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：
7896471
负责人：
PAMELA OUYANG
金额：
$ 12.47万
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 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7896471
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

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

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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 and diabetes. There is biological plausibility for an association between oxidative stress levels and vascular dysfunction in individuals with metabolic syndrome or diabetes. 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 and diabetes are 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 or diabetes 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.

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氟酸的效果，以确定最佳剂量，以减少代谢综合征和糖尿病的氧化应激。具有代谢综合征或糖尿病患者的氧化应激水平与血管功能障碍之间的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。代谢综合征和糖尿病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，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或糖尿病患者在一系列α脂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。