基于临床病证的传统无毒中药肝毒性客观辨识及机制研究

In recent years, adverse reactions of traditional Chinese medicine (TCM), especially nontoxic TCM, has been reported repeatedly, which has caused a matter of growing concern about the safety of TCM, while there is an argument about the objectivity of the hepatotoxicity. The issue “how to cognize the side effects of nontoxic TCM” has become one of the most challenging international problems in TCM safety research field. Previous research has mainly inquired the toxic substances and mechanism from the drugs, and few attentions has been paid to the organic factor-mediated drug induced liver injury. In recent years, the applicant proposed and established the safety evaluation strategy and method of traditional Chinese medicine based on clinical efficacy. This project select Zhuanggu Guanjie Pill, the Chinese medicine for the treatment of rheumatoid bone diseases, as the research subject and apply medicine epidemiology, network pharmacology (toxicology), pharmacogenomics and other technical methods to clarify the relationship between the immune factors and the liver injury susceptibility, and to screen susceptible populations and biomarkers with plentiful resources of drug-induced liver injury in 302 Hospital, in order to provide a scientific basis for the clinical safety of medication. On the basis of the study, the integrated evaluation method with toxicity and efficacy of TCM based on clinical disease and syndromes would be established and perfected for the development of the TCM toxicology theory.

近年来中药不良反应特别是传统无毒中药的肝毒性问题屡有报道，引起人们对中药安全性的严重担忧，与此同时其肝毒性的客观性在业内外也存在巨大争议。如何科学认知传统无毒中药的毒副作用已成为本领域最具挑战性的国际性难题。既往研究多拘泥于从药物角度寻找毒性物质及致毒机制，对可能由患者机体因素差异介导的中药肝毒性鲜有关注和研究。为此近年来申请者提出并建立基于临床功效的中药安全性评价策略和方法体系。本项目利用302医院丰富的药物性肝病临床资源，以风湿骨病治疗中成药—壮骨关节丸为研究载体，应用药物流行病学、网络药（毒）理学、药物基因组学等技术方法，以免疫调控为切入点，系统阐明机体病证因素与中药肝损伤易感性关系、毒性相关物质基础及损伤机制，筛查可能的易感人群及生物标志物，为临床对症治疗和安全用药提供科学依据和对策。在上述基础上，建立并完善基于临床病证的中药毒与效整合评价模式和方法，推动临床中药学的创新发展。

近年来中药不良反应特别是传统无毒中药的肝毒性问题屡有报道，引起人们对中药安全性的严重担忧，与此同时其肝毒性的客观性在业内外也存在巨大争议。如何科学认知传统无毒中药的毒副作用已成为本领域最具挑战性的国际性难题。既往研究多拘泥于从药物角度寻找毒性物质及致毒机制，对可能由患者机体因素差异介导的中药肝毒性鲜有关注和研究。为此，本项目提出并建立基于临床功效的中药安全性评价策略和方法体系，结合药物性肝病临床病例分析和基础研究，以免疫调控为切入点，系统阐明机体病证因素与中药肝损伤易感性关系、毒性相关物质基础及损伤机制，筛查可能的易感人群及生物标志物，创建中草药肝毒性防控评价体系并提出合理用药与风险控制对策。本项目首创药源性肝损伤精准辨识策略和方法—“整合证据链法”（integrated evidence chain method，iEC），以其为技术核心，领衔研制中草药相关肝损伤诊疗与防控的“学会-国家-国际”三级指南；利用自主创建的iEC法等技术手段，证实了壮骨关节丸和仙灵骨葆以及何首乌相关制剂致肝损伤的客观性和免疫特异质属性；基于病证毒理学模型研究证实机体免疫应激是壮骨关节丸诱发肝损伤的主要病证基础，发现“淫羊藿与补骨脂”是一对新的中药配伍禁忌组合并揭示了其产生的病证基础，系统揭示了补骨脂配伍淫羊藿诱导特异质肝损伤的免疫学分子机制；阐明了淫羊藿、补骨脂和何首乌诱导免疫特异质肝损伤的易感物质及成因机制，提出并证实了中药免疫特异质肝损伤“三因致毒”机制假说；创建中药安全风险“人-药-用”三维防控策略和方法，成功用于淫羊藿、补骨脂和何首乌相关制剂安全性风险防控对策制定，牵头起草制定了《何首乌安全用药指南》。本项目建立并完善基于临床病证的中药毒效整合评价模式和方法体系，为科学认识传统无毒中药肝毒性的客观性和风险因素提供新思路新方法，丰富和发展了中药毒理学、临床中药学研究的理论及方法。