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: 7532195
• 负责人: ROY L HAWKE
• 金额: $ 14.75万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532195
• 关键词: Accounting; Address; Adverse effects; Affinity; Alternative Medicine; Antioxidants; Appendix; 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; Daily; 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; Public Health; Publishing; Randomized Clinical Trials; Reactive Oxygen Species; Relative (related person); Research Design; Risk; Route; Safety; Sampling; Schedule; Serum; Silymarin; Site; Source; Standard Preparations; Time; Treatment Protocols; UDP-Glucuronosyltransferase 1A1; UGT1A1 enzyme; UGT1A1 gene; Unspecified or Sulfate Ion Sulfates; Urine; Variant; Virus Diseases; Week; base; cohort; compliance behavior; cost; day; design; efficacy trial; glucuronide; human disease; isoprostaglandin F2alpha type-III; liver metabolism; novel strategies; pill; polyphenol; 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）：本申请涉及一种新策略的探索，该策略通过利用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，来增加植物产品中所含多酚类抗氧化剂的通常低的生物利用度。许多先前的临床研究的主要限制是他们使用不充分的口服剂量方案，未能解释多酚类抗氧化剂的快速消除和低生物利用度，导致这些潜在保护性化合物的稳态暴露较低，并可能解释其缺乏疗效。CAM草药鸡尾酒的基本原理设计应导致这些强效抗氧化剂的稳态浓度急剧增加，其累加或协同药效学效应可能是鸡尾酒中所含的每种植物产品共同或独特的。超过50%的慢性丙型肝炎患者要么有禁忌症，要么对治疗没有持续的病毒学应答，并且可能从替代药物的可用性中获益。我们的假设是，共同管理的水飞蓟素与CAM鸡尾酒含有结构多样的多酚类天然产物的混合物将提高水飞蓟素的抗氧化活性，通过药代动力学相互作用，将减缓消除途径的水飞蓟素，或通过药效学相互作用，导致从抗氧化剂或其他有益的特性的CAM鸡尾酒是添加剂或协同作用与水飞蓟素。拟进行的双盲、安慰剂对照、随机临床试验的目的是描述CAM草药鸡尾酒在基因型1型慢性丙型肝炎感染且既往未接受过聚乙二醇干扰素治疗的患者中的药代动力学，并证明其安全性、耐受性和抗氧化活性。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色茶提取物的CAM草药鸡尾酒对患者暴露于主要水飞蓟素黄酮木脂体的影响。对于特定目标2，我们将确定并使用8-异前列烷F2测定的最佳程序，作为氧化应激的指标，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选择的丙型肝炎患者提供替代药物。 公共卫生相关性：尽管公众对植物产品的安全性和有效性有积极的看法，但缺乏使用高剂量草药组合以优化健康结果的数据，并且需要对不良反应保持警惕。本提案的目的是评估使用高剂量草药鸡尾酒治疗肝病的潜在有益草药相互作用的安全性，耐受性和有效性，其中治疗方案不可用。