CAM Herbal Cocktails for Boosting Antioxident Activity to Treat Liver Disease

CAM 草药鸡尾酒可增强抗氧化活性，治疗肝病

• 批准号: 7921054
• 负责人: ROY L HAWKE
• 金额: $ 23.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921054
• 关键词: Accounting; Address; Adverse effects; Affinity; Alternative Medicine; Antioxidants; Area Under Curve; Attenuated; Biological; Biological Assay; Biological Availability; Biological Factors; Black Tea; Blood; Botanicals; Camellia sinensis; Catechin; Characteristics; Chronic; Chronic Hepatitis C; Clinical; Clinical Trials; Complex; Control Groups; Coronary Arteriosclerosis; Data; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Drug Kinetics; Effectiveness; Enzyme-Linked Immunosorbent Assay; Epigallocatechin Gallate; Etiology; Exhibits; Exposure to; Failure; Fibrosis; Flavonoids; Flavonolignans; Frequencies; Future; Genotype; Glucuronides; Goals; Green tea; Half-Life; Health; Hepatic; Hepatitis C; Hepatitis C virus; Infection; Inorganic Sulfates; Knowledge; Literature; Liver; Liver diseases; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Metabolism; Milk Thistle; Multicenter Trials; Oral; Oral Administration; Outcome; Oxidative Stress; Pathway interactions; Patients; Perception; Pharmacodynamics; Phase; Placebo Control; Plasma; Procedures; Production; Property; Publishing; Randomized Clinical Trials; Reactive Oxygen Species; Regimen; Relative (related person); Research Design; Risk; Route; Safety; Sampling; Schedule; Serum; Silymarin; Site; Source; Standard Preparations; Time; UGT1A1 enzyme; UGT1A1 gene; Unspecified or Sulfate Ion Sulfates; Urine; Variant; Virus Diseases; active control; base; cohort; compliance behavior; cost; design; effective therapy; efficacy trial; human disease; isoprostaglandin F2alpha type-III; liver metabolism; novel strategies; pill; polyphenol; public health relevance; response; silibinin; uptake; vigilance

DESCRIPTION (provided by applicant): This application concerns the exploration of a novel strategy to increase the normally low bioavailability of polyphenolic antioxidants contained in botanical products by using knowledge of their metabolism to target specific herbal-herbal interactions. A major limitation of many prior clinical investigations is their use of inadequate oral dose regimens that failed to account for the rapid elimination and low bioavailability of polyphenolic antioxidants that results in low steady-state exposures to these potentially protective compounds and presumably accounts for their lack of efficacy. The rationale design of CAM herbal cocktails should result in dramatic increases in the steady-state concentrations of these potent antioxidants in additive or synergistic pharmacodynamic effects that may be common or unique for each of the botanical products contained in the cocktail. More than 50% of patients with chronic hepatitis C either have contraindications or do not achieve sustained virological response to therapy and would potentially benefit from the availability of alternative medicines. Our hypothesis is that the coadministration of silymarin with a CAM cocktail containing a structurally diverse mixture of polyphenolic natural products will boost silymarin's antioxidant activity either through pharmacokinetic interactions that will slow elimination pathways for silymarin, or through pharmacodynamic interactions that result from the antioxidant or other beneficial properties of the CAM cocktail that are additive or synergistic with silymarin. The goal of the proposed double blind, placebo controlled, randomized clinical trial is to describe the pharmacokinetics, and to demonstrate the safety, tolerability, and antioxidant activity of a CAM herbal cocktail in patients with chronic hepatitis C genotype 1 infection and who have not received prior peginterferon-based therapies. In Specific Aim 1 we will perform a pharmacokinetic study that will determine the effects of a CAM herbal cocktail containing milk thistle and green tea extracts on the exposures of patients to major silymarin flavonolignans. For Specific Aim 2, we will identify and use an optimal procedure for the assay of 8-isoprostane F2, as a measure of oxidative stress, to determine the antioxidant activity of the CAM herbal cocktail in patients with chronic HCV. The goal of this study is to provide an alternative medicine for patients with hepatitis C where treatment options are unavailable. PUBLIC HEALTH RELEVANCE: Regardless of the positive public perceptions regarding the safety and efficacy of botanical products, data on the use of high doses of herbal combinations to optimize health outcomes are lacking and vigilance regarding adverse effects is warranted. The goal of this proposal is to evaluate the safety, tolerability, and effectiveness of potentially beneficial herbal-herbal interactions using high dose herbal cocktails for the treatment of liver diseases where treatment options are not available.

描述（由申请人提供）：本申请涉及探索一种新的策略，通过利用植物产品中含有的多酚类抗氧化剂的代谢知识来靶向特定的草药-草药相互作用，从而提高植物产品中通常较低的生物利用度。许多先前临床研究的一个主要限制是它们使用了不适当的口服剂量方案，未能解释多酚类抗氧化剂的快速消除和低生物利用度，从而导致这些潜在保护化合物的低稳态暴露，并可能解释它们缺乏功效。CAM草药鸡尾酒的基本原理设计应该导致这些强效抗氧化剂在添加或协同药效学效应中的稳态浓度急剧增加，这可能是鸡尾酒中包含的每种植物产品的共同或独特的。超过50%的慢性丙型肝炎患者要么有禁忌症，要么对治疗没有实现持续的病毒学反应，他们可能会从替代药物的可用性中获益。我们的假设是，水飞蓟素与含有结构多样的多酚类天然产物混合物的CAM鸡尾酒共同服用，可以通过药代动力学相互作用来提高水飞蓟素的抗氧化活性，这种药代动力学相互作用会减缓水飞蓟素的消除途径，或者通过药效学相互作用产生的抗氧化作用或CAM鸡尾酒的其他有益特性与水飞蓟素相加或协同作用。提出的双盲、安慰剂对照、随机临床试验的目的是描述药代动力学，并证明CAM草药鸡尾酒对慢性丙型肝炎基因1型感染患者的安全性、耐受性和抗氧化活性，这些患者之前没有接受过聚乙二醇干扰素治疗。在具体目标1中，我们将进行一项药代动力学研究，以确定含有奶蓟和绿茶提取物的CAM草药鸡尾酒对暴露于主要水飞蓟黄酮木质素的患者的影响。在特异性目标2中，我们将确定并使用一种最佳程序来测定8-异前列腺素F2，作为氧化应激的测量，以确定CAM草药鸡尾酒在慢性HCV患者中的抗氧化活性。本研究的目的是为无法获得治疗方案的丙型肝炎患者提供一种替代药物。