加强转化研究 促进药物性肝损伤的科学监管

Strengthening transformation research and promoting scientific supervision of drug-induced liver injury

药物性肝损伤(DILI)是新药上市前研发失败、上市后增加警示以及撤市的最主要原因,是药物安全性监测的重要组成部分。重视药物的肝脏安全性,开展相应的转化研究,对科学监管和临床实践至关重要。科学监管的前提是必须具备对DILI的发生机制、风险因素、临床诊断和评估、预后预测、有效干预措施以及风险/获益整体评估等的全面了解。DILI的发生机制,涉及药物代谢、肝细胞死亡机制及相应的信号传导调控途径、线粒体功能损伤、免疫损伤、遗传和环境因素等诸多环节。预测DILI发生风险的生物标记物研究,一直是DILI领域的研究重点和热点。对某些药物而言,蛋白酪氨酸磷酸酶非受体型22与人类白细胞抗原的联合检测,有望成为筛查DILI高风险人群的重要手段。由于缺乏特异性的诊断标记物,DILI的诊断面临挑战。DILI复杂的临床表型也给诊断增加了困难。欧美国家相继建立了专门的DILI协作网络,前瞻性地纳入DILI患者进行随访并建立生物样本库,有效推动了DILI领域的研究进展。我国专门针对DILI建立的Hepatox网络平台(www. hepatox.org)已上线并建立了超过3万例真实世界DILI患者的数据库,为后续的转化研究奠定了良好的基础。

Drug-induced liver injury(DILI)is the main reason for the failure of new drug research and development before marketing,waring increase post-marketing and withdrawal from the market,which is an important part of drug safety monitoring.It is very important for scientifie supervision and clinical practice to pay attention to the liver safety of drugs and cary out corresponding transformation research.The premise of scientific supervision for DILI is to have a comprehensive understanding for its mechanism,risk factors,clinical diagnosis and evaluation,prediction for prognosis,effective interventions and overall assessment for risk/benefit.The mechanism of DILI is related to many links such as drug metabolism,hepatocyte death mechanism,signal transduction pathway,mitochondrial function damage,immune damage,genetic and environmental factors,and etc.For some drugs.combined detection of protein tyrosine phosphatase non-receptor type 22 and human leukocyte antigen is expected to be an important method to screen the high-risk population of DILI.Due to the lack of speeife dignostie markers,the diagnosis of DILI is facing challenges.The complex clinical phenotype of DILI also makes diagnosis more difficult.European and American countries have set up a special cooperative network of DILI,in which DILI patients were prospectively entered for follow-up and biological sample database were established,ffctively promoting the research progress in DILI field.The Hepatox network platform(www.hepatox.org)established specially for DILI in China has been launched and more than 30000 real world databases on DILI patients have been established,which lays a good foundation for subsequent transformation research.