Dose Ranging study of the Effects of Alpha Acid on Oxidative Stress

描述（由申请方提供）：这项探索性小型临床研究将确定口服α-硫辛酸的效应特征，以确定降低代谢综合征中氧化应激的最佳剂量。在代谢综合征中，氧化应激水平与血管功能障碍之间的相关性具有生物学上的合理性。代谢综合征是一组异常，包括肥胖、高血压、高脂血症和糖尿病，并与心血管疾病风险增加相关。这些因素可能与胰岛素抵抗有关。代谢综合征与更大的氧化应激有关。这种增加的氧化应激影响脂肪细胞、肝细胞和内皮细胞，引起炎性细胞因子的释放并导致血管功能受损。这些变化与动脉粥样硬化风险增加有关。减少氧化应激可导致炎症减少和血管功能改善。α-硫辛酸是一种有效的抗氧化剂，可降低糖尿病模型中的氧化应激。在脂肪细胞中的研究显示，硫辛酸刺激质膜靶向的GLUT 1和GLUT 4（重要的细胞内葡萄糖转运蛋白）易位。硫辛酸还通过晚期糖基化终产物抑制内皮细胞NF-κ B活化和细胞粘附分子的表达。在糖尿病动物模型中，α-硫辛酸降低氧化应激并提高葡萄糖利用率。在内皮舒张功能受损的肥胖大鼠模型中，α-硫辛酸激活主动脉内皮AMP活化蛋白激酶（一种细胞代谢调节剂），并改善一氧化氮合成和血管舒张功能。人类数据更为有限，没有发表的研究评估在一系列α-硫辛酸剂量范围内代谢综合征患者的抗氧化作用。我们提出了一项安慰剂对照剂量范围研究，以确定1）降低氧化应激标志物水平的α-硫辛酸剂量，2）α-硫辛酸是否通过对氧化应激的影响改善血管功能，3）微粒释放是否被α-硫辛酸抑制，以及4）剂量范围的不良反应特征。这项研究将确定在未来更大规模的研究中应该研究的有效剂量，以评估α-硫辛酸治疗是否改善血管功能。 公共卫生相关性：代谢综合征是一组因素，包括肥胖、高血压、高胆固醇和糖尿病，增加了心血管疾病的风险，并与氧自由基的过度产生有关，导致更严重的炎症、血管异常和葡萄糖处理异常。这项研究将测量不同剂量的α-硫辛酸（一种有效的抗氧化剂）是否会减少氧化应激的血液标志物并改善血管功能。如果α-硫辛酸是有效的，这项研究的信息可能会导致更大规模的药物试验，以评估它是否可以降低代谢综合征患者的心血管风险。

DESCRIPTION (provided by applicant): This exploratory small clinical study will determine the effect profile of oral alpha lipoic acid to determine the optimum dose to reduce oxidative stress in the metabolic syndrome. There is biological plausibility for an association between oxidative stress levels and vascular dysfunction in the metabolic syndrome. Metabolic syndrome is a cluster of abnormalities that includes obesity, hypertension, hyperlipidemia, and diabetes, and is associated with increased risk for cardiovascular disease. These factors may be linked by insulin resistance. Metabolic syndrome is associated with greater oxidatave stress. This increased oxidative stress affects adipocytes, hepatocytes, and endothelial cells, causing release of inflammatory cytokines and results in impaired vascular function. These changes are associated with an increased atherosclerotic risk. Reducing oxidative stress could result in decreased inflammation and improved vascular function. Alpha lipoic acid is a potent antioxidant and reduces oxidative stress in models of diabetes. Studies in fat cells show lipoic acid stimulates the plasma membrane targeted translocation of GLUT1 and GLUT 4, important intracellular glucose transporters. Lipoic acid also suppresses the endothelial cell NF-kappaB activation and the expression of cell adhesion molecules by advanced glycation end-products. In animal models of diabetes, alpha lipoic acid decreases oxidative stress and improves glucose utilization. In obese rat models with impaired endothelial vasodilator function, alpha lipoic acid activates aortic endothelial AMP-activated protein kinase, a regulator of cellular metabolism, and improves nitric oxide synthesis and vasodilator function. Human data is more limited with no published studies evaluating the antioxidant effects in individuals with metabolic syndrome over a range of alpha lipoic acid doses. We propose a placebo controlled dose ranging study to determine 1) the dose of alpha lipoic acid that reduces levels of oxidative stress markers, 2) whether alpha lipoic acid improves vascular function through effects on oxidative stress, 3) whether micoparticle release is inhibited by alpha lipoic acid and 4) adverse effect profile of the dose range. This study will determine the effective dose that should be studied in future larger studies powered to evaluate whether alpha lipoic acid therapy improves vascular function. PUBLIC HEALTH RELEVANCE: The metabolic syndrome, a cluster of factors including obesity, high blood pressure, high cholesterol and diabetes, carries increased risk of cardiovascular disease and is associated with the overproduction of oxygen free radicals that lead to greater inflammation, vascular abnormalities and abnormal glucose handling. This study will measure whether different doses of alpha lipoic acid, a potent antioxidant, will reduce blood markers of oxidative stress and improve vascular function. If alpha lipoic acid is effective, the information from this study could lead to larger trials of the drug to assess whether it can reduce cardiovascular risk in individuals with metabolic syndrome.