A phase I/II randomized, placebo controlled trial of silymarin for hepatitis C

描述(申请人提供)：在过去十年中，慢性丙型肝炎的抗病毒治疗领域取得了重大进展。在接受聚乙二醇干扰素和利巴韦林联合治疗的患者中，大约50%的患者实现了持续的病毒学应答。不幸的是，其余的人要么没有反应，要么由于不良事件而不得不过早停止治疗。此外，相当数量的慢性丙型肝炎患者从未得到治疗，因为他们对目前可用的药物治疗的严酷程度有禁忌症。需要更多的治疗选择。几个世纪以来，草药产品一直被用作治疗各种人类疾病的替代药物。水飞蓟素，或水飞蓟素，主要用于其据称对肝脏疾病的有益作用，包括抗炎、抗氧化和抗纤维化活性。然而，临床试验中几乎没有证据支持使用水飞蓟素作为肝病的治疗方法。先前关于水飞蓟素保肝作用的临床研究的几个主要局限性包括：1)非标准化水飞蓟素提取物的使用；2)对水飞蓟素剂量与水飞蓟素潜在活性异构体稳态暴露之间的关系的不完全了解，混淆了安全性和有效性的评估；以及3)使用不同的患者群体和可变的终点来评估治疗反应。在这项申请中，我们将重点设计一项I期药代动力学研究，该研究将表征高剂量水飞蓟素与受试者暴露于水飞蓟素四种异构体之间的关系。从第一阶段研究中获得的信息将使人们对用于第二阶段研究的剂量做出合理的决定，然后将进行第二阶段研究，以评估水飞蓟素对以前接受传统疗法治疗的慢性丙型肝炎患者的安全性和有效性。我们申请作为临床中心参与这项合作研究，将强调肝脏项目和北卡罗来纳大学教堂山分校药学院的教师在药物开发方面的独特属性和专业知识，这将确保成功完成这一合作项目。

DESCRIPTION (provided by applicant): Major advances have been made over the last decade in the field of antiviral therapy for chronic hepatitis C. Approximately 50% of patients treated with the combination of peginterferon and ribavirin achieve a sustained virological response. Unfortunately, the remainder either fails to respond or must discontinue treatment prematurely due to adverse events. In addition, a significant number of patients with chronic hepatitis C are never offered therapy because they have contraindications to the rigors of treatment with currently available medications. Additional therapeutic options are needed. Herbal products have been used empirically for centuries as alternative medicines to treat a variety of human disorders. Silybum marianum, or silymarin, is primarily used for its purported beneficial effects in disorders of the liver, which include anti-inflammatory, anti-oxidant, and anti-fibrogenic activities. However, there is little evidence from clinical trials to support the use of silymarin as a treatment for diseases of the liver. Several major limitations of prior clinical investigations on the hepatoprotective effects of silymarin include: 1) the use of non- standardized silymarin extracts 2) the incomplete understanding of the relationship between silymarin dose and steady-state exposures to the potentially active isomers of silymarin, confounding the evaluation of safety and efficacy; and 3) the use of heterogeneous patient populations and variable endpoints to assess therapeutic response. In this application we will focus on the design of a phase I pharmacokinetic study that will characterize relationships between high silymarin doses and subject exposure to the four isomers of silymarin. The information obtained from the phase I study will allow a rational decision regarding dosages to be used for a phase II study that will then be performed to evaluate the safety and efficacy of silymarin for the treatment on subjects with chronic hepatitis C who were previously treated with conventional therapies. Our application to participate as a Clinical Center for this cooperative study will emphasize the unique attributes and expertise in drug development of the Liver Program and the faculty at the School of Pharmacy at the University of North Carolina at Chapel Hill that will ensure successful completion of this collaborative project.