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Effect of Maximal Daily Doses of Acetaminophen on the Liver of Alcoholic Patients
A Randomized, Double-blind, Placebo-Controlled Trial
Edwin K. Kuffner, MD;
Richard C. Dart, MD, PhD;
Gregory M. Bogdan, PhD;
Robert E. Hill, BSMJ;
Edmund Casper, MD;
Lisa Darton, MD
Arch Intern Med. 2001;161:2247-2252.
ABSTRACT
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Background Retrospective reports suggest that therapeutic doses of acetaminophen
may be associated with fulminant hepatic failure and death in alcoholic patients.
Millions of patients use acetaminophen; the prevalence of alcoholism in the
United States is 5% to 10%.
Objective To determine if hepatic injury was associated with maximal therapeutic
dosing of acetaminophen to chronic alcohol abuse patients immediately following
cessation of alcohol intake (the presumed time of maximal vulnerability).
Methods Patients entering an alcohol detoxification center were enrolled in
a randomized, double-blind, placebo-controlled trial. Exclusion criteria were
baseline values of aspartate or alanine aminotransferase greater than 120
U/L, international normalized ratio greater than 1.5, serum acetaminophen
level greater than 20 mg/L, or a history of ingesting more than 4 g/d of acetaminophen.
Acetaminophen, 1000 mg, or placebo was administered orally 4 times daily for
2 consecutive days and liver test results were monitored for 2 more days.
Acetaminophen was not administered until the alcohol had been eliminated.
Results There were 102 patients in the acetaminophen-treated group and 99 patients
in the placebo-treated (control) group. Demographic data, alcohol history,
and baseline blood test results were similar in both groups. The mean (SD)
aspartate aminotransferase level on day 4 was 38.0 ± 26.7 U/L in the
acetaminophen-treated group and 37.5 ± 27.6 U/L in the placebo-treated
group. There were 4 patients in the acetaminophen-treated group and 5 in the
placebo-treated group who developed an increase in their serum aspartate aminotransferase
level to greater than 120 U/L; it did not exceed 200 U/L in any patient. The
mean (SD) international normalized ratio on day 4 was 0.96 ± 0.09 in
the acetaminophen-treated group and 0.98 ± 0.11 in the placebo-treated
group.
Conclusion Repeated administration of the maximum recommended daily doses of acetaminophen
to long-term alcoholic patients was not associated with evidence of liver
injury.
INTRODUCTION
ACETAMINOPHEN is a safe and effective analgesic and antipyretic when
used appropriately. When taken in overdose, particularly large intentional
overdose, acetaminophen can cause fulminant hepatic failure and death. In
recent years, retrospective case reports and case series have suggested that
alcoholic patients may be at risk of acetaminophen-induced hepatic injury
and even death following the ingestion of recommended therapeutic doses of
acetaminophen.1 Since the prevalence of alcoholism
in the United States is 5% to 10%,2 a potentially
fatal drug-drug interaction could have far-reaching public health consequences.
Acetaminophen and alcohol are metabolized by hepatic cytochrome P450
isoenzymes, particularly CYP2E1.3-4
The primary metabolites of acetaminophen following a therapeutic dose are
nontoxic. However, metabolism produces a small amount of a potentially toxic
metabolite, N-acetyl-p-benzoquinoneimine
(NAPQI), which is rapidly detoxified by conjugation with glutathione and excreted
in the urine as a mercapturic acid metabolite. When the amount of NAPQI formed
overwhelms this detoxification mechanism, however, hepatic injury may develop.5
Conditions that increase production of NAPQI or that decrease cellular
defenses against NAPQI have been hypothesized to increase the injury associated
with a dose of acetaminophen. For example, long-term alcohol use has been
shown in animals to induce the activity of CYP2E1, increase the amount of
NAPQI produced, and increase the hepatic injury caused by a single, large
dose of acetaminophen.6 Case reports and retrospective
case series have described alcoholic patients who developed fulminant hepatic
failure in association with doses of acetaminophen reportedly within the recommended
4 g/d.1, 7 However, data from human
studies are conflicting and the preponderance of data do not indicate that
the amount of reactive intermediate produced is increased in the alcoholic
patient.3, 8-10
These retrospective reports have convinced some practitioners to recommend
a decreased dose or complete avoidance of acetaminophen in the alcoholic patient.1 Extensive coverage in the lay press has discouraged
patients who drink alcohol from using acetaminophen. If the alcoholic patient
is to be advised to avoid acetaminophen, however, the potential adverse effects
of this advice must be considered. It seems likely that patients will seek
alternative over-the-counter pain medications. Nearly all of these products
are nonsteroidal anti-inflammatory agents. Since nonsteroidal medications
can produce gastric ulcers and increase the risk of death,11
their use in alcoholic patients can be dangerous.12
Because of the serious implications, the magnitude of over-the-counter analgesic
and alcohol use and the lack of prospective data, we performed a randomized
controlled trial to determine if hepatic injury was associated with maximal
therapeutic dosing of acetaminophen to chronic alcohol abuse patients immediately
following cessation of alcohol intake (the presumed time of maximal vulnerability).
In addition, we assessed the effect of acetaminophen on the subgroups of patients
potentially malnourished or exposed to agents that induce the activity of
cytochrome P450 enzymes.
SUBJECTS AND METHODS
STUDY DESIGN AND SUBJECTS
Alcoholic patients were administered placebo or acetaminophen in a randomized,
double-blinded, placebo-controlled trial. The study period spanned 4 days:
2 days for acetaminophen administration followed by 2 days of monitoring.
The dose of acetaminophen was 1 g, 4 times daily. The study was approved by
the institutional review board and included informed consent. Patients received
a total of $15 for participation.
Patients 18 years or older entering Denver CARES (Comprehensive Alcohol
Receiving and Emergency Services), an alcohol and drug detoxification facility,
were eligible for enrollment. Exclusion criteria included a baseline serum
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level greater
than 120 U/L, a baseline international normalized ratio (INR) greater than
1.5, a baseline serum acetaminophen level greater than 20 mg/L (therapeutic
range, 10-20 mg/L), a positive serum pregnancy test result, a history of ingesting
more than 4 g/d of acetaminophen for any of the 4 days preceding enrollment,
a history of allergy to acetaminophen, enrollment in any other trial within
the preceding 3 months, or clinical alcohol intoxication at the time the first
dose of study medication was administered.
A structured medical history was obtained, including specific alcohol,
medication, and nutritional components. The alcohol history included the CAGE
questionnaire and the Brief Michigan Alcoholism Screening Test (MAST), 2 validated
measures of alcoholism.13-14 The
medication history included common drugs that may induce or inhibit the cytochrome
P450 microsomal enzyme system. The physical examination included height, weight,
and a clinical assessment of nutritional status. The study investigator clinically
classified each patient into 1 of the following nutritional categories: normal
nutritional status, mild malnutrition, moderate malnutrition, or severe malnutrition.15 The body mass index (BMI) (the weight, in kilograms,
divided by the height, in meters, squared) was calculated.16
Laboratory specimens were drawn before the first dose of study medication
and in the morning of days 2 and 4 and assayed in the clinical laboratory
of Denver Health Medical Center. Baseline laboratory studies included the
following: serum acetaminophen level, complete blood cell count, serum electrolyte
levels, renal function test results, AST, ALT, and  -glutamyl transferase
(GGT) levels, and INR. Female patients underwent  -human chorionic gonadotropin
level testing. On days 2 and 4 of the study, serum electrolyte levels, renal
function test results, AST and ALT levels, and INR were determined or evaluated.
Alcohol levels were determined at the time of the initial presentation, usually
the evening before enrollment, using a breath alcohol analyzer (Intoxilyzer
300; CMI Inc, Owensboro, Ky).
Each patient who met the inclusion criteria was individually randomized
using statistical software (StatMate version 1.01I; GraphPad Software Inc,
San Diego, Calif). An investigator (G.M.B.) not involved with patient care
generated the randomization schedule and maintained the randomization code
throughout the trial.
Group assignments were blinded for patients, staff, and investigators.
Patients received either acetaminophen purchased commercially (two 500-mg
Extra Strength Tylenol tablets; McNeil Consumer Healthcare, Fort Washington,
Pa) or 2 placebo tablets in identical pill casings. Study medications were
dispensed either by nursing staff or study investigator and recorded on a
drug dispensing form. Patients had 24-hour nursing supervision. Patients who
left the detoxification facility during the study were dropped from the trial.
Patients received the study drug on days 1 and 2 at 9 AM and at 1, 5,
and 9 PM. Phlebotomy was performed between 8 and 9 AM by a study investigator
(E.K.K.) on day 2 prior to administration of the study drug and on day 4 prior
to discharge from the study.
DATA COLLECTION AND STATISTICAL ANALYSIS
Data were entered into Access 7.0 (Microsoft Corp, Redmond, Wash) and
imported into InStat 3.0 (GraphPad Software Inc) for statistical analysis.
Categorical variables (sex, race, number of self-reported alcoholic subjects,
CAGE answers, number of subjects with a score of 6 or more on the Brief MAST,
duration of most recent drinking binge, number of subjects with a detectable
blood alcohol level) are presented as frequency of occurrence and were compared
by  2 test for independence. Continuous variables (age, BMI,
baseline values for GGT, AST, ALT, INR, Brief MAST mean score, and mean blood
alcohol level) are presented as mean ± SD and comparisons performed
using t tests to compare excluded subjects (those
who failed the screening criteria and those who withdrew before treatment)
with those included in the study (both treatment arms), and to compare the
2 treatment groups (acetaminophen-treated vs placebo-treated [control] group).
A BMI less than 22 for men and less than 21 for women was used to divide the
groups and is suggestive of clinical malnutrition.
A 2-way analysis of variance (ANOVA) was used to assess the significance
of changes in liver function test results (ALT level, AST level, and INR,
log-transformed) over time following the administration of acetaminophen or
placebo, and to test for differences between the acetaminophen-treated and
placebo-treated groups. The model was factorial for the treatment group (2
levels: acetaminophen and placebo) and repeated measures for time (3 levels:
at baseline, at 2 hours, and at 4 hours after dosing) with interactions. The
general linear model calculations were performed using the SPSS statistical
package (SPSS, Inc, Chicago, Ill). The Fisher exact test was used to compare
the proportion of groups for (1) development of an increase in the level of
serum AST or ALT or an INR above baseline; (2) development of an increase
in the level of serum AST or ALT above 120 U/L; (3) presence of clinical malnutrition;
and (4) use of CYP2E1 inducers and inhibitors.
RESULTS
There were 284 subjects screened for eligibility: 30 subjects were excluded
based on a baseline AST or ALT level greater than 120 U/L, 19 withdrew before
randomization, and 5 had previously participated in the trial (Figure 1). The remaining 230 subjects were randomized as follows:
118 to the acetaminophen-treated group and 112 to the placebo-treated group.
After randomization, 29 subjects elected not to stay at the facility for the
required 4 days. No patient withdrew from the study because of an adverse
event. One patient in the study was diagnosed as having a subdural hematoma
that was related to head trauma suffered prior to study enrollment. Of the
16 subjects in the acetaminophen-treated group who withdrew, 2 received a
single dose, 5 received 2 to 4 doses, and 9 received 5 to 8 doses. Telephone
follow-up and medical record review revealed that all subjects who withdrew
from the placebo-treated group and 15 of 16 subjects from the acetaminophen-treated
group were located and reported no apparent illness following withdrawal from
the study. One patient could not be located.
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Study schematic. AST indicates aspartate aminotransferase level;
ALT, alanine aminotransferase level; and INR, international normalized ratio.
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Overall, 201 subjects completed the study: 102 received acetaminophen
and 99 received placebo. A comparison of the randomized acetaminophen-treated
and placebo-treated groups showed no statistically significant differences
(all P>.05) in age; sex; race; BMI; baseline levels
of GGT, AST, and ALT; and INR values or measures of alcohol use (Table 1 and Table 2). A comparison between subjects who participated in the
study and those who failed screening or withdrew before treatment showed that
the experimental and excluded groups did not differ significantly for sex,
race, BMI, or baseline AST, ALT, and INR values. Excluded subjects were about
3 years younger than included subjects (P = .01),
had higher GGT values (227 U/L vs 127 U/L, P<.001),
and had fewer self-reported alcoholic subjects (83% vs 99%, P<.001).
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Table 1. Comparison of Baseline Characteristics for Experimental Groups
and Excluded or Withdrawn Subjects*
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Table 2. Measures of Alcohol Use for Experimental Groups and Excluded
or Withdrawn Subjects
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Two-way ANOVA showed that there was a significant change in the liver
enzyme concentrations over time (for both groups combined), but no significant
difference between the groups. The study had a power of 95% to detect a mean
difference in the AST level of 13.9 U/L, in the ALT level of 16.6 U/L, and
in the INR of 0.05. However, the AST level differed over time in the acetaminophen-treated
group, decreased on day 2, and then returned to baseline value. The AST level
remained unchanged over time in the placebo-treated group. Four patients in
the acetaminophen-treated group and 5 patients in the placebo-treated group
developed an AST or ALT level greater than 120 U/L (Table 3). No subject in either group developed a serum AST or ALT
level above 200 U/L. The highest ALT or AST level was 197 U/L and occurred
in the placebo-treated group. The highest INR was 1.75 and also occurred in
the placebo-treated group.
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Table 3. Hepatic Aminotransferase Levels After Drug Dosing of Subjects*
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A BMI consistent with clinical malnutrition (<22 for men and <21
for women) was found in 34 subjects (33.3 %) in the acetaminophen-treated
group and 30 subjects (30.3 %) in the placebo-treated group (P = .65). Post hoc subgroup analysis showed no increase in enzyme levels
among subjects with a low BMI or those judged malnourished by clinical judgment.
A history of use of CYP2E1-inducing drugs was common: tobacco (78 subjects
in each group), phenytoin sodium (4 acetaminophen-treated subjects, 7 placebo-treated
subjects), valproate sodium (1 acetaminophen-treated subject, 2 placebo-treated
subjects), and phenobarbital sodium (2 placebo-treated subjects). The only
subject in the study who reported use of a P450 inhibitor was in the placebo-treated
group; the subject was was receiving disulfiram. There was no statistical
difference between the 2 groups. Post hoc subgroup analysis showed no increase
in either AST or ALT levels in subjects receiving CYP2E1 inducers.
COMMENT
Our study was designed to detect a small change in serum AST and ALT
levels, should the administration of acetaminophen in therapeutic doses to
an alcoholic subject produce any degree of hepatotoxic reaction. We found
no difference between placebo-treated and alcoholic subjects who received
the maximum recommended daily dose of acetaminophen. The study power was 95%
to detect a difference in the mean AST level of 14 U/L. Further, subgroup
analyses of putative high-risk groups showed no effect on serum AST and ALT
levels or on the INR of subjects in our study. Neither the alcoholic subjects
with evidence of malnutrition nor those who were treated long-term with agents
expected to induce the activity of the cytochrome P450 system showed evidence
of increased AST or ALT levels or an INR. A plausible subset of subjects with
increased vulnerability to therapeutic doses of acetaminophen has yet to be
demonstrated in a study with appropriate experimental design.
Benson17 administered acetaminophen to
patients with chronic liver disease in a prospective study. In a pilot phase,
6 patients with various types of liver cirrhosis were treated with 4 g/d of
acetaminophen for 5 days. No change in the AST level was found. Subsequently,
20 patients with liver disease (alcoholic liver disease, Laennec cirrhosis,
postnecrotic cirrhosis, chronic active hepatitis, chronic persistent hepatitis,
and primary biliary cirrhosis) were randomly assigned to receive either acetaminophen
or placebo for 13 days in a crossover trial. There was no difference in the
bilirubin, AST, and ALT levels or other studies between the acetaminophen-treated
and placebo-treated groups.
In contrast to the evidence from prospective trials, case reports and
retrospective case series have described an association of severe hepatic
injury and the reported ingestion of therapeutic doses of acetaminophen by
alcoholic patients. A systematic review described 25 patients in 20 reports
over a 23-year period that described development of hepatic injury in association
with the reported use of therapeutic doses of acetaminophen by an alcoholic
patient.18 Only 5 of these case reports contain
enough information to credibly implicate acetaminophen. One other case series
described a registry of 67 patients in whom hepatic injury developed after
ingestion of acetaminophen.1 The article states
that 40% of these patients reported ingestion of therapeutic doses of acetaminophen,
but includes data insufficient to assess the relationship to acetaminophen
ingestion. The difficulty in interpreting retrospective reports is that they
suffer from many methodological weaknesses: incomplete and inaccurate data
collection resulting in missing and conflicting data, inaccuracies in the
history regarding the dose of acetaminophen ingested, acetaminophen levels
that in many cases contradict the reported history of ingestion, and the failure
to rule out other causes of hepatotoxic reaction.18
All reports contained 1 or both of 2 serious flaws: (1) they relied on the
patient's history to estimate the dose ingested or (2) other causes of liver
injury were not evaluated.
The history is a particularly troublesome challenge in the case of the
alcoholic subject. Studies have demonstrated that recent memory is impaired
in the alcoholic subject.19 For example, nearly
all of the reports of hepatic injury associated with therapeutic use of acetaminophen
include obviously conflicting data such as serum acetaminophen levels inconsistent
with therapeutic doses of acetaminophen, hepatic histologic abnormalities
inconsistent with acetaminophen toxic reactions, suicidal gestures that presumably
involved a therapeutic dose, and other contradictions. Because of their retrospective
design and the frequently conflicting data, causation cannot be ascertained
from the data available.
Our study avoided the weakness of retrospective reports. We administered
a known dose of acetaminophen, beginning at the time of maximal CYP2E1 induction.
Although we did not measure CYP2E1 activity in our subjects directly, the
population had a very high incidence of alcoholism as assessed by 2 valid
standard alcoholism screening tools. Further, nearly all of our subjects were
intoxicated at the time of enrollment. Since studies have shown that acute
and concurrent alcohol intoxication may actually protect against acetaminophen-induced
hepatotoxic reactions,6, 20 we
initiated administration of study medications soon after the subject achieved
sobriety, thereby assuring that they were at maximal vulnerability for developing
a toxic reaction. If subjects did not develop hepatic damage when they were
not intoxicated with alcohol, it is unlikely that they would have developed
a hepatotoxic reaction when they were intoxicated and protected against acetaminophen-induced
hepatotoxic reaction. Also if subjects did not develop hepatic damage when
their CYP2E1 was maximally induced, it is unlikely that they would have developed
a hepatotoxic reaction as their CYP2E1 induction waned.21
Our subjects were at maximal vulnerability for developing a toxic reaction.
Substantial variations in the AST and ALT levels were observed in our
subjects at all periods throughout our study (Table 3). These fluctuations emphasize the importance of a randomized
placebo-controlled trial in the evaluation of a hepatotoxic reaction in alcoholic
subjects. If we had administered acetaminophen to all subjects, instead of
including a placebo comparison group, these data would have indicated that
83 subjects (41%) experienced a rise in their serum AST level and that 1 subject's
level reached 197 U/L. Further, an INR as high as 1.75 could theoretically
have been attributed to acetaminophen treatment. The inclusion of a placebo
group allowed us to demonstrate that fluctuations in the AST and ALT levels
should be expected in the alcoholic subject population.
Limitations of our study include that the acetaminophen dose did not
exceed the maximum therapeutic daily dose of acetaminophen and was administered
for only 2 days. Therefore, our data should not be applied to supratherapeutic
or overdose ingestions of acetaminophen. Our study also excluded subjects
who had AST or ALT elevations greater than 120 U/L. Although unlikely based
on human CYP2E1-induction data,21 it is possible
that administration of acetaminophen for a longer period than 2 days is required
for alcoholic patients to manifest a hepatotoxic reaction. It is also possible
that a hepatotoxic reaction from therapeutic dosing of acetaminophen is an
idiosyncratic and rare event that would only be detected in a study with an
extremely large sample size.
Despite the weakness of retrospective data, some authors1
have asserted that alcoholic patients should use reduced doses of acetaminophen
or avoid it entirely. This recommendation creates a therapeutic dilemma: the
common alternatives to acetaminophen are aspirin and other nonsteroidal anti-inflammatory
agents. Unfortunately, these drugs have been shown to cause life-threatening
gastrointestinal bleeding in both normal subjects and alcoholic subjects.11-12 Recommendations to lower the acetaminophen
dose in alcoholic subjects are based on retrospective information. Since this
study and other prospective studies have failed to find evidence of liver
injury in humans,17-18 even in
purportedly high-risk groups, we believe that such a recommendation is unwarranted.
AUTHOR INFORMATION
Accepted for publication March 29, 2001.
This research was supported by a grant from McNeil Consumer Healthcare,
Fort Washington, Pa.
Presented at the North American Congress of Clinical Toxicology, San
Diego, Calif, October 2, 1999.
We thank the counseling, nursing, and support staff at Denver CARES
and the laboratory staff at the Denver Health Medical Center for their help
in conducting this trial.
Corresponding author: Edwin K. Kuffner, MD, Rocky Mountain Poison
and Drug Center, 1010 Yosemite Cir, Denver, CO 80230 (e-mail: EKuffner{at}rmpdc.org).
From the Rocky Mountain Poison and Drug Center, Denver Health Authority
(Drs Kuffner, Dart, and Bogdan and Mr Hill); Department of Psychiatry, Denver
Health Medical Center, Denver Health Authority (Drs Casper and Darton); and
Department of Surgery, University of Colorado Health Sciences Center (Drs
Kuffner and Dart and Mr Hill), Denver.
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