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PubMed1986

Reactions of N-acetyl-p-benzoquinone imine with reduced glutathione, acetaminophen, and NADPH.

Synthetic N-acetyl-p-benzoquinone imine reacted with reduced glutathione (GSH), [14C]acetaminophen, and NADPH. It reacted rapidly with GSH to yield acetaminophen (33%) and 3-(glutathion-S-yl)acetaminophen (67%), and with acetaminophen or NADPH to yield acetaminophen polymers. The data suggested that N-acetyl-p-benzoquinone imine was reduced by GSH to form acetaminophen but primarily reacted with GSH to form 3-(glutathion-S-yl)acetaminophen. The evidence further suggested that N-acetyl-p-benzoquinone imine comproportionated with [14C]acetaminophen to yield a mixture of radioactive and nonradioactive N-acetyl-p-benzosemiquinone imine which subsequently formed acetaminophen polymers by a radical coupling reaction. [14C]Acetaminophen was incorporated into the acetaminophen polymers. The amount of 14C incorporation was dependent on the initial concentration of [14C]acetaminophen and N-acetyl-p-benzoquinone imine. An increase in the ratio of [14C]acetaminophen to N-acetyl-p-benzoquinone imine resulted in an increase in [14C] acetaminophen incorporation into the acetaminophen polymers. NADPH reduced N-acetyl-p-benzoquinone imine to acetaminophen and acetaminophen polymers were formed. When [14C]N-acetyl-p-benzoquinone imine was incubated without acetaminophen, only minor amounts of acetaminophen polymerization were observed.

Acetaminophen↗

PubMedDate not supplied

Mechanism of acetaminophen-induced hepatotoxicity: covalent binding versus oxidative stress.

The hepatotoxicity of acetaminophen is believed to be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine; however, the mechanism by which this metabolite produces the toxicity is unknown. The metabolite, which is both an electrophile and an oxidizing agent, may covalently bind to critical proteins, or it may initiate oxidative damage. We have previously developed a Western blot assay for detection of acetaminophen covalently bound to protein and have reported the relationship between covalent binding and the development of hepatotoxicity. Recently, we developed a Western blot assay for protein aldehyde formation, which may occur via the reactive oxygen species, the hydroxyl radical. In this paper, we have compared covalent binding to protein aldehyde formation. Toxic doses of acetaminophen (400 mg/kg) were administered to mice, and the mice were subsequently killed at 0, 1, 2, 4, and 6 h. Since the oxidizing agent FeSO4 has been reported to potentiate lipid peroxidation when administered with acetaminophen, other mice received FeSO4 (100 mg/kg) plus acetaminophen. Compared to saline-treated control mice, acetaminophen treatment significantly increased serum alanine aminotransferase levels, an index of hepatotoxicity, at 4 and 6 h, but not at 1 or 2 h. Acetaminophen plus FeSO4 treatment of mice significantly increased serum alanine aminotransferase levels at 2, 4, and 6 h compared to controls. Levels of alanine aminotransferase in serum of acetaminophen plus ferrous sulfate-treated mice were higher at 4 and 6 h than those of acetaminophen-treated mice, but not significantly different. FeSO4 alone did not increase alanine aminotransferase levels. Western blot assays revealed that acetaminophen did not cause an increase in protein aldehydes over control at any time, nor did acetaminophen plus FeSO4; however, FeSO4 alone increased the intensity of staining of the immunoblot for protein aldehydes over control at all times after 0 time. Acetaminophen-protein adducts were detected in acetaminophen- and acetaminophen plus FeSO4-treated mice. In vitro experiments indicated that FeSO4 plus tert-butyl hydroperoxide in the presence of bovine serum albumin increased protein aldehyde formation. Inclusion of acetaminophen in the incubation mixture inhibited protein oxidation of bovine serum albumin in a concentration dependent manner. The data indicate that acetaminophen quenches protein oxidation, presumably by reacting with the hydroxyl radical. These data are consistent with the theory that acetaminophen covalent binding is the primary mechanism of toxicity and argue against a role for protein oxidation in acetaminophen hepatotoxicity.

Acetaminophen↗

PubMed2003

Effects of acetaminophen on myocardial infarct size in rats.

OBJECTIVE: Acetaminophen is widely prescribed as an analgesic agent in hospitals and clinics. However, acetaminophen theoretically could influence myocardial infarct size by reducing prostaglandin synthesis in vivo. To date, the effect of acetaminophen on myocardial infarct size is unknown. The present study investigated (1) whether acetaminophen has any effect on myocardial infarct size when given in an analgesic dose and (2) whether acetaminophen can affect the cardioprotective effect of the early phase of ischemic preconditioning in rats. METHODS: Female Sprague-Dawley rats were randomly assigned to four groups (n=12 each). Group 1 (no preconditioning): Vehicle (intravenous ethanol, 0.9 mL/kg) was given 39 minutes prior to ischemia. Group 2 (acetaminophen plus no preconditioning): intravenous acetaminophen (125 mg/kg) was given 39 minutes prior to ischemia. Group 3 (preconditioning): The heart was preconditioned before ischemia, and the vehicle (intravenous ethanol, 0.9 mL/kg) was given 39 minutes prior to the ischemia. Group 4 (acetaminophen plus preconditioning): The heart was preconditioned before ischemia, and intravenous acetaminophen (125 mg/kg) was given 39 minutes prior to the ischemia. The preconditioning protocol consisted of three cycles of 3 minutes of coronary occlusion and 5 minutes of reperfusion. The left coronary artery was then occluded for 60 minutes, followed by 3 hours of reperfusion. The end points were hemodynamics, body temperature, and risk area and area of necrosis of the left ventricle. RESULTS: The area of risk was similar among the four groups. The area of necrosis, expressed as a percentage of the area at risk, was 55.7% +/- 6.1% in the no-preconditioning group, 62.8% +/- 2.4% in the acetaminophen plus no-preconditioning group, 24.7% +/- 7.3% in the preconditioning group, and 17.2% +/- 6.4% in the acetaminophen plus preconditioning group. The area of necrosis/area at risk was decreased significantly in the preconditioning group and in the acetaminophen plus preconditioning group compared with the no-preconditioning group (P<.05); but there were no significant differences between the no-preconditioning group and the acetaminophen plus no-preconditioning group (P=.29), or between the preconditioning group and acetaminophen plus preconditioning group (P=.45). Among the four groups, heart rate and body temperature were similar. The infusion of the vehicle or acetaminophen increased blood pressure in the four groups, but to a lesser extent in the acetaminophen group. However, during coronary artery occlusion and reperfusion, the four groups had comparable blood pressures. CONCLUSION: Acetaminophen had no beneficial or adverse effects on infarct size in nonpreconditioned rats, and the beneficial effects of preconditioning were not blocked or prevented by acetaminophen at this analgesic dose.

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PubMed1993

NTP Toxicology and Carcinogenesis Studies of Acetaminophen (CAS No. 103-90-2) in F344 Rats and B6C3F1 Mice (Feed Studies).

Acetaminophen is a widely consumed analgesic found in several nonprescription pharmaceuticals. Toxicology and carcinogenesis studies were conducted by administering acetaminophen (purity >99%) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-DAY STUDIES: Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls. Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received 12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls. 13-WEEK STUDIES: Rats and mice were fed diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or 25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or 25,000 ppm were indicative of poor feed palatability. Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast, tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live (chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm. Dose selection for the 2-year studies was based on reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm. 2-YEAR STUDIES: Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology, urinalysis, and clinical chemistry parameters. Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50). Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was present in one low-dose and one high-dose male. GENETIC TOXICOLOGY: Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 witr TA98 with or without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm. Nonneoplastic lesions associated with exposure to acetaminophen included increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased incidences of thyroid follicular cell hyperplasia in male and female mice. Synonyms: 4-Hydroxyacetanilide, N-Acetyl-p-aminophenol, Paracetamol

Journal Article↗

PubMed1983

Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo.

N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as reduction of the quinoneimine might be responsible for the clinical efficacy of N-acetylcysteine. After the administration to rats of acetaminophen (1 g/kg) intraduodenally (i.d.) and of [(35)S]-N-acetylcysteine (1.2 g/kg i.d.), the specific activity of the N-acetylcysteine adduct of acetaminophen (mercapturic acid) isolated from urine and assayed by high pressure liquid chromatography averaged 76+/-6% of the specific activity of the glutathione-acetaminophen adduct excreted in bile, indicating that virtually all N-acetylcysteine-acetaminophen originated from the metabolism of the glutathione-acetaminophen adduct rather than from a direct reaction with the toxic metabolite. N-Acetylcysteine promptly reversed the acetaminophen-induced depletion of glutathione by increasing glutathione synthesis from 0.54 to 2.69 mumol/g per h. Exogenous N-acetylcysteine did not increase the formation of the N-acetylcysteine and glutathione adducts of acetaminophen in fed rats. However, when rats were fasted before the administration of acetaminophen, thereby increasing the stress on the glutathione pool, exogenous N-acetylcysteine significantly increased the formation of the acetaminophen-glutathione adduct from 57 to 105 nmol/min per 100 g. Although the excretion of acetaminophen sulfate increased from 85+/-15 to 211+/-17 mumol/100 g per 24 h after N-acetylcysteine, kinetic simulations showed that increased sulfation does not significantly decrease formation of the toxic metabolite. Reduction of the benzoquinoneimine by N-acetylcysteine should result in the formation of N-acetylcysteine disulfides and glutathione disulfide via thiol-disulfide exchange. Acetaminophen alone depleted intracellular glutathione, and led to a progressive decrease in the biliary excretion of glutathione and glutathione disulfide. N-Acetylcysteine alone did not affect the biliary excretion of glutathione disulfide. However, when administered after acetaminophen. N-acetylcysteine produced a marked increase in the biliary excretion of glutathione disulfide from 1.2+/-0.3 nmol/min per 100 g in control animals to 5.7+/-0.8 nmol/min per 100 g. Animals treated with acetaminophen and N-acetylcysteine excreted 2.7+/-0.8 nmol/min per 100 g of N-acetylcysteine disulfides (measured by high performance liquid chromatography) compared to 0.4+/-0.1 nmol/min per 100 g in rats treated with N-acetylcysteine alone. In conclusion, exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of acetaminophen in the rat in vivo but increases glutathione synthesis, thus providing more substrate for the detoxification of the reactive metabolite in the early phase of an acetaminophen intoxication when the critical reaction with vital macromolecules occurs.

Acetaminophen↗

PubMed1984

Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man.

Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine has been shown to inhibit the hepatic oxidation of a number of drugs and to protect rats from acetaminophen-induced hepatic necrosis. The aim of this study was to define the mechanism by which cimetidine reduced acetaminophen-induced hepatic necrosis and to determine whether inhibition of formation of the reactive metabolite(s) of acetaminophen occurred also in man. In vivo cimetidine pretreatment decreased covalent binding of [3H]acetaminophen to the liver from 552 +/- 23.8 to 170 +/- 31.6 nmol/g protein 2 h after a toxic dose of acetaminophen in 3-methylcholanthrene pretreated rats (P less than 0.05). Cimetidine pretreatment also significantly reduced the rate of hepatic glutathione depletion. Both cimetidine and metiamide produced dose-dependent inhibition of acetaminophen oxidation in vitro, whereas inhibition by ranitidine and cimetidine sulfoxide was quantitatively less. Inhibition of acetaminophen oxidation by cimetidine and metiamide was primarily competitive with an inhibition constant (Ki) of 130 +/- 16 and 200 +/- 50 microM, respectively. By contrast, cimetidine inhibited acetaminophen glucuronidation minimally with a Ki of 1.39 +/- 0.23 mM. Similar results were obtained using human liver microsomes as a source of enzymes. In a dose-related fashion, cimetidine also reduced acetaminophen-induced toxicity to human lymphocytes when incubated with microsomes and NADPH. Pharmacokinetics of acetaminophen elimination were studied in normal volunteers with and without co-administration of cimetidine 300 mg every 6 h. In normal volunteers, cimetidine decreased the fractional clearance of the oxidized (potentially toxic) metabolites of acetaminophen more than the conjugated metabolites. This finding confirmed the hypothesis that cimetidine is a relatively selective inhibitor of the oxidation of acetaminophen to reactive metabolites in man as well as in animals. When considered together with the results of previous studies showing improved survival and decreased hepatoxicity in acetaminophen-poisoned animals, the present results provide a rational basis for assessing possible benefits of cimetidine treatment of acetaminophen overdoses in man.

Acetaminophen↗

PubMed2002

Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial.

CONTEXT: Osteoarthritis (OA) is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or specific inhibitors of cyclooxygenase 2 (COX-2). OBJECTIVE: To assess the relative therapeutic efficacy of rofecoxib, celecoxib, and acetaminophen in adults with OA. DESIGN AND SETTING: Randomized, parallel-group, double-blind trial, conducted from June 1999 to February 2000, in 29 clinical centers in the United States. PATIENTS: Three hundred eighty-two patients aged at least 40 years who had OA of the knee that was previously treated with NSAIDs or acetaminophen. INTERVENTIONS: Patients were randomly assigned to receive rofecoxib, 12.5 mg/d (n = 96); rofecoxib, 25 mg/d (n = 95); celecoxib, 200 mg/d (n = 97); or acetaminophen, 4000 mg/d (n = 94) for 6 weeks. MAIN OUTCOME MEASURES: Assessments over days 1 to 6 and over 6 weeks included pain on walking, night pain, pain at rest, and morning stiffness as measured on a Western Ontario McMaster Universities Osteoarthritis Index (100-mm visual analog scale [VAS]) and global response to therapy compared among 4 treatment groups. RESULTS: 79% of patients completed the study. More patients treated with acetaminophen discontinued early due to lack of efficacy than patients treated with COX-2 inhibitors (31% vs 18%-19%). Efficacy assessed in the first 6 days of therapy showed greatest response to rofecoxib, 25 mg/d, followed by rofecoxib, 12.5 mg/d, celecoxib, and acetaminophen, respectively, in terms of relief of pain on walking (-32.2, - 29.0, - 26.4, and -20.6 mm change on the VAS; P</=.04 for all others vs acetaminophen; P =.05 for 25-mg rofecoxib vs celecoxib), rest pain (-21.8, - 18.6, - 15.5, and - 12.5 mm; P</=.02 for either dose of rofecoxib vs acetaminophen and P =.02 for rofecoxib, 25 mg/d, vs celecoxib), night pain (-25.2, - 22.0, - 18.7, and - 18.8 mm; P =.04 for rofecoxib, 25 mg/d, vs both acetaminophen and celecoxib), and morning stiffness (-30.4, - 28.4, - 25.7, and - 20.9 mm; P</=.02 for either dose of rofecoxib vs acetaminophen). Over 6 weeks, rofecoxib, 25 mg/d, provided greatest response for night pain (P<.002 vs celecoxib and P =.006 vs acetaminophen and P =.02 vs rofecoxib, 12.5 mg/d), composite pain subscale (P</=.03 vs all other treatments), stiffness subscale (P</=.04 vs celecoxib and acetaminophen), and physical function subscale (P =.001 vs acetaminophen). Global responses over 6 weeks showed a similar pattern (good or excellent response at week 6: 60%, 56%, 46%, and 39%, respectively; P</=.03 for rofecoxib, 25 mg/d, vs celecoxib and acetaminophen; P =.02 for rofecoxib, 12.5 mg/d, vs acetaminophen). All treatments were generally safe and well tolerated. CONCLUSION: Rofecoxib, 25 mg/d, provided efficacy advantages over acetaminophen, 4000 mg/d, celecoxib, 200 mg/d, and rofecoxib, 12.5 mg, for symptomatic knee OA.

Acetaminophen↗

PubMed1996

Decrease of plasma and urinary oxidative metabolites of acetaminophen after consumption of watercress by human volunteers.

To investigate the effect of the consumption of watercress (Nasturtium officinale R. Br.), a cruciferous vegetable, on acetaminophen metabolism, the pharmacokinetics of acetaminophen and its metabolites were studied in a crossover trial of human volunteers. A single oral dose of acetaminophen (1 gm) was given 10 hours after ingestion of watercress homogenates (50 gm). In comparison with acetaminophen only, the ingestion of watercress resulted in a significant reduction in the area under the plasma cysteine acetaminophen (Cys-acetaminophen) concentration-time curve and in the peak plasma Cys-acetaminophen concentration by 28% +/- 3% and by 21% +/- 4% (mean +/- SE; n = 7; p < 0.005), respectively. Correspondingly, the Cys-acetaminophen formation rate constant and Cys-acetaminophen formation fraction were decreased by 55% +/- 9% and 52% +/- 7% (p < 0.01), respectively. Consistent with the results obtained from the plasma, the total urinary excretion of Cys-acetaminophen in 24 hours was also reduced. A decrease of mercapturate acetaminophen, a Cys-acetaminophen metabolite, was also shown in the plasma and urine samples. However, the plasma pharmacokinetic processes and the urinary excretions of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were not altered significantly by the watercress treatment. These results suggest that the consumption of watercress causes a decrease in the levels of oxidative metabolites of acetaminophen, probably due to inhibition of oxidative metabolism of this drug.

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PubMed1999

Predictive properties of a qualitative urine acetaminophen screen in patients with self-poisoning.

OBJECTIVE: Screening for acetaminophen toxicity is recommended in almost all cases of self poisoning. We compared a qualitative urine acetaminophen screen to the quantitative serum acetaminophen to test the hypothesis that a negative urine acetaminophen screen would be predictive of a negative serum acetaminophen level. METHODS: All adults with intentional ingestions evaluated in our Emergency Department during 1995 were retrospectively identified based on Emergency Department International Classification of Disease--9th edition codes. Laboratory data from each patient including serum and urine toxicologic assays were examined. Predictive properties of urine acetaminophen screens for serum acetaminophen were evaluated. RESULTS: A total of 88 patients were identified who had both a serum acetaminophen and a urine acetaminophen performed. The sensitivity of the urine acetaminophen screen was 100% (95% CI 72-100%) and the specificity was 87% (95% CI 80-95%). All patients with negative urine acetaminophen screens had negative serum acetaminophen levels (negative predictive value 100%; 95% CI 96-100%). Accuracy of the urine acetaminophen screen was 89%. CONCLUSION: A negative urine acetaminophen screen was highly predictive of negative serum acetaminophen levels. It is possible that negative urine acetaminophen screens may obviate the need for 4-hour quantitative serum levels. Further validation in a prospective study is needed.

Acetaminophen↗

PubMed2000

Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia.

OBJECTIVE: Because there is controversy regarding the efficacy of acetaminophen in rheumatic diseases and because apparently safer nonsteroidal antiinflammatory drugs (NSAIDs) are being produced, we surveyed rheumatic disease patients about their preferences for these agents to determine the degree to which one type of therapeutic agent is preferred over the other. METHODS: In 1998, we surveyed by mailed questionnaire 1,799 patients with osteoarthritis (OA), rheumatoid arthritis, or fibromyalgia who were participating in a long-term outcome study. Patients who had taken acetaminophen rated the effectiveness of acetaminophen, compared its effectiveness with that of NSAIDs, and then rated their overall satisfaction with acetaminophen compared with NSAIDs when both effectiveness and side effects were considered. RESULTS: Two-thirds of study participants had taken acetaminophen. About 37% of patients who had taken acetaminophen found it to be moderately or very effective and about 63% indicated that it was not effective or was only slightly effective. One-fourth of the patients found acetaminophen and NSAIDs to be equally effective, but >60% found acetaminophen to be much less effective or somewhat less effective. About 12% preferred acetaminophen to NSAIDs. When both effectiveness and side effects were considered together, 25% of the patients had no preference, 60% preferred NSAIDs, and 14% preferred acetaminophen. CONCLUSION: There was a considerable and statistically significant preference for NSAIDs compared with acetaminophen among the 3 groups of rheumatic disease patients. Although this preference decreased slightly with age and was less pronounced in OA patients, the preference was noted among all categories of patients and was not altered by disease severity. If safety and cost are not issues, there would hardly ever be a reason to recommend acetaminophen over NSAIDs, since patients generally preferred NSAIDs and fewer than 14% preferred acetaminophen. If safety and costs are issues, then the recommendation of the American College Rheumatology that acetaminophen be tried first seems correct, since 38.2% found acetaminophen to be as effective or more effective than NSAIDs.

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PubMed2006

Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management.

The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of acetaminophen. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of acetaminophen alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care. The panel's recommendations follow. These recommendations are provided in chronological order of likely clinical use. The grade of recommendation is provided in parentheses. 1) The initial history obtained by the specialist in poison information should include the patient's age and intent (Grade B), the specific formulation and dose of acetaminophen, the ingestion pattern (single or multiple), duration of ingestion (Grade B), and concomitant medications that might have been ingested (Grade D). 2) Any patient with stated or suspected self-harm or who is the recipient of a potentially malicious administration of acetaminophen should be referred to an emergency department immediately regardless of the amount ingested. This referral should be guided by local poison center procedures (Grade D). 3) Activated charcoal can be considered if local poison center policies support its prehospital use, a toxic dose of acetaminophen has been taken, and fewer than 2 hours have elapsed since the ingestion (Grade A). Gastrointestinal decontamination could be particularly important if acetylcysteine cannot be administered within 8 hours of ingestion. Acute, single, unintentional ingestion of acetaminophen: 1) Any patient with signs consistent with acetaminophen poisoning (e.g., repeated vomiting, abdominal tenderness in the right upper quadrant or mental status changes) should be referred to an emergency department for evaluation (Grade D). 2) Patients less than 6 years of age should be referred to an emergency department if the estimated acute ingestion amount is unknown or is 200 mg/kg or more. Patients can be observed at home if the dose ingested is less than 200 mg/kg (Grade B). 3) Patients 6 years of age or older should be referred to an emergency department if they have ingested at least 10 g or 200 mg/kg (whichever is lower) or when the amount ingested is unknown (Grade D). 4) Patients referred to an emergency department should arrive in time to have a stat serum acetaminophen concentration determined at 4 hours after ingestion or as soon as possible thereafter. If the time of ingestion is unknown, the patient should be referred to an emergency department immediately (Grade D). 5) If the initial contact with the poison center occurs more than 36 hours after the ingestion and the patient is well, the patient does not require further evaluation for acetaminophen toxicity (Grade D). Repeated supratherapeutic ingestion of acetaminophen (RSTI): 1) Patients under 6 years of age should be referred to an emergency department immediately if they have ingested: a) 200 mg/kg or more over a single 24-hour period, or b) 150 mg/kg or more per 24-hour period for the preceding 48 hours, or c) 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer (Grade C). 2) Patients 6 years of age or older should be referred to an emergency department if they have ingested: a) at least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period, or b) at least 6 g or 150 mg/kg (whichever is less) per 24-hour period for the preceding 48 hours or longer. In patients with conditions purported to increase susceptibility to acetaminophen toxicity (alcoholism, isoniazid use, prolonged fasting), the dose of acetaminophen considered as RSTI should be greater than 4 g or 100 mg/kg (whichever is less) per day (Grade D). 3) Gastrointestinal decontamination is not needed (Grade D). Other recommendations: 1) The out-of-hospital management of extended-release acetaminophen or multi-drug combination products containing acetaminophen is the same as an ingestion of acetaminophen alone (Grade D). However, the effects of other drugs might require referral to an emergency department in accordance with the poison center's normal triage criteria. 2) The use of cimetidine as an antidote is not recommended (Grade A).

Acetaminophen↗

PubMed1981

Direct protection against acetaminophen hepatotoxicity by propylthiouracil. In vivo and in vitro studies in rats and mice.

Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [(3)H]acetaminophen, liver microsomes from phenobarbital-pretreated rats, and an NADPH-generating system, we found that PTU had a dose-dependent additive effect with GSH on inhibition of acetaminophen covalent binding. PTU administration also resulted in a dose-dependent decrease in both GSH depletion and covalent binding in vivo in acetaminophen-treated mice. To examine the possible mechanisms by which PTU exerts its protective effect, we studied the action of PTU on both acetaminophen conjugation and metabolic activation. PTU had no effect upon acetaminophen pharmacokinetics in phenobarbital-pretreated rats, as examined by measuring acetaminophen concentration in bile, urine, and blood after an intraperitoneal dose, nor did it alter the total amount of polar conjugates formed. Microsomes from PTU-treated rats were unaltered in cytochrome P-450 concentrations and p-nitroanisole-O-demethylase, benzo-alpha-pyrene hydroxylase, and cytochrome c-reductase activities. Furthermore PTU did not decrease acetaminophen-GSH adduct formation in vitro, suggesting that there was no reduction in drug activation. However, in bile from [(35)S]PTU and [(3)H]acetaminophen treated rats, as well as in incubates of the two drugs with liver microsomes, a new (35)S- and (3)H-containing product could be identified. By both thin layer chromatography and high pressure liquid chromatography this new product, which co-eluted with [(3)H]acetaminophen, was separated from unreacted [(35)S]PTU. The formation of this product in vitro was a function of PTU concentration and reached a maximum of 0.06 mumol/min per mg protein at 0.5 mM PTU. In vivo, the total biliary excretion of this product over 4 h (116 nmol) equaled the net reduction in acetaminophen metabolite covalent binding in the liver of phenobarbital-pretreated rats (108 nmol). We conclude that PTU, independent of its antithyroid effect, diminishes hepatic macromolecular covalent binding of acetaminophen reactive metabolite both in vivo and in vitro, and it does so by detoxifying the reactive metabolite through direct chemical interaction in a manner similar to GSH. These observations may define the mechanism by which PTU is protective against liver injury caused by acetaminophen.

Acetaminophen↗

PubMed1999

Characteristics and risk factors of acetaminophen-induced hepatitis in Taiwan.

BACKGROUND: Overdose of acetaminophen may cause hepatic injury and fatal fulminant hepatic failure. Acetaminophen is the most common form of drug-induced hepatic injury in Western countries. However, there is no formal report of this important issue in Taiwan. To assess the clinical characteristics and risk factors of acetaminophen-induced hepatitis in Taiwan, we conducted this study. METHODS: A total of 71 patients who were intoxicated or overdosed with acetaminophen at Veterans General Hospital-Taipei between February, 1991 and June, 1997 were enrolled in this study. Acetaminophen-induced hepatitis was defined according to the Paris international consensus criteria. RESULTS: Suicide attempt was the major cause (67/71) of acetaminophen overdose. Sixty-two of the patients were female. The mean patient age was 24.5 +/- 9.7 years (+/- standard deviation, SD). Nineteen of 71 patients had acetaminophen-induced hepatitis. The peak serum alanine aminotransferase, aspartate aminotransferase and total bilirubin concentrations were 4,181.0 +/- 931.4 IU/l (mean +/- SD), 4,148.0 +/- 1,147.5 IU/l and 2.6 +/- 0.4 mg/dl, respectively. The hepatitis group had higher ingested acetaminophen doses and serum peak acetaminophen levels than did those of the nonhepatitis group (24.9 g vs 12.9 g, p = 0.004; 132.0 mg/l vs 61.7 mg/l, p = 0.013). A higher percentage of alcohol consumption was also noted in the hepatitis group than in the nonhepatitis group (32% vs 12%, p = 0.05). After logistic regression for multivariate analysis, alcohol consumption was the most important risk factor for acetaminophen-induced hepatitis (odds ratio = 8.14, p = 0.018), followed by ingested acetaminophen dose (odds ratio = 1.21, p = 0.001). Most patients received acetylcysteine treatment in time. Two of the 19 patients with hepatitis died. CONCLUSIONS: The majority of acetaminophen-induced hepatitis in Taiwan occurs in young females who attempt suicide. Alcohol consumption and the dose of acetaminophen ingested were the significant risk factors for acetaminophen-induced hepatitis. Alcohol should not be concomitantly used with acetaminophen. Early diagnosis and administration of the antidote are crucial to decrease mortality.

Acetaminophen↗

PubMed1990

Biphasic modulation of acetaminophen bioactivation and hepatotoxicity by pretreatment with the interferon inducer polyinosinic-polycytidylic acid.

Interferons and interferon induction can inhibit cytochromes P-450 and reduce the bioactivation and hepatotoxicity of acetaminophen. However, since P-450 inhibition often is followed by P-450 induction, which would enhance acetaminophen hepatotoxicity, the possibility of a biphasic modulation of acetaminophen hepatotoxicity by interferons was investigated. Outbred male CD-1 mice of various ages, and young inbred male C57BL/6 mice were given the interferon inducer, polyinosinic-polycytidylic acid (Poly I-C), 10 mg/kg intraperitoneally, followed 1 to 48 days later by a single dose of acetaminophen, 300 to 450 mg/kg intraperitoneally. Hepatotoxicity was assessed by the peak plasma concentration of alanine aminotransferase (ALT) occurring between 0 and 48 hr after acetaminophen treatment. Poly I-C inhibited the hepatotoxicity of acetaminophen given within 8 days, with maximal inhibition between 1 and 4 days. Conversely, a maximal 7-fold enhancement of ALT concentration was observed in CD-1 mice when 300 mg/kg of acetaminophen was given 32 days after Poly I-C (P less than 0.05). In the C57BL/6 strain, Poly I-C inhibited the hepatotoxicity of acetaminophen when given within 16 days, whereas a maximal 20-fold enhancement of ALT concentration was observed when 300 mg/kg of acetaminophen was given 24 days after Poly I-C (P less than 0.05). The mechanism of toxicologic enhancement was examined in male C57BL/6 mice using the same treatment regimen. Biochemical assessment of hepatotoxicity was confirmed by detailed histologic evaluation. Plasma concentrations of acetaminophen and metabolites were determined by high-performance liquid chromatography. Acetaminophen bioactivation was quantified by production of the glutathione-derived cysteine and mercapturic acid conjugates of acetaminophen. Poly I-C pretreatment produced a 5-fold increase in acetaminophen-induced ALT release (P less than 0.05), which correlated with histologic evidence of centrilobular necrosis. Poly I-C pretreatment produced respective 3-fold and 1.3-fold increases in the production of cysteine and mercapturic acid conjugates (P less than 0.05), which correlated with peak ALT concentrations (cysteine, r = 0.92, P less than 0.001; mercapturic acid, r = 0.75, P = 0.006). Thus, the hepatotoxicity of acetaminophen can be inhibited when given within days after interferon induction, and conversely enhanced when given after several weeks. The toxicologic enhancement appears to be due to increased P-450-catalyzed bioactivation of acetaminophen.

Acetaminophen↗

PubMed1987

A sensitive immunochemical assay for acetaminophen-protein adducts.

The hepatotoxicity of acetaminophen may be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine which binds covalently to protein primarily as 3-(cystein-S-yl)acetaminophen. We have developed an avidin biotin-amplified competitive enzyme-linked immunosorbent assay to detect protein-bound acetaminophen. This assay utilizes antisera from rabbits immunized with 3-(N-acetyl-L-cystein-S-yl)acetaminophen coupled via the carboxyl group to primary amino groups on the protein keyhole-limpet hemocyanin. The competitive enzyme-linked immunosorbent assay utilizes metallothionein derivatized with N-acetyl-p-benzoquinone imine (acetaminophen-bound metallothionein) and quantitation was obtained by competition of acetaminophen-derivatives for a limited amount of antibody in the presence of excess solid phase acetaminophen-bound metallothionein. Synthetic 3-(N-acetyl-L-cystein-S-yl)acetaminophen, acetaminophen bound to mouse 9,000 X g supernatant, 100,000 X g supernatant, microsomes, as well as acetaminophen-bound metallothionein were inhibitory. The 50% inhibition for 3-(N-acetyl-L-cystein-S-yl)acetaminophen was 110 fmol/well. In contrast, free acetaminophen was 6200 times less efficient as an inhibitor. The mean 50% inhibition for protein-bound acetaminophen was 2.89 pmol/well. The utility of the method to detect acetaminophen-protein adducts in biological samples was confirmed by detection of NADPH-dependent binding of acetaminophen to microsomal proteins.

Acetaminophen↗

PubMed1984

Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans.

The renal clearances of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were determined in eight healthy adults 2 h after administration of 1.5 g of acetaminophen. The renal clearance ratios (relative to creatinine) were 0.058 +/- 0.026, 0.890 +/- 0.153, and 1.43 +/- 0.250 (mean +/- SD), respectively. The renal clearance of acetaminophen increased with increasing urine flow rate, and that of acetaminophen sulfate decreased with increasing serum concentration of the conjugate. A strong positive correlation was found between the renal clearances of acetaminophen glucuronide and acetaminophen sulfate, possibly due to blood perfusion rate-dependent renal tubular secretion of the two conjugates. The serum protein binding of acetaminophen (congruent to 20%) and acetaminophen glucuronide (less than 10%) are minor. Acetaminophen sulfate is greater than 50% protein bound, as determined by equilibrium dialysis and ultrafiltration. The results of these studies are (a) consistent with previous reports of animal studies, indicating that renal excretion of acetaminophen involves glomerular filtration and passive reabsorption and that acetaminophen sulfate is subject to active renal tubular secretion, and (b) compatible with the reported occurrence of renal tubular secretion of acetaminophen glucuronide in animals.

Acetaminophen↗

PubMed2006

Influence on platelet aggregation of i.v. parecoxib and acetaminophen in healthy volunteers.

BACKGROUND: Acetaminophen (paracetamol) alone or in combination with other analgesics is widely used for postoperative analgesia. While acetaminophen and non-steroidal anti-inflammatory drugs inhibit platelet function, the cyclooxygenase-2 (COX-2) selectively inhibiting coxibs show no interference with platelet function. The authors studied the effect of a combination of i.v. parecoxib and acetaminophen on platelet function in healthy volunteers. METHODS: Eighteen healthy, male volunteers (22-33 yr) received i.v. acetaminophen 1 g, parecoxib 40 mg+acetaminophen 1 g or placebo in a double-blind, crossover study. Platelet function was assessed by photometric aggregometry and by measuring the release of thromboxane B(2). Plasma acetaminophen concentrations were measured by high-performance liquid chromatography. RESULTS: Platelet aggregation (median area under the curve) triggered with arachidonic acid 500 microM was 24.6, 3.9 and 4.2x10(3) area units (P=0.02, all groups) after placebo, acetaminophen and parecoxib+acetaminophen, respectively. Inhibition of platelet aggregation showed no difference between acetaminophen alone and the combination (P=0.82). Aggregation triggered with arachidonic acid 750 or 1000 microM, adenosine diphosphate (ADP) 1.5 or 3 microM, or epinephrine 5 microM showed no differences between the groups. Release of thromboxane B(2) in response to ADP was inhibited similarly by both acetaminophen and the combination. Plasma acetaminophen concentrations were similar after acetaminophen and the combination. CONCLUSIONS: Acetaminophen and parecoxib showed no interaction in inhibiting platelet function. In combination they cause a mild degree of COX-1 inhibition corresponding to that of acetaminophen alone.

Acetaminophen↗

PubMed2004

Silent acetaminophen-induced hepatotoxicity in febrile children: does this entity exist?

UNLABELLED: Several descriptions of acetaminophen-associated liver injury caused by therapeutic or a dosage slightly above the recommended dosage have been described. Our hypothesis is that in sick febrile infants and children, who may also be calorie depleted, there might be an increased hepatic vulnerability to acetaminophen. AIM: (1) To correlate serum acetaminophen levels in febrile infants and children with the following parameters: aspartate aminotransferase (AST) levels, fever, vomiting and/or decreased caloric intake; and (2) to assess parental knowledge regarding the medication dosage and hazards of acetaminophen. METHODS: Healthy children with an acute febrile illness, who had received acetaminophen, were eligible to participate in the study. AST and acetaminophen levels were drawn, and a detailed questionnaire was completed for every child. RESULTS: 107 children participated in the study; 50 girls and 57 boys with ages ranging from 1 mo to 16 y (mean 33 mo). All serum acetaminophen levels were within the safety range. Although 32% of parents administered a single acetaminophen dose above 15 mg/kg and 46% gave a daily dose above 60 mg/kg/d, no significant differences were observed in the serum acetaminophen and AST levels compared to those who received the appropriate dose. In about 60% of cases, the high doses were recommended by a physician. Young age and high fever were associated with significantly higher acetaminophen levels. We could not find an association between acetaminophen levels and vomiting, decreased caloric intake and AST levels. Only 24 parents (22%) were aware of the possible toxicity of acetaminophen. CONCLUSIONS: No evidence of increased hepatic vulnerability to acetaminophen was noted in a cohort of febrile infants and children. Furthermore, significant numbers of parents and physicians were unaware of acetaminophen dangers.

Acetaminophen↗