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

基本信息

批准号：
7665060
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
项目类别：
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/7665060
关键词：
3-nitrotyrosine 5&apos -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 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 Obesity Oral Oxidative Stress Pathway interactions Peroxidases Pharmaceutical Preparations Placebo Control Placebos Prevalence Publishing Randomized 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 antioxidant therapy base cardiovascular disorder risk cardiovascular risk factor cytokine design diabetic dosage free radical oxygen human data improved indexing inflammatory marker insulin sensitivity oxidation oxidized lipid public health relevance randomized placebo controlled trial response treatment effect urinary vascular inflammation

项目摘要

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）：这项探索性小型临床研究将确定口服α硫辛酸的效果，以确定减少代谢综合征氧化应激的最佳剂量。代谢综合征中氧化应激水平与血管功能障碍之间的关联具有生物学合理性。代谢综合征是一系列异常现象，包括肥胖、高血压、高脂血症和糖尿病，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会影响脂肪细胞、肝细胞和内皮细胞，导致炎症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。减少氧化应激可以减少炎症并改善血管功能。 α-硫辛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。对脂肪细胞的研究表明，硫辛酸会刺激重要的细胞内葡萄糖转运蛋白 GLUT1 和 GLUT 4 的质膜靶向易位。硫辛酸还通过晚期糖基化终产物抑制内皮细胞 NF-kappaB 激活和细胞粘附分子的表达。在糖尿病动物模型中，α-硫辛酸可减少氧化应激并提高葡萄糖利用率。在内皮血管舒张功能受损的肥胖大鼠模型中，α-硫辛酸可激活主动脉内皮 AMP 激活蛋白激酶（细胞代谢调节剂），并改善一氧化氮合成和血管舒张功能。人类数据较为有限，尚未发表研究评估代谢综合征患者在一定剂量的α-硫辛酸剂量下的抗氧化作用。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) α 硫辛酸是否抑制微粒释放硫辛酸和 4) 剂量范围的不良反应概况。这项研究将确定未来更大规模研究中应研究的有效剂量，这些研究旨在评估α硫辛酸治疗是否可以改善血管功能。公众健康相关性：代谢综合征是一系列因素，包括肥胖、高血压、高胆固醇和糖尿病，它会增加患心血管疾病的风险，并与氧自由基的过量产生有关，从而导致更严重的炎症、血管异常和异常。葡萄糖处理。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）是否会降低氧化应激的血液标志物并改善血管功能。如果α硫辛酸有效，这项研究的信息可能会导致对该药物进行更大规模的试验，以评估它是否可以降低代谢综合征患者的心血管风险。