Michigan Hepatotoxicity Clinical Research Network

密歇根肝毒性临床研究网络

• 批准号: 6949007
• 负责人: ROBERT J FONTANA
• 金额: $ 18.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949007
• 关键词: biomedical facility; biopsy; clinical research; cooperative study; data management; diagnosis design /evaluation; disease /disorder proneness /risk; genetic registry /resource /referral center; hepatotoxin; human subject; liver disorder; liver disorder diagnosis; longitudinal human study; pathologic process; tissue resource /registry

DESCRIPTION (provided by applicant): An increasing awareness of the importance of drug induced liver injury (DILl) has come from the large number of prescription drugs either being withdrawn or failing to gain regulatory approval due to hepatotoxicity. In addition, DILl has been identified as the leading cause of acute liver failure in the United States. However, the incidence and risk factors for drug, toxin, and complementary medication induced liver injury remain ill defined due to their unpredictable nature, varying clinical manifestations, and lack of diagnostic tests. Aberrant host immune responses, metabolic activation of the parent drug, and altered metabolite detoxification have been implicated in the pathogenesis of DILl but the molecular mechanisms involved in most cases remains unknown. The majority of DILl clinical studies have been uncontrolled, retrospective case-series involving small numbers of patients and individual agents. The primary aim of this proposal is to develop standardized instruments and methods to identify and characterize cases of drug, toxin, and complementary medication induced liver injury. Simple, reproducible causality assessment instruments will be developed and validated to provide more accurate case definitions. The secondary aim of this proposal is to develop a hepatotoxicity clinical research network that will prospectively enroll a large number of drug, toxin, and complementary medication induced liver injury cases as well as case controls that received the suspect drug but did not develop toxicity. A prospective case-control study design will help identify potential clinical, immunological, and genetic risk factors for DILl. Collection of clinical data, blood, urine, DNA, and liver tissue samples will allow for subsequent studies of the molecular pathogenesis of drug, toxin, and complementary medication induced liver injury and potentially help identify high risk individuals.

描述（由申请人提供）： 对药物诱导的肝损伤（DIL1）的重要性的认识日益提高，这来自于大量处方药由于肝毒性而被撤回或未能获得监管批准。此外，DILl已被鉴定为美国急性肝衰竭的主要原因。然而，药物、毒素和辅助药物诱导的肝损伤的发生率和风险因素由于其不可预测的性质、不同的临床表现和缺乏诊断测试而仍然不明确。异常的宿主免疫应答、母体药物的代谢活化和改变的代谢物解毒已经涉及DILl的发病机制，但在大多数情况下涉及的分子机制仍然未知。大多数DIL1临床研究是未控制的、回顾性病例系列，涉及少量患者和个体药剂。该提案的主要目的是开发标准化的工具和方法，以识别和表征药物、毒素和辅助药物引起的肝损伤病例。将开发和验证简单、可重复的因果关系评估工具，以提供更准确的病例定义。本提案的次要目的是建立一个肝毒性临床研究网络，该网络将前瞻性招募大量药物、毒素和补充药物诱导的肝损伤病例以及接受可疑药物但未发生毒性的病例对照。前瞻性病例对照研究设计将有助于鉴定DILl的潜在临床、免疫学和遗传风险因素。临床数据、血液、尿液、DNA和肝组织样本的收集将允许对药物、毒素和补充药物诱导的肝损伤的分子发病机制进行后续研究，并可能有助于识别高风险个体。