Michigan Hepatotoxicity Clinical Research Network Renewal 2018

密歇根肝毒性研究网络2018年更新 摘要 在过去5年中，药物性肝损伤网络（DILIN）的累计入组人数有所增加 在正在进行的前瞻性和回顾性登记研究中，对2000多名成人和儿童患者进行了研究。 此外，“急性”DILI方案收集了一系列早期生物样品，用于机制研究。 生物标志物研究已经开发和实施。其他网络目标包括调查 遗传多态性在DILI易感性和结局中的作用，因果关系改善的发展 评估方法和LiverTox网站的扩展。密歇根大学的研究小组由 博士丰塔纳在设计、实现和分析初级和 自2003年成立以来，对DILIN进行了辅助研究。密歇根州不仅在所有的招生中处于领先地位， 正在进行的登记研究，但也在多个DILIN委员会中提供了重要的领导， 举措密歇根大学的研究小组现在为DILIN提出了一系列新颖可行的研究目标 退款本提案的主要目的是继续招募和入组高因果关系成人， 将儿科DILI病例纳入遗传学、免疫学、生物标志物和机制的登记研究 问题研究密歇根肝毒性网络有具体的计划，以增加种族的入学率， 通过密歇根州东南部和其他地方的肝病学家/合作者的参与， 照顾大量的非洲裔美国人、西班牙裔和亚洲病人。此外，进一步 开发自然语言处理算法，以搜索密歇根大学的电子病历 以方便登记。化学品的定性、定量和毒理学研究 草药和膳食补充剂（HDS）产品中的成分， DILI病例将通过与国家产品中心的持续合作扩大 Research.本提案的第二个目的是进行试点/可行性临床试验，以改善 严重急性DILI患者和有发生慢性DILI风险的患者的结局。提出 研究设计包括一个12周的简单和安全的口服抗炎药或 抗氧化剂（例如布地奈德、SAMe、维生素E）用于选定的重度急性DILI风险患者 对不良后果负责。此外，12至24周的安全有效的口服抗- 可以降低血清胆汁酸的胆汁淤积剂如回肠顶端胆盐转运抑制剂， 建议用于慢性DILI风险受试者。最后，磁共振的前瞻性研究 弹性成像和MRCP成像的建议，以提高我们的理解的严重性和自然 DILI的历史该提案的第三个目标是进一步扩大LiverTox网站， 关于HDS DILI的附加章节，开发并实施计算机因果关系评估 工具，并组建工作委员会，以确保网站内容保持最新， 中肯最后，DILIN与美国FDA和其他监管机构之间的其他合作 建议各机构加强DILIN对DILI新原因的药物警戒能力 和随时间的时间变化。

Michigan Hepatotoxicity Research Network 2018 Renewal ABSTRACT In the past 5 years, the Drug Induced Liver Injury Network (DILIN) has increased cumulative enrollment to over 2000 adult and pediatric patients in the ongoing Prospective and Retrospective registry studies. In addition, an “Acute” DILI protocol with collection of serial early biological samples for mechanistic biomarker studies was developed and implemented. Other network aims included investigation of the role of genetic polymorphisms in DILI susceptibility and outcome, development of improved causality assessment methods, and expansion of the LiverTox website. The University of Michigan team led by Dr. Fontana has played an important role in the design, implementation, and analysis of the primary and ancillary DILIN studies since its inception in 2003. Michigan has not only been a leading enroller in all of the ongoing Registry studies but also provided important leadership in multiple DILIN committees and initiatives. The Michigan team now proposes a series of novel and feasible study aims for the DILIN renewal. The PRIMARY AIM of this proposal is to continue to recruit and enroll high causality adult and pediatric DILI cases into the registry studies for genetic, immunologic, biomarker and mechanistic studies. The Michigan Hepatotoxicity Network has specific plans to increase the enrollment of ethnic minorities via the engagement of hepatologists/ collaborators in southeastern Michigan and elsewhere that care for a large number of African American, Hispanic, and Asian patients. In addition, further development of natural language processing algorithms to search the EMR at the University of Michigan are proposed to facilitate enrollment. Qualitative, quantitative and toxicological studies of the chemical constituents in the herbal and dietary supplement (HDS) products implicated in a growing proportion of DILI cases will be expanded via an ongoing collaboration with the National Center for National Products Research. The SECOND AIM of this proposal is to conduct pilot/ feasibility clinical trials to improve the outcomes of patients with severe acute DILI and those at risk for developing chronic DILI. Proposed study designs include a 12 week course of a simple and safe, orally administered anti-inflammatory or anti-oxidant agent (e.g. budesonide, SAMe, vitamin E) in selected patients with severe acute DILI at risk for adverse outcomes. In addition, 12 to 24 week studies of a safe and effective orally administered anti- cholestatic agent such as an ileal apical bile salt transport inhibitor that may reduce serum bile acids are proposed for subjects at risk of chronic DILI. Lastly, prospective studies of magnetic resonance elastography and MRCP imaging are proposed to improve our understanding of the severity and natural history of DILI. The THIRD AIM of this proposal is to further expand the LiverTox website to include additional chapters on HDS DILI, develop and implement a computerized causality assessment instrument, and assemble working committees to insure that the website content remains up to date and pertinent. Finally, additional collaborations between DILIN and the US FDA and other regulatory agencies are proposed to enhance the pharmacovigilance capabilities of DILIN for new causes of DILI and temporal changes over time.