MONITORING GLUTATHIONE LEVELS AFTER THE INGESTION OF A LIPOSOMAL GLUTATHIONE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 最近提交给美国国立卫生研究院的一项申请，要求资助一项关于口服脂质体谷胱甘肽制剂潜在健康益处的研究。该申请没有得到资助，但收到了许多积极的评论，加德纳博士和同事们打算重新提交。一位评论家的一个特别建议是，只收集2-3人的初步药代动力学数据，并在下一次提交时提交。该GCRC应用程序的目的是生成所请求的初步数据。 这里给出了NIH最初应用的摘要，尽管它并不是特别相关，因为我们目前向GCRC提出的建议只是运行药代动力学。 背景：许多观察和实验研究表明，动脉粥样硬化和心血管疾病的公认危险因素促进了血管系统的炎性氧化环境，有利于内皮的病理变化。现在有大量证据表明，内皮功能障碍是动脉粥样硬化的先兆，也是加速动脉粥样硬化的因素。因此，抗氧化性营养素可能有助于减少内皮功能障碍和减少心血管事件的发生率。然而，以前在临床试验中使用抗氧化剂补充剂(如维生素E和C，β-胡萝卜素)的结果令人失望和有争议。尽管最近的试验结果为零，但抗氧化剂潜在益处的生物学合理性仍然很强。在测试具有抗氧化性能的各种化合物以及确定作为有效治疗剂的特定抗氧化剂方面还需要继续工作。 目的：这项研究将确定含有谷胱甘肽的膳食补充剂是否会降低炎症标志物的水平，以及补充精氨酸的存在或不存在是否会增加谷胱甘肽治疗的有效性。 设计：这是一项随机、双盲、安慰剂对照、平行对照的可行性研究。90名动脉粥样硬化和心脏病风险因素升高的成年人将被随机分配到8周内：1)谷胱甘肽(GSH，n=30)，2)谷胱甘肽+精氨酸(GSH+Arg，n=30)或安慰剂(PLAC，n=30)。数据将在基线、2周、4周和8周收集。主要研究结果是血清炎症标志物，包括C反应蛋白(CRP)、白介素6(IL-6)、肿瘤坏死因子-α(TNF-α)和可溶性细胞间黏附分子-1(sICAM-1)。次要结果包括血压、血胆固醇、血清异前列腺素(氧化应激指标)和S亚硝基谷胱甘肽(一种稳定的含一氧化氮化合物)。 如果谷胱甘肽，+/-精氨酸，可以有效地降低炎症标志物，这将表明一种安全和相对便宜的治疗方法，以降低心血管疾病的风险。最近的研究表明，氧化应激和与之相关的炎症在普通人群中非常常见，因此在这一领域发现的任何有益的治疗方法都将产生广泛的好处。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. An application as recently submitted to NIH for funding of a study of the potential health benefits of an oral liposomal glutathione preparation. The application was not funded but received many positive comments and Dr. Gardner and colleagues intend to resubmit. One particular suggestion from a reviewer was that preliminary pharmacokinetic data be gathered on just 2-3 people, and presented with the next submission. It is the intent of this GCRC application to generate that requested preliminary data. The abstract for the original NIH application is presented here, although it is not particularly relevant since our current proposal to the GCRC is simply to run the pharmacokinetics. BACKGROUND: A number of observational and experimental studies have shown that the recognized risk factors for atherosclerosis and cardiovascular disease promote an inflammatory oxidative environment in the vasculature that is conducive to pathologic changes in the endothelium. Considerable evidence now exists that endothelial dysfunction both precedes and accelerates atherosclerosis. Antioxidant nutrients may therefore be presumed likely to contribute to a decrease of endothelial dysfunction and to diminish the incidence of cardiovascular events. However, the previous use of antioxidant supplements in clinical trials (e.g., Vitamins E and C, beta-carotene) has yielded disappointing and controversial results. Despite the null findings from recent trials, the biological plausibility of potential benefits from antioxidants remains strong. Continued work is needed in testing various compounds with antioxidant properties, and identifying the specific antioxidants that are effective therapeutic agents. OBJECTIVE: This study will determine whether a dietary supplement containing glutathione will lower levels of inflammatory markers, and whether the presence or absence of supplemental arginine will add to the effectiveness of the glutathione therapy. DESIGN: This is a randomized, double blind, placebo-controlled, parallel-arm, feasibility study. Ninety adults with elevated risk factors for atherosclerosis and heart disease will be randomly assigned for 8 weeks to either: 1) glutathione (GSH, n=30), 2) glutathione + arginine (GSH+Arg, n=30) or placebo (Plac, n=30). Data will be collected at baseline, 2, 4, and 8 weeks. Primary study outcomes are serum markers of inflammation including c-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a) and soluble intercellular adhesion molecule-1 (sICAM-1). Secondary outcomes include blood pressure, blood cholesterol, serum isoprostanes (a measure of oxidative stress) and s-nitrosyl glutathione (a stable, nitric oxide containing compound). IMPLICATIONS: If glutathione, +/- arginine, can effectively lower inflammatory markers, this would suggest a safe and relatively inexpensive therapy to reduce the risk of cardiovascular disease. Recent studies have shown that oxidative stress and the inflammation associated with it are very common in the general population, and so any beneficial therapies found in this area would have widespread benefits.