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PubMed1997

Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long-term isoniazid.

OBJECTIVE: To determine in patients receiving isoniazid prophylaxis whether an increase in the CYP2E1 dependent formation clearance of acetaminophen (paracetamol) to N-acetyl-p-benzoquinone imine (NAPQI) occurs during a normal 24-hour isoniazid dose interval and whether the interaction is dependent on acetylation status. METHODS: Acetaminophen elimination kinetics were determined on four different occasions. Ten subjects were assigned to receive acetaminophen either simultaneously with the 8 am dose of isoniazid or 12 hours after the isoniazid dose. One week later, on the last day of isoniazid therapy, subjects received acetaminophen at the alternate time of day. The control phase acetaminophen administrations were repeated 1 and 2 weeks later, following the initial randomization. Isoniazid acetylation (NAT2) genotype was determined by analysis of genomic DNA obtained from peripheral blood leukocytes. RESULTS: The mean NAPQI formation clearance was inhibited 57% when acetaminophen and isoniazid were coadministered but was unchanged compared with time-matched control when acetaminophen was given 12 hours after the isoniazid dose. However, when data from subjects was segregated according to isoniazid (INH) acetylation phenotype, the mean ratio of NAPQI formation clearances (+INH/-INH) with 8 PM acetaminophen was significantly higher for fast acetylators compared with slow acetylators (1.36 versus 0.68; p = 0.006). CONCLUSIONS: Fast metabolizers of isoniazid appeared to clear the inducer or inhibitor from the active site of CYP2E1 more rapidly, which resulted in an increased formation of NAPQI 12 hours after the isoniazid dose. In contrast, formation of NAPQI for slow isoniazid metabolizers remained inhibited.

Acetaminophen↗
PubMed2001

Therapeutic effect of S-allylmercaptocysteine on acetaminophen-induced liver injury in mice.

S-allylmercaptocysteine is one of the water-soluble organosulfur compounds in ethanol extracts of garlic (Allium sativum L.). We had demonstrated earlier that treatment with S-allylmercaptocysteine before acetaminophen administration protects mice against acetaminophen-induced hepatotoxicity. In this study, we examined the therapeutic effect of S-allylmercaptocysteine treatment after acetaminophen administration. A single dose of S-allylmercaptocysteine (200 mg/kg, p.o.) to mice 0.5 h after acetaminophen administration (500 mg/kg, p.o.) significantly suppressed both the increase in plasma alanine aminotransferase activity and the hepatic necrosis, and also reduced acetaminophen-induced mortality from 43% to 0%. These data indicate that S-allylmercaptocysteine is useful as an antidote for acetaminophen overdose. S-allylmercaptocysteine significantly suppressed hepatic cytochrome P450 2E1 (CYP2E1) activity and induction of inducible 70-kDa heat shock protein, a marker of acetaminophen arylation of protein. These results suggest that S-allylmercaptocysteine exerts its protective effect by inhibition of CYP2E1 activity, which leads to the suppression of acetaminophen arylation of hepatic protein.

Acetaminophen↗
PubMed1987

Therapeutic doses of acetaminophen stimulate the turnover of cysteine and glutathione in man.

In spite of the importance of glutathione (GSH) in the detoxification of toxic metabolites of drugs, virtually nothing is known about the regulation of hepatic GSH homeostasis in man. In order to estimate the turnover of hepatic GSH and to assess the effect of different doses of acetaminophen (paracetamol) on the synthesis of GSH in man, [3H]cystine and varying doses of acetaminophen were administered to healthy volunteers, and the time course of the specific activity of the cysteine moiety of N-acetylcysteinyl-acetaminophen excreted in urine was followed. The fractional rate of turnover of the tracer in N-acetylcysteinyl-acetaminophen increased significantly from 0.031 +/- 0.007 h-1 after doses of acetaminophen ranging from 50 to 300 mg to 0.045 +/- 0.011 and 0.121 +/- 0.027 h-1 following 600 and 1200 mg of acetaminophen, respectively. The data indicate that therapeutic doses of acetaminophen markedly stimulate the rate of turnover of the pool of cysteine available for the synthesis of GSH, most likely due to an increased rate of synthesis of GSH which is required to detoxify the toxic metabolite of acetaminophen. Patients who are not able to respond to a similar demand on their stores of GSH by increasing the synthesis of GSH may be at higher risk of developing hepatic injury from drugs that require GSH for their detoxification.

Acetaminophen↗
PubMed1997

Expression of liver functions following sub-lethal and non-lethal doses of allyl alcohol and acetaminophen in the rat.

BACKGROUND/AIMS: To relate severity of intoxication with allyl alcohol and acetaminophen to modulated hepatic gene expression of liver functions and regeneration. METHODS: Rats fasted for 12 h received acetaminophen 3.5 or 5.6 g per kg body weight, or allyl alcohol 100 or 125 microl by gastric tube, doses producing no and about 30% mortality, respectively, within 2 days. In the morning 2, 6, 12, 24, and 36 h after intoxication, RNA was extracted from liver tissue. By slot blot hybridization mRNA levels were determined for acute phase proteins, enzymes involved in ammonia elimination and urea synthesis, and for proteins related to liver regeneration. RESULTS: After allyl alcohol, mRNA of "positive" acute phase proteins was higher than after acetaminophen and increased with the dose, whereas after acetaminophen it decreased with the dose. The mRNA of the urea cycle enzymes and glutamine synthetase was uniformly reduced by allyl alcohol, whereas that of most urea cycle enzymes was above the controls after the non-lethal, but not after the sub-lethal, dose of acetaminophen. The mRNA of glutamine synthetase was significantly more reduced by acetaminophen than by allyl alcohol. The mRNA of cell-cycle dependent proteins was greatly reduced after both toxins, more after the higher dose. CONCLUSIONS: The study shows that acetaminophen intoxication inhibits or fails to induce the expression of acute phase proteins in contrast to allyl alcohol intoxication. Allyl alcohol suppressed the expression of urea cycle enzymes, whereas that of the rate limiting enzymes carbamoylphosphate synthase and argininosuccinate synthetase was increased by the non-lethal but not by the sub-lethal dose of acetaminophen. The expression of the cell-cycle dependent proteins was more suppressed after the sub-lethal than after the non-lethal dose of both toxins. The data support the view that a fatal outcome of the intoxications depends more on the ability to regenerate than on the maintenance of liver-specific functions.

1-Propanol↗
PubMed1993

Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?

STUDY OBJECTIVES: To investigate the ability of a supranormal dose of N-acetylcysteine to overcome the effects of activated charcoal on N-acetylcysteine bioavailability and to determine the effects of activated charcoal on serum acetaminophen levels. DESIGN, SETTING, AND PARTICIPANTS: Ten healthy adult volunteers participated in a controlled cross-over experiment. During phase I (control), subjects ingested 3 g acetaminophen, followed one hour later by the normal loading dose of N-acetylcysteine (140 mg/kg). During phase II (charcoal), subjects ingested 3 g acetaminophen, followed one hour later by 60 g activated charcoal and a supranormal loading dose of N-acetylcysteine (235 mg/kg). MAIN OUTCOME MEASURES: Serum levels of N-acetylcysteine were measured every 30 minutes for six hours. A serum acetaminophen level was measured at four hours. RESULTS: The area under the curve for N-acetylcysteine was significantly higher for phase II than phase I (P < .05, two-tailed paired t-test). Peak N-acetylcysteine and time to peak were not significantly different. The four-hour serum acetaminophen level was significantly lower for phase II than phase I (P < .05, two-tailed paired t-test). Diarrhea occurred during both phases, but N-acetylcysteine was otherwise well tolerated. CONCLUSION: These results suggest that activated charcoal can be used safely for victims of acetaminophen overdose. A beneficial effect in preventing acetaminophen absorption can be expected if it is given within one hour after ingestion. If N-acetylcysteine is needed because of a toxic serum acetaminophen level, bioavailability can be ensured by increasing the N-acetylcysteine loading dose from 140 mg/kg to 235 mg/kg.

Acetaminophen↗
PubMed1994

4-Methylpyrazole blocks acetaminophen hepatotoxicity in the rat.

STUDY OBJECTIVE: To determine whether 4-methylpyrazole inhibits the hepatotoxic effects of acetaminophen in a rat model. DESIGN AND TYPE OF PARTICIPANTS: A nonblinded experiment using male Sprague-Dawley rats. INTERVENTIONS: Animals were divided into four groups. Groups 1 through 3 received 2,000 mg/kg acetaminophen by gavage; group 4 acted as a control. At four or eight hours, group 2 received 400 mg/kg 4-methylpyrazole; group 3 received 50 mg/kg 4-methylpyrazole. Blood samples were taken for measurements of serum AST and ALT levels. Livers were removed for microscopic examination and grading of necrosis. RESULTS: Lower AST and ALT levels were obtained for both the 400-mg/kg (P < .01) and 50-mg/kg (P < .05) doses of 4-methylpyrazole administered four hours after acetaminophen. Although mean AST and ALT levels also were lower when 400 and 50 mg/kg 4-methylpyrazole were administered eight hours after acetaminophen, these results were not statistically significant. Median necrosis scores were 3 for rats receiving acetaminophen alone, 0.5 for those receiving acetaminophen and 400 mg/kg 4-methylpyrazole (P < .05), 1 for those receiving acetaminophen and 50 mg/kg 4-methylpyrazole (P < .05), and 0 for control rats (P < .05). CONCLUSION: When administered four hours after a toxic dose of acetaminophen, 4-methylpyrazole significantly inhibits hepatotoxicity in the rat, as reflected by lower levels of serum transaminases and lesser degrees of hepatic necrosis.

Acetaminophen↗
PubMed1995

The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction.

STUDY OBJECTIVE: It is often taught that acetaminophen-induced liver dysfunction occurs only after a latent period of 24 to 48 hours. This study was designed to evaluate the temporal profile of transaminase levels in patients with acetaminophen-induced hepatotoxicity. DESIGN: Prospective data collection using standard poison control center data sheets. PARTICIPANTS: Hospitalized patients with acetaminophen exposure who were reported to the Long Island Poison Control Center between January 1993 and June 1994. Patients who presented within 24 hours of ingestion and in whom increased aspartate aminotransferase (AST) levels developed during hospitalization were included in the data analysis. Patients who presented more than 24 hours after ingestion, who had ingested another potentially hepatotoxic agent, or who had ingested acetaminophen over a period of more than 2 hours were excluded. RESULTS: Of 1,825 patients with reported acetaminophen exposure, 779 had potentially toxic ingestions and were examined in an emergency department. Of 291 patients with toxic acetaminophen levels who were admitted, 36 (12%) had increased levels of AST at some point during hospitalization. All received oral N-acetylcysteine within 2.5 hours of presentation. In 11 of 19 patients who met all inclusion criteria (58%), AST levels were noted to be increased in the 24 hours after ingestion. The median peak AST level was 422 IU/L (range, 74 to 8,538 IU/L). AST levels peaked within 48 hours in 4 patients (21%) and within 72 hours in 18 patients (95%). Six of eight patients with peak AST levels greater than 1,000 IU/L had increased transaminase levels during the 24 hours after acetaminophen ingestion. CONCLUSION: Acetaminophen poisoning may cause the serum transaminase level to increase during the 24 hours after ingestion.

Acetaminophen↗
PubMed1999

Acetaminophen-induced antinociception via central 5-HT(2A) receptors.

Acetaminophen is one of the most widely used analgesic drugs. Although the mechanism of analgesic action of acetaminophen is still not known, the involvement of the central serotonin (5-hydroxytryptamine: 5-HT) system is one possibility. In the present study, we examined the antinociceptive effect of acute and chronic intraperitoneally (i.p.) administered acetaminophen by tail flick latency measurements in the rat. A significantly increased tail flick latency was observed in acute and 15-day acetaminophen-treated rats, but not in 30-day acetaminophen-treated rats, at a dose of 400 mg/kg/day. To investigate the plasticity of receptors at postsynaptic membrane, we conducted a series of experiments by radioligand binding method on frontal cortex and brainstem membrane. The technique involved radioligand binding with [phenyl-4-3H]spiperone and ketanserin for studying 5-HT(2A) receptor characteristics. A significant decrease in the maximum number of 5-HT(2A) binding sites (Bmax) was demonstrated in all treatment groups with acetaminophen 300 and 400 mg/kg on frontal cortex membrane, whereas the value of the dissociation equilibrium constant (Kd) remained unchanged. The down-regulation of 5-HT(2A) binding sites in frontal cortex was of a lesser magnitude after 30 days of treatment and the tail flick latency was as in the control animals. These results suggest that down-regulation of 5-HT(2A) receptor in response to 5-HT release is a major step in the mechanism underlying analgesia produced by this agent. On the contrary, chronic use of acetaminophen may result in 5-HT depletion, which in turn produces re-adaptation of postsynaptic 5-HT(2A) receptors. These data provide further evidence for a central 5-HT-dependent antinociceptive effect of acetaminophen.

Acetaminophen↗
PubMed1997

Comparison of covalent binding of acetaminophen and the regioisomer 3'-hydroxyacetanilide to mouse liver protein.

The hepatotoxicity of the analgesic acetaminophen has been previously attributed to metabolic activation by cytochrome P450 to the reactive intermediate N-acetyl-p-benzoquinone imine. At therapeutic doses this species is detoxified by reaction with glutathione; however, following a hepatotoxic dose, liver glutathione levels are depleted and the metabolite covalently binds primarily to cysteine groups on proteins as 3-(cystein-S-yl)acetaminophen adducts. Altered function of critical proteins has been postulated to be the mechanism of hepatotoxicity. Covalent binding has been studied by both radiochemical methods and immunochemical methods. Utilizing Western blot analysis with an antiserum which recognizes acetaminophen we have previously shown that covalent binding occurs on a number of proteins in various hepatic fractions. In an effort to better understand the role of covalent binding in the toxicity, others have studied the non-hepatotoxic isomer 3'-hydroxyacetanilide. Administration of large doses of radiolabeled acetaminophen or 3'-hydroxyacetanilide resulted in similar levels of covalent binding to proteins. To better understand the role of covalent binding in toxicity we have administered mice 3'-hydroxyacetanilide and acetaminophen, and analyzed liver fractions for protein adducts using anti-3-(cystein-S-yl)acetaminophen and anti-arylacetamide antisera in Western blot assays. Analysis of liver fractions from acetaminophen-treated mice, with both antisera showed, as has been previously reported, that acetaminophen covalently binds to a number of hepatic proteins. In liver from 3'-hydroxyacetanilide-treated mice, covalent adducts were detected with an anti-arylacetamide antiserum only. A major 3'-hydroxyacetanilide protein adduct was observed in microsomes at 50 kDa. Minor adducts were observed at 47 kDa in microsomes and 56 kDa in cytosol. 3'-Hydroxyacetanilide protein adducts were not observed in the 10,000 x g pellet. Densitometric analysis of a time course of 3'-hydroxyacetanilide protein adducts indicated that peak levels of the 50 kDa microsomal protein adduct occurred at 1 h and subsequently decreased.

Acetaminophen↗
PubMed1999

Deferoxamine delays the development of the hepatotoxicity of acetaminophen in mice.

The hepatotoxicity of acetaminophen is conventionally ascribed to metabolism by CYP450 to N-acetyl-p-benzoquinone imine and covalent binding to proteins. We investigated a potential role for oxidative stress by determining the effect of the ferric chelator deferoxamine (Desferal) on acetaminophen (paracetamol)-induced hepatotoxicity in mice. Administration of deferoxamine (75 mg/kg) 1 h after a toxic dose of acetaminophen (300 mg/kg) significantly delayed the development of the toxicity without altering covalent binding. In saline-treated mice serum ALT was 18 +/- 2 IU/l. In acetaminophen-treated mice serum alanine aminotransferase (ALT) was 779 +/- 271 at 2 h, 7421 +/- 552 IU/l at 4 h, 5732 +/- 523 IU/l at 8 h, and 5984 +/- 497 IU/l at 24 h. In acetaminophen plus deferoxamine-treated mice, serum ALT was 80 +/- 10 at 2 h, 472 +/- 74 IU/l at 4 h, 2149 +/- 597 IU/l at 8 h, and 5766 +/- 388 at 24 h. Deferoxamine at 1 h after acetaminophen did not decrease serum ALT at 12 h; however, deferoxamine at 1 and 4 h, or deferoxamine at 1 h plus N-acetylcysteine at 4 h to replete hepatic glutathione, decreased the toxicity from 5625 +/- 310 IU/l to 3436 +/- 546 IU/l and 3003 +/- 282 IU/l, respectively. Deferoxamine plus N-acetylcysteine at 1.25 h after acetaminophen was more effective at decreasing the 24 h toxicity than N-acetylcysteine alone. In acetaminophen treated mice, higher doses of deferoxamine (150-300 mg/kg) at 1 h greatly increased the observed hepatotoxicity at 4 h in a dose responsive manner, but deferoxamine alone was nontoxic.

Acetaminophen↗
PubMed2001

Pharmacokinetics of acetaminophen in Hong Kong Chinese subjects.

The pharmacokinetics of acetaminophen have been well studied in different populations, especially in Caucasians. However, limited studies on acetaminophen pharmacokinetics have been conducted in the native Chinese and few such data have been reported in the English language literature. Previous published studies suggested that environmental and genetic factors may cause inter-individual difference in acetaminophen disposition, thus we investigated the pharmacokinetics of acetaminophen in Hong Kong Chinese subjects. A single 500 mg oral dose of acetaminophen was administered to 12 healthy male Chinese subjects under fasting conditions. Multiple blood samples were obtained after drug administration. Plasma acetaminophen concentrations were determined using HPLC, and its main pharmacokinetic parameters were generated. In comparison to other published data, acetaminophen half-life was considerably longer (15-62%), and oral clearance was lower (16-56%) in Hong Kong Chinese as compared to Australian Chinese, Caucasians (USA, UK, Australia), and subjects from Pakistan, Denmark, Spain and South Africa. Similarities however were found in the pharmacokinetic parameters between Hong Kong Chinese and Mainland Chinese subjects. The observed pharmacokinetic parameters of acetaminophen in Hong Kong Chinese subjects may be different from other ethnic populations. Further studies are needed to verify this hypothesis.

Acetaminophen↗
PubMed2002

Chronic acetaminophen toxicity: a case report and review of the literature.

Acetaminophen is one of the most frequently used medications in the United States. While usual dosing of acetaminophen is considered harmless, both acute and chronic overdoses can be fatal. The majority of reported cases of chronic acetaminophen toxicity in adults occur in chronic alcohol abusers, patients taking P450-inducing medications, or following massive dosing. We describe a case of toxic hepatitis free of the aforementioned risk factors associated with chronic ingestion of moderately excessive doses of acetaminophen. Our patient ingested approximately 5.0 to 6.5 g of acetaminophen daily for 6 to 8 weeks via multiple medications. The inclusion of acetaminophen in numerous medications combined with the frequency of use of acetaminophen necessitates an increased concern for not only acute but also chronic acetaminophen toxicity.

Acetaminophen↗
PubMed2006

Transformation of acetaminophen by chlorination produces the toxicants 1,4-benzoquinone and N-acetyl-p-benzoquinone imine.

The reaction of the common pain reliever acetaminophen (paracetamol, 4-acetamidophenol) with hypochlorite was investigated over time under conditions that simulate wastewater disinfection. Initially, the reaction was studied in pure water at neutral pH (7.0), a range of reaction times (2-90 min), and a molar excess of hypochlorite (2-57 times) relative to the acetaminophen concentration. The reaction was monitored using reversed-phase liquid chromatography (LC) with ultraviolet absorbance, electrochemical, and mass spectrometric detection. At 1 micromol/L (150 ppb) and 10 micromol/L (1.5 ppm) levels, acetaminophen readily reacted to form at least 11 discernible products, all of which exhibited greater LC retention than the parent. Two of the products were unequivocally identified as the toxic compounds 1,4-benzoquinone and N-acetyl-p-benzoquinone imine (NAPQI), which is the toxicant associated with lethality in acetaminophen overdoses. With a hypochlorite dose of 57 micromol/L (4 ppm as Cl2), 88% of the acetaminophen (10 micromol/L initial) was transformed in 1 h. The two quinoidal oxidation products 1,4-benzoquinone and NAPQI accounted for 25% and 1.5% of the initial acetaminophen concentration, respectively, at a 1 h reaction time. Other products that were identified included two ring chlorination products, chloro-4-acetamidophenol and dichloro-4-acetamidophenol, which combined were approximately 7% of the initial acetaminophen concentration at 1 h. The reaction was also studied in wastewater, where similar reactivity was noted. These results demonstrate that acetaminophen is likely to be transformed significantly during wastewater chlorination. The reactivity of the chlorine-transformation products was also studied with sulfite to simulate dechlorination, and 1,4-benzoquinone and NAPQI were completely reduced.

Acetaminophen↗
PubMed1996

Glutamate dehydrogenase covalently binds to a reactive metabolite of acetaminophen.

The mechanism of the hepatotoxicity of the analgesic acetaminophen is believed to be mediated by covalent binding to protein; however, critical targets which effect the toxicity are unknown. It has been shown that mitochondrial respiration in vivo is inhibited in mice as early as 1 h following a hepatotoxic dose of acetaminophen, and it is postulated that covalent binding to critical mitochondrial proteins may be important. A time course of mitochondrial proteins stained with anti-acetaminophen in an immunoblot detected two major adducts of 50 and 67 kDa as early as 30 min after a hepatotoxic dose of acetaminophen in mice. To further understand the role of covalent binding to mitochondrial proteins and acetaminophen hepatotoxicity, we have purified and identified a 50 kDa mitochondrial protein which becomes covalently bound to a reactive metabolite of acetaminophen. An N-terminal sequence of the 50 kDa adduct was 100% homologous with the deduced amino acid sequence of glutamate dehydrogenase. In addition, the purified protein was immunochemically reactive with rat liver anti-glutamate dehydrogenase. Enzyme activity of glutamate dehydrogenase was significantly decreased in mice 1 h following hepatotoxic treatment with acetaminophen. These data suggest that acetaminophen hepatotoxicity may in part be mediated by covalent binding to glutamate dehydrogenase.

Acetaminophen↗
PubMed1988

Effect of taurolithocholate on in vivo sulfation and glucuronidation of acetaminophen in rats.

Taurolithocholate produces a prompt, complete, and reversible cessation of bile flow in rats. This is associated with impaired hepatic oxidative drug-metabolizing activity. The purpose of this study was to examine the effects of taurolithocholate-induced cholestasis on in vivo conjugation. The pharmacokinetics of acetaminophen and the two major processes specifically responsible for its elimination, namely, the formations of acetaminophen sulfate and acetaminophen glucuronide, were used to assess hepatic conjugating activity. A 30-mg/kg bolus of acetaminophen was administered intravenously to rats 2 hr (acute cholestasis) or 20 hr (postcholestasis) after intravenous pretreatment with sodium taurolithocholate, 5 mumol/100 g body weight. Acute cholestasis increased the total clearance of acetaminophen 20%, the partial clearance to acetaminophen sulfate 12%, and the partial clearance to acetaminophen glucuronide 85%. Postcholestasis, these parameters had significantly decreased compared to those during acute cholestasis and were comparable to control values. The results show that cholestasis does not impair acetaminophen conjugation in the rat.

Acetaminophen↗
PubMed2004

Acetaminophen and experimental acute myocardial infarction.

Acetaminophen is a widely used analgesic, and recent studies have shown that it has some benefits in the ischemic heart. The purpose of this study was to test the effects of acetaminophen on infarct size, regional myocardial blood flow and the "no-reflow" phenomenon in a rabbit model of coronary artery occlusion (CAO) and reperfusion. Rabbits were assigned to one of four groups: (1) acetaminophen, 75 mg/kg in 75% ethanol, 30 min before CAO, (2) vehicle at 30 min before CAO, (3) acetaminophen at 18 min after CAO (12 min before reperfusion), or (4) vehicle at 18 min of CAO ( n = 10 each group). All rabbits received 30 min of CAO followed by 3 hr reperfusion. The extent of ischemia was similar in all groups comprising 24-27% of the left ventricle. Infarct size (% ischemic zone) was 51 +/- 5, 56 +/- 3 in groups 1 and 2 ( p = ns), 43 +/- 3 and 40 +/- 4 in groups 3 and 4 ( p = ns). Thus acetaminophen did not affect the development of necrosis. Heart rate and blood pressure were unchanged by acetaminophen treatment. Regional myocardial blood flow was similar in all groups during occlusion and at the end of reperfusion. Acetaminophen had no effect on the size of the anatomic zone of no-reflow that developed by 3 hours of reperfusion. We conclude that acetaminophen has a neutral effect in this experimental model of ischemia/reperfusion and appears to be safe in the course of experimental myocardial infarction.

Acetaminophen↗
PubMed1983

Acetaminophen in chronic liver disease.

The safety of acetaminophen in therapeutic doses was evaluated in subjects with stable chronic liver disease. Six subjects with chronic liver disease were given 4.0 gm daily for 5 days. Although the mean half-life (t 1/2) acetaminophen was 3.42 hr, there was no evidence of drug cumulation or hepatotoxicity. A double-blind, two-period crossover design was also used to evaluate acetaminophen in 20 subjects. Acetaminophen, at a dose of 4.0 gm daily for 13 days, was well tolerated by these subjects with stable chronic liver disease. One subject developed symptoms, which worsened and were associated with deterioration in the results of laboratory studies, while taking acetaminophen. Subsequent challenges with 4.0 gm acetaminophen daily for periods of 10 and 14 days were well tolerated, which indicates that the deterioration was not related to the drug. During this study there were no abnormalities indicative of an adverse reaction to acetaminophen. There is, therefore, no contraindication to the use of acetaminophen in therapeutic doses in the presence of stable chronic liver disease.

Acetaminophen↗
PubMed1986

Ketorolac and acetaminophen for orthopedic postoperative pain.

In a double-blind, single-dose, parallel-group study, ketorolac (5, 10, or 20 mg) was compared with acetaminophen (500 or 1000 mg) when taken by mouth for postoperative orthopedic pain. Analgesic measurements were made by trained nurse observers who used standard verbal rating and visual analog scales. Acetaminophen, 1000 mg, was statistically superior to 500 mg acetaminophen, demonstrating assay sensitivity. Ketorolac, 20 mg, was distinguished from 500 mg acetaminophen, 5 mg ketorolac, and 10 mg ketorolac, but not from 1000 mg acetaminophen. The higher doses of ketorolac induced a longer lasting peak analgesic effect than did acetaminophen, but the magnitude of the peak pain relief was changed little by an increased ketorolac dose. Overall, 10 mg ketorolac appeared equivalent to 1000 mg acetaminophen. Acetaminophen, 500 mg, induced less sedation than the higher doses of ketorolac, but neither drug caused untoward side effects.

Acetaminophen↗