Novel strategies for the treatment of acetaminophen hepatotoxicity.
Novel strategies for the treatment of acetaminophen hepatotoxicity.
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DOI：
10.1080/17425255.2020.1817896
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发表时间：
2020-11
影响因子：
4.3
通讯作者：
Jaeschke H
中科院分区：
文献类型：
--
作者：
Akakpo JY;Ramachandran A;Jaeschke H
对乙酰氨基酚（APAP）肝毒性是西方国家急性肝功能衰竭的主要原因。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，最近已经做出了更多的努力，将机制的见解转化为识别治疗靶点和用于该适应症的潜在新药。在对APAP诱导的肝损伤和恢复的病理生理学中的关键事件进行简短回顾后，讨论了将病理生理学中的各个步骤作为治疗靶点的利弊。虽然重新使用的药物fomepizole（4-甲基吡唑）和新实体calmangafodipir是基于对其作用机制的理解最先进的，但也考虑了几种草药提取物及其单个成分。Fomepizole（4-甲基吡唑）是安全的，并已在临床前模型、人肝细胞和志愿者中显示出对APAP过量的有效性。已证实钙锰福地匹在APAP过量患者中的安全性，但缺乏可靠的临床前疗效研究。这两种药物都需要进行对照III期试验才能获得监管部门的批准。所有关于草药提取物和成分的研究都存在实验设计不佳的问题，这对它们在这一点上的临床效用提出了质疑。
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.
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4-甲基吡唑可预防小鼠和原发性肝细胞中的对乙酰氨基酚肝毒性。
影响因子：
2.8
作者：
Akakpo JY;Ramachandran A;Kandel SE;Ni HM;Kumer SC;Rumack BH;Jaeschke H
通讯作者：
Jaeschke H
影响因子：
13.5
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通讯作者：
Michalopoulos, George K.
影响因子：
3.9
作者：
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通讯作者：
Gonzalez, FJ
影响因子：
11.8
作者：
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通讯作者：
Kaldis, Philipp
影响因子：
13.5
作者：
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通讯作者：
Pohl, LR