Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center , Kansas City, KS, USA.
Expert Opin Drug Metab Toxicol. 2020 Nov;16(11):1039-1050. doi: 10.1080/17425255.2020.1817896. Epub 2020 Sep 14.
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.
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.
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.
对乙酰氨基酚（APAP）肝毒性是西方世界急性肝衰竭的主要原因。尽管对细胞死亡的机制进行了广泛的研究，但只有一种解毒剂，N-乙酰半胱氨酸，在临床上使用。然而，最近有更多的努力将机制见解转化为针对该适应症的治疗靶点和潜在新药的鉴定。
在简要回顾了 APAP 诱导的肝损伤和恢复的病理生理学中的关键事件之后，讨论了将病理生理学中的各个步骤作为治疗靶点的优缺点。虽然基于对其作用机制的理解，重新定位的药物 fomepizole（4-甲基吡唑）和新实体 calmangafodipir 最为先进，但几种草药提取物及其单个成分也被认为是如此。
fomepizole（4-甲基吡唑）在临床前模型、人肝细胞和志愿者中对 APAP 过量使用的安全性和疗效已得到证实。calmangafodipir 在 APAP 过量患者中的安全性已得到证实，但缺乏有效的临床前疗效研究。这两种药物都需要进行对照 III 期试验以获得监管部门的批准。所有草药提取物和成分的研究都存在实验设计不佳的问题，这在现阶段质疑了它们的临床实用性。
