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

水飞蓟素治疗丙型肝炎的 I/II 期随机、安慰剂对照试验

• 批准号: 7497799
• 负责人: MICHAEL W FRIED
• 金额: $ 4.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497799
• 关键词: Adverse event; Affect; Alternative Medicine; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antiviral Therapy; Apoptosis; Biochemical; Biological Markers; Chronic; Chronic Hepatitis C; Clinical; Clinical Trials; Collaborations; Controlled Clinical Trials; Development; Disease; Disease Progression; Dose; Drug Kinetics; End Point; Ensure; Evaluation; Exhibits; Exposure to; Faculty; Future; Hepatic; Hepatitis C; Hepatitis C virus; Human; Immune response; Inflammation; Isomerism; Liver; Liver diseases; Measures; Milk Thistle; Monitor; Multicenter Studies; Multicenter Trials; North Carolina; Numbers; Oral; Oxidative Stress; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacy Schools; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Placebos; Population; Preparation; Property; Randomized; Range; Ribavirin; Risk; Safety; Serum; Silymarin; Study Subject; Surrogate Markers; Therapeutic; Universities; cooperative study; day; design; dosage; drug development; fibrogenesis; in vivo; interest; nonalcoholic steatohepatitis; programs; randomized placebo controlled trial; response

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.

在过去的十年中，慢性丙型肝炎的抗病毒治疗领域取得了重大进展。 大约50%的患者用聚乙二醇干扰素和利巴韦林的组合治疗， 持续的病毒学反应。不幸的是，其余的组织要么没有作出反应，要么必须停止活动。 由于不良事件而过早治疗。此外，大量慢性病患者 丙型肝炎从来没有提供治疗，因为他们有禁忌症的严格治疗， 目前可用的药物。需要额外的治疗选择。草药产品已经 几个世纪以来，它一直被经验性地用作治疗各种人类疾病的替代药物。Silybum marianum或silymarin主要用于治疗肝脏疾病， 包括抗炎、抗氧化和抗纤维化活性。然而，几乎没有证据表明， 临床试验，以支持使用水飞蓟素作为治疗肝脏疾病。几大局限性 关于水飞蓟素的肝保护作用的先前临床研究包括：1）使用非- 标准化的水飞蓟素提取物2）对水飞蓟素剂量之间关系的不完全理解 和稳态暴露于潜在的活性异构体的水飞蓟素，混淆的评价 安全性和有效性;以及3）使用异质性患者人群和可变终点来评估 治疗反应。在本申请中，我们将重点关注I期药代动力学研究的设计， 将描述高水飞蓟素剂量和受试者暴露于四种异构体之间的关系， 水飞蓟素从第一阶段研究中获得的信息将允许合理决定剂量 将用于II期研究，然后将进行评估水飞蓟素的安全性和有效性， 既往接受过常规治疗的慢性丙型肝炎受试者的治疗。 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 肝脏项目和药学院教师在药物开发方面的属性和专业知识 在查佩尔山的北卡罗来纳州大学，将确保成功完成这一合作 项目