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Record 1
from database: MEDLINE
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- Title
- Drug kinetics and alcohol ingestion.
- Author
- Sellers EM; Holloway MR
- Address
-
- Source
- Clin Pharmacokinet, 1978 Nov, 3:6,
440-52
- Abstract
- Acute and chronic ethanol ingestion
can alter both the pharmacodynamics
and pharmacokinetics of other drugs.
For psychotherapeutic drugs,
modification of drug action by alcohol
is much more important than kinetic
interaction, such as ethanol induced
drug metabolism. In contrast, the
importance of the effects of alcohol
on the kinetics of other classes of
drug is incomplete. The probability
and mechanism of alcohol kinetic
interactions with other drugs can
nevertheless be anticipated, in part,
on the basis of the extent of binding
of the drug to plasma proteins, the
capacity of the liver for extracting
the drug from blood passing through
the liver and the true distribution
space of the drug. Highly bound drugs
with low intrinsic hepatic clearance
are among the most commonly reported
to have their kinetics altered by
ethanol (e.g. benzodiazepines,
phenytoin, tolbutamide and warfarin).
Less highly bound drugs are less
consistently affected (e.g.
meprobamate, glutethimide,
pentobarbitone and phenobarbitone).
Acute administration of ethanol to
laboratory animals or incubation of
microsomal preparations with ethanol
inhibits the mixed function oxidase
activity. In the human, the
elimination half-life of meprobamate,
pentobarbitone and tolbutamide is
increased by acute ethanol
administration. Chronic administration
of ethanol to rats and humans causes
proliferation of the smooth
endoplasmic reticulum, increase in
microsomal protein content and
cytochrome P450 and results in an
augmentation in drug metabolising
ability of the microsomes in vitro.
Even though the plasma half-life of
some drugs is decreased by chronic
ethanol ingestion, the clinical
determination of the mechanism is
incomplete because few studies have
measured drug metabolite levels. In
addition, alcohol effects on drug
distribution have not been studied
very extensively. The effects of
chronic alcohol ingestion on drugs
with low and high hepatic extraction,
high and low binding, important tissue
localisation and microsomal and non-microsomal
metabolism will be quite different.
Systematic studies of the mechanism of
alcohol kinetic interactions are
needed. Such kinetic studies should be
combined with pharmacodynamic measures
in order to establish the clinical
importance of changes in drug
kinetics.
- Language of Publication
- English
- Unique Identifier
- 79064344
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- MeSH Heading (Major)
- Ethanol|*PD; Pharmaceutical
Preparations|*ME
- MeSH Heading
- Alcoholism|ME; Anti-Anxiety Agents,
Benzodiazepine|ME; Antipyrine|ME;
Biological Availability; Blood
Proteins|ME; Chloral Hydrate|ME;
Glutethimide|ME; Human; Intestinal
Absorption; Kinetics; Liver|ME;
Meprobamate|ME; Pentobarbital|ME;
Phenytoin|ME; Protein Binding; Tissue
Distribution; Tolbutamide|ME;
Warfarin|ME
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0312-5963
- Country of Publication
- UNITED STATES
Record 2
from database: MEDLINE
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- Title
- The protein binding of phenytoin,
propranolol, diazepam, and AL01576 (an
aldose reductase inhibitor) in human
and rat diabetic serum.
- Author
- McNamara PJ; Blouin RA; Brazzell RK
- Address
- College of Pharmacy, University of
Kentucky, Lexington 40536.
- Source
- Pharm Res, 1988 May, 5:5, 261-5
- Abstract
- The extent of serum protein binding
of AL01576, phenytoin (DPH), diazepam
(DIAZ), and propranolol (PRO) was
evaluated in a group of nondiabetic
and a group of insulin-dependent
diabetic subjects, as well as in
streptozotocin-treated rats. Both
serum glucose and glucosylated protein
levels were elevated in the diabetic
patient population (179 and 150% of
control values, respectively). The
mean free fractions (fp) of AL01576,
DPH, and PRO were not statistically
different for the two human groups.
The DIAZ fp was slightly elevated (P
less than 0.05) in the diabetic
patients (mean = 0.016) compared to
the control group (mean fp = 0.014).
An acute (less than 3 days) and
chronic (greater than 20 days)
diabetic rodent model was evaluated
using Sprague-Dawley rats following
streptozotocin administration (60
mg/kg i.p.). Both diabetic rat groups
exhibited substantial increases in
serum glucose, free fatty acids (FFA),
and protein glucosylation compared to
controls. The fp of AL01576 was
increased in both the acute (mean =
0.248) and the chronic (mean = 0.202)
condition compared to controls (mean =
0.163). The fp of DPH was also
markedly increased in the acute (mean
= 0.348) and the chronic (mean =
0.280) models compared to untreated
controls (mean = 0.207). DIAZ and PRO
binding was largely unaffected by the
streptozotocin treatment. In vitro
studies of purified human albumin
suggest that a considerable degree of
glucosylation would need to be present
in diabetic serum before it would
effectively alter drug binding. Our
data suggest that only minor
drug-serum binding changes occur in
diabetic patients who are otherwise
healthy and whose disease is well
controlled.
- Language of Publication
- English
- Unique Identifier
- 89220771
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- MeSH Heading (Major)
- Aldehyde Reductase|*AI; Diabetes
Mellitus|*BL; Diazepam|*BL; Fluorenes|*BL;
Hydantoins|*BL; Phenytoin|*BL;
Propranolol|*BL; Sugar Alcohol
Dehydrogenases|*AI
- MeSH Heading
- Adult; Animal; Blood Glucose|ME;
Blood Proteins|ME; Diabetes Mellitus,
Experimental|BL; Human; Male; Protein
Binding; Rats; Rats, Inbred Strains;
Species Specificity
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0724-8741
- Country of Publication
- UNITED STATES
Record 3
from database: MEDLINE
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- Title
- Medical causes of seizures [see
comments]
- Author
- Delanty N; Vaughan CJ; French JA
- Address
- Department of Neurology, Hospital of
the University of Pennsylvania,
Philadelphia 19104-4283, USA. normandy@mail.med.upenn.edu
- Source
- Lancet, 1998 Aug, 352:9125, 383-90
- Abstract
- Seizures are commonly encountered in
patients who do not have epilepsy.
Factors that may provoke such seizures
include organ failure, electrolyte
imbalance, medication and medication
withdrawal, and hypersensitive
encephalopathy. There is usually one
underlying cause, which may be
reversible in some patients. A full
assessment should be done to rule out
primary neurological disease.
Treatment of seizures in medically ill
patients is aimed at correction of the
underlying cause with appropriate
short-term anticonvulsant medication.
Phenytoin is ineffective in the
management of seizures secondary to
alcohol withdrawal, and in those due
to theophylline or isoniazid toxicity.
Control of blood pressure is important
in patients with renal failure and
seizures. Non-convulsive status
epilepticus should be considered in
any patient with confusion or coma of
unclear cause, and
electroencephalography should be done
at the earliest opportunity. Most ill
patients with secondary seizures do
not have epilepsy, and this should be
explained to patients and their
families. Only those patients with
recurrent seizures and uncorrectable
predisposing factors need long-term
treatment with anticonvulsant
medication.
- Language of Publication
- English
- Unique Identifier
- 98382043
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- MeSH Heading (Major)
- Seizures|CI/DT/*ET
- MeSH Heading
- Anticonvulsants|TU; Antitubercular
Agents|AE; Blood Pressure; Brain
Diseases|CO; Bronchodilator Agents|AE;
Coma|DI; Confusion|DI; Drug Therapy|AE;
Electroencephalography; Ethanol|AE;
Human; Isoniazid|AE; Kidney Failure,
Acute|CO; Multiple Organ Failure|CO;
Phenytoin|TU; Status Epilepticus|DI;
Substance Withdrawal Syndrome;
Theophylline|AE; Water-Electrolyte
Imbalance|CO
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW,
TUTORIAL
- ISSN
- 0140-6736
- Country of Publication
- ENGLAND
Record 4
from database: MEDLINE
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- Title
- Acetaldehyde adducts with serum
proteins are not responsible for
decreased drug binding in alcoholic
patients.
- Author
- Lucas D; Pennec Y; Ménez JF; Floch
HH; Le Menn G
- Address
-
- Source
- Drug Alcohol Depend, 1986 May, 17:1,
67-71
- Abstract
- Decreased plasma binding of
phenytoin and diazepam has previously
been described in patients with
alcoholic liver diseases. It has been
attributed to hypoalbuminemia,
endogenous displacers and/or
qualitative changes in albumin such as
formation of adducts with
acetaldehyde, a highly reactive
metabolite of ethanol. In the present
report this hypothesis was tested.
After treating the sera with activated
charcoal to remove the endogenous
displacers and adjusting albumin
concentration to a constant level, the
binding parameters of both drugs,
phenytoin and diazepam, were
determined in 14 healthy men and 16
alcoholic patients by equilibrium
dialysis. In these conditions, no
significant difference in the number
of binding sites nor in the affinity
constant was observed, which suggests
that acetaldehyde adducts with
proteins do not contribute, to a major
extent, to the defect of drug binding
observed in alcoholic patients.
- Language of Publication
- English
- Unique Identifier
- 86247105
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- MeSH Heading (Major)
- Acetaldehyde|*ME; Alcoholism|*BL;
Diazepam|*BL; Phenytoin|*BL
- MeSH Heading
- Adult; Albumins|ME; Blood
Proteins|ME; Female; Human; Male;
Middle Age; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0376-8716
- Country of Publication
- SWITZERLAND
Record 5
from database: MEDLINE
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- Title
- Effect of short- and long-term
alcohol use on phenytoin kinetics in
chronic alcoholics.
- Author
- Sandor P; Sellers EM; Dumbrell M;
Khouw V
- Address
-
- Source
- Clin Pharmacol Ther, 1981 Sep, 30:3,
390-7
- Abstract
- Phenytoin kinetics during long-term
alcohol use and withdrawal were
studied in 11 male alcoholics with a
history of withdrawal seizures and no
evidence of chronic liver disease.
Ethanol, 20% v/v, was given for 6 days
after admission to maintain the blood
alcohol level between 500 and 800 mg/l
and phenytoin suspension, 150 mg, was
given orally or intravenously (on
three occasions) every 12 hr for 20
days. The mean (+/- SD) total
phenytoin clearance in 9 of 11
subjects was 0.023 +/- 0.006 l/kg/hr
during the alcohol ingestion period.
Clearance rose to 0.033 +/- 0.013
l/kg/hr (P less than 0.05) during
alcohol withdrawal. Total steady-state
concentration after 3 wk ranged from
3.4 to 29.9 mg/l, while the
weight-corrected dose range was only
3.7 to 5.5 mg/kg/day. Inter- and
intra-subject variation in
bioavailability was small (0.93 to
1.03). Phenytoin free fractions ranged
from 9.09% to 17.75% and changes in
total and free phenytoin concentration
correlated (r2 = 0.92, P less than
0.001). The data are compatible with
the hypothesis that increased
phenytoin clearance during alcohol
withdrawal is due to the increased
metabolic rate of the drug secondary
to enzyme induction by ethanol, which
becomes unmasked on cessation of
drinking. In most alcoholics
standard-dose phenytoin (300 mg/l)
will induce lower than usual plasma
concentrations.
- Language of Publication
- English
- Unique Identifier
- 82003032
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- MeSH Heading (Major)
- Alcoholism|CO/*ME; Ethanol|ME/*PD;
Phenytoin|*ME
- MeSH Heading
- Administration, Oral; Adult;
Biological Availability; Human;
Injections, Intravenous; Kinetics;
Male; Metabolic Clearance Rate|DE;
Middle Age; Substance Withdrawal
Syndrome|ET; Time Factors
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0009-9236
- Country of Publication
- UNITED STATES
Record 6
from database: MEDLINE
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- Title
- The effect of low-dose phenytoin on
high-density lipoprotein cholesterol.
- Author
- McKenney JM; Petrizzi KS; Briggs GC;
Wright JT Jr
- Address
- Medical College of Virginia,
Richmond 23298.
- Source
- Pharmacotherapy, 1992, 12:3, 183-8
- Abstract
- We examined whether low doses of
phenytoin, which should be associated
with few dose-related side effects,
may increase the levels of
high-density lipoprotein (HDL)
cholesterol. Of 35 healthy adult men
who consented to participate, 31
completed the study. They took no
medications and consumed no alcohol
during the study. We used a three-arm,
parallel, prospective, randomized,
double-blind research design. Subjects
took a single-blind placebo capsule
once daily at bedtime for 2 weeks and
then were randomly assigned to receive
identical-appearing capsules
containing 30 mg or 100 mg of
phenytoin or placebo, once daily at
bedtime for 4 weeks. The HDL
cholesterol and HDL subfractions were
determined from 12-hour fasting blood
samples obtained at the beginning and
end of the single-blind period and at
the end of the third and fourth weeks
of the double-blind period. Mean
differences between baseline and
posttreatment HDL cholesterol levels
with placebo, 30 mg phenytoin, and 100
mg phenytoin were 0.010 mmol/L (0.4
mg/dl), 0.005 mmol/L (0.2 mg/dl), and
0.096 mmol/L (3.7 mg/dl), respectively
(p = 0.2947); baseline and
posttreatment HDL2 and HDL3 levels
were not different among the groups.
Total cholesterol levels were
significantly higher in subjects
taking phenytoin 100 mg than in those
taking phenytoin 30 mg or placebo. The
results suggest that phenytoin in
dosages of up to 100 mg daily for 4
weeks has no substantial effect on HDL
cholesterol or HDL subfractions.
- Language of Publication
- English
- Unique Identifier
- 92302086
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- MeSH Heading (Major)
- Lipoproteins, HDL Cholesterol|*BL;
Phenytoin|AD/*PD
- MeSH Heading
- Adolescence; Adult; Comparative
Study; Double-Blind Method; Human;
Lipoproteins|BL; Male; Prospective
Studies; Single-Blind Method
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE;
RANDOMIZED CONTROLLED TRIAL
- ISSN
- 0277-0008
- Country of Publication
- UNITED STATES
Record 7
from database: MEDLINE
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- Title
- Potential of concentration
monitoring data for a short half-life
drug: analysis of pharmacokinetic
variability for moclobemide.
- Author
- Gex Fabry M; Balant Gorgia AE;
Balant LP
- Address
- Clinical Research Unit, University
Psychiatric Institutions, Geneva,
Switzerland.
- Source
- Ther Drug Monit, 1995 Feb, 17:1,
39-46
- Abstract
- The pharmacokinetic variability of
moclobemide, a new short half-life
reversible selective inhibitor of
monoamine oxidase (MAO) was
investigated through analysis of
concentrations measured during early
open clinical use. Eighty-nine
depressed patients, aged 21-96 years,
were included in the present study.
Doses ranged from 200 to 900 mg/day,
and the time interval between blood
sampling and last drug intake on the
previous day was between 8 and 23 h.
Intraindividual variability was
generally moderate, with a few
patients displaying consistently high
concentrations despite moderate doses.
Interindividual variability for
measured concentrations was
approximately 300-fold. After
concentration decrease with time was
taken into account (average half-life
estimate of 4.6 h), age was identified
as a major factor responsible for
between-patient variability. Average
concentration increase per decade of
age was 38%. Neither gender, weight,
height, smoking, nor alcohol intake
explained a significant additional
part of the variance. Analysis of
residuals also suggested that
phenytoin co-medication may induce
moclobemide metabolism. The present
study indicates that concentration
monitoring of a newly marketed drug
can contribute to gaining insight into
its pharmacokinetic behavior and to
enhancing its rational use in clinical
practice.
- Language of Publication
- English
- Unique Identifier
- 95242378
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- MeSH Heading (Major)
- Benzamides|BL/*PK/TU; Monoamine
Oxidase Inhibitors|BL/*PK/TU
- MeSH Heading
- Adult; Aged; Aged, 80 and over;
Aging|ME; Chromatography, Gas;
Depressive Disorder|DT; Drug
Interactions; Drug Monitoring; Female;
Half-Life; Human; Male; Middle Age;
Phenytoin|PK
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE
- ISSN
- 0163-4356
- Country of Publication
- UNITED STATES
Record 8
from database: MEDLINE
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- Title
- Propofol and seizures.
- Author
- Sutherland MJ; Burt P
- Address
- Woden Valley Hospital, Canberra,
Australian Capital Territory.
- Source
- Anaesth Intensive Care, 1994 Dec,
22:6, 733-7
- Abstract
- It is now clear that "seizure
activity", excitatory phenomena,
and/or a disorder of muscle tone are
potential complications of the use of
propofol. Whether this "seizure
activity" is primarily,
secondarily, or not at all a cerebral
cortical event is still to be
elucidated. Clearly propofol does have
anticonvulsant activity, and also
clearly it can produce an involuntary
movement disorder, in certain
patients, under certain conditions.
Propofol is not the first anaesthetic
drug to be implicated in the causation
of seizures or abnormal movements nor
indeed the first to appear to have
anti-convulsant and proconvulsant
activity (e.g. Althesin). While
propofol has undoubtedly proved a very
useful drug, the problem of convulsive
phenomena creates a degree of
background concern about its use. More
needs to be known about the mechanism
of this complication and any risk
factors involved in determining who
may have a seizure after propofol. In
the clinical setting, the reporting of
seizures possibly related to propofol
should include--medical history,
including personal or family history
of epilepsy and movement disorders; a
history of previous anaesthetics and
whether propofol was used; regular
medications; use of drugs or alcohol;
history of chemical dependency;
emotional state prior to induction;
presence of hyperventilation or fever;
a description of the alleged seizure,
including rate of administration of
propofol and amount given, time of
onset of seizure in relation to time
of drug administration, speed of onset
of signs, quality of the abnormal
movements, part of body involved,
duration, any indication of a
postictal state, any cardiovascular
changes which may have accompanied the
seizure, and any other possible
triggers for the reaction such as
other drugs used, including
premedication; post seizure
investigations including temperature,
blood sugar, electrolytes, arterial
gas analysis, neurological
examination, EEG and CT scan. These
actions and these investigations
concerning propofol should not be
delayed. It would appear appropriate
to recommend to patients who
experience apparent convulsive
phenomena after propofol that they not
be re-exposed to the drug.
- Language of Publication
- English
- Unique Identifier
- 95200106
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- MeSH Heading (Major)
- Anesthesia, Intravenous|*AE;
Epilepsy, Tonic-Clonic|*CI/DT;
Propofol|*AE/AI; Seizures|*CI/DT
- MeSH Heading
- Adult; Case Report; Female; Human;
Male; Middle Age; Phenytoin|TU;
Thiopental|TU
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW,
TUTORIAL
- ISSN
- 0310-057X
- Country of Publication
- AUSTRALIA
Record 9
from database: MEDLINE
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- Title
- Ethnic differences in drug
metabolism.
- Author
- Kalow W
- Address
-
- Source
- Clin Pharmacokinet, 1982 Sep, 7:5,
373-400
- Abstract
- Interethnic differences in drug-metabolising
capacity may be substantial, and they
are sufficiently frequent to warrant
attention. Such differences may
consist of different mean values of
quantitative traits in separate
populations, or of different frequency
distributions as produced by the
occurrence of genetic enzyme variants.
The collection of population data
requires the investigation of
substantial numbers of subjects. This
may be no problem if drug-metabolising
enzymes occur in blood or are
sufficiently stable in their tissues
to allow investigation in vitro.
However, if investigations require the
use of probe drugs, new efforts are
needed to adapt pharmacokinetic
methods to make them suitable for
population studies. This development
of methods is further called for
because genetic variants seem to be
more easily detected through the
assessment of particular metabolites
than through the determination of
pharmacokinetic parameters of the
parent drug. Many studies with probe
drugs comparing different populations
have given results that are equivocal
in terms of the nature-nurture
interplay. However, a set of data with
antipyrine has pointed to
environmental factors as the principal
determinant of differences in
metabolising capacity, while data with
debrisoquine have indicated
monogenically controlled variation of
one facet of the cytochrome P-450
system. In several instances,
statistically significant differences
between population means have been
established by testing small numbers
of subjects, numbers insufficient to
establish distribution patterns that
would allow the recognition of genetic
polymorphism. The populations studied
range from Greenlanders to South
African Blacks, but most comparisons
pertain to Caucasians and Orientals.
- Language of Publication
- English
- Unique Identifier
- 83051809
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- MeSH Heading (Major)
- Ethnic Groups|*; Pharmaceutical
Preparations|*ME
- MeSH Heading
- Acetylation; Alcohol
Oxidoreductases|AN; Amobarbital|ME;
Antipyrine|ME; Cholinesterases|BL;
Debrisoquin|ME; Diphenhydramine|ME;
Ethanol|ME; Human; Kinetics; Methods;
Mixed Function Oxidases|AN;
Phenytoin|ME
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0312-5963
- Country of Publication
- UNITED STATES
Record
10 from database: MEDLINE
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- Title
- Phenytoin toxicity: predictors of
clinical course.
- Author
- Curtis DL; Piibe R; Ellenhorn MJ;
Wasserberger J; Ordog G
- Address
- Department of Emergency Medicine,
Charles R Drew/UCLA School of
Medicine.
- Source
- Vet Hum Toxicol, 1989 Apr, 31:2,
162-3
- Abstract
- The records of 46 patients who were
admitted to a general hospital with
the diagnosis of phenytoin toxicity
were retrospectively studied to
identify factors present at the time
of admission which correlated with
severity of illness and which would
therefore be of prognostic value.
Length of hospital stay was used as a
measure of severity of illness.
Correlations were made between the
length of hospital stay and 18
variables studied at the time of
admission, including severity of
symptoms, use of other drugs (sedative
hypnotics, anticonvulsants and
phenothiazines), history (seizures,
cardiac arrhythmias, and alcohol
abuse), laboratory evidence of liver
disease or renal disease, electrolyte
abnormalities, coagulopathies, prior
suicide attempts, glucose levels, and
white blood cell counts. Significant
correlations related the length of
hospital stay with the severity of
symptoms, concurrent phenothiazine
usage, and the presence of abnormal
liver function tests on admission, but
not with other factors studied.
Admission phenytoin serum levels
following an overdose were not a
useful predictor of length of hospital
stay in this series of patients.
- Language of Publication
- English
- Unique Identifier
- 89188375
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- MeSH Heading (Major)
- Phenytoin|BL/*PO
- MeSH Heading
- Hospitals, General; Human; Length of
Stay; Prognosis; Retrospective Studies
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0145-6296
- Country of Publication
- UNITED STATES
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