Michigan Hepatotoxicity Clinical Research Network Renewal 2018

密歇根州肝毒性研究网络2018年更新 摘要 在过去的5年里，药物诱导的肝损伤网络(DILIN)增加了累积注册人数 在正在进行的前瞻性和回溯性登记研究中，向2000多名成人和儿科患者提供服务。 此外，一项“急性”帝力方案收集了一系列早期生物样本，用于机械 开发并实施了生物标记物研究。其他网络目标包括调查 遗传多态在DILI易感性和结局中的作用以及改善的因果关系的发展 评估方法，以及livertox网站的扩展。密歇根大学的团队由 丰塔纳博士在设计、实施和分析初级和 自2003年成立以来的辅助DILIN研究。密歇根州不仅是全美 正在进行的注册处研究，但也在多个DILIN委员会和 首创精神。密歇根大学的团队现在为DILIN提出了一系列新颖而可行的研究目标 更新。这项提案的主要目的是继续招募和招收高因果关系的成年人和 儿科DILI病例纳入遗传学、免疫学、生物标志物和发病机制研究 学习。密歇根州肝毒性网络有具体的计划来增加种族的登记 通过密歇根东南部和其他地方的肝病专家/合作者的参与，帮助少数族裔 它照顾了大量的非裔美国人、西班牙裔和亚洲患者。此外，还进一步 密歇根大学电子病历自然语言处理算法的开发 都是为了方便招生。该化学物质的定性、定量和毒理学研究 草药和膳食补充剂(HDS)产品中的成分与越来越多的 帝力案件将通过与国家国家产品中心的持续合作来扩大 研究。这项建议的第二个目标是进行试点/可行性临床试验，以改善 严重急性DILI患者和有发展为慢性DILI风险的患者的结局。建议 研究设计包括为期12周的简单而安全的口服抗炎或 抗氧化剂(如布地奈德、Same、维生素E)在危重急性DILI患者中的应用 以应对不利的后果。此外，12至24周的安全有效口服抗病毒药物的研究 胆汁淤积剂，如回肠尖端胆盐转运抑制剂，可能会降低血清胆汁酸 建议用于有慢性DILI风险的受试者。最后，磁共振的前瞻性研究 弹性成像和mrcp成像的提出，以提高我们对严重程度和自然的了解。 帝力的历史。这项提议的第三个目的是进一步扩大livertox网站，使其包括 关于HDS帝力的其他章节，开发和实施计算机化的因果关系评估 工具，并组建工作委员会，以确保网站内容保持最新和 切合实际。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新病因的药物警戒能力 随着时间的推移也会发生时间变化。

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.