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Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review. Pourbagher-Shahri Ali Mohammad,Schimmel Jonathan,Shirazi Farshad M,Nakhaee Samaneh,Mehrpour Omid Toxicology letters INTRODUCTION:Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity. METHODS:A scoping review was performed using standardized search terms from inception through July 2021. RESULTS:Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects. CONCLUSION:Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence. 10.1016/j.toxlet.2021.11.005
Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away? Lee William M Journal of hepatology Acetaminophen (APAP) is the most commonly used drug for the treatment of pain and fever around the world. At the same time, APAP can cause dose-related hepatocellular necrosis, responsible for nearly 500 deaths annually in the United States (US) alone, as well as 100,000 calls to US Poison Control Centers, 50,000 emergency room visits and 10,000 hospitalisations per year. As an over-the-counter and prescription product (with opioids), APAP toxicity dwarfs all other prescription drugs as a cause of acute liver failure in the US and Europe, but it is not regulated in any significant way. In this review the ongoing controversy surrounding the proper role for this ubiquitous pain reliever: its history, pathogenesis, clinical challenges in recognition and management, and current regulatory status are highlighted. A new solution to a 50-year-old problem is proposed. 10.1016/j.jhep.2017.07.005