英文医学文献精读

Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure.

Novel Therapeutic Approaches(新型治疗方法)。

Acetaminophen-induced Liver Injury（对乙酰氨基酚诱导的肝损伤）。

Abstract：

Liver injury and acute liver failure caused by acetaminophen (APAP, （对乙酰氨基酚）N-acetyl-p-aminophenol, paracetamol) overdose（超剂量使用） is a significant clinical problem in most western countries. The only clinically approved antidote（解毒剂） is N-acetylcysteine (NAC)（唯一获得临床批准的解毒剂是 N-乙酰半胱氨酸 （NAC），）, which promotes the recovery of hepatic GSH（肝性谷胱甘肽）.

If administered during the metabolism phase, GSH scavenges the reactive metabolite N-acetyl-p-benzoquinone imine. （GSH清除反应性代谢物N-乙酰基对苯醌亚胺）.

More recently, it was shown that NAC（N-乙酰半胱氨酸） can also reconstitute mitochondrial GSH levels and scavenge reactive oxygen/peroxynitrite（线粒体 GSH 水平和清除活性氧/过氧亚硝酸盐） and can support mitochondrial bioenergetics（线粒体生物能量学）. However, NAC has side effects and may not be efficacious after high overdoses. Repurposing of additional drugs based on their alternate mechanisms of action could be a promising approach. 4-Methylpyrazole (4MP) （4-甲基吡唑）was shown to be highly effective against APAP toxicity by inhibiting cytochrome P450 enzymes in mice and humans. In addition, 4MP（4-甲基吡唑） is a potent c-Jun N-terminal kinase inhibitor （一种有效的c-Jun N-末端激酶抑制剂）expanding its therapeutic window. Calmangafodipir (CMFP)（卡尔曼加福迪皮尔）is a SOD mimetic（SOD模拟物）, which is well tolerated in patients and has the potential to be effective after severe overdoses. Other drugs approved for humans such as metformin（二甲双胍）and methylene blu（亚甲蓝）e were shown to be protective in mice at high doses or at human therapeutic doses, respectively. Additional protective strategies such as enhancing antioxidant activities（增强抗氧化活性）, Nrf2-dependent gene induction and autophagy activation by herbal medicine components （草药成分的Nrf2依赖性基因诱导和自噬激活）are being evaluated(正在评估草药成分的 Nrf2 依赖性基因诱导和自噬激活). However, at this point, their mechanistic insight is limited, and the doses used are high. More rigorous mechanistic studies are needed to advance these herbal compounds(需要更严格的机制研究来推进这些草药化合物). Nevertheless(不过), based on recent studies, 4-methylpyrazole（4-甲基吡唑） and calmangafodipir（卡尔曼加福迪皮尔）have realistic prospects to become complimentary or even alternative antidotes to NAC for APAP overdose（成为 NAC 的补充甚至替代解毒剂，用于 APAP 过量。）.

Keywords: 4-methylpyrazole（4-甲基吡唑）; acetaminophen hepatotoxicity（对乙酰氨基酚肝毒性）; calmangafodipir（卡尔曼加福迪皮尔）; fomepizole（福美吡唑）; metformin（二甲双胍）; methylene blue（亚甲蓝）。

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