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

α酸对氧化应激影响的剂量范围研究

• 批准号: 7472034
• 负责人: PAMELA OUYANG
• 金额: $ 18.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472034
• 关键词: 3-nitrotyrosine; 5' -AMP-activated protein kinase; Acids; Adipocytes; Advanced Glycosylation End Products; Adverse effects; Affect; Aftercare; Animal Model; Antioxidants; Atherosclerosis; Autoantibodies; Biological; Biological Assay; Biological Markers; Blood; Blood Platelets; Blood Vessels; C-reactive protein; Cardiovascular Diseases; Cause of Death; Cell Adhesion Molecules; Cell membrane; Cholesterol; Clinical Research; Clinical Trials; Data; Diabetes Mellitus; Dose; Double-Blind Method; Endothelial Cells; Endothelium; Enzymes; Fasting; Fatty acid glycerol esters; Functional disorder; Future; GLUT4 gene; Glucose; Glucose Transporter; Hepatocyte; High Blood Pressure; Hyperlipidemia; Hypertension; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Intervention Studies; Isoprostanes; Lead; Link; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Measurement; Measures; Mediating; Metabolic syndrome; Metabolism; Modeling; NF-kappa B; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Oral; Oxidative Stress; Pathway interactions; Peroxidase; Pharmaceutical Preparations; Placebo Control; Placebos; Prevalence; Public Health; Publishing; Randomized; Range; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Reporting; Research; Risk; SLC2A1 gene; Safety; Serum; Stress; Testing; Thiobarbituric Acid Reactive Substances; Thioctic Acid; Tissues; Vasodilator Agents; Week; antioxidant therapy; base; cardiovascular disorder risk; cardiovascular risk factor; cytokine; design; diabetic; dosage; free radical oxygen; human data; improved; indexing; insulin sensitivity; oxidation; oxidized lipid; randomized placebo controlled trial; response; treatment effect; urinary; vascular inflammation; 3-nitrotyrosine; 5' -AMP-activated protein kinase; Acids; Adipocytes; Advanced Glycosylation End Products; Adverse effects; Affect; Aftercare; Animal Model; Antioxidants; Atherosclerosis; Autoantibodies; Biological; Biological Assay; Biological Markers; Blood; Blood Platelets; Blood Vessels; C-reactive protein; Cardiovascular Diseases; Cause of Death; Cell Adhesion Molecules; Cell membrane; Cholesterol; Clinical Research; Clinical Trials; Data; Diabetes Mellitus; Dose; Double-Blind Method; Endothelial Cells; Endothelium; Enzymes; Fasting; Fatty acid glycerol esters; Functional disorder; Future; GLUT4 gene; Glucose; Glucose Transporter; Hepatocyte; High Blood Pressure; Hyperlipidemia; Hypertension; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Intervention Studies; Isoprostanes; Lead; Link; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Measurement; Measures; Mediating; Metabolic syndrome; Metabolism; Modeling; NF-kappa B; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Oral; Oxidative Stress; Pathway interactions; Peroxidase; Pharmaceutical Preparations; Placebo Control; Placebos; Prevalence; Public Health; Publishing; Randomized; Range; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Reporting; Research; Risk; SLC2A1 gene; Safety; Serum; Stress; Testing; Thiobarbituric Acid Reactive Substances; Thioctic Acid; Tissues; Vasodilator Agents; Week; antioxidant therapy; base; cardiovascular disorder risk; cardiovascular risk factor; cytokine; design; diabetic; dosage; free radical oxygen; human data; improved; indexing; insulin sensitivity; oxidation; oxidized lipid; randomized placebo controlled trial; response; treatment effect; urinary; vascular inflammation

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.

描述（由申请人提供）：这项探索性的小临床研究将确定口服α脂酸的效果，以确定最佳剂量以减少代谢综合征中的氧化应激。在代谢综合征中氧化应激水平与血管功能障碍之间存在关联是有生物学上的。代谢综合征是一群异常，包括肥胖，高血压，高脂血症和糖尿病，与心血管疾病的风险增加有关。这些因素可以通过胰岛素抵抗联系起来。代谢综合征与更大的氧化抗应激有关。这种增加的氧化应激会影响脂肪细胞，肝细胞和内皮细胞，从而导致炎症细胞因子释放，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。减少氧化应激可能导致炎症减少和血管功能改善。 α脂酸是一种有效的抗氧化剂，可减少糖尿病模型中的氧化应激。在脂肪细胞中的研究表明，lipoic酸刺激了质膜的靶向易位，glut1和Glut 4，重要的细胞内葡萄糖转运蛋白。 lipoic酸还可以抑制内皮细胞NF-kappab激活和通过晚期糖基化终产物的细胞粘附分子的表达。在糖尿病的动物模型中，α氟酸会降低氧化应激并改善葡萄糖利用率。在肥胖的大鼠模型中，内皮血管扩张剂功能受损，α氟酸激活主动脉内皮AMP激活的蛋白激酶，这是细胞代谢的调节剂，并改善一氧化氧化物同步和加速剂功能。人类数据受到更大的限制，没有发表的研究评估代谢综合征患者在一系列α脂肪酸剂量上的抗氧化作用。我们提出了一项安慰剂控制的剂量范围研究，以确定1）降低氧化应激标记水平的α脂酸的剂量，2）2）α-脂肪酸是否通过对氧化应激的影响来改善血管功能，3）是否会抑制米微颗粒释放的α-脂肪酸和4）不体效应的脂肪范围。这项研究将确定应在未来的较大研究中研究的有效剂量，该研究有助于评估α氟酸治疗是否改善血管功能。 公共卫生相关性：代谢综合征，包括肥胖症，高血压，高胆固醇和糖尿病的一系列因素，会增加患心血管疾病的风险，并且与氧气自由基的过度生产有关，这些自由基导致更大的炎症，血管异常和异常的葡萄糖处理。这项研究将衡量不同剂量的α氟酸（一种有效的抗氧化剂）是否会降低氧化应激的血液标志物并改善血管功能。如果α氟酸是有效的，那么这项研究的信息可能会导致对药物进行更大的试验，以评估它是否可以降低代谢综合征患者的心血管风险。