Hepatotoxicity Clinical Research Network

描述(由申请人提供)： 肝毒性，或药物性肝功能损害(DILL)，是目前美国暴发性肝功能衰竭最常见的原因，也是市场停药的主要适应症，因此，它是一个具有巨大的医疗、金融、法律和监管重要性的问题。尽管大量的药物、毒素和替代药物有可能导致肝毒性，但严重的DILL是一个足够罕见的问题，需要一大群专注的研究人员协同工作，以更好地了解DILL的发病机制，并制定有效的预防和治疗策略。这项提议汇集了一个独特的、多学科的研究人员和资源联盟，该联盟集中在加利福尼亚州北部，但也包括全国各地的地点，并计划在肝毒性临床研究网络(HCRN)中建立一个参与的临床中心。我们的研究计划首先描述了建立一个大型多成分临床中心患者数据库，这将有助于拟议的多中心HCRN。拟议的DILL患者信息数据库、血清、DNA和组织库将包括一个来自几个来源的预期队列，每个来源都提供不同的流行病学方面和研究潜力。这些项目包括加州大学旧金山分校、斯坦福大学和加州太平洋医学中心的肝脏移植计划，旧金山综合医院、波士顿大学、埃默里大学、波多黎各大学和路易斯安那健康科学中心的结核病诊所，以及旧金山综合医院的艾滋病毒诊所。在每个地点，我们都制定了战略，以前瞻性的方式识别明确界定的毒素引起的肝损伤病例，以便仔细收集详细的流行病学和临床信息，以及用于生化、药理学和遗传学研究的血清、DNA和组织样本。我们计划根据拟议的操作诊断标准初步识别潜在的DILL患者，然后使用有效的因果关系评估工具进一步评估病例。为了更好地确定DILL的自然病史，使用该仪器被分类为“极有可能”的DILL的患者将被前瞻性地跟踪观察。识别这种与DILL相关的多态是制定合理的基于基因的预防策略的关键的第一步。我们预计我们的临床中心将从种族和种族多样化的患者群体中招募大约120名病例和匹配良好的对照人员到全国HCRN网络。我们拥有一个由医生、科学家和研究护士组成的组织严密的多学科小组，他们致力于这个临床中心和整个国家肝毒性临床研究网络的成功。

DESCRIPTION (provided by applicant): Hepatotoxicity, or drug-induced liver inury (DILl), is currently the most common cause of fulminant hepatic failure in the United States and the main indication for market withdrawal of drugs and, thus, it is a problem of enormous medical, financial, legal and regulatory importance. Although a vast number of drugs, toxins and alternative medications have the potential to cause hepatotoxcity, severe DILl is a problem of sufficient rarity that a large group of dedicated investigators working in a coordinated effort will be required to better understand the pathogenesis of DILl and develop effective prevention and treatment strategies. This proposal brings together a unique, multi-disciplinary consortium of investigators and resources, concentrated within Northern California but also including sites across the country, with a plan for a participating Clinical Center in the Hepatotoxicity Clinical Research Network (HCRN). Our research plan describes, firstly, the establishment of a large multicomponent Clinical Center patient database that would contribute to the proposed multicenter HCRN. The proposed DILl patient informational database, serum, DNA and tissue bank will comprise a prospective cohort derived from several sources, each providing distinct epidemiological facets and research potential. These include the Liver Transplant Programs at UCSF, Stanford University and California Pacific Medical Center, the Tuberculosis Clinics at San Francisco General Hospital, Boston University, Emory University, University of Puerto Rico, and Louisiana Health Sciences Center, and the HIV Clinic at San Francisco General Hospital. At each site, we have developed strategies to identify well-defined cases of toxin-induced liver injury in a prospective manner that will permit careful collection of detailed epidemiological and clinical information, as well as serum, DNA and tissue samples for biochemical, pharmacological and genetic studies. We plan to initially identify patients with potential DILl based on proposed operational diagnostic criteria and then further evaluate cases using a validated causality assessment instrument. Patients classified as having "highly probable" DILl using this instrument will be followed prospectively in order to better define the natural history of DILl. Identification of such DILl-associated polymorphisms is an essential first step in the development of a rational gene-based prevention strategy. We anticipate that our Clinical Center will recruit approximately 120 cases and well-matched controls from an ethnically and racially diverse patient population to the national HCRN network. We have a well-organized, multi-disciplinary group of physicians, scientists, and research nurses who are dedicated to the success of this Clinical Center and the overall National Hepatoxicity Clinical Research Network.