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

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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.