DRUG- AND CAM-INDUCED LIVER INJURY

药物和凸轮引起的肝损伤

• 批准号: 7719121
• 负责人: Petr Protiva
• 金额: $ 0.43万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7719121
• 关键词: Affect; Age; Biological; Blood; Case Study; Chronic; Clinical; Clinical Data; Computer Retrieval of Information on Scientific Projects Database; DNA; Detection; Diagnosis; Drug Exposure; Drug Formulations; Enrollment; Environmental Risk Factor; Epidemiologic Studies; Etiology; Exposure to; Food Additives; Frequencies; Funding; Future; Gastroenterologist; Genetic; Goals; Grant; Health; Hepatotoxicity; Injury; Institution; Liver; Mandatory Reporting; Mediating; Medical; Medical Surveillance; Monitor; Natural History; Patients; Pharmaceutical Preparations; Prospective Studies; Public Health; Qualifying; Recording of previous events; Reporting; Research; Research Design; Research Personnel; Resources; Sampling; Signal Transduction; Source; Specimen; System; Terminology; Testing; Time; Tissues; United States; United States Food and Drug Administration; United States National Institutes of Health; Urine; Withdrawal; authority; clinical research site; clinically significant; drug development; experience; follow-up; genetic risk factor; improved; indexing; instrument; post-market; prescription document; prescription procedure; prospective

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Rationale: Liver injury due to prescription and non-prescription medication use is a medical, scientific, and public health problem of increasing frequency and importance in the United States. Indeed, drug-induced liver injury (DILI) is the most common reason for nonapproval, withdrawal, limitation in use, and clinical monitoring by the Food and Drug Administration (FDA). However, detection of signals for liver injury frequently relies upon the reporting of cases by practitioners to health authorities in post-marketing surveillance. Under-reporting of cases, lack of mandatory reporting systems, and difficulties in establishing a diagnosis make the current system sub-optimal. Moreover, with the growing use of complementary and alternative medications (CAM), there have also been increasing reports of liver toxicity due to various non-prescription herbal, dietary, and food additive supplements. Because the manufacturing, dispensing, and testing of these products is not regulated, the hepatotoxic potential of these formulations is poorly characterized or completely unknown. As a result, there is a great need to develop an improved means of detecting, defining, and studying DILI in the United States. The DILIN prospective study is a multi-center study designed to gather clinical information and biological specimens on cases of suspected liver injury due to drugs and CAM. The goals of this study include the earlier recognition of DILI, especially due to newer drugs, development of standardized instruments and terminology to help identify cases of DILI, investigating clinical and genetic risk factors that predict DILI, and performing a careful longitudinal follow-up of DILI subjects. The biological samples collected will be used in future studies of the mechanisms and genetics of DILI. Specific Aims and Objectives: The primary objective of this study is to prospectively identify bona fide cases of liver injury due to drugs and complementary and alternative medications within 6 months of presentation. Secondary objectives include collecting clinical data and biological specimens including blood, DNA, urine, and liver tissue from affected patients and matched controls for future mechanistic and genetic studies. We will also investigate the clinical, immunological, and environmental risk factors of drug-mediated hepatotoxicity by comparing DILI cases to matched controls with a similar drug exposure history but no evidence of clinically significant liver injury. The natural history of drug- and CAM-induced DILI will be tracked for at least 6 months following enrollment, with longer follow-up for those in whom there is evidence of chronic liver injury at 6 months. We will also develop and test causality assessment instruments for drug and CAM-induced liver injury that are sensitive, specific, and reproducible. Basic Study Design: The DILIN Prospective Study is a multi-center, prospective, epidemiological study. Patients who are referred to one of the DILIN clinical sites and who, in the opinion of a gastroenterologist / hepatologist, experienced a drug-induced liver injury will be enrolled. Detailed clinical data and biological specimens will be collected. Clinical data will be reviewed by the DILIN Causality Committee, and it will make the final determination of whether the subject qualifies as a bona fide DILI case. Up to three matched controls will be individually matched to each index case. They will be matched by age, duration of exposure to the implicated medication, and from the same clinical site. DILI cases (only) will be followed for at least 6 months to derive the longitudinal profile of drug- and CAM-induced liver injury. Detailed clinical data and biological specimens will be collected at this time point. Patients who satisfy the definition of chronic DILI will be evaluated at 12 months and yearly thereafter.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 背景和依据：由于处方和非处方药物使用导致的肝损伤是美国日益频繁和重要的医学，科学和公共卫生问题。 事实上，药物性肝损伤（DILI）是美国食品药品监督管理局（FDA）不予批准、撤回、限制使用和临床监测的最常见原因。 然而，肝损伤信号的检测通常依赖于从业人员在上市后监测中向卫生监管机构报告病例。 病例报告不足，缺乏强制性报告制度，以及难以作出诊断，使目前的制度不够理想。 此外，随着补充和替代药物（CAM）的使用越来越多，由于各种非处方草药，饮食和食品添加剂补充剂而引起的肝毒性报告也越来越多。 由于这些产品的生产、分配和检测不受监管，因此这些制剂的肝毒性潜力特征不佳或完全未知。 因此，在美国非常需要开发一种改进的检测、定义和研究DILI的方法。 DILIN前瞻性研究是一项多中心研究，旨在收集药物和CAM引起的疑似肝损伤病例的临床信息和生物样本。 本研究的目标包括早期识别DILI，特别是由于新药，开发标准化工具和术语以帮助识别DILI病例，调查预测DILI的临床和遗传风险因素，并对DILI受试者进行仔细的纵向随访。 收集的生物样本将用于DILI机制和遗传学的未来研究。 具体目的和目标：本研究的主要目的是前瞻性地确定在6个月内由于药物和补充和替代药物引起的真正肝损伤病例。 次要目的包括收集临床数据和生物标本，包括受影响患者和匹配对照的血液、DNA、尿液和肝组织，用于未来的机制和遗传研究。 我们还将通过比较DILI病例与具有相似药物暴露史但无临床显著肝损伤证据的匹配对照，研究药物介导的肝毒性的临床、免疫学和环境风险因素。 药物和CAM诱导的DILI的自然史将在入组后跟踪至少6个月，对于6个月时有慢性肝损伤证据的患者，将进行更长时间的随访。 我们还将开发和测试药物和CAM诱导的肝损伤的因果关系评估工具，这些工具具有敏感性，特异性和可重复性。 基础研究设计：DILIN前瞻性研究是一项多中心、前瞻性、流行病学研究。 将入组转诊至DILIN临床中心之一且胃肠病学家/肝脏病学家认为经历了药物性肝损伤的患者。 将收集详细的临床数据和生物样本。 临床数据将由DILIN因果关系委员会进行审查，并最终确定受试者是否符合真实DILI病例的条件。 每个索引病例最多匹配3个匹配对照。 他们将根据年龄、暴露于相关药物的持续时间以及来自同一临床研究中心进行匹配。 DILI病例（仅）将随访至少6个月，以得出药物和CAM诱导的肝损伤的纵向特征。 将在该时间点收集详细的临床数据和生物标本。 符合慢性DILI定义的患者将在12个月时进行评价，此后每年进行评价。