Collaborative Clinical Research on Hepatotoxicity

描述（由申请人提供）：本申请是根据RFA DK-13-003提交的，RFA DK-13-003要求合格的研究人员申请药物性肝损伤网络（DILIN）的延续。印第安纳大学是五个创始临床中心之一，自DILIN成立以来一直积极参与其所有业务。我们提出以下具体目标，以实现该区域合作协定的目标。具体目标1：将大量疑似DILI的符合条件的成人纳入正在进行的DILIN研究。我们建议从印第安纳州中部的多个来源收集疑似DILI的潜在病例，每个病例都具有独特的流行病学方面和研究潜力。具体目标2：将大量疑似DILI的符合条件的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，以显著增加纳入正在进行的DILIN研究的儿童人数。具体目标# 3:DILI目前是一种排除性诊断，它可能是一种具有挑战性的诊断。我们建议进行两项辅助研究，以开发有助于DILI诊断的检测方法：(i)我们将对肝损伤发病两周内由DILI和非DILI病因引起的急性肝损伤患者进行发现蛋白质组学研究，以确定DILI引起的急性肝损伤的特异性生物标志物；（ii） DILI有时可以模拟自身免疫性肝炎，很难与新发自身免疫性肝炎区分。为了解决这一临床难题，我们将在以下患者中进行一项自身抗体分析的初步研究：(1)具有自身免疫性肝炎样特征的急性DILI，(2)没有自身免疫性肝炎特征的急性DILI，以及(3)没有药物暴露的急性自身免疫性肝炎。具体目标# 4:DILI具有相当高的死亡率和发病率，但除了停用致病药物外，没有其他治疗方法。为了解决这一未满足的治疗需求，我们建议在符合预定资格标准的肝细胞性DILI患者中进行一项随机、双盲、安慰剂对照的布地奈德先导研究。我们的假设是口服布地奈德，一种具有高糖皮质激素活性和大量首过消除的类固醇，减轻肝损伤并改善肝细胞性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.