Phase II studies of gamma tocopherol as an intervention for environmental asthma

γ-生育酚作为环境性哮喘干预措施的 II 期研究

• 批准号: 9057036
• 负责人: David B. Peden
• 金额: $ 87.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057036
• 关键词: Acute; Air Pollutants; Air Pollution; Allergens; Allergic; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arachidonate 5-Lipoxygenase; Asthma; Basophils; Biological; Biological Markers; Breathing; Cells; Chronic; Cytokine Signaling; DNA; Data; Dehydration; Development; Dose; Double-Blind Method; Endotoxins; Enrollment; Eosinophilia; Eotaxin; Epidemiologic Studies; Epithelial Cells; Exhalation; Extrinsic asthma; Gene Proteins; Genes; Genotype; Glutathione; Goals; Health; Homozygote; Hour; Human; IgE; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Intervention; LOX gene; Lipids; Lipopolysaccharides; Lung; Lung diseases; MAPK3 gene; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mucins; Mucociliary Clearance; Mucous body substance; Neutrophilia; Nitrogen; Nutritional; Oxidants; Oxygen; Ozone; Participant; Particulate; Pathologic; Peripheral Blood Mononuclear Cell; Peroxonitrite; Phase; Phosphorylation; Placebo Control; Plasma; Population; Preparation; Production; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Proteins; Protocols documentation; Public Health; Reactive Oxygen Species; Recruitment Activity; Reporting; Respiratory System; Respiratory tract structure; Risk; Risk Factors; Rodent; Rodent Model; Role; Sampling; Serum; Signal Transduction; Source; Sputum; Stress; Supplementation; Testing; Therapeutic; Tissues; Tobacco smoke; Tocopherols; United States; Variant; Vitamin E; airway inflammation; asthmatic; biomass smoke; cost; cost effective; cytokine; design; efficacy testing; environmental intervention; eosinophil; eosinophilic inflammation; gamma-Tocopherol; granulocyte; healthy volunteer; injured airway; monocyte; neutrophil; novel; phase 2 study; phase 3 study; placebo controlled study; pollutant; prevent; randomized placebo controlled trial; response; targeted treatment; volunteer

DESCRIPTION (provided by applicant): Allergic asthma (AA) is the most commonly encountered respiratory disease in the United States and is a leading cause of morbidity worldwide The goals of this project are to undertake phase IIa studies of a gamma tocopherol enriched mixed tocopherol (γT-mT) preparation on chronic eosinophilic inflammation and acute increases in neutrophilic inflammation in allergic asthmatics (AAs) associated with LPS and O3 challenge. Endotoxin (lipopolysaccharide or LPS) is a component of coarse and fine mode PM, bioaerosols, tobacco and biomass smoke. Ozone (O3) is the most commonly encountered ambient air pollutant in the US. Epidemiological studies have shown that both LPS and O3 are important asthma triggers. In challenge studies of AAs, we have shown that LPS and O3 induces influx of neutrophils (PMNs) and eosinophils in AAs as well as augmenting response to inhaled allergens. O3 is also an oxidant, and both O3 and LPS increase radical production by airway cells, with both nutritional and genetically defined antioxidant deficiencies (such as the GSTM1 null genotype) being associated with increased risk for pollutant-induced asthma exacerbation. In challenge studies, we have reported that LPS and O3 PMN responses are increased in GSTM1 null volunteers. Gamma tocopherol has known antioxidant and anti-inflammatory actions. We have shown that γT prevents allergen, O3 and LPS-induced respiratory tract inflammation in rodents. Our phase I human studies with γT-mT established a dose which maintains γT and its anti-inflammatory metabolites, decreases monocyte responses to LPS and IgE-mediated basophil response to allergen. Data from our initial double-blinded, placebo controlled phase IIa study in healthy volunteers demonstrates that γT-mT inhibits LPS-induced granulocyte influx. Successful completion of this phase IIa study in AAs will guide development of a phase III efficacy study of this low cost nutriceutical intervention for preventio of pollutant-induced asthma exacerbations.

描述（申请人提供）：过敏性哮喘（Allergic asthma，AA）是美国最常见的呼吸系统疾病，也是世界范围内发病的主要原因。本项目的目的是进行一项富含γ-生育酚的混合生育酚（γT-mT）制剂对过敏性哮喘（allergic asthma，AA）患者慢性嗜酸性粒细胞炎症和急性嗜酸性粒细胞炎症增加的IIa期研究。与LPS和O3刺激有关。内毒素（脂多糖或LPS）是粗模式和细模式PM、生物气溶胶、烟草和生物质烟雾的组分。臭氧（O3）是美国最常见的环境空气污染物。流行病学研究表明，LPS和O3都是重要的哮喘触发因素。在AA的挑战研究中，我们已经表明，LPS和O3诱导AAs中的中性粒细胞（PMNs）和嗜酸性粒细胞的流入，以及增强对吸入性过敏原的反应。O3也是一种氧化剂，O3和LPS都能增加气道细胞的自由基产生，营养和遗传定义的抗氧化剂缺乏（如GSTM 1缺失基因型）都与污染物诱导的哮喘急性发作风险增加有关。在激发研究中，我们已经报道了LPS和O3 PMN反应在GSTM 1空志愿者中增加。伽马生育酚具有已知的抗氧化和抗炎作用。我们已经证明，γT可以预防啮齿动物中过敏原、O3和LPS诱导的呼吸道炎症。我们对γT-mT的I期人体研究确立了维持γT及其抗炎代谢产物、降低单核细胞对LPS的反应和IgE介导的嗜碱性粒细胞对过敏原的反应的剂量。来自我们在健康志愿者中进行的初始双盲、安慰剂对照IIa期研究的数据表明，γT-mT抑制LPS诱导的粒细胞内流。在AA中成功完成这项IIa期研究将指导这种低成本营养干预预防污染物诱导的哮喘急性发作的III期疗效研究的开展。