CAM Herbal Cocktails for Boosting Antioxident Activity to Treat Liver Disease

描述(由申请人提供)：本申请涉及一种新策略的探索，通过利用植物产品中多酚抗氧化剂的新陈代谢知识来针对特定的草药相互作用来提高其通常较低的生物利用度。许多先前临床研究的一个主要局限性是，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，这导致了这些潜在保护性化合物的低稳态暴露，并可能解释了它们缺乏疗效的原因。CAM草本鸡尾酒的基本设计应该导致这些有效抗氧化剂的稳态浓度大幅增加，其添加或协同药效效应对于鸡尾酒中所含的每种植物产品来说可能是共同的或独特的。超过50%的慢性丙型肝炎患者要么有禁忌症，要么对治疗没有持续的病毒学反应，并可能从替代药物的可获得性中受益。我们的假设是，水飞蓟素与含有结构多样化的多酚天然产物混合物的CAM鸡尾酒共用将提高水飞蓟素的抗氧化活性，要么是通过减缓水飞蓟素消除途径的药代动力学相互作用，要么是通过与水飞蓟素相加或协同的CAM鸡尾酒的抗氧化剂或其他有益特性产生的药效相互作用。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1型感染患者中的安全性、耐受性和抗氧化活性，这些患者以前没有接受过基于聚乙二醇干扰素的治疗。在具体目标1中，我们将进行一项药代动力学研究，以确定含有水飞蓟和绿茶提取物的CAM草本鸡尾酒对患者暴露于主要水飞蓟素黄酮木脂素的影响。对于特定的目标2，我们将确定并使用8-异前列腺素F2的最佳检测程序，作为氧化应激的测量，以确定慢性丙型肝炎患者的CAM草药鸡尾酒的抗氧化活性。这项研究的目的是为没有治疗选择的丙型肝炎患者提供一种替代药物。 公共卫生相关性：尽管公众对植物性产品的安全性和有效性有积极的看法，但缺乏使用大剂量草药组合以优化健康结果的数据，而且有必要对不良反应保持警惕。这项建议的目标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。

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.