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）：本申请涉及探索一种新策略，通过利用其代谢知识来针对特定的草药-草药相互作用来提高植物产品中所含多酚抗氧化剂通常较低的生物利用度。许多先前的临床研究的一个主要限制是他们使用了不充分的口服剂量方案，未能解释多酚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量低，并可能解释了它们缺乏功效。 CAM 草药鸡尾酒的基本原理设计应导致这些有效抗氧化剂的稳态浓度急剧增加，从而产生附加或协同药效作用，这些作用对于鸡尾酒中所含的每种植物产品可能是常见的或独特的。超过 50% 的慢性丙型肝炎患者要么有禁忌症，要么没有对治疗产生持续的病毒学反应，可能会从替代药物的可用性中受益。我们的假设是，水飞蓟素与含有结构多样的多酚天然产物混合物的 CAM 混合物共同给药，将通过减缓水飞蓟素消除途径的药代动力学相互作用，或通过抗氧化剂或其他有益物质产生的药效相互作用，增强水飞蓟素的抗氧化活性。 CAM 鸡尾酒的特性与水飞蓟素具有相加或协同作用。拟议的双盲、安慰剂对照、随机临床试验的目标是描述药代动力学，并证明 CAM 草药鸡尾酒在慢性丙型肝炎基因 1 感染且未接受过治疗的患者中的安全性、耐受性和抗氧化活性。既往基于聚乙二醇干扰素的疗法。在具体目标 1 中，我们将进行一项药代动力学研究，以确定含有水飞蓟和绿茶提取物的 CAM 草药混合物对患者接触主要水飞蓟素黄酮木脂素的影响。对于具体目标 2，我们将确定并使用 8-异前列烷 F2 测定的最佳程序（作为氧化应激的衡量标准），以确定 CAM 草药鸡尾酒在慢性 HCV 患者中的抗氧化活性。这项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功效有积极的看法，但缺乏使用高剂量草药组合来优化健康结果的数据，因此有必要对不良反应保持警惕。该提案的目标是评估使用高剂量草药鸡尾酒治疗没有治疗选择的肝脏疾病时潜在有益的草药相互作用的安全性、耐受性和有效性。