Acetaminophen

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References

Brzeznicka EA, Piotrowski JK. Dynamics of glutathione levels in liver and indicatory enzymes in serum in acetaminophen intoxication in mice. Pol J Occup Med. 1989;2(1):15-22.

Campos R, et al. Acetaminophen hepatotoxicity in rats is attenuated by silybin dihemisuccinate. Prog Clin Biol Res. 1988;280:375-378.

Campos R, Garrido A, Guerra R, Valenzuela A. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989 Oct;55(5):417-419.
Abstract: Acetaminophen hepatotoxicity is characterized by glutathione depletion, cellular necrosis, and, in some instances, by the induction of lipid peroxidation. Silybin dihemisuccinate, a soluble form of the flavonoid silymarin, protects rats against liver glutathione depletion and lipid peroxidation induced by acute acetaminophen intoxication. Other biochemical parameters such as serum transaminases did not show the drastic increase observed under acetaminophen intoxication when animals were treated with the flavonoid. Preliminary results suggest that silybin dihemisuccinate may be another antidote against acetaminophen hepatotoxicity.

Chrungoo VJ, Singh K, Singh J. Silymarin mediated differential modulation of toxicity induced by carbon tetrachloride, paracetamol and D-galactosamine in freshly isolated rat hepatocytes. Indian J Exp Biol. 1997 Jun;35(6):611-617.
Abstract: Influence of silymarin on the modulation of hepatotoxicity induced by carbon tetrachloride (CCl4), paracetamol (AAP) and D-galactosamine (GalN) was examined in freshly isolated rat hepatocytes in suspension culture. While the three hepatotoxicants produced differential biochemical response, the flavone was able to restore biochemical alterations only in hepatocytes exposed to CCl4 and AAP induced toxicity. Silymarin at 0.4 mM was able to counteract lipid peroxidation and enzyme leakage induced by 3 mM CCl4 The flavone also offered protection by more than 60% in hepatocytes isolated from PB pre-treated rats where CCl4 at 2 mM produced enhanced toxicity over hepatocytes isolated from untreated control rats. Similarly, the flavone protected AAP-induced GSH depletion by more than 75% in hepatocytes isolated from untreated and 3-methylcholanthrene treated rats. However, instead of protecting GalN-induced depletion of UDP-glucuronic acid in hepatocytes, the flavone itself reduced the nucleotide content very rapidly compared to GalN, the later exerted time dependent effect. Silymarin at 0.4 mM reduced UDPGA by more than 60%. The results suggested that freshly isolated hepatocytes in suspension culture offer a simple and convenient method for evaluation of pharmaceutical agents of antihepatotxic potentials against various hepatotoxicants.

D'Arcy PF. Paracetamol. Adverse Drug React Toxicol Rev. 1997 Mar;16(1):9-14. (Review)

Donovan JW, Burkhart KK. N-acetylcysteine in treatment of acetaminophen overdose. J Clin Gastroenterol. 1992 Sep;15(2):169-170. (Letter)

Fairhurst S, Barber DJ, Clark B, Horton AA. Studies on paracetamol-induced lipid peroxidation. Toxicology. 1982;23(2-3):249-259.
Abstract: Post-mitochondrial supernatants isolated from livers of rats given a single large oral dose of paracetamol (800 mg/kg) showed rapid rates of lipid peroxidation when incubated in vitro. As a result of paracetamol administration the level of reduced glutathione (GSH) declined to approx. 20-25% of the peak physiological value. Addition of reduced GSH to the supernatant inhibited the peroxidation. Paracetamol-induced lipid peroxidation was inhibited in vitro by antioxidants (e.g. vitamin E) but was unaffected by superoxide dismutase and mannitol. N-acetyl cysteine and cysteamine inhibited lipid peroxidation in vitro in a cytosol-dependent manner in the absence of glutathione. Lipid peroxidation probably occurs simultaneously with the proposed covalent binding of the active metabolite of paracetamol. Since the former process is known to cause severe and extensive membrane damage, it may be a very important factor in paracetamol-induced liver necrosis.

Garrido A, Arancibia C, Campos R, Valenzuela A. Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin. Pharmacol Toxicol. 1991 Jul;69(1):9-12.
Abstract: Acetaminophen hepatotoxicity is characterized by glutathione depletion and the formation of the reactive electrophilic metabolite N-acetyl-p-benzoquinone imine. The induction of oxidative stress, expressed as lipid peroxidation, is controversial in acute acetaminophen intoxication. Isolated rat hepatocytes develop spontaneously or when incubated with buthionine sulfoximide, a progressive lipid peroxidation which may be inhibited by the antioxidant flavonoid silybin. When cells are incubated with acetaminophen, lipid peroxidation is not observed, this antilipoperoxidative effect being potentiated by silybin. It is proposed that when hepatocytes are incubated with a high concentration of acetaminophen, the drug may accumulate in the cells due to saturation and/or inhibition of detoxification pathways (as in the case of silybin). Under these conditions the development of hepatocyte oxidative stress may be inhibited due to the antioxidant behaviour of acetaminophen.

Houston JB, Levy G. Drug biotransformation interactions in man. VI: Acetaminophen and ascorbic acid. J Pharm Sci 1976;65:1218-1221.
Abstract: Oral administration of 3 g of ascorbic acid 1.5 hr after an oral dose of 1 g of acetaminophen caused a rapid and pronounced decrease in the excretion rate of acetaminophen sulfate in five healthy adult volunteers. There was a statistically significant increase in the fractions of the dose of acetaminophen excreted as such as as acetaminophen glucuronide but a decrease in the fraction excreted as acetaminophen sulfate. The apparent biological half-life of acetaminophen increased from 2.3 +/- 0.2 (mean +/- SD) to 3.1 +/- 0.5 hr. Concomitant administration of sodium sulfate prevented these effects. Ascorbic acid, which itself is metabolized in part to the sulfate, inhibits the conjugation of acetaminophen with sulfate by competing for available sulfate in the body.

Janbaz KH, Gilani AH. Evaluation of the protective potential of Artemisia maritima extract on acetaminophen- and CCl4-induced liver damage. J Ethnopharmacol 1995 Jun 23;47(1):43-47.
Abstract: The hepatoprotective activity of the aqueous-methanolic extract of Artemisia maritima was investigated against acetaminophen (paracetamol, 4-hydroxy acetanilide)- and carbon tetrachloride (CCl4)-induced hepatic damage. Acetaminophen produced 100% mortality at the dose of 1 g/kg in mice, while pretreatment of animals with the plant extract (500 mg/kg) reduced the death rate to 20%. Acetaminophen at the dose of 640 mg/kg produced liver damage in rats as manifested by the significant (P < 0.001) rise in serum levels of glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) to 1529 +/- 172 I.U./l and 904 +/- 116 I.U./l (n = 10), respectively, compared to respective control values of 87 +/- 12 I.U./l and 31 +/- 5 I.U./l. Pretreatment of rats with the plant extract (500 mg/kg) lowered significantly (P < 0.001) the respective serum GOT and GPT levels to 112 +/- 10 I.U./l and 47 +/- 11 I.U./l. Similarly, a hepatotoxic dose of CCl4 (1.5 ml/kg, orally) raised significantly (P < 0.01) the serum GOT and GPT levels to 463 +/- 122 I.U./l and 366 +/- 58 I.U./l (n = 10), respectively, compared to respective control values of 92 +/- 18 I.U./l and 35 +/- 9 I.U./l. The same dose of plant extract (500 mg/kg) was able to prevent significantly (P < 0.01) the CCl4-induced rise in serum transaminases and the estimated values of GOT and GPT were 105 +/- 29 I.U./l and 53 +/- 17 I.U./l, respectively. Moreover, it prevented CCl4-induced prolongation in pentobarbital sleeping time confirming hepatoprotectivity and validates the traditional use of this plant against liver damage.

Kamiyama T, Sato C, Liu J, Tajiri K, Miyakawa H, Marumo F. Role of lipid peroxidation in acetaminophen-induced hepatotoxicity: comparison with carbon tetrachloride. Toxicol Lett. 1993 Jan;66(1):7-12.

Lin CC, Shieh DE, Yen MH. Hepatoprotective effect of the fractions of Ban-zhi-lian on experimental liver injuries in rats. J Ethnopharmacol 1997 May;56(3):193-200.
Abstract: The hepatoprotective effect of various fractions (n-hexane, CHCl3, EtOAc, n-BuOH, and H2O) of Ban-zhi-lian derived from Scutellaria rivularis Benth was studied against carbon tetrachloride (CCl4), D-galactosamine (D-GalN) and acetaminophen (APAP)-induced acute hepatotoxicity in rats. Liver damage was assessed by quantifying serum activities of glutamate oxaloacetate transaminase (sGOT) and glutamate pyruvate transaminase (sGPT), as well as by histopathological examination. The results indicated that the CHCl3 fraction and EtOAc fractions exhibited the greatest hepatoprotective effects on CCl4-induced liver injuries, the CHCl3 fraction and n-hexane fraction are most potent against D-GalN-induced intoxication, and the CHCl3 fraction represented the most liver-protective effect on APAP-induced hepatotoxicity. The pathological changes of hepatic lesions caused by these three hepatotoxicants were improved by treatment with the fractions mentioned above, which were compared to Glycyrrhizin (GLZ) and Silymarin as standard reference medicines.

Mitra A, Kulkarni AP, Ravikumar VC, Bourcier DR. Effect of ascorbic acid esters on hepatic glutathione levels in mice treated with a hepatotoxic dose of acetaminophen. J Biochem Toxicol. 1991 Summer;6(2):93-100.
Abstract: Acetaminophen (APAP) with or without ascorbyl stearate (AS) or ascorbyl palmitate (AP) was administered by gavage to male Swiss-Webster mice at a dose of 600 mg/kg for each chemical. The biochemical markers of hepatotoxicity, serum transaminases (serum glutamate pyruvate transaminase [SGPT], serum glutamate oxaloacetic transaminase [SGOT]) and serum isocitrate dehydrogenase (SICD) activities were monitored after APAP and APAP + AP or AS dosing. There were significant reductions in serum transaminase and SICD activities in the APAP- + ascorbate ester-treated animals as compared to APAP-positive controls. Oral coadministration of APAP with AP or AS did not prevent the initial hepatic GSH depletion (15 min-4 hr postdosing). However, hepatic GSH content began to rise in the APAP + AS or AP-treated animals at 4 hr and reached control values within 12 hr postdosing. Urinary mercapturate conjugates were also significantly higher in the APAP + AP or AS-treated animals as compared to APAP alone when measured over a 60-min postdosing period. Plasma sulfobromophthalein (BSP) retention was approximately eight times higher in APAP-treated animals as compared to the APAP + ascorbate ester treatments indicating maintenance of hepatic excretory functions in presence of AP or AS. Prior depletion of hepatic GSH by diethyl maleate (DEM) did not alter hepatoprotective effects of AP or AS in the presence of APAP. Hepatic ascorbate levels also peaked at 4 hours after APAP + AP or AS treatments. The possible role of L-ascorbic acid esters in GSH regeneration following co-administration of a hepatotoxic dose and APAP is discussed.

Mitra A, Ravikumar VC, Bourn WM, Bourcier DR. Influence of ascorbic acid esters on acetaminophen-induced hepatotoxicity in mice. Toxicol Lett. 1988 Nov;44(1-2):39-46.
Abstract: Groups of male Swiss-Webster mice were gavaged with acetaminophen (APAP), APAP + ascorbyl stearate (AS), or APAP + ascorbyl palmitate (AP) at a dose of 600 mg/kg for each chemical. APAP alone caused a significant increase in liver weight/body weight ratio and hepatic glutathione (GSH) depletion. Co-administration of the ascorbate esters AP or AS with APAP prevented an increase in liver weight/body weight ratios and hepatic glutathione depletion. APAP + AS treatments caused significantly greater reductions in rectal temperature at 15-30 min post-dosing periods when compared to APAP + AP or AS treatments. Blood levels of APAP had the same relationship. The study indicates a correlation between APAP blood levels and antipyretic effect of APAP + AS and APAP + AP coadministrations. While both ascorbate esters probably afford protection against APAP-induced hepatotoxicity in mice by reducing the reactive intermediate back to the parent compound, the APAP + AS combination provides better therapeutic efficacy as an antipyretic at the 15-30 min post-dosing periods.

Montoya-Cabrera MA, Escalante-Galindo P, Nava-Juarez A, Terroba-Larios VM, Teran-Hernandez JA. [Evaluation of the efficacy of N-acetylcysteine administered alone or in combination with activated charcoal in the treatment of acetaminophen overdoses]. Gac Med Mex. 1999 May-Jun;135(3):239-243. [Article in Spanish]
Abstract: STUDY OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (N-AC) alone or combined with multiple-dose activated charcoal (AC) in the treatment of acetaminophen (ACT) overdose. DESIGN: Prospective observational case series of 14 consecutive pediatric patients. Group A (n = 7) were treated only with N-AC and group B (n = 7) with N-AC combined with AC. Plasma ACT concentrations were measured at 0.0, 24 and 48 h. As a measure of ACT disappearance, half-life of elimination (t1/2 beta) and exogenous body clearance (ClB) were calculated. RESULTS: Group A, Initial and final mean ACT plasmatic levels were 27 micrograms/mL and 4 micrograms/mL; t1/2 beta of 17 h and ClB 0.640 mL.kg.min. Group B, 27 micrograms/mL and 0.66 microgram/mL; t1/2 beta of 10 h and ClB 1.092 mL.kg.min. For both t1/2 beta and ClB differences, p < 0.05 (SS). CONCLUSION: N-AC significantly decreased the plasma ACT levels in both treatments; however, there were several advantages with the combined therapy: AC enhanced the efficacy of N-AC according with the higher elimination of the overdosed drug (97.6% vs. 85.2%), the t1/2 beta decreased 42%, and the ClB increased 70% in relation to the group A. Data of this study suggested that N-AC plus AC is more effective than N-AC alone in enhancing ACT elimination in overdosed patients and that it provided additional hepatoprotective benefit.

Muriel P, Garciapina T, Perez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol. 1992 Dec;12(6):439-442.
Abstract: The effect of silymarin on liver damage induced by acetaminophen (APAP) intoxication was studied. Wistar male rats pretreated (72 h) with 3-methylcholanthrene (3-MC) (20 mg kg-1 body wt. i.p.) were divided into three groups: animals in group 1 were treated with acetaminophen (APAP) (500 mg kg-1 body wt. p.o.), group 2 consisted of animals that received APAP plus silymarin (200 mg kg-1 body wt. p.o.) 24 h before APAP, and rats in group 3 (control) received the equivalent amount of the vehicles. Animals were sacrificed at different times after APAP administration. Reduced glutathione (GSH), lipid peroxidation and glycogen were measured in liver and alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGTP) and glutamic pyruvic transaminase (GPT) activities were measured in serum. After APAP intoxication, GSH and glycogen decreased very fast (1 h) and remained low for 6 h. Lipid peroxidation increased three times over the control 4 and 6 h after APAP treatment. Enzyme activities increased 18 h after intoxication. In the group receiving APAP plus silymarin, levels of lipid peroxidation and serum enzyme activities remained within the control values at any time studied. The fall in GSH was not prevented by silymarin, but glycogen was restored at 18 h. It was concluded that silymarin can protect against APAP intoxication through its antioxidant properties, possibly acting as a free-radical scavenger.

Ozdemirler G, Aykac G, Uysal M, Oz H. Liver lipid peroxidation and glutathione-related defence enzyme systems in mice treated with paracetamol. J Appl Toxicol. 1994 Jul-Aug;14(4):297-299.
Abstract: Glutathione levels were found to be decreased while lipid peroxide levels were increased in total liver homogenates 6 h following paracetamol treatment (500 mg kg-1 i.p.). Furthermore, it has been determined that cytosolic glutathione S-transferase (GST) activity was decreased and glutathione peroxidase (GSH-Px) activity remained unchanged. On the other hand, a decrease in liver microsomal lipid peroxide levels and an increase in GST and GSH-Px activity has been observed. We concluded that decreased lipid peroxide levels in microsomes could be a consequence of increased GSH-Px and GST enzyme activities. In this way, these glutathione-related defence enzyme systems may play an important role in protecting microsomes from lipid peroxidation.

Rainska T, Juzwiak S, Dutkiewicz T, Krasowska B, Olenderek B, Rozewicka L, Wojcicki J, Samochowiec L, Juzyszyn Z. Caffeine reduces the hepatotoxicity of paracetamol in mice. J Int Med Res. 1992 Aug;20(4):331-342.

Ryu BK, Ahn BO, Oh TY, Kim SH, Kim WB, Lee EB. Studies on protective effect of DA-9601, Artemisia asiatica extract, on acetaminophen- and CCl4-induced liver damage in rats. Arch Pharm Res 1998 Oct;21(5):508-513.
Abstract: The hepatoprotective effect of DA-9601, a quality-controlled extract of Artemisia asiatica, on liver damage induced by acetaminophen (APAP) and carbon tetrachloride (CCl4) was investigated by means of serum-biochemical, hepatic-biochemical, and histopathological examinations. Doses of DA-9601 (10, 30, or 100 mg/kg) were administered intragastrically to each rat on three consecutive days i.e. 48 h, 24 h and 2 h before a single administration of APAP (640 mg/kg, i.p.) or CCl4 (2 ml/kg, p.o.). Four h and 24 h after hepatotoxin treatment, the animals were sacrificed for evaluation of liver damage. Pretreatment of DA-9601 reduced the elevation of serum ALT, AST, LDH and histopathological changes such as centrilobular necrosis, vacuolar degeneration and inflammatory cell infiltration dose-dependently. DA-9601 also prevented APAP- and CCl4-induced hepatic glutathione (GSH) depletion and CCl4-induced increase of hepatic malondialdehyde (MDA), a parameter of lipid peroxidation, in a dose-dependent manner. These findings suggest that pretreatment with DA-9601 may reduce chemically induced liver injury by complex mechanisms.

Salgia AD, Kosnik SD. When acetaminophen use becomes toxic. Treating acute accidental and intentional overdose. Postgrad Med. 1999 Apr;105(4):81-84, 87, 90. (Review)

Schmidt LE, Dalhoff KP. [Side-effects of N-acetylcysteine treatment in patients with paracetamol poisoning]. Ugeskr Laeger. 1999 May 3;161(18):2669-2672. [Article in Danish]
Abstract: Treatment of paracetamol intoxication with N-acetylcysteine (NAC) is standard in Denmark. NAC is considered safe with relatively few side effects. It is recommended that all patients be treated irrespective of paracetamol dose or time from intoxication to treatment start. Consequently a higher number of patients will be treated with NAC than with previous regimens based on plasma concentrations of paracetamol. In this retrospective study we evaluated the incidence of side effects of NAC in 310 patients admitted to the Department of Hepatology, Rigshospitalet, Copenhagen, over a four-year period (1.1.1994-31.12.1997). Twenty-six (8.4%) patients developed side effects. Side effects were anaphylactoid, mainly from skin (25 rash, pruritus or flushing), in rare cases more serious (four bronchospasm, three angioedema, one hypotension). None were life-threatening and all patients received the full course of NAC. In all cases the recommended treatment with antihistamine or steroids against adverse effects was administered. We conclude that treatment with NAC is safe. Accordingly we find no reason to change the recommendation for treatment of paracetamol intoxication in Denmark.

Shiota G, Yamada S, Kawasaki H. Rapid induction of hepatocyte growth factor mRNA after administration of gomisin A, a lignan component of shizandra fruits. Res Commun Mol Pathol Pharmacol. 1996 Nov;94(2):141-146.
Abstract: Gomisin A (Go), a lignan component of shizandra fruits, protects the liver from injury by acetaminophen (AAP). One of its possible mechanisms is supposed to be related to the suppression of lipid peroxidation. Since hepatocyte growth factor (HGF) was reported to prevent hepatotoxin-induced liver damage, we tested HGF as the intermediary of Go effects. Simultaneous analyses of HGF mRNA expression and liver histology in rats were performed at 6 and 24 hr after treatment with AAP, Go or both. HGF mRNA rapidly expressed at 6 hr after Go treatment, while no HGF mRNA was observed at 6 hr after AAP treatment. Induction of HGF mRNA at 24 hr was observed after treatment with AAP or AAP plus Go. Histological findings indicate that massive necrosis and vacuolization in the liver of rats treated with both AAP and Go were reduced in comparison with rats treated with AAP only. These data suggest that Go rapidly induces HGF mRNA through different mechanisms from AAP-induced liver injury.

Takeda S, Maemura S, Sudo K, Kase Y, Arai I, Ohkura Y, Funo S, Fujii Y, Aburada M, Hosoya E. [Effects of gomisin A, a lignan component of Schizandra fruits, on experimental liver injuries and liver microsomal drug-metabolizing enzymes]. Nippon Yakurigaku Zasshi. 1986 Feb;87(2):169-187. [Article in Japanese]
Abstract: Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.

Threlkeld DS, ed. Central Nervous System Drugs, Acetaminophen. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Mar 1997, 247-247f.

Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995;346:547-552.

Valenzuela A, Aspillaga M, Vial S, Guerra R. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 1989;55:420-422.

Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994 Dec 21;272(23):1845-1850.
Abstract: OBJECTIVES--To evaluate the association of fasting and alcohol use with hepatotoxicity from acetaminophen ingested for therapeutic reasons. DESIGN -- Retrospective case series. SETTING--Hospitals of the University of Pittsburgh (Pa) Medical Center. PATIENTS--A total of 126,779 discharge summaries from January 1987 to July 1993 were reviewed using a comprehensive, whole-text-indexed medical database to identify all patients with acetaminophen ingestion and hepatotoxicity. These patients were categorized according to the intended acetaminophen use and dose of acetaminophen ingested. MAIN OUTCOMES MEASURED--The independent variables of chronic alcohol use, recent alcohol use, and recent fasting were determined for all patients. RESULTS--Forty-nine patients with acetaminophen hepatotoxicity (aspartate aminotransferase > 1000 U/L) were identified. Twenty-one patients (43%) ingested acetaminophen for therapeutic purposes. All patients with hepatotoxicity took more than the recommended limit of 4 g/d. Recent fasting was more common than recent alcohol use among those who suffered hepatotoxicity after a dose of 4 to 10 g of acetaminophen per day (P = .02). Recent alcohol use was more common in the group who took more than 10 g/d than in those who took 4 to 10 g/d (P = .004). CONCLUSION--Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use. Patients who developed hepatoxicity after taking acetaminophen doses of greater than 10 g/d for therapeutic purposes were alcohol users. Acetaminophen hepatotoxicity after an overdose appears to be enhanced by fasting in addition to alcohol ingestion.

Yamada S, Murawaki Y, Kawasaki H. Preventive effect of gomisin A, a lignan component of schizandra fruits, on acetaminophen-induced hepatotoxicity in rats. Biochem Pharmacol 1993 Sep 14;46(6):1081-1085.
Abstract: The preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats was examined by histological and biochemical analysis. Acetaminophen at a dose of 750 mg/kg was administered to male Wistar rats with or without pretreatment with 50 mg/kg of gomisin A. Gomisin A inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxides content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration and necrosis of hepatocytes. However, gomisin A did not affect the decrease in liver glutathione content. These results suggest that gomisin A protects the liver from injury after administration of acetaminophen through the suppression of lipid peroxidation.

Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose. Am J Health Syst Pharm 1999 Jun 1;56(11):1081-1091. (Review)