{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:45:53Z","timestamp":1792691153505,"version":"4.5.0"},"reference-count":135,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK102142"],"award-info":[{"award-number":["DK102142"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK125465"],"award-info":[{"award-number":["DK125465"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK120194"],"award-info":[{"award-number":["DK120194"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM103549"],"award-info":[{"award-number":["GM103549"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM118247"],"award-info":[{"award-number":["GM118247"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2022,2]]},"DOI":"10.1007\/s00204-021-03211-z","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T13:07:19Z","timestamp":1641215239000},"page":"453-465","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose"],"prefix":"10.1007","volume":"96","author":[{"given":"Jephte Y.","family":"Akakpo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anup","family":"Ramachandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Curry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry H.","family":"Rumack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8695-6980","authenticated-orcid":false,"given":"Hartmut","family":"Jaeschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,3]]},"reference":[{"key":"3211_CR1","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1177\/0960327118774902","volume":"37","author":"JY Akakpo","year":"2018","unstructured":"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\u20131322","journal-title":"Hum Exp Toxicol"},{"key":"3211_CR2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/toxsci\/kfz077","volume":"170","author":"JY Akakpo","year":"2019","unstructured":"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\u201368","journal-title":"Toxicol Sci"},{"key":"3211_CR3","doi-asserted-by":"crossref","first-page":"115317","DOI":"10.1016\/j.taap.2020.115317","volume":"409","author":"JY Akakpo","year":"2020","unstructured":"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","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR4","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1007\/s00204-021-03142-9","volume":"95","author":"JY Akakpo","year":"2021","unstructured":"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\u20133391","journal-title":"Arch Toxicol"},{"key":"3211_CR5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.etap.2018.05.015","volume":"61","author":"E Arzuk","year":"2018","unstructured":"Arzuk E, Turna B, S\u00f6zbilen 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\u201317","journal-title":"Environ Toxicol Pharmacol"},{"key":"3211_CR6","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.annemergmed.2004.05.014","volume":"44","author":"B Bailey","year":"2004","unstructured":"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\u2013406","journal-title":"Ann Emerg Med"},{"key":"3211_CR7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/toxsci\/kfl077","volume":"94","author":"ML Bajt","year":"2006","unstructured":"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\u2013225","journal-title":"Toxicol Sci"},{"key":"3211_CR8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1124\/jpet.107.129445","volume":"324","author":"ML Bajt","year":"2008","unstructured":"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\u201314","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR9","doi-asserted-by":"crossref","unstructured":"Baud FJ, Bismuth C, Garnier R, Galliot M, Astier A, Maistre G, Soffer M (1986\u20131987) 4-Methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man. J Toxicol Clin Toxicol 24:463\u2013483","DOI":"10.3109\/15563658608995388"},{"key":"3211_CR10","doi-asserted-by":"crossref","first-page":"424","DOI":"10.3109\/15563650.2010.497149","volume":"48","author":"VS Bebarta","year":"2010","unstructured":"Bebarta VS, Kao L, Froberg B, Clark RF, Lavonas E, Qi M, Delgado J, McDonagh J, Arnold T, Odujebe O, O\u2019Malley 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\u2013430","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR11","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1056\/NEJMra1208937","volume":"369","author":"W Bernal","year":"2013","unstructured":"Bernal W, Wendon J (2013) Acute liver failure. N Engl J Med 369:2525\u20132534","journal-title":"N Engl J Med"},{"key":"3211_CR12","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1586\/17512433.2014.904744","volume":"7","author":"M Blieden","year":"2014","unstructured":"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\u2013348","journal-title":"Expert Rev Clin Pharmacol"},{"key":"3211_CR13","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/0024-3205(70)90214-6","volume":"9","author":"R Blomstrand","year":"1970","unstructured":"Blomstrand R, Theorell H (1970) Inhibitory effect on ethanol oxidation in man after administration of 4-methylpyrazole. Life Sci II 9:631\u2013640","journal-title":"Life Sci II"},{"key":"3211_CR14","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1073\/pnas.76.7.3499","volume":"76","author":"R Blomstrand","year":"1979","unstructured":"Blomstrand R, Ostling-Wintzell H, L\u00f6f A, McMartin K, Tolf BR, Hedstr\u00f6m 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\u20133503","journal-title":"Proc Natl Acad Sci USA"},{"key":"3211_CR15","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1056\/NEJM199903183401102","volume":"340","author":"J Brent","year":"1999","unstructured":"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\u2013838","journal-title":"N Engl J Med"},{"key":"3211_CR16","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1056\/NEJM200102083440605","volume":"344","author":"J Brent","year":"2001","unstructured":"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\u2013429","journal-title":"N Engl J Med"},{"key":"3211_CR17","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1089\/ars.2019.7905","volume":"33","author":"R Brigelius-Floh\u00e9","year":"2020","unstructured":"Brigelius-Floh\u00e9 R, Floh\u00e9 L (2020) Regulatory phenomena in the glutathione peroxidase superfamily. Antioxid Redox Signal 33:498\u2013516","journal-title":"Antioxid Redox Signal"},{"key":"3211_CR18","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1081\/CLT-100102453","volume":"37","author":"NA Buckley","year":"1999","unstructured":"Buckley NA, Whyte IM, O\u2019Connell 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\u2013767","journal-title":"J Toxicol Clin Toxicol"},{"key":"3211_CR19","first-page":"115","volume":"69","author":"RF Burk","year":"1990","unstructured":"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\u2013118","journal-title":"Res Commun Chem Pathol Pharmacol"},{"key":"3211_CR20","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0196-0644(97)70060-X","volume":"30","author":"MJ Burns","year":"1997","unstructured":"Burns MJ, Graudins A, Aaron CK, McMartin K, Brent J (1997) Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med 30:829\u2013832","journal-title":"Ann Emerg Med"},{"key":"3211_CR21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3109\/15563650.2016.1159309","volume":"54","author":"DG Cairney","year":"2016","unstructured":"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\u2013410","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR22","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1080\/15563650.2017.1334915","volume":"55","author":"AL Chiew","year":"2017","unstructured":"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\u20131065","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR23","first-page":"6695967","volume":"2021","author":"MH Chiu","year":"2021","unstructured":"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","journal-title":"Case Rep Crit Care"},{"key":"3211_CR24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0041-008X(77)90175-2","volume":"39","author":"KL Clay","year":"1977","unstructured":"Clay KL, Murphy RC (1977) On the metabolic acidosis of ethylene glycol intoxication. Toxicol Appl Pharmacol 39:39\u201349","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR25","first-page":"54","volume":"238","author":"GB Corcoran","year":"1986","unstructured":"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\u201361","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR26","first-page":"864","volume":"232","author":"GB Corcoran","year":"1985","unstructured":"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\u2013872","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR27","first-page":"857","volume":"232","author":"GB Corcoran","year":"1985","unstructured":"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\u2013863","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR28","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1124\/jpet.105.088898","volume":"315","author":"C Cover","year":"2005","unstructured":"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\u2013887","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR29","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.toxrep.2021.03.031","volume":"8","author":"S Cuninghame","year":"2021","unstructured":"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\u2013807","journal-title":"Toxicol Rep"},{"key":"3211_CR30","first-page":"1497","volume":"273","author":"Y Dai","year":"1995","unstructured":"Dai Y, Cederbaum AI (1995) Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells. J Pharmacol Exp Ther 273:1497\u20131505","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR31","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1080\/15563650.2019.1675886","volume":"58","author":"A Daoud","year":"2020","unstructured":"Daoud A, Dalhoff KP, Christensen MB, B\u00f8gevig 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\u2013704","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR32","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1592\/phco.27.9.1219","volume":"27","author":"RC Dart","year":"2007","unstructured":"Dart RC, Bailey E (2007) Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 27:1219\u20131230","journal-title":"Pharmacotherapy"},{"key":"3211_CR33","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.annemergmed.2007.01.015","volume":"50","author":"RC Dart","year":"2007","unstructured":"Dart RC, Rumack BH (2007) Patient-tailored acetylcysteine administration. Ann Emerg Med 50:280\u2013281","journal-title":"Ann Emerg Med"},{"key":"3211_CR34","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000185117","volume":"50","author":"A Davenport","year":"1988","unstructured":"Davenport A, Finn R (1988) Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma. Nephron 50:55\u201356","journal-title":"Nephron"},{"issue":"5512","key":"3211_CR35","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1136\/bmj.2.5512.497","volume":"2","author":"DG Davidson","year":"1966","unstructured":"Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 2(5512):497\u2013499","journal-title":"Br Med J"},{"key":"3211_CR36","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/j.1553-2712.2008.00296.x","volume":"16","author":"S Doyon","year":"2009","unstructured":"Doyon S, Klein-Schwartz W (2009) Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose. Acad Emerg Med 16:34\u201339","journal-title":"Acad Emerg Med"},{"key":"3211_CR37","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.redox.2016.10.001","volume":"10","author":"K Du","year":"2016","unstructured":"Du K, Ramachandran A, Jaeschke H (2016) Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol 10:148\u2013156","journal-title":"Redox Biol"},{"issue":"Pt A","key":"3211_CR38","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.fct.2017.08.020","volume":"108","author":"K Du","year":"2017","unstructured":"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\u2013350","journal-title":"Food Chem Toxicol"},{"key":"3211_CR39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0041-008X(91)90325-9","volume":"107","author":"SG Emeigh Hart","year":"1991","unstructured":"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\u201315","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR40","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/toxsci\/59.1.169","volume":"59","author":"A Enomoto","year":"2001","unstructured":"Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O\u2019Connor 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\u2013177","journal-title":"Toxicol Sci"},{"key":"3211_CR41","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/bs.apha.2018.12.004","volume":"85","author":"ES Fisher","year":"2019","unstructured":"Fisher ES, Curry SC (2019) Evaluation and treatment of acetaminophen toxicity. Adv Pharmacol 85:263\u2013272","journal-title":"Adv Pharmacol"},{"key":"3211_CR42","doi-asserted-by":"crossref","first-page":"13565","DOI":"10.1074\/jbc.M708916200","volume":"283","author":"N Hanawa","year":"2008","unstructured":"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\u201313577","journal-title":"J Biol Chem"},{"key":"3211_CR43","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1006\/taap.1994.1116","volume":"126","author":"SG Hart","year":"1994","unstructured":"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\u2013275","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR44","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1006\/faat.1995.1029","volume":"24","author":"SG Hart","year":"1995","unstructured":"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\u2013274","journal-title":"Fundam Appl Toxicol"},{"key":"3211_CR45","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1006\/bbrc.2002.6541","volume":"291","author":"E Hazai","year":"2002","unstructured":"Hazai E, Vereczkey L, Monostory K (2002) Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun 291:1089\u20131094","journal-title":"Biochem Biophys Res Commun"},{"key":"3211_CR46","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.2174\/138920112802273146","volume":"13","author":"K Heard","year":"2012","unstructured":"Heard K, Green J (2012) Acetylcysteine therapy for acetaminophen poisoning. Curr Pharm Biotechnol 13:1917\u20131923","journal-title":"Curr Pharm Biotechnol"},{"key":"3211_CR47","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3109\/15563650.2011.583664","volume":"49","author":"K Heard","year":"2011","unstructured":"Heard K, Schaeffer TH (2011) Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol (phila) 49:423\u2013425","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR48","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3109\/15563650.2014.902955","volume":"52","author":"K Heard","year":"2014","unstructured":"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\u2013518","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR49","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1080\/15563650.2019.1579914","volume":"57","author":"RG Hendrickson","year":"2019","unstructured":"Hendrickson RG (2019) What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose? Clin Toxicol (phila) 57:686\u2013691","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR50","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1111\/j.1530-0277.1988.tb00235.x","volume":"12","author":"D Jacobsen","year":"1988","unstructured":"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\u2013522","journal-title":"Alcohol Clin Exp Res"},{"key":"3211_CR51","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/0736-4679(90)90176-V","volume":"8","author":"D Jacobsen","year":"1990","unstructured":"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\u2013461","journal-title":"J Emerg Med"},{"key":"3211_CR52","first-page":"935","volume":"255","author":"H Jaeschke","year":"1990","unstructured":"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\u2013941","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR53","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3109\/03602532.2011.602688","volume":"44","author":"H Jaeschke","year":"2012","unstructured":"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\u2013106","journal-title":"Drug Metab Rev"},{"key":"3211_CR54","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1007\/s00204-019-02597-1","volume":"93","author":"H Jaeschke","year":"2019","unstructured":"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\u20133502","journal-title":"Arch Toxicol"},{"key":"3211_CR55","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/toxsci\/kfaa002","volume":"174","author":"H Jaeschke","year":"2020","unstructured":"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\u2013167","journal-title":"Toxicol Sci"},{"key":"3211_CR56","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1093\/toxsci\/kfg181","volume":"75","author":"LP James","year":"2003","unstructured":"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\u2013467","journal-title":"Toxicol Sci"},{"key":"3211_CR57","first-page":"195","volume":"187","author":"DJ Jollow","year":"1973","unstructured":"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\u2013202","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR58","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s13181-019-00740-z","volume":"16","author":"AM Kang","year":"2020","unstructured":"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\u2013176","journal-title":"J Med Toxicol"},{"issue":"6809","key":"3211_CR59","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1136\/bmj.303.6809.1026","volume":"303","author":"R Keays","year":"1991","unstructured":"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\u20131029","journal-title":"BMJ"},{"key":"3211_CR60","first-page":"9301432","volume":"2019","author":"EA Kiernan","year":"2019","unstructured":"Kiernan EA, Fritzges JA, Henry KA, Katz KD (2019) A case report of massive acetaminophen poisoning treated with a novel \u201ctriple therapy\u201d: N-acetylcysteine, 4-methylpyrazole, and hemodialysis. Case Rep Emerg Med 2019:9301432","journal-title":"Case Rep Emerg Med"},{"key":"3211_CR61","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1517\/14656566.2011.537261","volume":"12","author":"W Klein-Schwartz","year":"2011","unstructured":"Klein-Schwartz W, Doyon S (2011) Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin Pharmacother 12:119\u2013130","journal-title":"Expert Opin Pharmacother"},{"key":"3211_CR62","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/toxsci\/62.2.212","volume":"62","author":"TR Knight","year":"2001","unstructured":"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\u2013220","journal-title":"Toxicol Sci"},{"key":"3211_CR63","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1124\/jpet.102.038968","volume":"303","author":"TR Knight","year":"2002","unstructured":"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\u2013475","journal-title":"J Pharmacol Exp Ther"},{"issue":"23","key":"3211_CR64","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1056\/NEJM197612022952306","volume":"295","author":"J Koch-Weser","year":"1976","unstructured":"Koch-Weser J (1976) Drug therapy. Acetaminophen. N Engl J Med 295(23):1297\u20131300","journal-title":"N Engl J Med"},{"key":"3211_CR65","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/hep.20437","volume":"40","author":"K Kon","year":"2004","unstructured":"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\u20131179","journal-title":"Hepatology"},{"key":"3211_CR66","doi-asserted-by":"crossref","first-page":"e1430","DOI":"10.1542\/peds.2009-3352","volume":"126","author":"EJ Lavonas","year":"2010","unstructured":"Lavonas EJ, Reynolds KM, Dart RC (2010) Therapeutic acetaminophen is not associated with liver injury in children: a systematic review. Pediatrics 126:e1430\u2013e1444","journal-title":"Pediatrics"},{"key":"3211_CR67","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.annemergmed.2008.05.008","volume":"53","author":"KJ Lepik","year":"2009","unstructured":"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\u2013450","journal-title":"Ann Emerg Med"},{"key":"3211_CR68","doi-asserted-by":"crossref","first-page":"892","DOI":"10.3891\/acta.chem.scand.23-0892","volume":"23","author":"TK Li","year":"1969","unstructured":"Li TK, Theorell H (1969) Human liver alcohol dehydrogenase: inhibition by pyrazole and pyrazole analogs. Acta Chem Scand 23:892\u2013902","journal-title":"Acta Chem Scand"},{"key":"3211_CR69","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2021.1996591","author":"SL Link","year":"2021","unstructured":"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)","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR70","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1111\/bcp.13214","volume":"83","author":"DJB Marks","year":"2017","unstructured":"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\u20131272","journal-title":"Br J Clin Pharmacol"},{"key":"3211_CR71","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jhep.2004.09.015","volume":"42","author":"Y Masubuchi","year":"2005","unstructured":"Masubuchi Y, Suda C, Horie T (2005) Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 42:110\u2013116","journal-title":"J Hepatol"},{"key":"3211_CR72","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1007\/s11095-013-1007-6","volume":"30","author":"MR McGill","year":"2013","unstructured":"McGill MR, Jaeschke H (2013) Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res 30:2174\u20132187","journal-title":"Pharm Res"},{"key":"3211_CR73","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1002\/hep.24132","volume":"53","author":"MR McGill","year":"2011","unstructured":"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\u2013982","journal-title":"Hepatology"},{"key":"3211_CR74","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1172\/JCI59755","volume":"122","author":"MR McGill","year":"2012","unstructured":"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\u20131583","journal-title":"J Clin Investig"},{"key":"3211_CR75","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.taap.2013.03.026","volume":"269","author":"MR McGill","year":"2013","unstructured":"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\u2013249","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR76","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/clpt.2010.157","volume":"88","author":"KE McMartin","year":"2010","unstructured":"McMartin KE (2010) Antidotes for alcohol and glycol toxicity: translating mechanisms into treatments. Clin Pharmacol Ther 88:400\u2013404","journal-title":"Clin Pharmacol Ther"},{"key":"3211_CR77","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/0006-2944(75)90171-4","volume":"13","author":"KE McMartin","year":"1975","unstructured":"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\u2013333","journal-title":"Biochem Med"},{"key":"3211_CR78","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/0003-9861(80)90318-5","volume":"199","author":"KE McMartin","year":"1980","unstructured":"McMartin KE, Hedstr\u00f6m 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\u2013614","journal-title":"Arch Biochem Biophys"},{"key":"3211_CR79","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2147\/OAEM.S5346","volume":"2","author":"B M\u00e9garbane","year":"2010","unstructured":"M\u00e9garbane B (2010) Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med 2:67\u201375","journal-title":"Open Access Emerg Med"},{"key":"3211_CR80","first-page":"185","volume":"187","author":"JR Mitchell","year":"1973","unstructured":"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\u2013194","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR81","first-page":"211","volume":"187","author":"JR Mitchell","year":"1973","unstructured":"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\u2013217","journal-title":"J Pharmacol Exp Ther"},{"key":"3211_CR82","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1002\/cpt1974164676","volume":"16","author":"JR Mitchell","year":"1974","unstructured":"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\u2013684","journal-title":"Clin Pharmacol Ther"},{"key":"3211_CR83","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1080\/15563650.2020.1798979","volume":"58","author":"ME Mullins","year":"2020","unstructured":"Mullins ME, Yeager LH, Freeman WE (2020) Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review. Clin Toxicol (phila) 58:1284\u20131296","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR84","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/0041-008X(74)90019-2","volume":"28","author":"RL Mundy","year":"1974","unstructured":"Mundy RL, Hall LM, Teague RS (1974) Pyrazole as an antidote for ethylene glycol poisoning. Toxicol Appl Pharmacol 28:320\u2013322","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR85","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1053\/j.gastro.2008.07.006","volume":"135","author":"H Nakagawa","year":"2008","unstructured":"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\u20131321","journal-title":"Gastroenterology"},{"key":"3211_CR86","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1007\/s00204-021-02985-6","volume":"95","author":"NT Nguyen","year":"2021","unstructured":"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\u20131473","journal-title":"Arch Toxicol"},{"key":"3211_CR87","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.toxlet.2020.12.005","volume":"338","author":"NT Nguyen","year":"2021","unstructured":"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\u201331","journal-title":"Toxicol Lett"},{"key":"3211_CR88","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/hep.24690","volume":"55","author":"HM Ni","year":"2012","unstructured":"Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX (2012) Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55:222\u2013232","journal-title":"Hepatology"},{"key":"3211_CR89","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.jhep.2016.04.025","volume":"65","author":"HM Ni","year":"2016","unstructured":"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\u2013362","journal-title":"J Hepatol"},{"key":"3211_CR90","doi-asserted-by":"crossref","first-page":"580289","DOI":"10.3389\/fphar.2020.580289","volume":"11","author":"N Ohashi","year":"2020","unstructured":"Ohashi N, Kohno T (2020) Analgesic effect of acetaminophen: a review of known and novel mechanisms of action. Front Pharmacol 11:580289","journal-title":"Front Pharmacol"},{"key":"3211_CR91","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1093\/ndt\/gfr050","volume":"26","author":"A O\u2019Riordan","year":"2011","unstructured":"O\u2019Riordan A, Brummell Z, Sizer E, Auzinger G, Heaton N, O\u2019Grady 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\u20133508","journal-title":"Nephrol Dial Transplant"},{"key":"3211_CR92","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1080\/15563650802245497","volume":"46","author":"N Pakravan","year":"2008","unstructured":"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\u2013702","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR93","first-page":"178","volume":"20","author":"KA Pauley","year":"2015","unstructured":"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\u2013185","journal-title":"J Pediatr Pharmacol Ther"},{"key":"3211_CR94","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1001\/jama.1977.03270490046025","volume":"237","author":"RG Peterson","year":"1977","unstructured":"Peterson RG, Rumack BH (1977) Treating acute acetaminophen poisoning with acetylcysteine. JAMA 237:2406\u20132407","journal-title":"JAMA"},{"issue":"7988","key":"3211_CR95","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/S0140-6736(76)90030-1","volume":"2","author":"E Piperno","year":"1976","unstructured":"Piperno E, Berssenbruegge DA (1976) Reversal of experimental paracetamol toxicosis with N-acetylcysteine. Lancet 2(7988):738\u2013739","journal-title":"Lancet"},{"issue":"5 Pt 2 Suppl","key":"3211_CR96","first-page":"880","volume":"62","author":"E Piperno","year":"1978","unstructured":"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\u2013889","journal-title":"Pediatrics"},{"issue":"7698","key":"3211_CR97","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0140-6736(71)91125-1","volume":"1","author":"LF Prescott","year":"1971","unstructured":"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\u2013522","journal-title":"Lancet"},{"issue":"7864","key":"3211_CR98","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/S0140-6736(74)91316-6","volume":"1","author":"LF Prescott","year":"1974","unstructured":"Prescott LF, Matthew H, Todd JW (1974) Cysteamine for paracetamol overdose (letter). Lancet 1(7864):998","journal-title":"Lancet"},{"issue":"8035","key":"3211_CR99","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/S0140-6736(77)90612-2","volume":"2","author":"LF Prescott","year":"1977","unstructured":"Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT (1977) Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 2(8035):432\u2013434","journal-title":"Lancet"},{"key":"3211_CR100","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1136\/bmj.2.6198.1097","volume":"2","author":"F Prescott","year":"1979","unstructured":"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\u20131100","journal-title":"Br Med J"},{"key":"3211_CR101","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1055\/s-0039-1679919","volume":"39","author":"A Ramachandran","year":"2019","unstructured":"Ramachandran A, Jaeschke H (2019) Acetaminophen hepatotoxicity. Semin Liver Dis 39:221\u2013234","journal-title":"Semin Liver Dis"},{"key":"3211_CR102","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1089\/ars.2021.0102","volume":"35","author":"A Ramachandran","year":"2021","unstructured":"Ramachandran A, Jaeschke H (2021) Oxidant stress and acetaminophen hepatotoxicity: mechanism-based drug development. Antioxid Redox Signal 35:718\u2013733","journal-title":"Antioxid Redox Signal"},{"key":"3211_CR103","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/24734306.2019.1705596","volume":"4","author":"G Rampon","year":"2020","unstructured":"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\u20134","journal-title":"Toxicol Commun"},{"key":"3211_CR104","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1080\/15563650.2019.1676899","volume":"58","author":"R Rasamison","year":"2020","unstructured":"Rasamison R, Besson H, Berleur MP, Schicchi A, M\u00e9garbane B (2020) Analysis of fomepizole safety based on a 16-year post-marketing experience in France. Clin Toxicol (phila) 58:742\u2013747","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR105","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1081\/CLT-120002882","volume":"40","author":"BH Rumack","year":"2002","unstructured":"Rumack BH (2002) Acetaminophen hepatotoxicity: the first 35\u00a0years. J Toxicol Clin Toxicol 40:3\u201320","journal-title":"J Toxicol Clin Toxicol"},{"key":"3211_CR106","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3109\/15563650.2012.659252","volume":"50","author":"BH Rumack","year":"2012","unstructured":"Rumack BH, Bateman DN (2012) Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol (phila) 50:91\u201398","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR107","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1542\/peds.55.6.871","volume":"55","author":"BH Rumack","year":"1975","unstructured":"Rumack BH, Matthew H (1975) Acetaminophen poisoning and toxicity. Pediatrics 55:871\u2013876","journal-title":"Pediatrics"},{"issue":"5 Pt 2 Suppl","key":"3211_CR108","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1542\/peds.62.5S.898","volume":"62","author":"BH Rumack","year":"1978","unstructured":"Rumack BH, Peterson RG (1978) Acetaminophen overdose: incidence, diagnosis, and management in 416 patients. Pediatrics 62(5 Pt 2 Suppl):898\u2013903","journal-title":"Pediatrics"},{"issue":"3 Spec No","key":"3211_CR109","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1001\/archinte.1981.00340030112020","volume":"141","author":"BH Rumack","year":"1981","unstructured":"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\u2013385","journal-title":"Arch Intern Med"},{"key":"3211_CR110","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.taap.2010.04.015","volume":"246","author":"C Saito","year":"2010","unstructured":"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\u201317","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR111","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/hep.23267","volume":"51","author":"C Saito","year":"2010","unstructured":"Saito C, Zwingmann C, Jaeschke H (2010b) Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51:246\u2013254","journal-title":"Hepatology"},{"key":"3211_CR112","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1080\/15563650.2020.1775847","volume":"59","author":"KR Shah","year":"2021","unstructured":"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\u201372","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR113","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/j.1742-7843.2004.pto950508.x","volume":"95","author":"AL Slitt","year":"2004","unstructured":"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\u2013248","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"3211_CR114","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1056\/NEJM198812153192401","volume":"319","author":"MJ Smilkstein","year":"1988","unstructured":"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\u20131562","journal-title":"N Engl J Med"},{"key":"3211_CR115","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0196-0644(05)81352-6","volume":"20","author":"MJ Smilkstein","year":"1991","unstructured":"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\u20131063","journal-title":"Ann Emerg Med"},{"key":"3211_CR116","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3109\/15563650.2015.1033629","volume":"53","author":"V Srinivasan","year":"2015","unstructured":"Srinivasan V, Corwin D, Verceles AC (2015) An accidental overdose of N-acetylcysteine during treatment for acetaminophen toxicity. Clin Toxicol (phila) 53:500","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR117","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.taap.2004.06.030","volume":"202","author":"ST Stern","year":"2005","unstructured":"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\u2013159","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR118","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.taap.2004.06.029","volume":"202","author":"ST Stern","year":"2005","unstructured":"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\u2013171","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR119","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.clinthera.2006.02.004","volume":"28","author":"AR Temple","year":"2006","unstructured":"Temple AR, Benson GD, Zinsenheim JR, Schweinle JE (2006) Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6\u201312\u00a0months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther 28:222\u2013235","journal-title":"Clin Ther"},{"key":"3211_CR120","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/0003-9861(72)90519-X","volume":"151","author":"H Theorell","year":"1972","unstructured":"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\u2013444","journal-title":"Arch Biochem Biophys"},{"key":"3211_CR121","doi-asserted-by":"crossref","first-page":"9814","DOI":"10.1016\/S0021-9258(18)81731-8","volume":"264","author":"MA Tirmenstein","year":"1989","unstructured":"Tirmenstein MA, Nelson SD (1989) Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3\u2032-hydroxyacetanilide, in mouse liver. J Biol Chem 264:9814\u20139819","journal-title":"J Biol Chem"},{"key":"3211_CR122","first-page":"983","volume":"56","author":"L Tortora","year":"2018","unstructured":"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\u2013984","journal-title":"Clin Toxicol"},{"key":"3211_CR123","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.cgh.2014.07.011","volume":"13","author":"SR Tujios","year":"2015","unstructured":"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\u2013359","journal-title":"Clin Gastroenterol Hepatol"},{"key":"3211_CR124","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.jhep.2013.04.024","volume":"59","author":"D Uzi","year":"2013","unstructured":"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\u2013503","journal-title":"J Hepatol"},{"key":"3211_CR125","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1001\/jama.1965.03090240065018","volume":"194","author":"WE Wacker","year":"1965","unstructured":"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\u20131233","journal-title":"J Am Med Assoc"},{"key":"3211_CR126","doi-asserted-by":"crossref","first-page":"35071","DOI":"10.1074\/jbc.M111.276089","volume":"286","author":"S Win","year":"2011","unstructured":"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\u201335078","journal-title":"J Biol Chem"},{"key":"3211_CR127","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1002\/hep.28486","volume":"63","author":"S Win","year":"2016","unstructured":"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\u20132003","journal-title":"Hepatology"},{"key":"3211_CR128","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.taap.2014.05.010","volume":"279","author":"Y Xie","year":"2014","unstructured":"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\u2013274","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR129","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.taap.2015.09.022","volume":"289","author":"Y Xie","year":"2015","unstructured":"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\u2013222","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR130","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2015.03.019","volume":"286","author":"Y Xie","year":"2015","unstructured":"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\u20139","journal-title":"Toxicol Appl Pharmacol"},{"key":"3211_CR131","doi-asserted-by":"crossref","first-page":"R55","DOI":"10.1186\/cc7782","volume":"13","author":"R Yang","year":"2009","unstructured":"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","journal-title":"Crit Care"},{"key":"3211_CR132","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.annemergmed.2009.05.010","volume":"54","author":"MC Yarema","year":"2009","unstructured":"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\u2013614","journal-title":"Ann Emerg Med"},{"key":"3211_CR133","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3109\/15563650.2016.1144889","volume":"54","author":"L Yip","year":"2016","unstructured":"Yip L, Heard K (2016) Potential adjunct treatment for high-risk acetaminophen overdose. Clin Toxicol (phila) 54:459","journal-title":"Clin Toxicol (phila)"},{"key":"3211_CR134","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1097\/MJT.0b013e3181ff7ac0","volume":"20","author":"M Zell-Kanter","year":"2013","unstructured":"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\u2013106","journal-title":"Am J Ther"},{"key":"3211_CR135","doi-asserted-by":"crossref","first-page":"e2903","DOI":"10.1038\/cddis.2017.295","volume":"8","author":"J Zhang","year":"2017","unstructured":"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","journal-title":"Cell Death Dis"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-021-03211-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-021-03211-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-021-03211-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T09:08:50Z","timestamp":1644570530000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-021-03211-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,3]]},"references-count":135,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["3211"],"URL":"https:\/\/doi.org\/10.1007\/s00204-021-03211-z","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,3]]},"assertion":[{"value":"9 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Jephte Akakpo, Anup Ramachandran: no disclosures. Barry Rumack, Steven Curry, Hartmut Jaeschke: consultation regarding acetaminophen hepatotoxicity for Johnson and Johnson Consumer Health. Steven Curry, Hartmut Jaeschke: received research grants on mechanism of acetaminophen hepatotoxicity from McNeil Consumer Health, Inc.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}