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Akakpo JY, Ramachandran A, Curry SC, et al. Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose. Arch Toxicol. 2022;doi: 10.1007/s00204-021-03211-z.
Akakpo, J. Y., Ramachandran, A., Curry, S. C., Rumack, B. H., & Jaeschke, H. (2022). Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose. Archives of toxicology, . https://doi.org/10.1007/s00204-021-03211-z
Akakpo, Jephte Y, et al. "Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose." Archives of toxicology vol. (2022). doi: https://doi.org/10.1007/s00204-021-03211-z
Akakpo JY, Ramachandran A, Curry SC, Rumack BH, Jaeschke H. Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose. Arch Toxicol. 2022 Jan 03; doi: 10.1007/s00204-021-03211-z. Epub 2022 Jan 03. PMID: 34978586.
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Arch Toxicol. 2022 Jan 03; doi: 10.1007/s00204-021-03211-z. Epub 2022 Jan 03.

Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.

Archives of toxicology

Jephte Y Akakpo, Anup Ramachandran, Steven C Curry, Barry H Rumack, Hartmut Jaeschke

Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA.
  2. Division of Clinical Data Analytics and Decision Support, and Division of Medical Toxicology and Precision Medicine, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
  3. Department of Emergency Medicine and Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
  4. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA. [email protected].

PMID: 34978586 DOI: 10.1007/s00204-021-03211-z

Abstract

Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.

© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Keywords: 4-Methylpyrazole; Acetaminophen; Fomepizole; Hepatotoxicity; N-Acetylcysteine; c-Jun N-terminal kinase

References

  1. Akakpo JY, Ramachandran A, Kandel SE, Ni HM, Kumer SC, Rumack BH, Jaeschke H (2018) 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Hum Exp Toxicol 37:1310–1322 - PubMed
  2. Akakpo JY, Ramachandran A, Duan L, Schaich MA, Jaeschke MW, Freudenthal BD, Ding WX, Rumack BH, Jaeschke H (2019) Delayed treatment with 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice by inhibition of c-jun N-terminal kinase. Toxicol Sci 170:57–68 - PubMed
  3. Akakpo JY, Ramachandran A, Orhan H, Curry SC, Rumack BH, Jaeschke H (2020) 4-Methylpyrazole protects against acetaminophen-induced acute kidney injury. Toxicol Appl Pharmacol 409:115317 - PubMed
  4. Akakpo JY, Jaeschke MW, Ramachandran A, Curry SC, Rumack BH, Jaeschke H (2021) Delayed administration of N-acetylcysteine blunts recovery after an acetaminophen overdose unlike 4-methylpyrazole. Arch Toxicol 95:3377–3391 - PubMed
  5. Arzuk E, Turna B, Sözbilen M, Orhan H (2018) Inter-individual and inter-organ variability in the bioactivation of paracetamol by human liver and kidney tissues. Environ Toxicol Pharmacol 61:8–17 - PubMed
  6. Bailey B, Blais R, Letarte A (2004) Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death. Ann Emerg Med 44:401–406 - PubMed
  7. Bajt ML, Cover C, Lemasters JJ, Jaeschke H (2006) Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci 94:217–225 - PubMed
  8. Bajt ML, Farhood A, Lemasters JJ, Jaeschke H (2008) Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 324:8–14 - PubMed
  9. Baud FJ, Bismuth C, Garnier R, Galliot M, Astier A, Maistre G, Soffer M (1986–1987) 4-Methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man. J Toxicol Clin Toxicol 24:463–483 - PubMed
  10. Bebarta VS, Kao L, Froberg B, Clark RF, Lavonas E, Qi M, Delgado J, McDonagh J, Arnold T, Odujebe O, O’Malley G, Lares C, Aguilera E, Dart R, Heard K, Stanford C, Kokko J, Bogdan G, Mendoza C, Mlynarchek S, Rhyee S, Hoppe J, Haur W, Tan HH, Tran NN, Varney S, Zosel A, Buchanan J, Al-Helial M (2010) A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose. Clin Toxicol (phila) 48:424–430 - PubMed
  11. Bernal W, Wendon J (2013) Acute liver failure. N Engl J Med 369:2525–2534 - PubMed
  12. Blieden M, Paramore LC, Shah D, Ben-Joseph R (2014) A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Rev Clin Pharmacol 7:341–348 - PubMed
  13. Blomstrand R, Theorell H (1970) Inhibitory effect on ethanol oxidation in man after administration of 4-methylpyrazole. Life Sci II 9:631–640 - PubMed
  14. Blomstrand R, Ostling-Wintzell H, Löf A, McMartin K, Tolf BR, Hedström KG (1979) Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: an approach to therapy against methanol poisoning. Proc Natl Acad Sci USA 76:3499–3503 - PubMed
  15. Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, Kulig K (1999) Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med 340:832–838 - PubMed
  16. Brent J, McMartin K, Phillips S, Aaron C, Kulig K (2001) Methylpyrazole for Toxic Alcohols Study Group. Fomepizole for the treatment of methanol poisoning. N Engl J Med 344:424–429 - PubMed
  17. Brigelius-Flohé R, Flohé L (2020) Regulatory phenomena in the glutathione peroxidase superfamily. Antioxid Redox Signal 33:498–516 - PubMed
  18. Buckley NA, Whyte IM, O’Connell DL, Dawson AH (1999) Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? J Toxicol Clin Toxicol 37:759–767 - PubMed
  19. Burk RF, Hill KE, Hunt RW Jr, Martin AE (1990) Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it. Res Commun Chem Pathol Pharmacol 69:115–118 - PubMed
  20. Burns MJ, Graudins A, Aaron CK, McMartin K, Brent J (1997) Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med 30:829–832 - PubMed
  21. Cairney DG, Beckwith HKS, Al-Hourani K, Eddleston M, Bateman DN, Dear JW (2016) Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine. Clin Toxicol (phila) 54:405–410 - PubMed
  22. Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA (2017) Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol (phila) 55:1055–1065 - PubMed
  23. Chiu MH, Jaworska N, Li NL, Yarema M (2021) Massive acetaminophen overdose treated successfully with N-acetylcysteine, fomepizole, and hemodialysis. Case Rep Crit Care 2021:6695967 - PubMed
  24. Clay KL, Murphy RC (1977) On the metabolic acidosis of ethylene glycol intoxication. Toxicol Appl Pharmacol 39:39–49 - PubMed
  25. Corcoran GB, Wong BK (1986) Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice. J Pharmacol Exp Ther 238:54–61 - PubMed
  26. Corcoran GB, Racz WJ, Smith CV, Mitchell JR (1985a) Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice. J Pharmacol Exp Ther 232:864–872 - PubMed
  27. Corcoran GB, Todd EL, Racz WJ, Hughes H, Smith CV, Mitchell JR (1985b) Effects of N-acetylcysteine on the disposition and metabolism of acetaminophen in mice. J Pharmacol Exp Ther 232:857–863 - PubMed
  28. Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, Jaeschke H (2005) Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 315:879–887 - PubMed
  29. Cuninghame S, Lotfy K, Cameron P (2021) Massive acetaminophen overdose with metabolic acidosis refractory to N-acetylcysteine, fomepizole, and renal replacement therapy. Toxicol Rep 8:804–807 - PubMed
  30. Dai Y, Cederbaum AI (1995) Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells. J Pharmacol Exp Ther 273:1497–1505 - PubMed
  31. Daoud A, Dalhoff KP, Christensen MB, Bøgevig S, Petersen TS (2020) Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine. Clin Toxicol (phila) 58:698–704 - PubMed
  32. Dart RC, Bailey E (2007) Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 27:1219–1230 - PubMed
  33. Dart RC, Rumack BH (2007) Patient-tailored acetylcysteine administration. Ann Emerg Med 50:280–281 - PubMed
  34. Davenport A, Finn R (1988) Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma. Nephron 50:55–56 - PubMed
  35. Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 2(5512):497–499 - PubMed
  36. Doyon S, Klein-Schwartz W (2009) Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose. Acad Emerg Med 16:34–39 - PubMed
  37. Du K, Ramachandran A, Jaeschke H (2016) Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol 10:148–156 - PubMed
  38. Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, Woolbright BL, Ding WX, Jaeschke H (2017) Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol 108(Pt A):339–350 - PubMed
  39. Emeigh Hart SG, Beierschmitt WP, Bartolone JB, Wyand DS, Khairallah EA, Cohen SD (1991) Evidence against deacetylation and for cytochrome P450-mediated activation in acetaminophen-induced nephrotoxicity in the CD-1 mouse. Toxicol Appl Pharmacol 107:1–15 - PubMed
  40. Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59:169–177 - PubMed
  41. Fisher ES, Curry SC (2019) Evaluation and treatment of acetaminophen toxicity. Adv Pharmacol 85:263–272 - PubMed
  42. Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N (2008) Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 283:13565–13577 - PubMed
  43. Hart SG, Beierschmitt WP, Wyand DS, Khairallah EA, Cohen SD (1994) Acetaminophen nephrotoxicity in CD-1 mice. I. Evidence of a role for in situ activation in selective covalent binding and toxicity. Toxicol Appl Pharmacol 126:267–275 - PubMed
  44. Hart SG, Cartun RW, Wyand DS, Khairallah EA, Cohen SD (1995) Immunohistochemical localization of acetaminophen in target tissues of the CD-1 mouse: correspondence of covalent binding with toxicity. Fundam Appl Toxicol 24:260–274 - PubMed
  45. Hazai E, Vereczkey L, Monostory K (2002) Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun 291:1089–1094 - PubMed
  46. Heard K, Green J (2012) Acetylcysteine therapy for acetaminophen poisoning. Curr Pharm Biotechnol 13:1917–1923 - PubMed
  47. Heard K, Schaeffer TH (2011) Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol (phila) 49:423–425 - PubMed
  48. Heard K, Rumack BH, Green JL, Bucher-Bartelson B, Heard S, Bronstein AC, Dart RC (2014) A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning. Clin Toxicol (phila) 52:512–518 - PubMed
  49. Hendrickson RG (2019) What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose? Clin Toxicol (phila) 57:686–691 - PubMed
  50. Jacobsen D, Sebastian CS, Blomstrand R, McMartin KE (1988) 4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses. Alcohol Clin Exp Res 12:516–522 - PubMed
  51. Jacobsen D, Sebastian CS, Barron SK, Carriere EW, McMartin KE (1990) Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans. J Emerg Med 8:455–461 - PubMed
  52. Jaeschke H (1990) Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther 255:935–941 - PubMed
  53. Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 44:88–106 - PubMed
  54. Jaeschke H, Ramachandran A, Chao X, Ding WX (2019) Emerging and established modes of cell death during acetaminophen-induced liver injury. Arch Toxicol 93:3491–3502 - PubMed
  55. Jaeschke H, Akakpo JY, Umbaugh DS, Ramachandran A (2020) Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure. Toxicol Sci 174:159–167 - PubMed
  56. James LP, McCullough SS, Lamps LW, Hinson JA (2003) Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation. Toxicol Sci 75:458–467 - PubMed
  57. Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 187:195–202 - PubMed
  58. Kang AM, Padilla-Jones A, Fisher ES, Akakpo JY, Jaeschke H, Rumack BH, Gerkin RD, Curry SC (2020) The effect of 4-methylpyrazole on oxidative metabolism of acetaminophen in human volunteers. J Med Toxicol 16:169–176 - PubMed
  59. Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, Williams R (1991) Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 303(6809):1026–1029 - PubMed
  60. Kiernan EA, Fritzges JA, Henry KA, Katz KD (2019) A case report of massive acetaminophen poisoning treated with a novel “triple therapy”: N-acetylcysteine, 4-methylpyrazole, and hemodialysis. Case Rep Emerg Med 2019:9301432 - PubMed
  61. Klein-Schwartz W, Doyon S (2011) Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin Pharmacother 12:119–130 - PubMed
  62. Knight TR, Kurtz A, Bajt ML, Hinson JA, Jaeschke H (2001) Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: role of mitochondrial oxidant stress. Toxicol Sci 62:212–220 - PubMed
  63. Knight TR, Ho YS, Farhood A, Jaeschke H (2002) Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmacol Exp Ther 303:468–475 - PubMed
  64. Koch-Weser J (1976) Drug therapy. Acetaminophen. N Engl J Med 295(23):1297–1300 - PubMed
  65. Kon K, Kim JS, Jaeschke H, Lemasters JJ (2004) Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 40:1170–1179 - PubMed
  66. Lavonas EJ, Reynolds KM, Dart RC (2010) Therapeutic acetaminophen is not associated with liver injury in children: a systematic review. Pediatrics 126:e1430–e1444 - PubMed
  67. Lepik KJ, Levy AR, Sobolev BG, Purssell RA, DeWitt CR, Erhardt GD, Kennedy JR, Daws DE, Brignall JL (2009) Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med 53:439–450 - PubMed
  68. Li TK, Theorell H (1969) Human liver alcohol dehydrogenase: inhibition by pyrazole and pyrazole analogs. Acta Chem Scand 23:892–902 - PubMed
  69. Link SL, Rampon G, Osmon S, Scalzo A, Rumack BH (2021) Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series. Clin Toxicol (phila). https://doi.org/10.1080/15563650.2021.1996591 (Online ahead of print) - PubMed
  70. Marks DJB, Dargan PI, Archer JRH, Davies CL, Dines AM, Wood DM, Greene SL (2017) Outcomes from massive paracetamol overdose: a retrospective observational study. Br J Clin Pharmacol 83:1263–1272 - PubMed
  71. Masubuchi Y, Suda C, Horie T (2005) Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 42:110–116 - PubMed
  72. McGill MR, Jaeschke H (2013) Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res 30:2174–2187 - PubMed
  73. McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins DE, Jaeschke H (2011) HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 53:974–982 - PubMed
  74. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Investig 122:1574–1583 - PubMed
  75. McGill MR, Lebofsky M, Norris HR, Slawson MH, Bajt ML, Xie Y, Williams CD, Wilkins DG, Rollins DE, Jaeschke H (2013) Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications. Toxicol Appl Pharmacol 269:240–249 - PubMed
  76. McMartin KE (2010) Antidotes for alcohol and glycol toxicity: translating mechanisms into treatments. Clin Pharmacol Ther 88:400–404 - PubMed
  77. McMartin KE, Makar AB, Martin G, Palese M, Tephly TR (1975) Methanol poisoning. I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole. Biochem Med 13:319–333 - PubMed
  78. McMartin KE, Hedström KG, Tolf BR, Ostling-Wintzell H, Blomstrand R (1980) Studies on the metabolic interactions between 4-methylpyrazole and methanol using the monkey as an animal model. Arch Biochem Biophys 199:606–614 - PubMed
  79. Mégarbane B (2010) Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med 2:67–75 - PubMed
  80. Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973a) Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 187:185–194 - PubMed
  81. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (1973b) Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 187:211–217 - PubMed
  82. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H (1974) Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 16:676–684 - PubMed
  83. Mullins ME, Yeager LH, Freeman WE (2020) Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review. Clin Toxicol (phila) 58:1284–1296 - PubMed
  84. Mundy RL, Hall LM, Teague RS (1974) Pyrazole as an antidote for ethylene glycol poisoning. Toxicol Appl Pharmacol 28:320–322 - PubMed
  85. Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A, Sakamoto K, Ogura K, Noguchi T, Karin M, Ichijo H, Omata M (2008) Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology 135:1311–1321 - PubMed
  86. Nguyen NT, Akakpo JY, Weemhoff JL, Ramachandran A, Ding WX, Jaeschke H (2021a) Impaired protein adduct removal following repeat administration of subtoxic doses of acetaminophen enhances liver injury in fed mice. Arch Toxicol 95:1463–1473 - PubMed
  87. Nguyen NT, Du K, Akakpo JY, Umbaugh DS, Jaeschke H, Ramachandran A (2021b) Mitochondrial protein adduct and superoxide generation are prerequisites for early activation of c-jun N-terminal kinase within the cytosol after an acetaminophen overdose in mice. Toxicol Lett 338:21–31 - PubMed
  88. Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX (2012) Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55:222–232 - PubMed
  89. Ni HM, McGill MR, Chao X, Du K, Williams JA, Xie Y, Jaeschke H, Ding WX (2016) Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. J Hepatol 65:354–362 - PubMed
  90. Ohashi N, Kohno T (2020) Analgesic effect of acetaminophen: a review of known and novel mechanisms of action. Front Pharmacol 11:580289 - PubMed
  91. O’Riordan A, Brummell Z, Sizer E, Auzinger G, Heaton N, O’Grady JG, Bernal W, Hendry BM, Wendon JA (2011) Acute kidney injury in patients admitted to a liver intensive therapy unit with paracetamol-induced hepatotoxicity. Nephrol Dial Transplant 26:3501–3508 - PubMed
  92. Pakravan N, Waring WS, Sharma S, Ludlam C, Megson I, Bateman DN (2008) Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol (phila) 46:697–702 - PubMed
  93. Pauley KA, Sandritter TL, Lowry JA, Algren DA (2015) Evaluation of an alternative intravenous N-acetylcysteine regimen in pediatric patients. J Pediatr Pharmacol Ther 20:178–185 - PubMed
  94. Peterson RG, Rumack BH (1977) Treating acute acetaminophen poisoning with acetylcysteine. JAMA 237:2406–2407 - PubMed
  95. Piperno E, Berssenbruegge DA (1976) Reversal of experimental paracetamol toxicosis with N-acetylcysteine. Lancet 2(7988):738–739 - PubMed
  96. Piperno E, Mosher AH, Berssenbruegge DA, Winkler JD, Smith RB (1978) Pathophysiology of acetaminophen overdosage toxicity: implications for management. Pediatrics 62(5 Pt 2 Suppl):880–889 - PubMed
  97. Prescott LF, Roscoe P, Wright N, Brown SS (1971) Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1(7698):519–522 - PubMed
  98. Prescott LF, Matthew H, Todd JW (1974) Cysteamine for paracetamol overdose (letter). Lancet 1(7864):998 - PubMed
  99. Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT (1977) Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 2(8035):432–434 - PubMed
  100. Prescott F, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT (1979) Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J 2:1097–1100 - PubMed
  101. Ramachandran A, Jaeschke H (2019) Acetaminophen hepatotoxicity. Semin Liver Dis 39:221–234 - PubMed
  102. Ramachandran A, Jaeschke H (2021) Oxidant stress and acetaminophen hepatotoxicity: mechanism-based drug development. Antioxid Redox Signal 35:718–733 - PubMed
  103. Rampon G, Wartman H, Osmon S, Scalzo A (2020) Use of fomepizole as an adjunct in the treatment of acetaminophen overdose: a case series. Toxicol Commun 4:1–4 - PubMed
  104. Rasamison R, Besson H, Berleur MP, Schicchi A, Mégarbane B (2020) Analysis of fomepizole safety based on a 16-year post-marketing experience in France. Clin Toxicol (phila) 58:742–747 - PubMed
  105. Rumack BH (2002) Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 40:3–20 - PubMed
  106. Rumack BH, Bateman DN (2012) Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol (phila) 50:91–98 - PubMed
  107. Rumack BH, Matthew H (1975) Acetaminophen poisoning and toxicity. Pediatrics 55:871–876 - PubMed
  108. Rumack BH, Peterson RG (1978) Acetaminophen overdose: incidence, diagnosis, and management in 416 patients. Pediatrics 62(5 Pt 2 Suppl):898–903 - PubMed
  109. Rumack BH, Peterson RC, Koch GG, Amara IA (1981) Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 141(3 Spec No):380–385 - PubMed
  110. Saito C, Lemasters JJ, Jaeschke H (2010a) c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 246:8–17 - PubMed
  111. Saito C, Zwingmann C, Jaeschke H (2010b) Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51:246–254 - PubMed
  112. Shah KR, Fox C, Geib AJ, Murphy C, Kopec K, Kerns Ii W, Dulaney A, Beuhler MC (2021) Fomepizole as an adjunctive treatment in severe acetaminophen ingestions: a case series. Clin Toxicol (phila) 59:71–72 - PubMed
  113. Slitt AL, Dominick PK, Roberts JC, Cohen SD (2004) Standard of care may not protect against acetaminophen-induced nephrotoxicity. Basic Clin Pharmacol Toxicol 95:247–248 - PubMed
  114. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH (1988) Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 319:1557–1562 - PubMed
  115. Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH (1991) Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med 20:1058–1063 - PubMed
  116. Srinivasan V, Corwin D, Verceles AC (2015) An accidental overdose of N-acetylcysteine during treatment for acetaminophen toxicity. Clin Toxicol (phila) 53:500 - PubMed
  117. Stern ST, Bruno MK, Hennig GE, Horton RA, Roberts JC, Cohen SD (2005a) Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine. Toxicol Appl Pharmacol 202:151–159 - PubMed
  118. Stern ST, Bruno MK, Horton RA, Hill DW, Roberts JC, Cohen SD (2005b) Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle. Toxicol Appl Pharmacol 202:160–171 - PubMed
  119. Temple AR, Benson GD, Zinsenheim JR, Schweinle JE (2006) Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6–12 months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther 28:222–235 - PubMed
  120. Theorell H, Chance B, Yonetani T, Oshino N (1972) The combustion of alcohol and its inhibition by 4-methyl-pyrazole in perfused rat livers. Arch Biochem Biophys 151:434–444 - PubMed
  121. Tirmenstein MA, Nelson SD (1989) Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J Biol Chem 264:9814–9819 - PubMed
  122. Tortora L, Ruha AM, Ramos KS, Jaeschke H, Rumack BH, Kang AM, Padilla-Jones A, Wilhelms K, Curry SC (2018) Pharmacogenomic analysis of a patient with severe hepatotoxicity and hemolysis after acetaminophen overdose despite early N-acetylcysteine therapy (abstract). Clin Toxicol 56:983–984 - PubMed
  123. Tujios SR, Hynan LS, Vazquez MA, Larson AM, Seremba E, Sanders CM, Lee WM, Acute Liver Failure Study Group (2015) Risk factors and outcomes of acute kidney injury in patients with acute liver failure. Clin Gastroenterol Hepatol 13:352–359 - PubMed
  124. Uzi D, Barda L, Scaiewicz V, Mills M, Mueller T, Gonzalez-Rodriguez A, Valverde AM, Iwawaki T, Nahmias Y, Xavier R, Chung RT, Tirosh B, Shibolet O (2013) CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 59:495–503 - PubMed
  125. Wacker WE, Haynes H, Druyan R, Fisher W, Coleman JE (1965) Treatment of ethylene glycol poisoning with ethyl alcohol. J Am Med Assoc 194:1231–1233 - PubMed
  126. Win S, Than TA, Han D, Petrovic LM, Kaplowitz N (2011) c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice. J Biol Chem 286:35071–35078 - PubMed
  127. Win S, Than TA, Min RW, Aghajan M, Kaplowitz N (2016) c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src. Hepatology 63:1987–2003 - PubMed
  128. Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, Forster J, Jaeschke H (2014) Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol 279:266–274 - PubMed
  129. Xie Y, McGill MR, Du K, Dorko K, Kumer SC, Schmitt TM, Ding WX, Jaeschke H (2015a) Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes. Toxicol Appl Pharmacol 289:213–222 - PubMed
  130. Xie Y, Ramachandran A, Breckenridge DG, Liles JT, Lebofsky M, Farhood A, Jaeschke H (2015b) Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury. Toxicol Appl Pharmacol 286:1–9 - PubMed
  131. Yang R, Miki K, He X, Killeen ME, Fink MP (2009) Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity. Crit Care 13:R55 - PubMed
  132. Yarema MC, Johnson DW, Berlin RJ, Sivilotti ML, Nettel-Aguirre A, Brant RF, Spyker DA, Bailey B, Chalut D, Lee JS, Plint AC, Purssell RA, Rutledge T, Seviour CA, Stiell IG, Thompson M, Tyberg J, Dart RC, Rumack BH (2009) Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med 54:606–614 - PubMed
  133. Yip L, Heard K (2016) Potential adjunct treatment for high-risk acetaminophen overdose. Clin Toxicol (phila) 54:459 - PubMed
  134. Zell-Kanter M, Coleman P, Whiteley PM, Leikin JB (2013) A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine. Am J Ther 20:104–106 - PubMed
  135. Zhang J, Min RWM, Le K, Zhou S, Aghajan M, Than TA, Win S, Kaplowitz N (2017) The role of MAP2 kinases and p38 kinase in acute murine liver injury models. Cell Death Dis 8:e2903 - PubMed

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