The O 0
possible O 0
influence O 0
of O 0
the O 0
hepatic B-Disease 1
damage I-Disease 1
, O 0
mainly O 0
hyperammonemia B-Disease 1
, O 0
upon O 0
the O 0
development O 0
of O 0
valproate B-Chemical 1
encephalopathy B-Disease 1
is O 0
discussed O 0
. O 0

Fatal O 0
intracranial B-Disease 1
bleeding I-Disease 1
associated O 0
with O 0
prehospital O 0
use O 0
of O 0
epinephrine B-Chemical 1
. O 0

We O 0
present O 0
a O 0
case O 0
of O 0
paramedic O 0
misjudgment O 0
in O 0
the O 0
execution O 0
of O 0
a O 0
protocol O 0
for O 0
the O 0
treatment O 0
of O 0
allergic B-Disease 1
reaction I-Disease 1
in O 0
a O 0
case O 0
of O 0
pulmonary B-Disease 1
edema I-Disease 1
with O 0
wheezing B-Disease 1
. O 0

The O 0
sudden O 0
onset O 0
of O 0
respiratory B-Disease 1
distress I-Disease 1
, O 0
rash B-Disease 1
, O 0
and O 0
a O 0
history O 0
of O 0
a O 0
new O 0
medicine O 0
led O 0
the O 0
two O 0
paramedics O 0
on O 0
the O 0
scene O 0
to O 0
administer O 0
subcutaneous O 0
epinephrine B-Chemical 1
. O 0

Subsequently O 0
, O 0
acute O 0
cardiac B-Disease 1
arrest I-Disease 1
and O 0
fatal O 0
subarachnoid B-Disease 1
hemorrhage I-Disease 1
occurred O 0
. O 0

Epinephrine B-Chemical 1
has O 0
a O 0
proven O 0
role O 0
in O 0
cardiac B-Disease 1
arrest I-Disease 1
in O 0
prehospital O 0
care O 0
; O 0
however O 0
, O 0
use O 0
by O 0
paramedics O 0
in O 0
patients O 0
with O 0
suspected O 0
allergic B-Disease 1
reaction I-Disease 1
and O 0
severe O 0
hypertension B-Disease 1
should O 0
be O 0
viewed O 0
with O 0
caution O 0
. O 0

Role O 0
of O 0
activation O 0
of O 0
bradykinin B-Chemical 1
B2 O 0
receptors O 0
in O 0
disruption O 0
of O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
during O 0
acute O 0
hypertension B-Disease 1
. O 0

Cellular O 0
mechanisms O 0
which O 0
account O 0
for O 0
disruption O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
during O 0
acute O 0
hypertension B-Disease 1
are O 0
not O 0
clear O 0
. O 0

The O 0
goal O 0
of O 0
this O 0
study O 0
was O 0
to O 0
determine O 0
the O 0
role O 0
of O 0
synthesis O 0
/ O 0
release O 0
of O 0
bradykinin B-Chemical 1
to O 0
activate O 0
B2 O 0
receptors O 0
in O 0
disruption O 0
of O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
during O 0
acute O 0
hypertension B-Disease 1
. O 0

Permeability O 0
of O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
was O 0
quantitated O 0
by O 0
clearance O 0
of O 0
fluorescent O 0
- O 0
labeled O 0
dextran B-Chemical 1
before O 0
and O 0
during O 0
phenylephrine B-Chemical 1
- O 0
induced O 0
acute O 0
hypertension B-Disease 1
in O 0
rats O 0
treated O 0
with O 0
vehicle O 0
and O 0
Hoe B-Chemical 1
- I-Chemical 1
140 I-Chemical 1
( O 0
0 O 0
. O 0
1 O 0
microM O 0
) O 0
. O 0

Phenylephrine B-Chemical 1
infusion O 0
increased O 0
arterial O 0
pressure O 0
, O 0
arteriolar O 0
diameter O 0
and O 0
clearance O 0
of O 0
fluorescent O 0
dextran B-Chemical 1
by O 0
a O 0
similar O 0
magnitude O 0
in O 0
both O 0
groups O 0
. O 0

These O 0
findings O 0
suggest O 0
that O 0
disruption O 0
of O 0
the O 0
blood O 0
- O 0
brain O 0
barrier O 0
during O 0
acute O 0
hypertension B-Disease 1
is O 0
not O 0
related O 0
to O 0
the O 0
synthesis O 0
/ O 0
release O 0
of O 0
bradykinin B-Chemical 1
to O 0
activate O 0
B2 O 0
receptors O 0
. O 0

Risk O 0
factors O 0
of O 0
sensorineural B-Disease 1
hearing I-Disease 1
loss I-Disease 1
in O 0
preterm O 0
infants O 0
. O 0

Among O 0
547 O 0
preterm O 0
infants O 0
of O 0
< O 0
or O 0
= O 0
34 O 0
weeks O 0
gestation O 0
born O 0
between O 0
1987 O 0
and O 0
1991 O 0
, O 0
8 O 0
children O 0
( O 0
1 O 0
. O 0
46 O 0
% O 0
) O 0
developed O 0
severe O 0
progressive O 0
and O 0
bilateral O 0
sensorineural B-Disease 1
hearing I-Disease 1
loss I-Disease 1
. O 0

Perinatal O 0
risk O 0
factors O 0
of O 0
infants O 0
with O 0
hearing B-Disease 1
loss I-Disease 1
were O 0
compared O 0
with O 0
those O 0
of O 0
two O 0
control O 0
groups O 0
matched O 0
for O 0
gestation O 0
and O 0
birth O 0
weight O 0
and O 0
for O 0
perinatal O 0
complications O 0
. O 0

Our O 0
observations O 0
demonstrated O 0
an O 0
association O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
with O 0
a O 0
higher O 0
incidence O 0
of O 0
perinatal O 0
complications O 0
. O 0

Ototoxicity B-Disease 1
appeared O 0
closely O 0
related O 0
to O 0
a O 0
prolonged O 0
administration O 0
and O 0
higher O 0
total O 0
dose O 0
of O 0
ototoxic B-Disease 1
drugs O 0
, O 0
particularly O 0
aminoglycosides B-Chemical 1
and O 0
furosemide B-Chemical 1
. O 0

Finally O 0
, O 0
we O 0
strongly O 0
recommend O 0
to O 0
prospectively O 0
and O 0
regularly O 0
perform O 0
audiologic O 0
assessment O 0
in O 0
sick O 0
preterm O 0
children O 0
as O 0
hearing B-Disease 1
loss I-Disease 1
is O 0
of O 0
delayed O 0
onset O 0
and O 0
in O 0
most O 0
cases O 0
bilateral O 0
and O 0
severe O 0
. O 0

Seizure B-Disease 1
resulting O 0
from O 0
a O 0
venlafaxine B-Chemical 1
overdose B-Disease 1
. O 0

OBJECTIVE O 0
: O 0
To O 0
report O 0
a O 0
case O 0
of O 0
venlafaxine B-Chemical 1
overdose B-Disease 1
. O 0

CASE O 0
SUMMARY O 0
: O 0
A O 0
40 O 0
- O 0
year O 0
- O 0
old O 0
woman O 0
with O 0
major B-Disease 1
depression I-Disease 1
took O 0
an O 0
overdose B-Disease 1
of O 0
venlafaxine B-Chemical 1
in O 0
an O 0
apparent O 0
suicide O 0
attempt O 0
. O 0

After O 0
the O 0
ingestion O 0
of O 0
26 O 0
venlafaxine B-Chemical 1
50 O 0
- O 0
mg O 0
tablets O 0
, O 0
the O 0
patient O 0
experienced O 0
a O 0
witnessed O 0
generalized O 0
seizure B-Disease 1
. O 0

She O 0
was O 0
admitted O 0
to O 0
the O 0
medical O 0
intensive O 0
care O 0
unit O 0
, O 0
venlafaxine B-Chemical 1
was O 0
discontinued O 0
, O 0
and O 0
no O 0
further O 0
sequelae O 0
were O 0
seen O 0
. O 0

DISCUSSION O 0
: O 0
To O 0
our O 0
knowledge O 0
, O 0
this O 0
is O 0
the O 0
first O 0
reported O 0
case O 0
of O 0
venlafaxine B-Chemical 1
overdose B-Disease 1
that O 0
resulted O 0
in O 0
a O 0
generalized O 0
seizure B-Disease 1
. O 0

Based O 0
on O 0
nonoverdose O 0
pharmacokinetics O 0
and O 0
pharmacodynamics O 0
of O 0
venlafaxine B-Chemical 1
and O 0
the O 0
potential O 0
risks O 0
of O 0
available O 0
interventions O 0
, O 0
no O 0
emergent O 0
therapy O 0
was O 0
instituted O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
venlafaxine B-Chemical 1
overdose B-Disease 1
in O 0
our O 0
patient O 0
resulted O 0
in O 0
a O 0
single O 0
episode O 0
of O 0
generalized O 0
seizure B-Disease 1
but O 0
elicited O 0
no O 0
further O 0
sequelae O 0
. O 0

Combined O 0
effects O 0
of O 0
prolonged O 0
prostaglandin B-Chemical 1
E1 I-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
and O 0
haemodilution B-Disease 1
on O 0
human O 0
hepatic O 0
function O 0
. O 0

Combined O 0
effects O 0
of O 0
prolonged O 0
prostaglandin B-Chemical 1
E1 I-Chemical 1
( O 0
PGE1 B-Chemical 1
) O 0
- O 0
induced O 0
hypotension B-Disease 1
and O 0
haemodilution B-Disease 1
on O 0
hepatic O 0
function O 0
were O 0
studied O 0
in O 0
30 O 0
patients O 0
undergoing O 0
hip O 0
surgery O 0
. O 0

The O 0
patients O 0
were O 0
randomly O 0
allocated O 0
to O 0
one O 0
of O 0
three O 0
groups O 0
; O 0
those O 0
in O 0
group O 0
A O 0
( O 0
n O 0
= O 0
10 O 0
) O 0
were O 0
subjected O 0
to O 0
controlled O 0
hypotension B-Disease 1
alone O 0
, O 0
those O 0
in O 0
group O 0
B O 0
( O 0
n O 0
= O 0
10 O 0
) O 0
to O 0
haemodilution B-Disease 1
alone O 0
and O 0
those O 0
in O 0
group O 0
C O 0
( O 0
n O 0
= O 0
10 O 0
) O 0
to O 0
both O 0
controlled O 0
hypotension B-Disease 1
and O 0
haemodilution B-Disease 1
. O 0

Haemodilution B-Disease 1
in O 0
groups O 0
B O 0
and O 0
C O 0
was O 0
produced O 0
by O 0
withdrawing O 0
approximately O 0
1000 O 0
mL O 0
of O 0
blood O 0
and O 0
replacing O 0
it O 0
with O 0
the O 0
same O 0
amount O 0
of O 0
dextran B-Chemical 1
solution O 0
, O 0
and O 0
final O 0
haematocrit O 0
values O 0
were O 0
21 O 0
or O 0
22 O 0
% O 0
. O 0

Controlled O 0
hypotension B-Disease 1
in O 0
groups O 0
A O 0
and O 0
C O 0
was O 0
induced O 0
with O 0
PGE1 B-Chemical 1
to O 0
maintain O 0
mean O 0
arterial O 0
blood O 0
pressure O 0
at O 0
55 O 0
mmHg O 0
for O 0
180 O 0
min O 0
. O 0

Measurements O 0
included O 0
arterial O 0
ketone O 0
body O 0
ratio O 0
( O 0
AKBR O 0
, O 0
aceto B-Chemical 1
- I-Chemical 1
acetate I-Chemical 1
/ O 0
3 B-Chemical 1
- I-Chemical 1
hydroxybutyrate I-Chemical 1
) O 0
and O 0
clinical O 0
hepatic O 0
function O 0
parameters O 0
. O 0

AKBR O 0
and O 0
biological O 0
hepatic O 0
function O 0
tests O 0
showed O 0
no O 0
change O 0
throughout O 0
the O 0
time O 0
course O 0
in O 0
groups O 0
A O 0
and O 0
B O 0
. O 0

In O 0
group O 0
C O 0
, O 0
AKBR O 0
showed O 0
a O 0
significant O 0
decrease O 0
at O 0
120 O 0
min O 0
( O 0
- O 0
40 O 0
% O 0
) O 0
and O 0
at O 0
180 O 0
min O 0
( O 0
- O 0
49 O 0
% O 0
) O 0
after O 0
the O 0
start O 0
of O 0
hypotension B-Disease 1
and O 0
at O 0
60 O 0
min O 0
( O 0
- O 0
32 O 0
% O 0
) O 0
after O 0
recovery O 0
of O 0
normotension O 0
, O 0
and O 0
SGOT O 0
, O 0
SGPT O 0
, O 0
LDH O 0
and O 0
total O 0
bilirubin B-Chemical 1
showed O 0
significant O 0
increases O 0
after O 0
operation O 0
. O 0

The O 0
results O 0
suggest O 0
that O 0
a O 0
prolonged O 0
combination O 0
of O 0
more O 0
than O 0
120 O 0
min O 0
of O 0
PGE1 B-Chemical 1
- O 0
induced O 0
hypotension B-Disease 1
and O 0
moderate O 0
haemodilution B-Disease 1
would O 0
cause O 0
impairment B-Disease 1
of I-Disease 1
hepatic I-Disease 1
function I-Disease 1
. O 0

Cardiovascular B-Disease 1
alterations I-Disease 1
in O 0
rat O 0
fetuses O 0
exposed O 0
to O 0
calcium B-Chemical 1
channel O 0
blockers O 0
. O 0

Preclinical O 0
toxicologic O 0
investigation O 0
suggested O 0
that O 0
a O 0
new O 0
calcium B-Chemical 1
channel O 0
blocker O 0
, O 0
Ro B-Chemical 1
40 I-Chemical 1
- I-Chemical 1
5967 I-Chemical 1
, O 0
induced O 0
cardiovascular B-Disease 1
alterations I-Disease 1
in O 0
rat O 0
fetuses O 0
exposed O 0
to O 0
this O 0
agent O 0
during O 0
organogenesis O 0
. O 0

The O 0
present O 0
study O 0
was O 0
designed O 0
to O 0
investigate O 0
the O 0
hypothesis O 0
that O 0
calcium B-Chemical 1
channel O 0
blockers O 0
in O 0
general O 0
induce O 0
cardiovascular B-Disease 1
malformations I-Disease 1
indicating O 0
a O 0
pharmacologic O 0
class O 0
effect O 0
. O 0

We O 0
studied O 0
three O 0
calcium B-Chemical 1
channel O 0
blockers O 0
of O 0
different O 0
structure O 0
, O 0
nifedipine B-Chemical 1
, O 0
diltiazem B-Chemical 1
, O 0
and O 0
verapamil B-Chemical 1
, O 0
along O 0
with O 0
the O 0
new O 0
agent O 0
. O 0

Pregnant O 0
rats O 0
were O 0
administered O 0
one O 0
of O 0
these O 0
calcium B-Chemical 1
channel O 0
blockers O 0
during O 0
the O 0
period O 0
of O 0
cardiac O 0
morphogenesis O 0
and O 0
the O 0
offspring O 0
examined O 0
on O 0
day O 0
20 O 0
of O 0
gestation O 0
for O 0
cardiovascular B-Disease 1
malformations I-Disease 1
. O 0

A O 0
low O 0
incidence O 0
of O 0
cardiovascular B-Disease 1
malformations I-Disease 1
was O 0
observed O 0
after O 0
exposure O 0
to O 0
each O 0
of O 0
the O 0
four O 0
calcium B-Chemical 1
channel O 0
blockers O 0
, O 0
but O 0
this O 0
incidence O 0
was O 0
statistically O 0
significant O 0
only O 0
for O 0
verapamil B-Chemical 1
and O 0
nifedipine B-Chemical 1
. O 0

All O 0
four O 0
agents O 0
were O 0
associated O 0
with O 0
aortic O 0
arch O 0
branching O 0
variants O 0
, O 0
although O 0
significantly O 0
increased O 0
only O 0
for O 0
Ro B-Chemical 1
40 I-Chemical 1
- I-Chemical 1
5967 I-Chemical 1
and O 0
verapamil B-Chemical 1
. O 0

The O 0
site O 0
of O 0
common O 0
side O 0
effects O 0
of O 0
sumatriptan B-Chemical 1
. O 0

Atypical B-Disease 1
sensations I-Disease 1
following O 0
the O 0
use O 0
of O 0
subcutaneous O 0
sumatriptan B-Chemical 1
are O 0
common O 0
, O 0
but O 0
of O 0
uncertain O 0
origin O 0
. O 0

They O 0
are O 0
almost O 0
always O 0
benign O 0
, O 0
but O 0
can O 0
be O 0
mistaken O 0
for O 0
a O 0
serious O 0
adverse O 0
event O 0
by O 0
the O 0
patient O 0
. O 0

Two O 0
patients O 0
are O 0
presented O 0
with O 0
tingling B-Disease 1
or I-Disease 1
burning I-Disease 1
sensations I-Disease 1
limited O 0
to O 0
areas O 0
of O 0
heat O 0
exposure O 0
or O 0
sunburn B-Disease 1
. O 0

In O 0
these O 0
individuals O 0
, O 0
side O 0
effects O 0
are O 0
most O 0
likely O 0
generated O 0
superficially O 0
in O 0
the O 0
skin O 0
. O 0

Macula O 0
toxicity B-Disease 1
after O 0
intravitreal O 0
amikacin B-Chemical 1
. O 0

BACKGROUND O 0
: O 0
Although O 0
intravitreal O 0
aminoglycosides B-Chemical 1
have O 0
substantially O 0
improved O 0
visual O 0
prognosis O 0
in O 0
endophthalmitis B-Disease 1
, O 0
macular O 0
infarction B-Disease 1
may O 0
impair O 0
full O 0
visual O 0
recovery O 0
. O 0

METHODS O 0
: O 0
We O 0
present O 0
a O 0
case O 0
of O 0
presumed O 0
amikacin B-Chemical 1
retinal B-Disease 1
toxicity I-Disease 1
following O 0
treatment O 0
with O 0
amikacin B-Chemical 1
and O 0
vancomycin B-Chemical 1
for O 0
alpha O 0
- O 0
haemolytic O 0
streptococcal B-Disease 1
endophthalmitis I-Disease 1
. O 0

RESULTS O 0
: O 0
Endophthalmitis B-Disease 1
resolved O 0
with O 0
improvement O 0
in O 0
visual O 0
acuity O 0
to O 0
6 O 0
/ O 0
24 O 0
at O 0
three O 0
months O 0
. O 0

Fundus O 0
fluorescein B-Chemical 1
angiography O 0
confirmed O 0
macular O 0
capillary O 0
closure O 0
and O 0
telangiectasis B-Disease 1
. O 0

CONCLUSIONS O 0
: O 0
Currently O 0
accepted O 0
intravitreal O 0
antibiotic O 0
regimens O 0
may O 0
cause O 0
retinal B-Disease 1
toxicity I-Disease 1
and O 0
macular O 0
ischaemia B-Disease 1
. O 0

Treatment O 0
strategies O 0
aimed O 0
at O 0
avoiding O 0
retinal B-Disease 1
toxicity I-Disease 1
are O 0
discussed O 0
. O 0

The O 0
role O 0
of O 0
nicotine B-Chemical 1
in O 0
smoking O 0
- O 0
related O 0
cardiovascular B-Disease 1
disease I-Disease 1
. O 0

Nicotine B-Chemical 1
activates O 0
the O 0
sympathetic O 0
nervous O 0
system O 0
and O 0
in O 0
this O 0
way O 0
could O 0
contribute O 0
to O 0
cardiovascular B-Disease 1
disease I-Disease 1
. O 0

Animal O 0
studies O 0
and O 0
mechanistic O 0
studies O 0
indicate O 0
that O 0
nicotine B-Chemical 1
could O 0
play O 0
a O 0
role O 0
in O 0
accelerating O 0
atherosclerosis B-Disease 1
, O 0
but O 0
evidence O 0
among O 0
humans O 0
is O 0
too O 0
inadequate O 0
to O 0
be O 0
definitive O 0
about O 0
such O 0
an O 0
effect O 0
. O 0

Almost O 0
certainly O 0
, O 0
nicotine B-Chemical 1
via O 0
its O 0
hemodynamic O 0
effects O 0
contributes O 0
to O 0
acute O 0
cardiovascular O 0
events O 0
, O 0
although O 0
current O 0
evidence O 0
suggests O 0
that O 0
the O 0
effects O 0
of O 0
nicotine B-Chemical 1
are O 0
much O 0
less O 0
important O 0
than O 0
are O 0
the O 0
prothrombotic O 0
effects O 0
of O 0
cigarette O 0
smoking O 0
or O 0
the O 0
effects O 0
of O 0
carbon B-Chemical 1
monoxide I-Chemical 1
. O 0

Nicotine B-Chemical 1
does O 0
not O 0
appear O 0
to O 0
enhance O 0
thrombosis B-Disease 1
among O 0
humans O 0
. O 0

Clinical O 0
studies O 0
of O 0
pipe O 0
smokers O 0
and O 0
people O 0
using O 0
transdermal O 0
nicotine B-Chemical 1
support O 0
the O 0
idea O 0
that O 0
toxins O 0
other O 0
than O 0
nicotine B-Chemical 1
are O 0
the O 0
most O 0
important O 0
causes O 0
of O 0
acute O 0
cardiovascular O 0
events O 0
. O 0

Finally O 0
, O 0
the O 0
dose O 0
response O 0
for O 0
cardiovascular O 0
events O 0
of O 0
nicotine B-Chemical 1
appears O 0
to O 0
be O 0
flat O 0
, O 0
suggesting O 0
that O 0
if O 0
nicotine B-Chemical 1
is O 0
involved O 0
, O 0
adverse O 0
effects O 0
might O 0
be O 0
seen O 0
with O 0
relatively O 0
low O 0
- O 0
level O 0
cigarette O 0
exposures O 0
. O 0

Iatrogenically O 0
induced O 0
intractable O 0
atrioventricular B-Disease 1
reentrant I-Disease 1
tachycardia I-Disease 1
after O 0
verapamil B-Chemical 1
and O 0
catheter O 0
ablation O 0
in O 0
a O 0
patient O 0
with O 0
Wolff B-Disease 1
- I-Disease 1
Parkinson I-Disease 1
- I-Disease 1
White I-Disease 1
syndrome I-Disease 1
and O 0
idiopathic B-Disease 1
dilated I-Disease 1
cardiomyopathy I-Disease 1
. O 0

In O 0
a O 0
patient O 0
with O 0
WPW B-Disease 1
syndrome I-Disease 1
and O 0
idiopathic B-Disease 1
dilated I-Disease 1
cardiomyopathy I-Disease 1
, O 0
intractable O 0
atrioventricular B-Disease 1
reentrant I-Disease 1
tachycardia I-Disease 1
( O 0
AVRT B-Disease 1
) O 0
was O 0
iatrogenically O 0
induced O 0
. O 0

QRS O 0
without O 0
preexcitation O 0
, O 0
caused O 0
by O 0
junctional O 0
escape O 0
beats O 0
after O 0
verapamil B-Chemical 1
or O 0
unidirectional O 0
antegrade O 0
block O 0
of O 0
accessory O 0
pathway O 0
after O 0
catheter O 0
ablation O 0
, O 0
established O 0
frequent O 0
AVRT B-Disease 1
attack O 0
. O 0

Epidemic O 0
of O 0
liver B-Disease 1
disease I-Disease 1
caused O 0
by O 0
hydrochlorofluorocarbons B-Chemical 1
used O 0
as O 0
ozone B-Chemical 1
- O 0
sparing O 0
substitutes O 0
of O 0
chlorofluorocarbons B-Chemical 1
. O 0

BACKGROUND O 0
: O 0
Hydrochlorofluorocarbons B-Chemical 1
( O 0
HCFCs B-Chemical 1
) O 0
are O 0
used O 0
increasingly O 0
in O 0
industry O 0
as O 0
substitutes O 0
for O 0
ozone B-Chemical 1
- O 0
depleting O 0
chlorofluorocarbons B-Chemical 1
( O 0
CFCs B-Chemical 1
) O 0
. O 0

Limited O 0
studies O 0
in O 0
animals O 0
indicate O 0
potential O 0
hepatotoxicity B-Disease 1
of O 0
some O 0
of O 0
these O 0
compounds O 0
. O 0

We O 0
investigated O 0
an O 0
epidemic O 0
of O 0
liver B-Disease 1
disease I-Disease 1
in O 0
nine O 0
industrial O 0
workers O 0
who O 0
had O 0
had O 0
repeated O 0
accidental O 0
exposure O 0
to O 0
a O 0
mixture O 0
of O 0
1 B-Chemical 1
, I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
dichloro I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
trifluoroethane I-Chemical 1
( O 0
HCFC B-Chemical 1
123 I-Chemical 1
) O 0
and O 0
1 B-Chemical 1
- I-Chemical 1
chloro I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
tetrafluoroethane I-Chemical 1
( O 0
HCFC B-Chemical 1
124 I-Chemical 1
) O 0
. O 0

All O 0
nine O 0
exposed O 0
workers O 0
were O 0
affected O 0
to O 0
various O 0
degrees O 0
. O 0

Both O 0
compounds O 0
are O 0
metabolised O 0
in O 0
the O 0
same O 0
way O 0
as O 0
1 B-Chemical 1
- I-Chemical 1
bromo I-Chemical 1
- I-Chemical 1
1 I-Chemical 1
- I-Chemical 1
chloro I-Chemical 1
- I-Chemical 1
2 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
, I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
trifluoroethane I-Chemical 1
( O 0
halothane B-Chemical 1
) O 0
to O 0
form O 0
reactive O 0
trifluoroacetyl B-Chemical 1
halide O 0
intermediates O 0
, O 0
which O 0
have O 0
been O 0
implicated O 0
in O 0
the O 0
hepatotoxicity B-Disease 1
of O 0
halothane B-Chemical 1
. O 0

We O 0
aimed O 0
to O 0
test O 0
whether O 0
HCFCs B-Chemical 1
123 I-Chemical 1
and I-Chemical 1
124 I-Chemical 1
can O 0
result O 0
in O 0
serious O 0
liver B-Disease 1
disease I-Disease 1
. O 0

METHODS O 0
: O 0
For O 0
one O 0
severely O 0
affected O 0
worker O 0
liver O 0
biopsy O 0
and O 0
immunohistochemical O 0
stainings O 0
for O 0
the O 0
presence O 0
of O 0
trifluoroacetyl B-Chemical 1
protein O 0
adducts O 0
were O 0
done O 0
. O 0

The O 0
serum O 0
of O 0
six O 0
affected O 0
workers O 0
and O 0
five O 0
controls O 0
was O 0
tested O 0
for O 0
autoantibodies O 0
that O 0
react O 0
with O 0
human O 0
liver O 0
cytochrome O 0
- O 0
P450 O 0
2E1 O 0
( O 0
P450 O 0
2E1 O 0
) O 0
and O 0
P58 O 0
protein O 0
disulphide O 0
isomerase O 0
isoform O 0
( O 0
P58 O 0
) O 0
. O 0

FINDINGS O 0
: O 0
The O 0
liver O 0
biopsy O 0
sample O 0
showed O 0
hepatocellular O 0
necrosis B-Disease 1
which O 0
was O 0
prominent O 0
in O 0
perivenular O 0
zone O 0
three O 0
and O 0
extended O 0
focally O 0
from O 0
portal O 0
tracts O 0
to O 0
portal O 0
tracts O 0
and O 0
centrilobular O 0
areas O 0
( O 0
bridging O 0
necrosis B-Disease 1
) O 0
. O 0

Trifluoroacetyl B-Chemical 1
- O 0
adducted O 0
proteins O 0
were O 0
detected O 0
in O 0
surviving O 0
hepatocytes O 0
. O 0

Autoantibodies O 0
against O 0
P450 O 0
2E1 O 0
or O 0
P58 O 0
, O 0
previously O 0
associated O 0
with O 0
halothane B-Disease 1
hepatitis I-Disease 1
, O 0
were O 0
detected O 0
in O 0
the O 0
serum O 0
of O 0
five O 0
affected O 0
workers O 0
. O 0

INTERPRETATION O 0
: O 0
Repeated O 0
exposure O 0
of O 0
human O 0
beings O 0
to O 0
HCFCs B-Chemical 1
123 I-Chemical 1
and I-Chemical 1
124 I-Chemical 1
can O 0
result O 0
in O 0
serious O 0
liver B-Disease 1
injury I-Disease 1
in O 0
a O 0
large O 0
proportion O 0
of O 0
the O 0
exposed O 0
population O 0
. O 0

Although O 0
the O 0
exact O 0
mechanism O 0
of O 0
hepatotoxicity B-Disease 1
of O 0
these O 0
agents O 0
is O 0
not O 0
known O 0
, O 0
the O 0
results O 0
suggest O 0
that O 0
trifluoroacetyl B-Chemical 1
- O 0
altered O 0
liver O 0
proteins O 0
are O 0
involved O 0
. O 0

In O 0
view O 0
of O 0
the O 0
potentially O 0
widespread O 0
use O 0
of O 0
these O 0
compounds O 0
, O 0
there O 0
is O 0
an O 0
urgent O 0
need O 0
to O 0
develop O 0
safer O 0
alternatives O 0
. O 0

Bile B-Disease 1
duct I-Disease 1
hamartoma I-Disease 1
occurring O 0
in O 0
association O 0
with O 0
long O 0
- O 0
term O 0
treatment O 0
with O 0
danazol B-Chemical 1
. O 0

We O 0
report O 0
a O 0
case O 0
of O 0
bile B-Disease 1
duct I-Disease 1
hamartoma I-Disease 1
which O 0
developed O 0
in O 0
a O 0
patient O 0
who O 0
had O 0
been O 0
on O 0
long O 0
- O 0
term O 0
danazol B-Chemical 1
treatment O 0
. O 0

Such O 0
patients O 0
should O 0
be O 0
under O 0
close O 0
follow O 0
- O 0
up O 0
, O 0
preferably O 0
with O 0
periodic O 0
ultrasound O 0
examination O 0
of O 0
the O 0
liver O 0
. O 0

If O 0
the O 0
patient O 0
develops O 0
a O 0
liver B-Disease 1
mass I-Disease 1
, O 0
because O 0
of O 0
non O 0
- O 0
specific O 0
clinical O 0
features O 0
and O 0
imaging O 0
appearances O 0
, O 0
biopsy O 0
may O 0
be O 0
the O 0
only O 0
way O 0
to O 0
achieve O 0
a O 0
definitive O 0
diagnosis O 0
. O 0

Endocrine O 0
screening O 0
in O 0
1 O 0
, O 0
022 O 0
men O 0
with O 0
erectile B-Disease 1
dysfunction I-Disease 1
: O 0
clinical O 0
significance O 0
and O 0
cost O 0
- O 0
effective O 0
strategy O 0
. O 0

PURPOSE O 0
: O 0
We O 0
reviewed O 0
the O 0
results O 0
of O 0
serum O 0
testosterone B-Chemical 1
and O 0
prolactin O 0
determination O 0
in O 0
1 O 0
, O 0
022 O 0
patients O 0
referred O 0
because O 0
of O 0
erectile B-Disease 1
dysfunction I-Disease 1
and O 0
compared O 0
the O 0
data O 0
with O 0
history O 0
, O 0
results O 0
of O 0
physical O 0
examination O 0
, O 0
other O 0
etiological O 0
investigations O 0
and O 0
effects O 0
of O 0
endocrine O 0
therapy O 0
to O 0
refine O 0
the O 0
rules O 0
of O 0
cost O 0
- O 0
effective O 0
endocrine O 0
screening O 0
and O 0
to O 0
pinpoint O 0
actual O 0
responsibility O 0
for O 0
hormonal O 0
abnormalities O 0
. O 0

MATERIALS O 0
AND O 0
METHODS O 0
: O 0
Testosterone B-Chemical 1
and O 0
prolactin O 0
were O 0
determined O 0
by O 0
radioimmunoassay O 0
. O 0

Every O 0
patient O 0
was O 0
screened O 0
for O 0
testosterone B-Chemical 1
and O 0
451 O 0
were O 0
screened O 0
for O 0
prolactin O 0
on O 0
the O 0
basis O 0
of O 0
low B-Disease 1
sexual I-Disease 1
desire I-Disease 1
, O 0
gynecomastia B-Disease 1
or O 0
testosterone B-Chemical 1
less O 0
than O 0
4 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0

Determination O 0
was O 0
repeated O 0
in O 0
case O 0
of O 0
abnormal O 0
first O 0
results O 0
. O 0

Prolactin O 0
results O 0
were O 0
compared O 0
with O 0
those O 0
of O 0
a O 0
previous O 0
personal O 0
cohort O 0
of O 0
1 O 0
, O 0
340 O 0
patients O 0
with O 0
erectile B-Disease 1
dysfunction I-Disease 1
and O 0
systematic O 0
prolactin O 0
determination O 0
. O 0

Main O 0
clinical O 0
criteria O 0
tested O 0
regarding O 0
efficiency O 0
in O 0
hormone O 0
determination O 0
were O 0
low B-Disease 1
sexual I-Disease 1
desire I-Disease 1
, O 0
small O 0
testes O 0
and O 0
gynecomastia B-Disease 1
. O 0

Endocrine O 0
therapy O 0
consisted O 0
of O 0
testosterone B-Chemical 1
heptylate I-Chemical 1
or O 0
human O 0
chorionic O 0
gonadotropin O 0
for O 0
hypogonadism B-Disease 1
and O 0
bromocriptine B-Chemical 1
for O 0
hyperprolactinemia B-Disease 1
. O 0

RESULTS O 0
: O 0
Testosterone B-Chemical 1
was O 0
less O 0
than O 0
3 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0
in O 0
107 O 0
patients O 0
but O 0
normal O 0
in O 0
40 O 0
% O 0
at O 0
repeat O 0
determination O 0
. O 0

The O 0
prevalence O 0
of O 0
repeatedly O 0
low O 0
testosterone B-Chemical 1
increased O 0
with O 0
age O 0
( O 0
4 O 0
% O 0
before O 0
age O 0
50 O 0
years O 0
and O 0
9 O 0
% O 0
50 O 0
years O 0
or O 0
older O 0
) O 0
. O 0

Two O 0
pituitary B-Disease 1
tumors I-Disease 1
were O 0
discovered O 0
after O 0
testosterone B-Chemical 1
determination O 0
. O 0

Most O 0
of O 0
the O 0
other O 0
low O 0
testosterone B-Chemical 1
levels O 0
seemed O 0
to O 0
result O 0
from O 0
nonorganic O 0
hypothalamic B-Disease 1
dysfunction I-Disease 1
because O 0
of O 0
normal O 0
serum O 0
luteinizing O 0
hormone O 0
and O 0
prolactin O 0
and O 0
to O 0
have O 0
only O 0
a O 0
small O 0
role O 0
in O 0
erectile B-Disease 1
dysfunction I-Disease 1
( O 0
definite O 0
improvement O 0
in O 0
only O 0
16 O 0
of O 0
44 O 0
[ O 0
36 O 0
% O 0
] O 0
after O 0
androgen O 0
therapy O 0
, O 0
normal O 0
morning O 0
or O 0
nocturnal O 0
erections O 0
in O 0
30 O 0
% O 0
and O 0
definite O 0
vasculogenic O 0
contributions O 0
in O 0
42 O 0
% O 0
) O 0
. O 0

Determining O 0
testosterone B-Chemical 1
only O 0
in O 0
cases O 0
of O 0
low B-Disease 1
sexual I-Disease 1
desire I-Disease 1
or O 0
abnormal O 0
physical O 0
examination O 0
would O 0
have O 0
missed O 0
40 O 0
% O 0
of O 0
the O 0
cases O 0
with O 0
low O 0
testosterone B-Chemical 1
, O 0
including O 0
37 O 0
% O 0
of O 0
those O 0
subsequently O 0
improved O 0
by O 0
androgen O 0
therapy O 0
. O 0

Prolactin O 0
exceeded O 0
20 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0
in O 0
5 O 0
men O 0
and O 0
was O 0
normal O 0
in O 0
2 O 0
at O 0
repeat O 0
determination O 0
. O 0

Only O 0
1 O 0
prolactinoma B-Disease 1
was O 0
discovered O 0
. O 0

These O 0
data O 0
are O 0
lower O 0
than O 0
those O 0
we O 0
found O 0
during O 0
the O 0
last O 0
2 O 0
decades O 0
( O 0
overall O 0
prolactin O 0
greater O 0
than O 0
20 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0
in O 0
1 O 0
. O 0
86 O 0
% O 0
of O 0
1 O 0
, O 0
821 O 0
patients O 0
, O 0
prolactinomas B-Disease 1
in O 0
7 O 0
, O 0
0 O 0
. O 0
38 O 0
% O 0
) O 0
. O 0

Bromocriptine B-Chemical 1
was O 0
definitely O 0
effective O 0
in O 0
cases O 0
with O 0
prolactin O 0
greater O 0
than O 0
35 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0

( O 0
8 O 0
of O 0
12 O 0
compared O 0
to O 0
only O 0
9 O 0
of O 0
22 O 0
cases O 0
with O 0
prolactin O 0
between O 0
20 O 0
and O 0
35 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0
) O 0
. O 0

Testosterone B-Chemical 1
was O 0
low O 0
in O 0
less O 0
than O 0
50 O 0
% O 0
of O 0
cases O 0
with O 0
prolactin O 0
greater O 0
than O 0
35 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0

CONCLUSIONS O 0
: O 0
Low O 0
prevalences O 0
and O 0
effects O 0
of O 0
low O 0
testosterone B-Chemical 1
and O 0
high O 0
prolactin O 0
in O 0
erectile B-Disease 1
dysfunction I-Disease 1
cannot O 0
justify O 0
their O 0
routine O 0
determination O 0
. O 0

However O 0
, O 0
cost O 0
- O 0
effective O 0
screening O 0
strategies O 0
recommended O 0
so O 0
far O 0
missed O 0
40 O 0
to O 0
50 O 0
% O 0
of O 0
cases O 0
improved O 0
with O 0
endocrine O 0
therapy O 0
and O 0
the O 0
pituitary B-Disease 1
tumors I-Disease 1
. O 0

We O 0
now O 0
advocate O 0
that O 0
before O 0
age O 0
50 O 0
years O 0
testosterone B-Chemical 1
be O 0
determined O 0
only O 0
in O 0
cases O 0
of O 0
low B-Disease 1
sexual I-Disease 1
desire I-Disease 1
and O 0
abnormal O 0
physical O 0
examination O 0
but O 0
that O 0
it O 0
be O 0
measured O 0
in O 0
all O 0
men O 0
older O 0
than O 0
50 O 0
years O 0
. O 0

Prolactin O 0
should O 0
be O 0
determined O 0
only O 0
in O 0
cases O 0
of O 0
low B-Disease 1
sexual I-Disease 1
desire I-Disease 1
, O 0
gynecomastia B-Disease 1
and O 0
/ O 0
or O 0
testosterone B-Chemical 1
less O 0
than O 0
4 O 0
ng O 0
. O 0
/ O 0
ml O 0
. O 0

Extrapyramidal O 0
side O 0
effects O 0
with O 0
risperidone B-Chemical 1
and O 0
haloperidol B-Chemical 1
at O 0
comparable O 0
D2 O 0
receptor O 0
occupancy O 0
levels O 0
. O 0

Risperidone B-Chemical 1
is O 0
an O 0
antipsychotic O 0
drug O 0
with O 0
high O 0
affinity O 0
at O 0
dopamine B-Chemical 1
D2 O 0
and O 0
serotonin B-Chemical 1
5 I-Chemical 1
- I-Chemical 1
HT2 I-Chemical 1
receptors O 0
. O 0

Previous O 0
clinical O 0
studies O 0
have O 0
proposed O 0
that O 0
risperidone B-Chemical 1
' O 0
s O 0
pharmacologic O 0
profile O 0
may O 0
produce O 0
improved O 0
efficacy O 0
for O 0
negative O 0
psychotic B-Disease 1
symptoms I-Disease 1
and O 0
decreased O 0
propensity O 0
for O 0
extrapyramidal O 0
side O 0
effects O 0
; O 0
features O 0
shared O 0
by O 0
so O 0
- O 0
called O 0
' O 0
atypical O 0
' O 0
neuroleptics O 0
. O 0

To O 0
determine O 0
if O 0
routine O 0
risperidone B-Chemical 1
treatment O 0
is O 0
associated O 0
with O 0
a O 0
unique O 0
degree O 0
of O 0
D2 O 0
receptor O 0
occupancy O 0
and O 0
pattern O 0
of O 0
clinical O 0
effects O 0
, O 0
we O 0
used O 0
[ O 0
123I O 0
] O 0
IBZM O 0
SPECT O 0
to O 0
determine O 0
D2 O 0
occupancy O 0
in O 0
subjects O 0
treated O 0
with O 0
routine O 0
clinical O 0
doses O 0
of O 0
risperidone B-Chemical 1
( O 0
n O 0
= O 0
12 O 0
) O 0
or O 0
haloperidol B-Chemical 1
( O 0
n O 0
= O 0
7 O 0
) O 0
. O 0

Both O 0
risperidone B-Chemical 1
and O 0
haloperidol B-Chemical 1
produced O 0
D2 O 0
occupancy O 0
levels O 0
between O 0
approximately O 0
60 O 0
and O 0
90 O 0
% O 0
at O 0
standard O 0
clinical O 0
doses O 0
. O 0

There O 0
was O 0
no O 0
significant O 0
difference O 0
between O 0
occupancy O 0
levels O 0
obtained O 0
with O 0
haloperidol B-Chemical 1
or O 0
risperidone B-Chemical 1
. O 0

Drug B-Disease 1
- I-Disease 1
induced I-Disease 1
parkinsonism I-Disease 1
was O 0
observed O 0
in O 0
subjects O 0
treated O 0
with O 0
risperidone B-Chemical 1
( O 0
42 O 0
% O 0
) O 0
and O 0
haloperidol B-Chemical 1
( O 0
29 O 0
% O 0
) O 0
and O 0
was O 0
observed O 0
at O 0
occupancy O 0
levels O 0
above O 0
60 O 0
% O 0
. O 0

Based O 0
on O 0
these O 0
observations O 0
, O 0
it O 0
is O 0
concluded O 0
that O 0
5 O 0
- O 0
HT2 O 0
blockade O 0
obtained O 0
with O 0
risperidone B-Chemical 1
at O 0
D2 O 0
occupancy O 0
rates O 0
of O 0
60 O 0
% O 0
and O 0
above O 0
does O 0
not O 0
appear O 0
to O 0
protect O 0
against O 0
the O 0
risk O 0
for O 0
extrapyramidal O 0
side O 0
effects O 0
. O 0

Treatment O 0
of O 0
previously O 0
treated O 0
metastatic O 0
breast B-Disease 1
cancer I-Disease 1
by O 0
mitoxantrone B-Chemical 1
and O 0
48 O 0
- O 0
hour O 0
continuous O 0
infusion O 0
of O 0
high O 0
- O 0
dose O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
and O 0
leucovorin B-Chemical 1
( O 0
MFL B-Chemical 1
) O 0
: O 0
low O 0
palliative O 0
benefit O 0
and O 0
high O 0
treatment O 0
- O 0
related O 0
toxicity B-Disease 1
. O 0

For O 0
previously O 0
treated O 0
advanced O 0
breast B-Disease 1
cancer I-Disease 1
, O 0
there O 0
is O 0
no O 0
standard O 0
second O 0
- O 0
line O 0
therapy O 0
. O 0

Combination O 0
chemotherapy O 0
with O 0
mitoxantrone B-Chemical 1
, O 0
high O 0
- O 0
dose O 0
5 B-Chemical 1
- I-Chemical 1
fluorouracil I-Chemical 1
( O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
) O 0
and O 0
leucovorin B-Chemical 1
( O 0
MFL B-Chemical 1
regimen I-Chemical 1
) O 0
had O 0
been O 0
reported O 0
as O 0
an O 0
effective O 0
and O 0
well O 0
tolerated O 0
regimen O 0
. O 0

From O 0
October O 0
1993 O 0
to O 0
November O 0
1995 O 0
, O 0
we O 0
treated O 0
13 O 0
patients O 0
with O 0
previously O 0
chemotherapy O 0
- O 0
treated O 0
metastatic O 0
breast B-Disease 1
cancer I-Disease 1
by O 0
mitoxantrone B-Chemical 1
, O 0
12 O 0
mg O 0
/ O 0
m2 O 0
, O 0
on O 0
day O 0
1 O 0
and O 0
continuous O 0
infusion O 0
of O 0
5 B-Chemical 1
- I-Chemical 1
FU I-Chemical 1
, O 0
3000 O 0
mg O 0
/ O 0
m2 O 0
, O 0
together O 0
with O 0
leucovorin B-Chemical 1
, O 0
300 O 0
mg O 0
/ O 0
m2 O 0
, O 0
for O 0
48 O 0
h O 0
from O 0
day O 0
1 O 0
to O 0
2 O 0
. O 0

Each O 0
course O 0
of O 0
chemotherapy O 0
was O 0
given O 0
every O 0
4 O 0
weeks O 0
. O 0

Most O 0
of O 0
these O 0
patients O 0
had O 0
more O 0
than O 0
two O 0
metastatic O 0
sites O 0
, O 0
with O 0
lung O 0
metastasis O 0
predominant O 0
. O 0

Seven O 0
patients O 0
had O 0
been O 0
treated O 0
with O 0
anthracycline B-Chemical 1
. O 0

Seven O 0
patients O 0
had O 0
previously O 0
received O 0
radiotherapy O 0
and O 0
seven O 0
had O 0
received O 0
hormone O 0
therapy O 0
. O 0

Median O 0
number O 0
of O 0
courses O 0
of O 0
MFL B-Chemical 1
regimen I-Chemical 1
given O 0
was O 0
six O 0
and O 0
the O 0
median O 0
cumulative O 0
dose O 0
of O 0
mitoxantrone B-Chemical 1
was O 0
68 O 0
. O 0
35 O 0
mg O 0
/ O 0
m2 O 0
. O 0

One O 0
patient O 0
had O 0
complete O 0
response O 0
, O 0
seven O 0
had O 0
stable O 0
disease O 0
, O 0
none O 0
had O 0
partial O 0
response O 0
and O 0
five O 0
had O 0
progressive O 0
disease O 0
. O 0

The O 0
overall O 0
objective O 0
response O 0
rate O 0
was O 0
7 O 0
. O 0
6 O 0
% O 0
. O 0

The O 0
median O 0
follow O 0
- O 0
up O 0
period O 0
was O 0
14 O 0
months O 0
. O 0

Median O 0
survival O 0
was O 0
16 O 0
months O 0
. O 0

Median O 0
progression O 0
- O 0
free O 0
survival O 0
was O 0
5 O 0
months O 0
. O 0

A O 0
complete O 0
responder O 0
had O 0
relapse O 0
- O 0
free O 0
survival O 0
up O 0
to O 0
17 O 0
months O 0
. O 0

Major O 0
toxicities B-Disease 1
were O 0
cardiotoxicity B-Disease 1
and O 0
leukopenia B-Disease 1
. O 0

Eight O 0
patients O 0
were O 0
dead O 0
in O 0
the O 0
last O 0
follow O 0
- O 0
up O 0
; O 0
two O 0
of O 0
them O 0
died O 0
of O 0
treatment O 0
- O 0
related O 0
toxicity B-Disease 1
. O 0

The O 0
MFL B-Chemical 1
regimen I-Chemical 1
achieves O 0
little O 0
palliative O 0
benefit O 0
and O 0
induces O 0
severe O 0
toxicity B-Disease 1
at O 0
a O 0
fairly O 0
high O 0
rate O 0
. O 0

Administration O 0
of O 0
this O 0
regimen O 0
to O 0
breast B-Disease 1
cancer I-Disease 1
patients O 0
who O 0
have O 0
been O 0
treated O 0
by O 0
chemotherapy O 0
and O 0
those O 0
with O 0
impaired B-Disease 1
heart I-Disease 1
function I-Disease 1
requires O 0
careful O 0
attention O 0
. O 0

Ticlopidine B-Chemical 1
- O 0
induced O 0
aplastic B-Disease 1
anemia I-Disease 1
: O 0
report O 0
of O 0
three O 0
Chinese O 0
patients O 0
and O 0
review O 0
of O 0
the O 0
literature O 0
. O 0

In O 0
this O 0
study O 0
, O 0
three O 0
Chinese O 0
patients O 0
with O 0
ticlopidine B-Chemical 1
- O 0
induced O 0
aplastic B-Disease 1
anemia I-Disease 1
were O 0
reported O 0
and O 0
another O 0
13 O 0
patients O 0
in O 0
the O 0
English O 0
literature O 0
were O 0
reviewed O 0
. O 0

We O 0
attempted O 0
to O 0
find O 0
underlying O 0
similarities O 0
, O 0
evaluate O 0
the O 0
risk O 0
factors O 0
, O 0
and O 0
identify O 0
appropriate O 0
treatment O 0
for O 0
this O 0
complication O 0
. O 0

All O 0
but O 0
one O 0
of O 0
the O 0
patients O 0
were O 0
over O 0
60 O 0
years O 0
old O 0
, O 0
and O 0
the O 0
6 O 0
who O 0
died O 0
were O 0
all O 0
older O 0
than O 0
65 O 0
. O 0

Therefore O 0
, O 0
old O 0
age O 0
may O 0
be O 0
a O 0
risk O 0
factor O 0
for O 0
developing O 0
this O 0
complication O 0
. O 0

Agranulocytosis B-Disease 1
occurred O 0
3 O 0
- O 0
20 O 0
weeks O 0
after O 0
initiation O 0
of O 0
ticlopidine B-Chemical 1
, O 0
so O 0
frequent O 0
examination O 0
of O 0
white O 0
cell O 0
count O 0
during O 0
treatment O 0
is O 0
recommended O 0
. O 0

There O 0
seemed O 0
to O 0
be O 0
no O 0
direct O 0
correlation O 0
between O 0
the O 0
dose O 0
or O 0
duration O 0
used O 0
and O 0
the O 0
severity O 0
of O 0
bone B-Disease 1
marrow I-Disease 1
suppression I-Disease 1
. O 0

Treatment O 0
for O 0
ticlopidine B-Chemical 1
- O 0
induced O 0
aplastic B-Disease 1
anemia I-Disease 1
with O 0
colony O 0
- O 0
stimulating O 0
factors O 0
seemed O 0
to O 0
have O 0
little O 0
effect O 0
. O 0

The O 0
fact O 0
that O 0
5 O 0
of O 0
the O 0
6 O 0
patients O 0
who O 0
received O 0
concurrent O 0
calcium B-Chemical 1
channel O 0
blockers O 0
died O 0
, O 0
should O 0
alert O 0
clinicians O 0
to O 0
be O 0
more O 0
cautious O 0
when O 0
using O 0
these O 0
two O 0
drugs O 0
simultaneously O 0
. O 0

Upregulation O 0
of O 0
the O 0
expression O 0
of O 0
vasopressin B-Chemical 1
gene O 0
in O 0
the O 0
paraventricular O 0
and O 0
supraoptic O 0
nuclei O 0
of O 0
the O 0
lithium B-Chemical 1
- O 0
induced O 0
diabetes B-Disease 1
insipidus I-Disease 1
rat O 0
. O 0

The O 0
expression O 0
of O 0
arginine B-Chemical 1
vasopressin I-Chemical 1
( O 0
AVP B-Chemical 1
) O 0
gene O 0
in O 0
the O 0
paraventricular O 0
( O 0
PVN O 0
) O 0
and O 0
supraoptic O 0
nuclei O 0
( O 0
SON O 0
) O 0
was O 0
investigated O 0
in O 0
rats O 0
with O 0
lithium B-Chemical 1
( O 0
Li B-Chemical 1
) O 0
- O 0
induced O 0
polyuria B-Disease 1
, O 0
using O 0
in O 0
situ O 0
hybridization O 0
histochemistry O 0
and O 0
radioimmunoassay O 0
. O 0

The O 0
male O 0
Wistar O 0
rats O 0
consuming O 0
a O 0
diet O 0
that O 0
contained O 0
LiCl B-Chemical 1
( O 0
60 O 0
mmol O 0
/ O 0
kg O 0
) O 0
for O 0
4 O 0
weeks O 0
developed O 0
marked O 0
polyuria B-Disease 1
. O 0

The O 0
Li B-Chemical 1
- O 0
treated O 0
rats O 0
produced O 0
a O 0
large O 0
volume O 0
of O 0
hypotonic O 0
urine O 0
with O 0
low O 0
ionic O 0
concentrations O 0
. O 0

Plasma O 0
sodium B-Chemical 1
concentrations O 0
were O 0
found O 0
to O 0
be O 0
slightly O 0
increased O 0
in O 0
the O 0
Li B-Chemical 1
- O 0
treated O 0
rats O 0
compared O 0
with O 0
those O 0
in O 0
controls O 0
. O 0

Plasma O 0
concentration O 0
of O 0
AVP B-Chemical 1
and O 0
transcripts O 0
of O 0
AVP B-Chemical 1
gene O 0
in O 0
the O 0
PVN O 0
and O 0
SON O 0
were O 0
significantly O 0
increased O 0
in O 0
the O 0
Li B-Chemical 1
- O 0
treated O 0
rats O 0
compared O 0
with O 0
controls O 0
. O 0

These O 0
results O 0
suggest O 0
that O 0
dehydration B-Disease 1
and O 0
/ O 0
or O 0
the O 0
activation O 0
of O 0
visceral O 0
afferent O 0
inputs O 0
may O 0
contribute O 0
to O 0
the O 0
elevation O 0
of O 0
plasma O 0
AVP B-Chemical 1
and O 0
the O 0
upregulation O 0
of O 0
AVP B-Chemical 1
gene O 0
expression O 0
in O 0
the O 0
PVN O 0
and O 0
the O 0
SON O 0
of O 0
the O 0
Li B-Chemical 1
- O 0
induced O 0
diabetes B-Disease 1
insipidus I-Disease 1
rat O 0
. O 0

Antinociceptive O 0
and O 0
antiamnesic O 0
properties O 0
of O 0
the O 0
presynaptic O 0
cholinergic O 0
amplifier O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
. O 0

The O 0
antinociceptive O 0
effect O 0
of O 0
3 B-Chemical 1
alpha I-Chemical 1
- I-Chemical 1
tropyl I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
p I-Chemical 1
- I-Chemical 1
bromophenyl I-Chemical 1
) I-Chemical 1
propionate I-Chemical 1
[ O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
] O 0
( O 0
10 O 0
- O 0
40 O 0
mg O 0
kg O 0
- O 0
1 O 0
s O 0
. O 0
c O 0
. O 0
; O 0
30 O 0
- O 0
60 O 0
mg O 0
kg O 0
- O 0
1 O 0
p O 0
. O 0
o O 0
. O 0
; O 0
10 O 0
- O 0
30 O 0
mg O 0
kg O 0
- O 0
1 O 0
i O 0
. O 0
v O 0
. O 0
; O 0
10 O 0
- O 0
30 O 0
micrograms O 0
/ O 0
mouse O 0
i O 0
. O 0
c O 0
. O 0
v O 0
. O 0
) O 0
was O 0
examined O 0
in O 0
mice O 0
, O 0
rats O 0
and O 0
guinea O 0
pigs O 0
by O 0
use O 0
of O 0
the O 0
hot O 0
- O 0
plate O 0
, O 0
abdominal O 0
- O 0
constriction O 0
, O 0
tail O 0
- O 0
flick O 0
and O 0
paw O 0
- O 0
pressure O 0
tests O 0
. O 0

( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
antinociception O 0
peaked O 0
15 O 0
min O 0
after O 0
injection O 0
and O 0
then O 0
slowly O 0
diminished O 0
. O 0

The O 0
antinociception O 0
produced O 0
by O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
was O 0
prevented O 0
by O 0
the O 0
unselective O 0
muscarinic O 0
antagonist O 0
atropine B-Chemical 1
, O 0
the O 0
M1 O 0
- O 0
selective O 0
antagonists O 0
pirenzepine B-Chemical 1
and O 0
dicyclomine B-Chemical 1
and O 0
the O 0
acetylcholine B-Chemical 1
depletor O 0
hemicholinium B-Chemical 1
- I-Chemical 1
3 I-Chemical 1
, O 0
but O 0
not O 0
by O 0
the O 0
opioid O 0
antagonist O 0
naloxone B-Chemical 1
, O 0
the O 0
gamma B-Chemical 1
- I-Chemical 1
aminobutyric I-Chemical 1
acidB I-Chemical 1
antagonist O 0
3 B-Chemical 1
- I-Chemical 1
aminopropyl I-Chemical 1
- I-Chemical 1
diethoxy I-Chemical 1
- I-Chemical 1
methyl I-Chemical 1
- I-Chemical 1
phosphinic I-Chemical 1
acid I-Chemical 1
, O 0
the O 0
H3 O 0
agonist O 0
R B-Chemical 1
- I-Chemical 1
( I-Chemical 1
alpha I-Chemical 1
) I-Chemical 1
- I-Chemical 1
methylhistamine I-Chemical 1
, O 0
the O 0
D2 O 0
antagonist O 0
quinpirole B-Chemical 1
, O 0
the O 0
5 B-Chemical 1
- I-Chemical 1
hydroxytryptamine4 I-Chemical 1
antagonist O 0
2 B-Chemical 1
- I-Chemical 1
methoxy I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
amino I-Chemical 1
- I-Chemical 1
5 I-Chemical 1
- I-Chemical 1
chlorobenzoic I-Chemical 1
acid I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
diethylamino I-Chemical 1
) I-Chemical 1
ethyl I-Chemical 1
ester I-Chemical 1
hydrochloride O 0
, O 0
the O 0
5 B-Chemical 1
- I-Chemical 1
hydroxytryptamin1A I-Chemical 1
antagonist O 0
1 B-Chemical 1
- I-Chemical 1
( I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
methoxyphenyl I-Chemical 1
) I-Chemical 1
- I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
[ I-Chemical 1
4 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
phthalimido I-Chemical 1
) I-Chemical 1
butyl I-Chemical 1
] I-Chemical 1
piperazine I-Chemical 1
hydrobromide O 0
and O 0
the O 0
polyamines O 0
depletor O 0
reserpine B-Chemical 1
. O 0

Based O 0
on O 0
these O 0
data O 0
, O 0
it O 0
can O 0
be O 0
postulated O 0
that O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
exerted O 0
an O 0
antinociceptive O 0
effect O 0
mediated O 0
by O 0
a O 0
central O 0
potentiation O 0
of O 0
cholinergic O 0
transmission O 0
. O 0

( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
( O 0
10 O 0
- O 0
40 O 0
mg O 0
kg O 0
- O 0
1 O 0
i O 0
. O 0
p O 0
. O 0
) O 0
was O 0
able O 0
to O 0
prevent O 0
amnesia B-Disease 1
induced O 0
by O 0
scopolamine B-Chemical 1
( O 0
1 O 0
mg O 0
kg O 0
- O 0
1 O 0
i O 0
. O 0
p O 0
. O 0
) O 0
and O 0
dicyclomine B-Chemical 1
( O 0
2 O 0
mg O 0
kg O 0
- O 0
1 O 0
i O 0
. O 0
p O 0
. O 0
) O 0
in O 0
the O 0
mouse O 0
passive O 0
- O 0
avoidance O 0
test O 0
. O 0

Affinity O 0
profiles O 0
of O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
for O 0
muscarinic O 0
receptor O 0
subtypes O 0
, O 0
determined O 0
by O 0
functional O 0
studies O 0
( O 0
rabbit O 0
vas O 0
deferens O 0
for O 0
M1 O 0
, O 0
guinea O 0
pig O 0
atrium O 0
for O 0
M2 O 0
, O 0
guinea O 0
pig O 0
ileum O 0
for O 0
M3 O 0
and O 0
immature O 0
guinea O 0
pig O 0
uterus O 0
for O 0
putative O 0
M4 O 0
) O 0
, O 0
have O 0
shown O 0
an O 0
M4 O 0
/ O 0
M1 O 0
selectivity O 0
ratio O 0
of O 0
10 O 0
. O 0
2 O 0
that O 0
might O 0
be O 0
responsible O 0
for O 0
the O 0
antinociception O 0
and O 0
the O 0
anti O 0
- O 0
amnesic B-Disease 1
effect O 0
induced O 0
by O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
through O 0
an O 0
increase O 0
in O 0
acetylcholine B-Chemical 1
extracellular O 0
levels O 0
. O 0

In O 0
the O 0
antinociceptive O 0
and O 0
antiamnesic O 0
dose O 0
range O 0
, O 0
( O 0
+ O 0
/ O 0
- O 0
) O 0
- O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
did O 0
not O 0
impair O 0
mouse O 0
performance O 0
evaluated O 0
by O 0
the O 0
rota O 0
- O 0
rod O 0
test O 0
and O 0
Animex O 0
apparatus O 0
. O 0

The O 0
effect O 0
of O 0
different O 0
anaesthetic O 0
agents O 0
in O 0
hearing B-Disease 1
loss I-Disease 1
following O 0
spinal O 0
anaesthesia O 0
. O 0

The O 0
cause O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
after O 0
spinal O 0
anaesthesia O 0
is O 0
unknown O 0
. O 0

Up O 0
until O 0
now O 0
, O 0
the O 0
only O 0
factor O 0
studied O 0
has O 0
been O 0
the O 0
effect O 0
of O 0
the O 0
diameter O 0
of O 0
the O 0
spinal O 0
needle O 0
on O 0
post O 0
- O 0
operative O 0
sensorineural B-Disease 1
hearing I-Disease 1
loss I-Disease 1
. O 0

The O 0
aim O 0
of O 0
this O 0
study O 0
was O 0
to O 0
describe O 0
this O 0
hearing B-Disease 1
loss I-Disease 1
and O 0
to O 0
investigate O 0
other O 0
factors O 0
influencing O 0
the O 0
degree O 0
of O 0
hearing B-Disease 1
loss I-Disease 1
. O 0

Two O 0
groups O 0
of O 0
22 O 0
similar O 0
patients O 0
were O 0
studied O 0
: O 0
one O 0
group O 0
received O 0
6 O 0
mL O 0
prilocaine B-Chemical 1
2 O 0
% O 0
; O 0
and O 0
the O 0
other O 0
received O 0
3 O 0
mL O 0
bupivacaine B-Chemical 1
0 O 0
. O 0
5 O 0
% O 0
. O 0

Patients O 0
given O 0
prilocaine B-Chemical 1
were O 0
more O 0
likely O 0
to O 0
develop O 0
hearing B-Disease 1
loss I-Disease 1
( O 0
10 O 0
out O 0
of O 0
22 O 0
) O 0
than O 0
those O 0
given O 0
bupivacaine B-Chemical 1
( O 0
4 O 0
out O 0
of O 0
22 O 0
) O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

The O 0
average O 0
hearing B-Disease 1
loss I-Disease 1
for O 0
speech O 0
frequencies O 0
was O 0
about O 0
10 O 0
dB O 0
after O 0
prilocaine B-Chemical 1
and O 0
15 O 0
dB O 0
after O 0
bupivacaine B-Chemical 1
. O 0

None O 0
of O 0
the O 0
patients O 0
complained O 0
of O 0
subjective O 0
hearing B-Disease 1
loss I-Disease 1
. O 0

Long O 0
- O 0
term O 0
follow O 0
- O 0
up O 0
of O 0
the O 0
patients O 0
was O 0
not O 0
possible O 0
. O 0

A O 0
transient O 0
neurological B-Disease 1
deficit I-Disease 1
following O 0
intrathecal O 0
injection O 0
of O 0
1 O 0
% O 0
hyperbaric O 0
bupivacaine B-Chemical 1
for O 0
unilateral O 0
spinal O 0
anaesthesia O 0
. O 0

We O 0
describe O 0
a O 0
case O 0
of O 0
transient O 0
neurological B-Disease 1
deficit I-Disease 1
that O 0
occurred O 0
after O 0
unilateral O 0
spinal O 0
anaesthesia O 0
with O 0
8 O 0
mg O 0
of O 0
1 O 0
% O 0
hyperbaric O 0
bupivacaine B-Chemical 1
slowly O 0
injected O 0
through O 0
a O 0
25 O 0
- O 0
gauge O 0
pencil O 0
- O 0
point O 0
spinal O 0
needle O 0
. O 0

The O 0
surgery O 0
and O 0
anaesthesia O 0
were O 0
uneventful O 0
, O 0
but O 0
3 O 0
days O 0
after O 0
surgery O 0
, O 0
the O 0
patient O 0
reported O 0
an O 0
area O 0
of O 0
hypoaesthesia O 0
over O 0
L3 O 0
- O 0
L4 O 0
dermatomes O 0
of O 0
the O 0
leg O 0
which O 0
had O 0
been O 0
operated O 0
on O 0
( O 0
loss B-Disease 1
of I-Disease 1
pinprick I-Disease 1
sensation I-Disease 1
) O 0
without O 0
reduction O 0
in O 0
muscular O 0
strength O 0
. O 0

Sensation O 0
in O 0
this O 0
area O 0
returned O 0
to O 0
normal O 0
over O 0
the O 0
following O 0
2 O 0
weeks O 0
. O 0

Prospective O 0
multicentre O 0
studies O 0
with O 0
a O 0
large O 0
population O 0
and O 0
a O 0
long O 0
follow O 0
- O 0
up O 0
should O 0
be O 0
performed O 0
in O 0
order O 0
to O 0
evaluate O 0
the O 0
incidence O 0
of O 0
this O 0
unusual O 0
side O 0
effect O 0
. O 0

However O 0
, O 0
we O 0
suggest O 0
that O 0
a O 0
low O 0
solution O 0
concentration O 0
should O 0
be O 0
preferred O 0
for O 0
unilateral O 0
spinal O 0
anaesthesia O 0
with O 0
a O 0
hyperbaric O 0
anaesthetic O 0
solution O 0
( O 0
if O 0
pencil O 0
- O 0
point O 0
needle O 0
and O 0
slow O 0
injection O 0
rate O 0
are O 0
employed O 0
) O 0
, O 0
in O 0
order O 0
to O 0
minimize O 0
the O 0
risk O 0
of O 0
a O 0
localized O 0
high O 0
peak O 0
anaesthetic O 0
concentration O 0
, O 0
which O 0
might O 0
lead O 0
to O 0
a O 0
transient O 0
neurological B-Disease 1
deficit I-Disease 1
. O 0

Transient B-Disease 1
neurologic I-Disease 1
symptoms I-Disease 1
after O 0
spinal O 0
anesthesia O 0
: O 0
a O 0
lower O 0
incidence O 0
with O 0
prilocaine B-Chemical 1
and O 0
bupivacaine B-Chemical 1
than O 0
with O 0
lidocaine B-Chemical 1
. O 0

BACKGROUND O 0
: O 0
Recent O 0
evidence O 0
suggests O 0
that O 0
transient B-Disease 1
neurologic I-Disease 1
symptoms I-Disease 1
( O 0
TNSs B-Disease 1
) O 0
frequently O 0
follow O 0
lidocaine B-Chemical 1
spinal O 0
anesthesia O 0
but O 0
are O 0
infrequent O 0
with O 0
bupivacaine B-Chemical 1
. O 0

However O 0
, O 0
identification O 0
of O 0
a O 0
short O 0
- O 0
acting O 0
local O 0
anesthetic O 0
to O 0
substitute O 0
for O 0
lidocaine B-Chemical 1
for O 0
brief O 0
surgical O 0
procedures O 0
remains O 0
an O 0
important O 0
goal O 0
. O 0

Prilocaine B-Chemical 1
is O 0
an O 0
amide O 0
local O 0
anesthetic O 0
with O 0
a O 0
duration O 0
of O 0
action O 0
similar O 0
to O 0
that O 0
of O 0
lidocaine B-Chemical 1
. O 0

Accordingly O 0
, O 0
the O 0
present O 0
, O 0
prospective O 0
double O 0
- O 0
blind O 0
study O 0
compares O 0
prilocaine B-Chemical 1
with O 0
lidocaine B-Chemical 1
and O 0
bupivacaine B-Chemical 1
with O 0
respect O 0
to O 0
duration O 0
of O 0
action O 0
and O 0
relative O 0
risk O 0
of O 0
TNSs B-Disease 1
. O 0

METHODS O 0
: O 0
Ninety O 0
patients O 0
classified O 0
as O 0
American O 0
Society O 0
of O 0
Anesthesiologists O 0
physical O 0
status O 0
I O 0
or O 0
II O 0
who O 0
were O 0
scheduled O 0
for O 0
short O 0
gynecologic O 0
procedures O 0
under O 0
spinal O 0
anesthesia O 0
were O 0
randomly O 0
allocated O 0
to O 0
receive O 0
2 O 0
. O 0
5 O 0
ml O 0
2 O 0
% O 0
lidocaine B-Chemical 1
in O 0
7 O 0
. O 0
5 O 0
% O 0
glucose B-Chemical 1
, O 0
2 O 0
% O 0
prilocaine B-Chemical 1
in O 0
7 O 0
. O 0
5 O 0
% O 0
glucose B-Chemical 1
, O 0
or O 0
0 O 0
. O 0
5 O 0
% O 0
bupivacaine B-Chemical 1
in O 0
7 O 0
. O 0
5 O 0
% O 0
glucose B-Chemical 1
. O 0

All O 0
solutions O 0
were O 0
provided O 0
in O 0
blinded O 0
vials O 0
by O 0
the O 0
hospital O 0
pharmacy O 0
. O 0

Details O 0
of O 0
spinal O 0
puncture O 0
, O 0
extension O 0
and O 0
regression O 0
of O 0
spinal O 0
block O 0
, O 0
and O 0
the O 0
times O 0
to O 0
reach O 0
discharge O 0
criteria O 0
were O 0
noted O 0
. O 0

In O 0
the O 0
evening O 0
of O 0
postoperative O 0
day O 0
1 O 0
, O 0
patients O 0
were O 0
evaluated O 0
for O 0
TNSs B-Disease 1
by O 0
a O 0
physician O 0
unaware O 0
of O 0
the O 0
drug O 0
administered O 0
and O 0
the O 0
details O 0
of O 0
the O 0
anesthetic O 0
procedure O 0
. O 0

RESULTS O 0
: O 0
Nine O 0
of O 0
30 O 0
patients O 0
receiving O 0
lidocaine B-Chemical 1
experienced O 0
TNSs B-Disease 1
, O 0
1 O 0
of O 0
30 O 0
patients O 0
receiving O 0
prilocaine B-Chemical 1
( O 0
P O 0
= O 0
0 O 0
. O 0
03 O 0
) O 0
had O 0
them O 0
, O 0
and O 0
none O 0
of O 0
30 O 0
patients O 0
receiving O 0
bupivacaine B-Chemical 1
had O 0
TNSs B-Disease 1
. O 0

Times O 0
to O 0
ambulate O 0
and O 0
to O 0
void O 0
were O 0
similar O 0
after O 0
lidocaine B-Chemical 1
and O 0
prilocaine B-Chemical 1
( O 0
150 O 0
vs O 0
. O 0
165 O 0
min O 0
and O 0
238 O 0
vs O 0
. O 0
253 O 0
min O 0
, O 0
respectively O 0
) O 0
but O 0
prolonged O 0
after O 0
bupivacaine B-Chemical 1
( O 0
200 O 0
and O 0
299 O 0
min O 0
, O 0
respectively O 0
; O 0
P O 0
< O 0
0 O 0
. O 0
05 O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
Prilocaine B-Chemical 1
may O 0
be O 0
preferable O 0
to O 0
lidocaine B-Chemical 1
for O 0
short O 0
surgical O 0
procedures O 0
because O 0
it O 0
has O 0
a O 0
similar O 0
duration O 0
of O 0
action O 0
but O 0
a O 0
lower O 0
incidence O 0
of O 0
TNSs B-Disease 1
. O 0

Suxamethonium B-Chemical 1
- O 0
induced O 0
cardiac B-Disease 1
arrest I-Disease 1
and O 0
death B-Disease 1
following O 0
5 O 0
days O 0
of O 0
immobilization O 0
. O 0

The O 0
present O 0
report O 0
describes O 0
a O 0
case O 0
of O 0
cardiac B-Disease 1
arrest I-Disease 1
and O 0
subsequent O 0
death B-Disease 1
as O 0
a O 0
result O 0
of O 0
hyperkalaemia B-Disease 1
following O 0
the O 0
use O 0
of O 0
suxamethonium B-Chemical 1
in O 0
a O 0
23 O 0
- O 0
year O 0
- O 0
old O 0
Malawian O 0
woman O 0
. O 0

Five O 0
days O 0
after O 0
the O 0
onset O 0
of O 0
the O 0
symptoms O 0
of O 0
meningitis B-Disease 1
, O 0
the O 0
patient O 0
aspirated O 0
stomach O 0
contents O 0
and O 0
needed O 0
endotracheal O 0
intubation O 0
. O 0

Forty O 0
seconds O 0
after O 0
injection O 0
of O 0
suxamethonium B-Chemical 1
, O 0
bradycardia B-Disease 1
and O 0
cardiac B-Disease 1
arrest I-Disease 1
occurred O 0
. O 0

Attempts O 0
to O 0
resuscitate O 0
the O 0
patient O 0
were O 0
not O 0
successful O 0
. O 0

The O 0
serum O 0
level O 0
of O 0
potassium B-Chemical 1
was O 0
observed O 0
to O 0
be O 0
8 O 0
. O 0
4 O 0
mequiv O 0
L O 0
- O 0
1 O 0
. O 0

Apart O 0
from O 0
the O 0
reduction O 0
in O 0
the O 0
patient O 0
' O 0
s O 0
level O 0
of O 0
consciousness O 0
, O 0
there O 0
were O 0
no O 0
signs O 0
of O 0
motor O 0
neurone O 0
damage O 0
or O 0
of O 0
any O 0
of O 0
the O 0
other O 0
known O 0
predisposing O 0
conditions O 0
for O 0
hyperkalaemia B-Disease 1
following O 0
the O 0
administration O 0
of O 0
suxamethonium B-Chemical 1
. O 0

It O 0
is O 0
postulated O 0
that O 0
her O 0
death B-Disease 1
was O 0
caused O 0
by O 0
hypersensitivity B-Disease 1
to O 0
suxamethonium B-Chemical 1
, O 0
associated O 0
with O 0
her O 0
5 O 0
- O 0
day O 0
immobilization O 0
. O 0

Acute O 0
hepatitis B-Disease 1
, O 0
autoimmune B-Disease 1
hemolytic I-Disease 1
anemia I-Disease 1
, O 0
and O 0
erythroblastocytopenia B-Disease 1
induced O 0
by O 0
ceftriaxone B-Chemical 1
. O 0

An O 0
80 O 0
- O 0
yr O 0
- O 0
old O 0
man O 0
developed O 0
acute O 0
hepatitis B-Disease 1
shortly O 0
after O 0
ingesting O 0
oral O 0
ceftriaxone B-Chemical 1
. O 0

Although O 0
the O 0
transaminases O 0
gradually O 0
returned O 0
to O 0
baseline O 0
after O 0
withholding O 0
the O 0
beta B-Chemical 1
lactam I-Chemical 1
antibiotic O 0
, O 0
there O 0
was O 0
a O 0
gradual O 0
increase O 0
in O 0
serum O 0
bilirubin B-Chemical 1
and O 0
a O 0
decrease O 0
in O 0
hemoglobin O 0
concentration O 0
caused O 0
by O 0
an O 0
autoimmune B-Disease 1
hemolytic I-Disease 1
anemia I-Disease 1
and O 0
erythroblastocytopenia B-Disease 1
. O 0

These O 0
responded O 0
to O 0
systemic O 0
steroids B-Chemical 1
and O 0
immunoglobulins O 0
. O 0

Despite O 0
the O 0
widespread O 0
use O 0
of O 0
these O 0
agents O 0
this O 0
triad O 0
of O 0
side O 0
effects O 0
has O 0
not O 0
previously O 0
been O 0
reported O 0
in O 0
connection O 0
with O 0
beta B-Chemical 1
lactam I-Chemical 1
antibiotics O 0
. O 0

Thyroxine B-Chemical 1
abuse O 0
: O 0
an O 0
unusual O 0
case O 0
of O 0
thyrotoxicosis B-Disease 1
in O 0
pregnancy O 0
. O 0

Eating B-Disease 1
disorders I-Disease 1
and O 0
the O 0
associated O 0
behavioural O 0
problems O 0
and O 0
drug B-Disease 1
abuse I-Disease 1
are O 0
uncommon O 0
in O 0
pregnancy O 0
. O 0

When O 0
they O 0
do O 0
occur O 0
they O 0
are O 0
often O 0
unrecognized O 0
because O 0
of O 0
denial O 0
but O 0
when O 0
significant O 0
may O 0
pose O 0
a O 0
risk O 0
to O 0
both O 0
the O 0
mother O 0
and O 0
her O 0
fetus O 0
. O 0

This O 0
case O 0
illustrates O 0
a O 0
number O 0
of O 0
problems O 0
that O 0
may O 0
be O 0
encountered O 0
in O 0
women O 0
with O 0
eating B-Disease 1
disorders I-Disease 1
in O 0
pregnancy O 0
, O 0
including O 0
prolonged O 0
and O 0
recurrent O 0
metabolic O 0
disturbances O 0
and O 0
diuretic O 0
abuse O 0
. O 0

In O 0
particular O 0
it O 0
illustrates O 0
the O 0
derangements O 0
of O 0
thyroid O 0
function O 0
seen O 0
in O 0
pregnant O 0
women O 0
with O 0
eating B-Disease 1
disorders I-Disease 1
and O 0
reminds O 0
us O 0
that O 0
when O 0
a O 0
cause O 0
for O 0
thyrotoxicosis B-Disease 1
remains O 0
obscure O 0
, O 0
thyroxine B-Chemical 1
abuse O 0
should O 0
be O 0
considered O 0
and O 0
explored O 0
. O 0

Repeated O 0
trimipramine B-Chemical 1
induces O 0
dopamine B-Chemical 1
D2 O 0
/ O 0
D3 O 0
and O 0
alpha1 O 0
- O 0
adrenergic O 0
up O 0
- O 0
regulation O 0
. O 0

Trimipramine B-Chemical 1
( O 0
TRI B-Chemical 1
) O 0
, O 0
which O 0
shows O 0
a O 0
clinical O 0
antidepressant B-Chemical 1
activity O 0
, O 0
is O 0
chemically O 0
related O 0
to O 0
imipramine B-Chemical 1
but O 0
does O 0
not O 0
inhibit O 0
the O 0
reuptake O 0
of O 0
noradrenaline B-Chemical 1
and O 0
5 B-Chemical 1
- I-Chemical 1
hydroxytryptamine I-Chemical 1
, O 0
nor O 0
does O 0
it O 0
induce O 0
beta O 0
- O 0
adrenergic O 0
down O 0
- O 0
regulation O 0
. O 0

The O 0
mechanism O 0
of O 0
its O 0
antidepressant B-Chemical 1
activity O 0
is O 0
still O 0
unknown O 0
. O 0

The O 0
aim O 0
of O 0
the O 0
present O 0
study O 0
was O 0
to O 0
find O 0
out O 0
whether O 0
TRI B-Chemical 1
given O 0
repeatedly O 0
was O 0
able O 0
to O 0
induce O 0
adaptive O 0
changes O 0
in O 0
the O 0
dopaminergic O 0
and O 0
alpha1 O 0
- O 0
adrenergic O 0
systems O 0
, O 0
demonstrated O 0
by O 0
us O 0
previously O 0
for O 0
various O 0
antidepressants B-Chemical 1
. O 0

TRI B-Chemical 1
was O 0
given O 0
to O 0
male O 0
Wistar O 0
rats O 0
and O 0
male O 0
Albino O 0
Swiss O 0
mice O 0
perorally O 0
twice O 0
daily O 0
for O 0
14 O 0
days O 0
. O 0

In O 0
the O 0
acute O 0
experiment O 0
TRI B-Chemical 1
( O 0
given O 0
i O 0
. O 0
p O 0
. O 0
) O 0
does O 0
not O 0
antagonize O 0
the O 0
reserpine B-Chemical 1
hypothermia B-Disease 1
in O 0
mice O 0
and O 0
does O 0
not O 0
potentiate O 0
the O 0
5 B-Chemical 1
- I-Chemical 1
hydroxytryptophan I-Chemical 1
head O 0
twitches O 0
in O 0
rats O 0
. O 0

TRI B-Chemical 1
given O 0
repeatedly O 0
to O 0
rats O 0
increases O 0
the O 0
locomotor O 0
hyperactivity B-Disease 1
induced O 0
by O 0
d B-Chemical 1
- I-Chemical 1
amphetamine I-Chemical 1
, O 0
quinpirole B-Chemical 1
and O 0
( O 0
+ O 0
) O 0
- O 0
7 O 0
- O 0
hydroxy O 0
- O 0
dipropyloaminotetralin O 0
( O 0
dopamine B-Chemical 1
D2 O 0
and O 0
D3 O 0
effects O 0
) O 0
. O 0

The O 0
stereotypies O 0
induced O 0
by O 0
d B-Chemical 1
- I-Chemical 1
amphetamine I-Chemical 1
or O 0
apomorphine B-Chemical 1
are O 0
not O 0
potentiated O 0
by O 0
TRI B-Chemical 1
. O 0

It O 0
increases O 0
the O 0
behaviour O 0
stimulation O 0
evoked O 0
by O 0
phenylephrine B-Chemical 1
( O 0
given O 0
intraventricularly O 0
) O 0
in O 0
rats O 0
, O 0
evaluated O 0
in O 0
the O 0
open O 0
field O 0
test O 0
as O 0
well O 0
as O 0
the O 0
aggressiveness B-Disease 1
evoked O 0
by O 0
clonidine B-Chemical 1
in O 0
mice O 0
, O 0
both O 0
these O 0
effects O 0
being O 0
mediated O 0
by O 0
an O 0
alpha1 O 0
- O 0
adrenergic O 0
receptor O 0
. O 0

It O 0
may O 0
be O 0
concluded O 0
that O 0
, O 0
like O 0
other O 0
tricyclic O 0
antidepressants B-Chemical 1
studied O 0
previously O 0
, O 0
TRI B-Chemical 1
given O 0
repeatedly O 0
increases O 0
the O 0
responsiveness O 0
of O 0
brain O 0
dopamine B-Chemical 1
D2 O 0
and O 0
D3 O 0
( O 0
locomotor O 0
activity O 0
but O 0
not O 0
stereotypy O 0
) O 0
as O 0
well O 0
as O 0
alpha1 O 0
- O 0
adrenergic O 0
receptors O 0
to O 0
their O 0
agonists O 0
. O 0

A O 0
question O 0
arises O 0
whether O 0
the O 0
reuptake O 0
inhibition O 0
is O 0
of O 0
any O 0
importance O 0
to O 0
the O 0
adaptive O 0
changes O 0
induced O 0
by O 0
repeated O 0
antidepressants B-Chemical 1
, O 0
suggested O 0
to O 0
be O 0
responsible O 0
for O 0
the O 0
antidepressant B-Chemical 1
activity O 0
. O 0

Pethidine B-Chemical 1
- O 0
associated O 0
seizure B-Disease 1
in O 0
a O 0
healthy O 0
adolescent O 0
receiving O 0
pethidine B-Chemical 1
for O 0
postoperative B-Disease 1
pain I-Disease 1
control O 0
. O 0

A O 0
healthy O 0
17 O 0
- O 0
year O 0
- O 0
old O 0
male O 0
received O 0
standard O 0
intermittent O 0
doses O 0
of O 0
pethidine B-Chemical 1
via O 0
a O 0
patient O 0
- O 0
controlled O 0
analgesia O 0
( O 0
PCA O 0
) O 0
pump O 0
for O 0
management O 0
of O 0
postoperative B-Disease 1
pain I-Disease 1
control O 0
. O 0

Twenty O 0
- O 0
three O 0
h O 0
postoperatively O 0
he O 0
developed O 0
a O 0
brief O 0
self O 0
- O 0
limited O 0
seizure B-Disease 1
. O 0

Both O 0
plasma O 0
pethidine B-Chemical 1
and O 0
norpethidine B-Chemical 1
were O 0
elevated O 0
in O 0
the O 0
range O 0
associated O 0
with O 0
clinical O 0
manifestations O 0
of O 0
central O 0
nervous O 0
system O 0
excitation O 0
. O 0

No O 0
other O 0
risk O 0
factors O 0
for O 0
CNS O 0
toxicity B-Disease 1
were O 0
identified O 0
. O 0

This O 0
method O 0
allowed O 0
frequent O 0
self O 0
- O 0
dosing O 0
of O 0
pethidine B-Chemical 1
at O 0
short O 0
time O 0
intervals O 0
and O 0
rapid O 0
accumulation O 0
of O 0
pethidine B-Chemical 1
and O 0
norpethidine B-Chemical 1
. O 0

The O 0
routine O 0
use O 0
of O 0
pethidine B-Chemical 1
via O 0
PCA O 0
even O 0
for O 0
a O 0
brief O 0
postoperative O 0
analgesia O 0
should O 0
be O 0
reconsidered O 0
. O 0

An O 0
unusual O 0
toxic O 0
reaction O 0
to O 0
axillary O 0
block O 0
by O 0
mepivacaine B-Chemical 1
with O 0
adrenaline B-Chemical 1
. O 0

An O 0
increase B-Disease 1
in I-Disease 1
blood I-Disease 1
pressure I-Disease 1
, O 0
accompanied O 0
by O 0
atrial B-Disease 1
fibrillation I-Disease 1
, O 0
agitation B-Disease 1
, O 0
incomprehensible B-Disease 1
shouts I-Disease 1
and O 0
loss B-Disease 1
of I-Disease 1
consciousness I-Disease 1
, O 0
was O 0
observed O 0
in O 0
an O 0
elderly O 0
, O 0
ASA O 0
classification O 0
group O 0
II O 0
, O 0
cardiovascularly O 0
medicated O 0
male O 0
, O 0
12 O 0
min O 0
after O 0
performance O 0
of O 0
axillary O 0
block O 0
with O 0
mepivacaine B-Chemical 1
850 O 0
mg O 0
containing O 0
adrenaline B-Chemical 1
0 O 0
. O 0
225 O 0
mg O 0
, O 0
for O 0
correction O 0
of O 0
Dupuytren B-Disease 1
' I-Disease 1
s I-Disease 1
contracture I-Disease 1
. O 0

After O 0
intravenous O 0
administration O 0
of O 0
labetalol B-Chemical 1
, O 0
metoprolol B-Chemical 1
and O 0
midazolam B-Chemical 1
the O 0
patient O 0
' O 0
s O 0
condition O 0
improved O 0
, O 0
and O 0
15 O 0
min O 0
later O 0
he O 0
woke O 0
up O 0
. O 0

The O 0
block O 0
was O 0
successful O 0
and O 0
surgery O 0
was O 0
conducted O 0
as O 0
scheduled O 0
despite O 0
persisting O 0
atrial B-Disease 1
fibrillation I-Disease 1
. O 0

Postoperatively O 0
, O 0
the O 0
patient O 0
refused O 0
DC O 0
cardioversion O 0
and O 0
was O 0
treated O 0
medically O 0
. O 0

Both O 0
the O 0
temporal O 0
relationship O 0
of O 0
events O 0
and O 0
the O 0
response O 0
to O 0
treatment O 0
suggest O 0
that O 0
a O 0
rapid O 0
systemic O 0
absorption O 0
of O 0
mepivacaine B-Chemical 1
with O 0
adrenaline B-Chemical 1
and O 0
/ O 0
or O 0
interaction O 0
of O 0
these O 0
drugs O 0
with O 0
the O 0
patient O 0
' O 0
s O 0
cardiovascular O 0
medications O 0
were O 0
responsible O 0
for O 0
the O 0
perioperative O 0
complications O 0
. O 0

Drug O 0
- O 0
associated O 0
acute O 0
- O 0
onset O 0
vanishing B-Disease 1
bile I-Disease 1
duct I-Disease 1
and O 0
Stevens B-Disease 1
- I-Disease 1
Johnson I-Disease 1
syndromes I-Disease 1
in O 0
a O 0
child O 0
. O 0

Acute O 0
vanishing B-Disease 1
bile I-Disease 1
duct I-Disease 1
syndrome O 0
is O 0
a O 0
rare O 0
but O 0
established O 0
cause O 0
of O 0
progressive O 0
cholestasis B-Disease 1
in O 0
adults O 0
, O 0
is O 0
most O 0
often O 0
drug O 0
or O 0
toxin O 0
related O 0
, O 0
and O 0
is O 0
of O 0
unknown O 0
pathogenesis O 0
. O 0

It O 0
has O 0
not O 0
been O 0
reported O 0
previously O 0
in O 0
children O 0
. O 0

Stevens B-Disease 1
- I-Disease 1
Johnson I-Disease 1
syndrome I-Disease 1
is O 0
a O 0
well O 0
- O 0
recognized O 0
immune O 0
complex O 0
- O 0
mediated O 0
hypersensitivity B-Disease 1
reaction O 0
that O 0
affects O 0
all O 0
age O 0
groups O 0
, O 0
is O 0
drug O 0
or O 0
infection B-Disease 1
induced O 0
, O 0
and O 0
has O 0
classic O 0
systemic O 0
, O 0
mucosal O 0
, O 0
and O 0
dermatologic O 0
manifestations O 0
. O 0

A O 0
previously O 0
healthy O 0
child O 0
who O 0
developed O 0
acute O 0
, O 0
severe O 0
, O 0
rapidly O 0
progressive O 0
vanishing B-Disease 1
bile I-Disease 1
duct I-Disease 1
syndrome I-Disease 1
shortly O 0
after O 0
Stevens B-Disease 1
- I-Disease 1
Johnson I-Disease 1
syndrome I-Disease 1
is O 0
described O 0
; O 0
this O 0
was O 0
temporally O 0
associated O 0
with O 0
ibuprofen B-Chemical 1
use O 0
. O 0

Despite O 0
therapy O 0
with O 0
ursodeoxycholic B-Chemical 1
acid I-Chemical 1
, O 0
prednisone B-Chemical 1
, O 0
and O 0
then O 0
tacrolimus B-Chemical 1
, O 0
her O 0
cholestatic B-Disease 1
disease I-Disease 1
was O 0
unrelenting O 0
, O 0
with O 0
cirrhosis B-Disease 1
shown O 0
by O 0
biopsy O 0
6 O 0
months O 0
after O 0
presentation O 0
. O 0

This O 0
case O 0
documents O 0
acute O 0
drug O 0
- O 0
related O 0
vanishing B-Disease 1
bile I-Disease 1
duct I-Disease 1
syndrome I-Disease 1
in O 0
the O 0
pediatric O 0
age O 0
group O 0
and O 0
suggests O 0
shared O 0
immune O 0
mechanisms O 0
in O 0
the O 0
pathogenesis O 0
of O 0
both O 0
Stevens B-Disease 1
- I-Disease 1
Johnson I-Disease 1
syndrome I-Disease 1
and O 0
vanishing B-Disease 1
bile I-Disease 1
duct I-Disease 1
syndrome I-Disease 1
. O 0

High O 0
incidence O 0
of O 0
primary B-Disease 1
pulmonary I-Disease 1
hypertension I-Disease 1
associated O 0
with O 0
appetite B-Chemical 1
suppressants I-Chemical 1
in O 0
Belgium O 0
. O 0

Primary B-Disease 1
pulmonary I-Disease 1
hypertension I-Disease 1
is O 0
a O 0
rare O 0
, O 0
progressive O 0
and O 0
incurable O 0
disease O 0
, O 0
which O 0
has O 0
been O 0
associated O 0
with O 0
the O 0
intake O 0
of O 0
appetite B-Chemical 1
suppressant I-Chemical 1
drugs O 0
. O 0

The O 0
importance O 0
of O 0
this O 0
association O 0
was O 0
evaluated O 0
in O 0
Belgium O 0
while O 0
this O 0
country O 0
still O 0
had O 0
no O 0
restriction O 0
on O 0
the O 0
prescription O 0
of O 0
appetite B-Chemical 1
suppressants I-Chemical 1
. O 0

Thirty O 0
- O 0
five O 0
patients O 0
with O 0
primary B-Disease 1
pulmonary I-Disease 1
hypertension I-Disease 1
and O 0
85 O 0
matched O 0
controls O 0
were O 0
recruited O 0
over O 0
32 O 0
months O 0
( O 0
1992 O 0
- O 0
1994 O 0
) O 0
in O 0
Belgium O 0
. O 0

Exposure O 0
to O 0
appetite B-Chemical 1
- I-Chemical 1
suppressants I-Chemical 1
was O 0
assessed O 0
on O 0
the O 0
basis O 0
of O 0
hospital O 0
records O 0
and O 0
standardized O 0
interview O 0
. O 0

Twenty O 0
- O 0
three O 0
of O 0
the O 0
patients O 0
had O 0
previously O 0
taken O 0
appetite B-Chemical 1
suppressants I-Chemical 1
, O 0
mainly O 0
fenfluramines B-Chemical 1
, O 0
as O 0
compared O 0
with O 0
only O 0
5 O 0
of O 0
the O 0
controls O 0
( O 0
66 O 0
versus O 0
6 O 0
% O 0
, O 0
p O 0
< O 0
0 O 0
. O 0
0001 O 0
) O 0
. O 0

Five O 0
patients O 0
died O 0
before O 0
the O 0
interview O 0
, O 0
all O 0
of O 0
them O 0
had O 0
taken O 0
appetite B-Chemical 1
suppressants I-Chemical 1
. O 0

In O 0
8 O 0
patients O 0
the O 0
diagnosis O 0
of O 0
primary B-Disease 1
pulmonary I-Disease 1
hypertension I-Disease 1
was O 0
uncertain O 0
, O 0
5 O 0
of O 0
them O 0
had O 0
taken O 0
appetite B-Chemical 1
suppressants I-Chemical 1
. O 0

The O 0
patients O 0
who O 0
had O 0
been O 0
exposed O 0
to O 0
appetite B-Chemical 1
suppressants I-Chemical 1
tended O 0
to O 0
be O 0
on O 0
average O 0
more O 0
severely O 0
ill O 0
, O 0
and O 0
to O 0
have O 0
a O 0
shorter O 0
median O 0
delay O 0
between O 0
onset O 0
of O 0
symptoms O 0
and O 0
diagnosis O 0
. O 0

A O 0
policy O 0
of O 0
unrestricted O 0
prescription O 0
of O 0
appetite B-Chemical 1
suppressants I-Chemical 1
may O 0
lead O 0
to O 0
a O 0
high O 0
incidence O 0
of O 0
associated O 0
primary B-Disease 1
pulmonary I-Disease 1
hypertension I-Disease 1
. O 0

Intake O 0
of O 0
appetite B-Chemical 1
suppressants I-Chemical 1
may O 0
accelerate O 0
the O 0
progression O 0
of O 0
the O 0
disease O 0
. O 0

Inappropriate O 0
use O 0
of O 0
carbamazepine B-Chemical 1
and O 0
vigabatrin B-Chemical 1
in O 0
typical O 0
absence B-Disease 1
seizures I-Disease 1
. O 0

Carbamazepine B-Chemical 1
and O 0
vigabatrin B-Chemical 1
are O 0
contraindicated O 0
in O 0
typical O 0
absence B-Disease 1
seizures I-Disease 1
. O 0

Of O 0
18 O 0
consecutive O 0
referrals O 0
of O 0
children O 0
with O 0
resistant O 0
typical O 0
absences O 0
only O 0
, O 0
eight O 0
were O 0
erroneously O 0
treated O 0
with O 0
carbamazepine B-Chemical 1
either O 0
as O 0
monotherapy O 0
or O 0
as O 0
an O 0
add O 0
- O 0
on O 0
. O 0

Vigabatrin B-Chemical 1
was O 0
also O 0
used O 0
in O 0
the O 0
treatment O 0
of O 0
two O 0
children O 0
. O 0

Frequency O 0
of O 0
absences O 0
increased O 0
in O 0
four O 0
children O 0
treated O 0
with O 0
carbamazepine B-Chemical 1
and O 0
two O 0
of O 0
these O 0
developed O 0
myoclonic B-Disease 1
jerks I-Disease 1
, O 0
which O 0
resolved O 0
on O 0
withdrawal O 0
of O 0
carbamazepine B-Chemical 1
. O 0

Absences O 0
were O 0
aggravated O 0
in O 0
both O 0
cases O 0
where O 0
vigabatrin B-Chemical 1
was O 0
added O 0
on O 0
to O 0
concurrent O 0
treatment O 0
. O 0

Optimal O 0
control O 0
of O 0
the O 0
absences O 0
was O 0
achieved O 0
with O 0
sodium B-Chemical 1
valproate I-Chemical 1
, O 0
lamotrigine B-Chemical 1
, O 0
or O 0
ethosuximide B-Chemical 1
alone O 0
or O 0
in O 0
combination O 0
. O 0

Choreoathetoid B-Disease 1
movements I-Disease 1
associated O 0
with O 0
rapid O 0
adjustment O 0
to O 0
methadone B-Chemical 1
. O 0

Choreatiform B-Disease 1
hyperkinesias I-Disease 1
are O 0
known O 0
to O 0
be O 0
occasional O 0
movement B-Disease 1
abnormalities I-Disease 1
during O 0
intoxications O 0
with O 0
cocaine B-Chemical 1
but O 0
not O 0
opiates O 0
. O 0

This O 0
is O 0
a O 0
case O 0
report O 0
of O 0
euphoria O 0
and O 0
choreoathetoid B-Disease 1
movements I-Disease 1
both O 0
transiently O 0
induced O 0
by O 0
rapid O 0
adjustment O 0
to O 0
the O 0
selective O 0
mu O 0
- O 0
opioid O 0
receptor O 0
agonist O 0
methadone B-Chemical 1
in O 0
an O 0
inpatient O 0
previously O 0
abusing O 0
heroine B-Chemical 1
and O 0
cocaine B-Chemical 1
. O 0

In O 0
addition O 0
, O 0
minor O 0
EEG O 0
abnormalities O 0
occurred O 0
. O 0

Possible O 0
underlying O 0
neurobiological O 0
phenomena O 0
are O 0
discussed O 0
. O 0

Adverse O 0
effects O 0
of O 0
the O 0
atypical O 0
antipsychotics O 0
. O 0

Collaborative O 0
Working O 0
Group O 0
on O 0
Clinical O 0
Trial O 0
Evaluations O 0
. O 0

Adverse O 0
effects O 0
of O 0
antipsychotics O 0
often O 0
lead O 0
to O 0
noncompliance O 0
. O 0

Thus O 0
, O 0
clinicians O 0
should O 0
address O 0
patients O 0
' O 0
concerns O 0
about O 0
adverse O 0
effects O 0
and O 0
attempt O 0
to O 0
choose O 0
medications O 0
that O 0
will O 0
improve O 0
their O 0
patients O 0
' O 0
quality O 0
of O 0
life O 0
as O 0
well O 0
as O 0
overall O 0
health O 0
. O 0

The O 0
side O 0
effect O 0
profiles O 0
of O 0
the O 0
atypical O 0
antipsychotics O 0
are O 0
more O 0
advantageous O 0
than O 0
those O 0
of O 0
the O 0
conventional O 0
neuroleptics O 0
. O 0

Conventional O 0
agents O 0
are O 0
associated O 0
with O 0
unwanted O 0
central O 0
nervous O 0
system O 0
effects O 0
, O 0
including O 0
extrapyramidal B-Disease 1
symptoms I-Disease 1
( O 0
EPS B-Disease 1
) O 0
, O 0
tardive B-Disease 1
dyskinesia I-Disease 1
, O 0
sedation O 0
, O 0
and O 0
possible O 0
impairment O 0
of O 0
some O 0
cognitive O 0
measures O 0
, O 0
as O 0
well O 0
as O 0
cardiac O 0
effects O 0
, O 0
orthostatic B-Disease 1
hypotension I-Disease 1
, O 0
hepatic O 0
changes O 0
, O 0
anticholinergic O 0
side O 0
effects O 0
, O 0
sexual B-Disease 1
dysfunction I-Disease 1
, O 0
and O 0
weight B-Disease 1
gain I-Disease 1
. O 0

The O 0
newer O 0
atypical O 0
agents O 0
have O 0
a O 0
lower O 0
risk O 0
of O 0
EPS B-Disease 1
, O 0
but O 0
are O 0
associated O 0
in O 0
varying O 0
degrees O 0
with O 0
sedation O 0
, O 0
cardiovascular O 0
effects O 0
, O 0
anticholinergic O 0
effects O 0
, O 0
weight B-Disease 1
gain I-Disease 1
, O 0
sexual B-Disease 1
dysfunction I-Disease 1
, O 0
hepatic O 0
effects O 0
, O 0
lowered O 0
seizure B-Disease 1
threshold O 0
( O 0
primarily O 0
clozapine B-Chemical 1
) O 0
, O 0
and O 0
agranulocytosis B-Disease 1
( O 0
clozapine B-Chemical 1
only O 0
) O 0
. O 0

Since O 0
the O 0
incidence O 0
and O 0
severity O 0
of O 0
specific O 0
adverse O 0
effects O 0
differ O 0
among O 0
the O 0
various O 0
atypicals O 0
, O 0
the O 0
clinician O 0
should O 0
carefully O 0
consider O 0
which O 0
side O 0
effects O 0
are O 0
most O 0
likely O 0
to O 0
lead O 0
to O 0
the O 0
individual O 0
' O 0
s O 0
dissatisfaction O 0
and O 0
noncompliance O 0
before O 0
choosing O 0
an O 0
antipsychotic O 0
for O 0
a O 0
particular O 0
patient O 0
. O 0

A O 0
randomized O 0
, O 0
placebo O 0
- O 0
controlled O 0
dose O 0
- O 0
comparison O 0
trial O 0
of O 0
haloperidol B-Chemical 1
for O 0
psychosis B-Disease 1
and O 0
disruptive B-Disease 1
behaviors I-Disease 1
in O 0
Alzheimer B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

OBJECTIVE O 0
: O 0
The O 0
goal O 0
of O 0
this O 0
study O 0
was O 0
to O 0
compare O 0
the O 0
efficacy O 0
and O 0
side O 0
effects O 0
of O 0
two O 0
doses O 0
of O 0
haloperidol B-Chemical 1
and O 0
placebo O 0
in O 0
the O 0
treatment O 0
of O 0
psychosis B-Disease 1
and O 0
disruptive B-Disease 1
behaviors I-Disease 1
in O 0
patients O 0
with O 0
Alzheimer B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

METHOD O 0
: O 0
In O 0
a O 0
6 O 0
- O 0
week O 0
random O 0
- O 0
assignment O 0
, O 0
double O 0
- O 0
blind O 0
, O 0
placebo O 0
- O 0
controlled O 0
trial O 0
( O 0
phase O 0
A O 0
) O 0
, O 0
haloperidol B-Chemical 1
, O 0
2 O 0
- O 0
3 O 0
mg O 0
/ O 0
day O 0
( O 0
standard O 0
dose O 0
) O 0
, O 0
and O 0
haloperidol B-Chemical 1
, O 0
0 O 0
. O 0
50 O 0
- O 0
0 O 0
. O 0
75 O 0
mg O 0
/ O 0
day O 0
( O 0
low O 0
dose O 0
) O 0
, O 0
were O 0
compared O 0
in O 0
71 O 0
outpatients O 0
with O 0
Alzheimer B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
. O 0

For O 0
the O 0
subsequent O 0
6 O 0
- O 0
week O 0
double O 0
- O 0
blind O 0
crossover O 0
phase O 0
( O 0
phase O 0
B O 0
) O 0
, O 0
patients O 0
taking O 0
standard O 0
- O 0
or O 0
low O 0
- O 0
dose O 0
haloperidol B-Chemical 1
were O 0
switched O 0
to O 0
placebo O 0
, O 0
and O 0
patients O 0
taking O 0
placebo O 0
were O 0
randomly O 0
assigned O 0
to O 0
standard O 0
- O 0
or O 0
low O 0
- O 0
dose O 0
haloperidol B-Chemical 1
. O 0

RESULTS O 0
: O 0
For O 0
the O 0
60 O 0
patients O 0
who O 0
completed O 0
phase O 0
A O 0
, O 0
standard O 0
- O 0
dose O 0
haloperidol B-Chemical 1
was O 0
efficacious O 0
and O 0
superior O 0
to O 0
both O 0
low O 0
- O 0
dose O 0
haloperidol B-Chemical 1
and O 0
placebo O 0
for O 0
scores O 0
on O 0
the O 0
Brief O 0
Psychiatric O 0
Rating O 0
Scale O 0
psychosis B-Disease 1
factor O 0
and O 0
on O 0
psychomotor B-Disease 1
agitation I-Disease 1
. O 0

Response O 0
rates O 0
according O 0
to O 0
three O 0
sets O 0
of O 0
criteria O 0
were O 0
greater O 0
with O 0
the O 0
standard O 0
dose O 0
( O 0
55 O 0
% O 0
- O 0
60 O 0
% O 0
) O 0
than O 0
the O 0
low O 0
dose O 0
( O 0
25 O 0
% O 0
- O 0
35 O 0
% O 0
) O 0
and O 0
placebo O 0
( O 0
25 O 0
% O 0
- O 0
30 O 0
% O 0
) O 0
. O 0

The O 0
advantage O 0
of O 0
standard O 0
dose O 0
over O 0
low O 0
dose O 0
was O 0
replicated O 0
in O 0
phase O 0
B O 0
. O 0

In O 0
phase O 0
A O 0
, O 0
extrapyramidal B-Disease 1
signs I-Disease 1
tended O 0
to O 0
be O 0
greater O 0
with O 0
the O 0
standard O 0
dose O 0
than O 0
in O 0
the O 0
other O 0
two O 0
conditions O 0
, O 0
primarily O 0
because O 0
of O 0
a O 0
subgroup O 0
( O 0
20 O 0
% O 0
) O 0
who O 0
developed O 0
moderate O 0
to O 0
severe O 0
signs O 0
. O 0

Low O 0
- O 0
dose O 0
haloperidol B-Chemical 1
did O 0
not O 0
differ O 0
from O 0
placebo O 0
on O 0
any O 0
measure O 0
of O 0
efficacy O 0
or O 0
side O 0
effects O 0
. O 0

CONCLUSIONS O 0
: O 0
The O 0
results O 0
indicated O 0
a O 0
favorable O 0
therapeutic O 0
profile O 0
for O 0
haloperidol B-Chemical 1
in O 0
doses O 0
of O 0
2 O 0
- O 0
3 O 0
mg O 0
/ O 0
day O 0
, O 0
although O 0
a O 0
subgroup O 0
developed O 0
moderate O 0
to O 0
severe O 0
extrapyramidal B-Disease 1
signs I-Disease 1
. O 0

A O 0
starting O 0
dose O 0
of O 0
1 O 0
mg O 0
/ O 0
day O 0
with O 0
gradual O 0
, O 0
upward O 0
dose O 0
titration O 0
is O 0
recommended O 0
. O 0

The O 0
narrow O 0
therapeutic O 0
window O 0
observed O 0
with O 0
haloperidol B-Chemical 1
may O 0
also O 0
apply O 0
to O 0
other O 0
neuroleptics O 0
used O 0
in O 0
Alzheimer B-Disease 1
' I-Disease 1
s I-Disease 1
disease I-Disease 1
patients O 0
with O 0
psychosis B-Disease 1
and O 0
disruptive B-Disease 1
behaviors I-Disease 1
. O 0

Effects O 0
of O 0
acetylsalicylic B-Chemical 1
acid I-Chemical 1
, O 0
dipyridamole B-Chemical 1
, O 0
and O 0
hydrocortisone B-Chemical 1
on O 0
epinephrine B-Chemical 1
- O 0
induced O 0
myocardial B-Disease 1
injury I-Disease 1
in O 0
dogs O 0
. O 0

A O 0
reproducible O 0
model O 0
for O 0
producing O 0
diffuse O 0
myocardial B-Disease 1
injury I-Disease 1
( O 0
epinephrine B-Chemical 1
infusion O 0
) O 0
has O 0
been O 0
developed O 0
to O 0
study O 0
the O 0
cardioprotective O 0
effects O 0
of O 0
agents O 0
or O 0
maneuvers O 0
which O 0
might O 0
alter O 0
the O 0
evolution O 0
of O 0
acute O 0
myocardial B-Disease 1
infarction I-Disease 1
. O 0

Infusions O 0
of O 0
epinephrine B-Chemical 1
( O 0
4 O 0
mug O 0
per O 0
kilogram O 0
per O 0
minute O 0
for O 0
6 O 0
hours O 0
) O 0
increased O 0
radiocalcium B-Chemical 1
uptakes O 0
into O 0
intact O 0
myocardium O 0
and O 0
each O 0
of O 0
its O 0
subcellular O 0
components O 0
with O 0
the O 0
mitochondrial O 0
fraction O 0
showing O 0
the O 0
most O 0
consistent O 0
changes O 0
when O 0
compared O 0
to O 0
saline O 0
- O 0
infused O 0
control O 0
animals O 0
( O 0
4 O 0
, O 0
957 O 0
vs O 0
. O 0
827 O 0
counts O 0
per O 0
minute O 0
per O 0
gram O 0
of O 0
dried O 0
tissue O 0
or O 0
fraction O 0
) O 0
. O 0

Myocardial O 0
concentrations O 0
of O 0
calcium B-Chemical 1
also O 0
increased O 0
significantly O 0
( O 0
12 O 0
. O 0
0 O 0
vs O 0
. O 0
5 O 0
. O 0
0 O 0
mg O 0
. O 0
per O 0
100 O 0
Gm O 0
. O 0
of O 0
fat O 0
- O 0
free O 0
dry O 0
weight O 0
) O 0
. O 0

Infusions O 0
of O 0
calcium B-Chemical 1
chloride I-Chemical 1
sufficient O 0
to O 0
raise O 0
serum O 0
calcium B-Chemical 1
concentrations O 0
2 O 0
mEq O 0
. O 0
per O 0
liter O 0
failed O 0
to O 0
increase O 0
calcium B-Chemical 1
influx O 0
into O 0
the O 0
myocardial O 0
cell O 0
. O 0

Mitochondrial O 0
radiocalcium B-Chemical 1
uptakes O 0
were O 0
significantly O 0
decreased O 0
in O 0
animals O 0
pretreated O 0
with O 0
acetylsalicylic B-Chemical 1
acid I-Chemical 1
or O 0
dipyridamole B-Chemical 1
or O 0
when O 0
hydrocortisone B-Chemical 1
was O 0
added O 0
to O 0
the O 0
epinephrine B-Chemical 1
infusion O 0
( O 0
2 O 0
, O 0
682 O 0
, O 0
2 O 0
, O 0
803 O 0
, O 0
and O 0
3 O 0
, O 0
424 O 0
counts O 0
per O 0
minute O 0
per O 0
gram O 0
of O 0
dried O 0
fraction O 0
, O 0
respectively O 0
) O 0
. O 0

Myocardial O 0
calcium B-Chemical 1
concentrations O 0
also O 0
were O 0
decreased O 0
( O 0
11 O 0
. O 0
2 O 0
, O 0
8 O 0
. O 0
3 O 0
, O 0
and O 0
8 O 0
. O 0
9 O 0
mg O 0
. O 0
per O 0
100 O 0
Gm O 0
. O 0
of O 0
fat O 0
- O 0
free O 0
dry O 0
weight O 0
, O 0
respectively O 0
) O 0
in O 0
the O 0
three O 0
treatment O 0
groups O 0
, O 0
being O 0
significantly O 0
decreased O 0
only O 0
in O 0
the O 0
last O 0
two O 0
. O 0

Evidence O 0
of O 0
microscopic O 0
damage O 0
was O 0
graded O 0
as O 0
less O 0
severe O 0
in O 0
the O 0
three O 0
treatment O 0
groups O 0
. O 0

Acetylsalicylic B-Chemical 1
acid I-Chemical 1
, O 0
dipyridamole B-Chemical 1
, O 0
and O 0
hydrocortisone B-Chemical 1
all O 0
appear O 0
to O 0
have O 0
cardioprotective O 0
effects O 0
when O 0
tested O 0
in O 0
this O 0
model O 0
. O 0

Clinical O 0
and O 0
histopathologic O 0
examination O 0
of O 0
renal O 0
allografts O 0
treated O 0
with O 0
tacrolimus B-Chemical 1
( O 0
FK506 B-Chemical 1
) O 0
for O 0
at O 0
least O 0
one O 0
year O 0
. O 0

BACKGROUND O 0
: O 0
We O 0
clinically O 0
and O 0
pathologically O 0
analyzed O 0
renal O 0
allografts O 0
from O 0
1 O 0
9 O 0
renal O 0
transplant O 0
patients O 0
treated O 0
with O 0
tacrolimus B-Chemical 1
( O 0
FK506 B-Chemical 1
) O 0
for O 0
more O 0
than O 0
1 O 0
year O 0
. O 0

METHODS O 0
: O 0
Twenty O 0
- O 0
six O 0
renal O 0
allograft O 0
biopsy O 0
specimens O 0
from O 0
1 O 0
9 O 0
renal O 0
transplant O 0
patients O 0
who O 0
underwent O 0
transplantations O 0
between O 0
1991 O 0
and O 0
1993 O 0
were O 0
evaluated O 0
. O 0

Thirteen O 0
biopsies O 0
were O 0
performed O 0
from O 0
stable O 0
functioning O 0
renal O 0
allografts O 0
with O 0
informed O 0
consent O 0
( O 0
nonepisode O 0
biopsy O 0
) O 0
and O 0
the O 0
other O 0
13 O 0
were O 0
from O 0
dysfunctional O 0
renal O 0
allografts O 0
with O 0
a O 0
clinical O 0
indication O 0
for O 0
biopsy O 0
( O 0
episode O 0
biopsy O 0
) O 0
. O 0

RESULTS O 0
: O 0
The O 0
main O 0
pathologic O 0
diagnoses O 0
( O 0
some O 0
overlap O 0
) O 0
were O 0
acute O 0
rejection O 0
( O 0
AR O 0
; O 0
n O 0
= O 0
4 O 0
) O 0
, O 0
chronic O 0
rejection O 0
( O 0
CR O 0
; O 0
n O 0
= O 0
5 O 0
) O 0
, O 0
AR O 0
+ O 0
CR O 0
( O 0
n O 0
= O 0
4 O 0
) O 0
, O 0
recurrent O 0
IgA B-Disease 1
nephropathy I-Disease 1
( O 0
n O 0
= O 0
5 O 0
) O 0
, O 0
normal O 0
findings O 0
( O 0
n O 0
= O 0
2 O 0
) O 0
, O 0
minimal O 0
- O 0
type O 0
chronic O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
( O 0
n O 0
= O 0
9 O 0
) O 0
, O 0
and O 0
mild O 0
- O 0
type O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
( O 0
n O 0
= O 0
11 O 0
) O 0
. O 0

Of O 0
the O 0
nonepisode O 0
biopsies O 0
, O 0
7 O 0
and O 0
4 O 0
biopsies O 0
showed O 0
minimal O 0
- O 0
type O 0
and O 0
mild O 0
- O 0
type O 0
chronic O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
, O 0
respectively O 0
. O 0

Chronic O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
consisted O 0
of O 0
rough O 0
and O 0
foamy O 0
tubular O 0
vacuolization O 0
( O 0
5 O 0
biopsies O 0
) O 0
, O 0
arteriolopathy O 0
( O 0
angiodegeneration O 0
of O 0
the O 0
arteriolar O 0
wall O 0
; O 0
20 O 0
biopsies O 0
) O 0
, O 0
focal B-Disease 1
segmental I-Disease 1
glomerulosclerosis I-Disease 1
( O 0
4 O 0
biopsies O 0
) O 0
and O 0
the O 0
striped O 0
form O 0
of O 0
interstitial B-Disease 1
fibrosis I-Disease 1
( O 0
11 O 0
biopsies O 0
) O 0
. O 0

The O 0
serum O 0
creatinine B-Chemical 1
levels O 0
of O 0
patients O 0
in O 0
the O 0
mild O 0
- O 0
type O 0
chronic O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
group O 0
, O 0
which O 0
included O 0
7 O 0
episode O 0
biopsies O 0
, O 0
were O 0
statistically O 0
higher O 0
than O 0
those O 0
in O 0
the O 0
minimum O 0
- O 0
type O 0
chronic O 0
FK506 B-Chemical 1
- O 0
nephropathy B-Disease 1
group O 0
( O 0
P O 0
< O 0
0 O 0
. O 0
001 O 0
) O 0
. O 0

CONCLUSIONS O 0
: O 0
This O 0
study O 0
demonstrates O 0
that O 0
chronic O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
consists O 0
primarily O 0
of O 0
arteriolopathy O 0
manifesting O 0
as O 0
insudative O 0
hyalinosis O 0
of O 0
the O 0
arteriolar O 0
wall O 0
, O 0
and O 0
suggests O 0
that O 0
mild O 0
- O 0
type O 0
chronic O 0
FK506 B-Chemical 1
nephropathy B-Disease 1
is O 0
a O 0
condition O 0
which O 0
may O 0
lead O 0
to O 0
deterioration O 0
of O 0
renal O 0
allograft O 0
function O 0
. O 0

Different O 0
lobular O 0
distributions O 0
of O 0
altered O 0
hepatocyte O 0
tight O 0
junctions O 0
in O 0
rat O 0
models O 0
of O 0
intrahepatic B-Disease 1
and I-Disease 1
extrahepatic I-Disease 1
cholestasis I-Disease 1
. O 0

Hepatocyte O 0
tight O 0
junctions O 0
( O 0
TJs O 0
) O 0
, O 0
the O 0
only O 0
intercellular O 0
barrier O 0
between O 0
the O 0
sinusoidal O 0
and O 0
the O 0
canalicular O 0
spaces O 0
, O 0
play O 0
a O 0
key O 0
role O 0
in O 0
bile O 0
formation O 0
. O 0

Although O 0
hepatocyte O 0
TJs O 0
are O 0
impaired O 0
in O 0
cholestasis B-Disease 1
, O 0
attempts O 0
to O 0
localize O 0
the O 0
precise O 0
site O 0
of O 0
hepatocyte O 0
TJ O 0
damage O 0
by O 0
freeze O 0
- O 0
fracture O 0
electron O 0
microscopy O 0
have O 0
produced O 0
limited O 0
information O 0
. O 0

Recently O 0
, O 0
several O 0
TJ O 0
- O 0
associated O 0
proteins O 0
like O 0
ZO O 0
- O 0
1 O 0
and O 0
7H6 O 0
have O 0
been O 0
identified O 0
and O 0
characterized O 0
. O 0

Immunolocalization O 0
of O 0
7H6 O 0
appears O 0
to O 0
closely O 0
correlate O 0
with O 0
paracellular O 0
permeability O 0
. O 0

We O 0
used O 0
rat O 0
models O 0
of O 0
intrahepatic B-Disease 1
cholestasis I-Disease 1
by O 0
ethinyl B-Chemical 1
estradiol I-Chemical 1
( O 0
EE B-Chemical 1
) O 0
treatment O 0
and O 0
extrahepatic B-Disease 1
cholestasis I-Disease 1
by O 0
bile O 0
duct O 0
ligation O 0
( O 0
BDL O 0
) O 0
to O 0
precisely O 0
determine O 0
the O 0
site O 0
of O 0
TJ O 0
damage O 0
. O 0

Alterations O 0
in O 0
hepatocyte O 0
TJs O 0
were O 0
assessed O 0
by O 0
double O 0
- O 0
immunolabeling O 0
for O 0
7H6 O 0
and O 0
ZO O 0
- O 0
1 O 0
using O 0
a O 0
confocal O 0
laser O 0
scanning O 0
microscope O 0
. O 0

In O 0
control O 0
rats O 0
, O 0
immunostaining O 0
for O 0
7H6 O 0
and O 0
ZO O 0
- O 0
1 O 0
colocalized O 0
to O 0
outline O 0
bile O 0
canaliculi O 0
in O 0
a O 0
continuous O 0
fashion O 0
. O 0

In O 0
contrast O 0
, O 0
7H6 O 0
and O 0
ZO O 0
- O 0
1 O 0
immunostaining O 0
was O 0
more O 0
discontinuous O 0
, O 0
outlining O 0
the O 0
bile O 0
canaliculi O 0
after O 0
BDL O 0
. O 0

Immunostaining O 0
for O 0
7H6 O 0
, O 0
not O 0
ZO O 0
- O 0
1 O 0
, O 0
decreased O 0
and O 0
predominantly O 0
appeared O 0
as O 0
discrete O 0
signals O 0
in O 0
the O 0
submembranous O 0
cytoplasm O 0
of O 0
periportal O 0
hepatocytes O 0
after O 0
BDL O 0
. O 0

After O 0
EE B-Chemical 1
treatment O 0
, O 0
changes O 0
in O 0
immunostaining O 0
for O 0
7H6 O 0
and O 0
ZO O 0
- O 0
1 O 0
were O 0
similar O 0
to O 0
those O 0
seen O 0
in O 0
periportal O 0
hepatocytes O 0
after O 0
BDL O 0
, O 0
but O 0
distributed O 0
more O 0
diffusely O 0
throughout O 0
the O 0
lobule O 0
. O 0

This O 0
study O 0
is O 0
the O 0
first O 0
to O 0
demonstrate O 0
that O 0
impairment O 0
of O 0
hepatocyte O 0
TJs O 0
occurs O 0
heterogenously O 0
in O 0
the O 0
liver O 0
lobule O 0
after O 0
BDL O 0
and O 0
suggests O 0
that O 0
BDL O 0
and O 0
EE B-Chemical 1
treatments O 0
produce O 0
different O 0
lobular O 0
distributions O 0
of O 0
increased O 0
paracellular O 0
permeability O 0
. O 0

Memory O 0
facilitation O 0
and O 0
stimulation O 0
of O 0
endogenous O 0
nerve O 0
growth O 0
factor O 0
synthesis O 0
by O 0
the O 0
acetylcholine B-Chemical 1
releaser O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
. O 0

The O 0
effects O 0
of O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
( O 0
3alpha B-Chemical 1
- I-Chemical 1
tropyl I-Chemical 1
2 I-Chemical 1
- I-Chemical 1
( I-Chemical 1
p I-Chemical 1
- I-Chemical 1
bromophenyl I-Chemical 1
) I-Chemical 1
propionate I-Chemical 1
) O 0
, O 0
the O 0
acetylcholine B-Chemical 1
releaser O 0
, O 0
on O 0
memory O 0
processes O 0
and O 0
nerve O 0
growth O 0
factor O 0
( O 0
NGF O 0
) O 0
synthesis O 0
were O 0
evaluated O 0
. O 0

In O 0
the O 0
mouse O 0
passive O 0
- O 0
avoidance O 0
test O 0
, O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
( O 0
10 O 0
- O 0
30 O 0
mg O 0
/ O 0
kg O 0
, O 0
i O 0
. O 0
p O 0
. O 0
) O 0
, O 0
administered O 0
20 O 0
min O 0
before O 0
the O 0
training O 0
session O 0
, O 0
prevented O 0
amnesia B-Disease 1
induced O 0
by O 0
both O 0
the O 0
non O 0
selective O 0
antimuscarinic O 0
drug O 0
scopolamine B-Chemical 1
and O 0
the O 0
M1 O 0
- O 0
selective O 0
antagonist O 0
S B-Chemical 1
- I-Chemical 1
( I-Chemical 1
- I-Chemical 1
) I-Chemical 1
- I-Chemical 1
ET I-Chemical 1
- I-Chemical 1
126 I-Chemical 1
. O 0

In O 0
the O 0
same O 0
experimental O 0
conditions O 0
, O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
( O 0
5 O 0
- O 0
20 O 0
microg O 0
per O 0
mouse O 0
, O 0
i O 0
. O 0
c O 0
. O 0
v O 0
. O 0
) O 0
was O 0
also O 0
able O 0
to O 0
prevent O 0
antimuscarine O 0
- O 0
induced O 0
amnesia B-Disease 1
, O 0
demonstrating O 0
a O 0
central O 0
localization O 0
of O 0
the O 0
activity O 0
. O 0

At O 0
the O 0
highest O 0
effective O 0
doses O 0
, O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
did O 0
not O 0
produce O 0
any O 0
collateral O 0
symptoms O 0
as O 0
revealed O 0
by O 0
the O 0
Irwin O 0
test O 0
, O 0
and O 0
it O 0
did O 0
not O 0
modify O 0
spontaneous O 0
motility O 0
and O 0
inspection O 0
activity O 0
, O 0
as O 0
revealed O 0
by O 0
the O 0
hole O 0
- O 0
board O 0
test O 0
. O 0

PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
was O 0
also O 0
able O 0
to O 0
increase O 0
the O 0
amount O 0
of O 0
NGF O 0
secreted O 0
in O 0
vitro O 0
by O 0
astrocytes O 0
in O 0
a O 0
dose O 0
- O 0
dependent O 0
manner O 0
. O 0

The O 0
maximal O 0
NGF O 0
contents O 0
obtained O 0
by O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
were O 0
17 O 0
. O 0
6 O 0
- O 0
fold O 0
of O 0
the O 0
control O 0
value O 0
. O 0

During O 0
culture O 0
, O 0
no O 0
morphological O 0
changes O 0
were O 0
found O 0
at O 0
effective O 0
concentrations O 0
of O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
. O 0

The O 0
current O 0
work O 0
indicates O 0
the O 0
ability O 0
of O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
to O 0
induce O 0
beneficial O 0
effects O 0
on O 0
cognitive O 0
processes O 0
and O 0
stimulate O 0
activity O 0
of O 0
NGF O 0
synthesis O 0
in O 0
astroglial O 0
cells O 0
. O 0

Therefore O 0
, O 0
PG B-Chemical 1
- I-Chemical 1
9 I-Chemical 1
could O 0
represent O 0
a O 0
potential O 0
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