RESUMO
INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.