Collaborative Clinical Research on Hepatotoxicity

描述(由申请人提供)：本申请是应RFA DK-13-003向合格调查人员征集继续药物性肝损伤网络(DILIN)的申请而提交的。印第安纳大学是五个创始临床中心之一，自成立以来一直积极参与DILIN的所有业务。我们提出以下具体目标，以实现本论坛的目标。具体目标1：招募大量符合条件的疑似DILI成人参加正在进行的DILIN研究。我们建议从印第安纳州中部的多个来源收集预期的DILI疑似病例，每个来源都提供了独特的流行病学方面和研究潜力。具体目标2：将大量符合条件的疑似DILI儿童纳入正在进行的DILIN研究。我们建议将辛辛那提儿童医院作为卫星站点，以显著增加参加正在进行的DILIN研究的儿童数量。具体目标#3：DILI目前被诊断为排斥性疾病，这可能是一个具有挑战性的诊断。我们提议进行两项辅助研究，以开发有助于诊断DILI的测试：(I)我们将对DILI引起的急性肝损伤和非DILI原因的急性肝损伤患者在肝损伤发生两周内进行一项发现蛋白质组研究，以确定DILI引起的急性肝损伤的特异性生物标志物；(Ii)DILI有时可以模仿自身免疫性肝炎，很难与从头发生的自身免疫性肝炎区分开来。为了解决这一临床难题，我们将使用自身抗原阵列分析在患有(I)具有自身免疫性肝炎样特征的急性DILI，(Ii)没有自身免疫性肝炎特征的急性DILI，以及(Iii)没有先例药物暴露的急性自身免疫性肝炎的个人中进行一项初步的自身抗体谱分析。具体目标4：帝力具有相当大的死亡率和发病率，但除了撤除致病剂外，没有其他治疗方法。为了解决这一未得到满足的治疗需求，我们建议对符合预定义资格标准的肝细胞DILI特征良好的患者进行一项随机、双盲、安慰剂对照的布地奈德试点研究。我们的假设是，口服布地奈德是一种类固醇，具有很高的糖皮质激素活性和基本的首次通过消除，可以减轻肝损伤，改善肝细胞DILI患者的预后。

DESCRIPTION (provided by applicant): This application is submitted in response to RFA DK-13-003 which solicits applications from qualified investigators for the continuation of the Drug Induced Liver Injury Network (DILIN). Indiana University is one of the five founding clinical centers and has robustly participated in all DILIN operations since its inception. We propose the following specific aims to meet the goals of this RFA. Specific Aim # 1: To enroll large number of eligible adults with suspected DILI into ongoing DILIN studies. We propose to collect prospective cases of suspected DILI from multiple sources in Central Indiana, each providing distinctive epidemiological facets and research potential. Specific Aim # 2: To enroll significant number of eligible children with suspected DILI into ongoing DILIN studies. We propose to include Cincinnati Children's Hospital as a satellite site to significantly increase the number of children enrolled into ongoing DILIN studies. Specific Aim # 3: The DILI is currently a diagnosis of exclusion and it can be a challenging diagnosis to make. We propose to conduct two ancillary studies in order to develop tests that facilitate the diagnosis of DILI: (i) we will conduct a discovery proteomic study of individuals with acute liver injury due to DILI and non-DILI etiologies enrolled within two weeks of liver injury onset to identify biomarkers specific for acut liver injury due to DILI; (ii) DILI can sometime mimic autoimmune hepatitis and it is difficult to distinguish it from de novo autoimmune hepatitis. To address this clinical conundrum, we will conduct a preliminary study for autoantibody profiling using an auto-antigen array assay among individuals with (i) acute DILI with autoimmune hepatitis-like features, (ii) acute DILI without autoimmune hepatitis features, and (iii) acute autoimmune hepatitis without precedent medication exposure. Specific Aim # 4: DILI carries considerable mortality and morbidity but there is no treatment available other than withdrawing the offending agent. In order to address this unmet therapeutic need, we propose to conduct a randomized, double-blind, placebo-controlled pilot study of budesonide in individuals with well characterized hepatocellular DILI meeting predefined eligibility criteria. Our hypothesis is that oral budesonide, a steroid with hig glucocorticoid activity and substantial first pass elimination, attenuates liver injury and improve outcomes of patients with hepatocellular DILI.