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

在过去的十年中，在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 持续的病毒学反应。不幸的是，其余的要么没有回应，要么必须停止 因不良事件而过早治疗。此外，相当数量的慢性病患者 丙型肝炎从未被提供治疗，因为他们对治疗的严格程度有禁忌症 目前可用的药物。需要更多的治疗选择。草药产品已经被 几个世纪以来一直被经验地用作治疗各种人类疾病的替代药物。水飞蓟 马利安，或水飞蓟素，主要用于其声称的有益于肝病，这是 包括抗炎、抗氧化和抗纤维化活性。然而，几乎没有证据表明 支持使用水飞蓟素作为肝病治疗的临床试验。几个主要限制 先前关于水飞蓟素保肝作用的临床研究包括：1)使用非水飞蓟素 标准化水飞蓟素提取物2)对水飞蓟素剂量关系的不完全认识 以及稳态暴露于水飞蓟素的潜在活性异构体，混淆了对 安全性和有效性；以及3)使用不同的患者群体和可变终点来评估 治疗反应。在本申请中，我们将重点设计一项I期药代动力学研究 将表征高剂量水飞蓟素与受试者暴露于四种水飞蓟素异构体之间的关系 水飞蓟素。从第一阶段研究获得的信息将使关于剂量的合理决定成为可能。 将用于第二阶段研究，然后将进行评估水飞蓟素对 对既往接受常规治疗的慢性丙型肝炎患者的治疗。 我们作为临床中心参与这项合作研究的提议将强调独特的 肝脏计划和药学院教员在药物开发方面的属性和专业知识 在北卡罗来纳大学教堂山分校，将确保成功完成这一合作 项目。

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 proposal 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.