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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 背景和理由：由于处方和非处方药的使用而引起的肝脏损伤是美国的医学，科学和公共卫生问题，即在美国的频率和重要性增加。 实际上，药物诱导的肝损伤（DILI）是食品和药物管理局（FDA）未批准，戒断，使用限制和临床监测的最常见原因。 但是，检测肝损伤的信号通常依赖于从业人员向卫生当局报告的案件报告。 案件报告不足，缺乏强制性报告系统以及建立诊断的困难使当前的系统次优。 此外，随着补充和替代药物（CAM）的日益增长，由于各种非处方草药，饮食和食物添加剂补充剂，肝脏毒性的报道也越来越多。 由于这些产品的制造，分配和测试不受调节，因此这些配方的肝毒性潜力很差或未知。 结果，非常需要开发一种改进的在美国检测，定义和研究DILI的方法。 Dilin前瞻性研究是一项多中心研究，旨在收集有关因药物和CAM引起的肝损伤病例的临床信息和生物标本。 这项研究的目标包括对DILI的较早认识，特别是由于新药物，标准化工具的开发和术语，以帮助识别DILI病例，研究预测DILI的临床和遗传危险因素，并进行了仔细的DILI受试者的纵向随访。 收集的生物样品将用于对DILI机制和遗传学的未来研究。 具体目的和目标：这项研究的主要目的是前瞻性地确定由于药物以及介绍后6个月内由于药物以及补充和替代药物而导致的肝损伤病例。 次要目标包括收集临床数据和生物标本，包括受影响患者的血液，DNA，尿液和肝组织，以及匹配的对照，以进行未来的机械和遗传研究。 我们还将通过将DILI病例与具有相似药物暴露病史的匹配对照进行比较，但没有临床上明显的肝损伤的证据，我们还将研究药物介导的肝毒性的临床，免疫和环境风险因素。 入选后至少6个月将追踪药物和CAM引起的DILI的自然病史，对于那些有慢性肝损伤的人的随访时间更长。 我们还将开发和测试针对药物和CAM诱导的肝损伤的因果关系评估工具，这些肝脏损伤具有敏感，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。 被称为Dilin临床部位之一的患者以及胃肠病学家 /肝病学家认为，将遇到药物诱发的肝损伤。 将收集详细的临床数据和生物标本。 临床数据将由Dilin因果关系委员会进行审查，并将最终确定该受试者是否符合善变的案例。 最多三个匹配的控件将与每个索引案例单独匹配。 它们将按年龄，暴露于牵连的药物的持续时间以及从同一临床部位匹配。 diLI病例（仅）将遵循至少6个月，以得出药物和CAM诱导的肝损伤的纵向特征。 此时将收集详细的临床数据和生物标本。 满足慢性DILI定义的患者将在12个月及以后每年评估。