青蒿素及其衍生物毒理学研究进展

Artemisinin and its derivatives: progress in toxicology

青蒿素及其衍生物是目前广泛应用的一线抗疟药,能杀灭多种寄生虫如疟原虫、血吸虫、弓形虫、利什曼原虫等,还能调节免疫用于治疗红斑狼疮和类风湿性关节炎,体外细胞实验证实对多种人源性肿瘤细胞具有明显杀伤作用。研究发现,此类化合物的结构中存在内过氧桥,催化断裂后产生的碳中心自由基和活性氧,是其发挥药理学和毒理学作用的结构基础。临床上大量的抗疟治疗迄今未见明显的严重不良反应,具有很高的安全性,而动物急性毒性和慢性毒性实验等临床前研究发现药物的高剂量或长期暴露能导致多个系统和器官的毒性效应。本文对青蒿素及其衍生物的神经毒性、胚胎毒性、遗传毒性、造血和免疫毒性、心脏毒性等,从体外细胞水平、整体动物水平和人体临床试验,以及药物代谢动力学研究新进展等方面进行综述,以总结青蒿素类药物毒理学研究的热点和方向,为以扩大青蒿素类药物临床适应证,选择安全的给药途径、剂量和检测指标为目的的毒理学评价和研究提供支持,更好地服务临床。

One of the most promising antimalarial drugs which are widely used throughout the world is the artemisinin （ARS）and its derivatives,e.g.,artemether,arteether,and artesunate.Their true potential lies in broader anti-disease applications.The mechanism of action of these compounds appears to involve the endoperoxide bridge to produce carbon-centred free radicals.Large clinical studies did not show serious side effects,however,there is a paucity of large-scale clinical trials suitable to detect rare but significant toxicity.Therefore,a final and definitive statement on the safety of artemisinins still cannot be made.In contrast,animal experiments at high doses shown considerable toxicity upon application of artemisinins.In the present review,the authors give a comprehensive overview on toxicity studies in cell culture and in animals （mice,rats,rabbits,dogs,and monkeys）as well as on toxicity reported in human clinical trials.The authors emphasize the current knowledge on neurotoxicity,embryotoxicity, genotoxicity,hemato-and immunotoxicity and cardiotoxicity.Rapid elimination of artemisinins after oral intake represents a relatively safe route of administration compared to delayed drug release after intra-muscular （im ） injection. There are drug-related differences, i.e., intramuscular application of artemether or arteether,but not to artesunate,which is safe and gives good profiles after im administra-tion in severe malaria.It might also be important in determining dose limitations for treatment of other diseases such as cancer.Questions about dosing regimens,safety of long-term use and possible inter-actions with existing therapies and toxicities that might be related to the treatment of tumors should be answered by appropriate clinical and preclinical studies.