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（由申请人提供）： 过敏性哮喘 (AA) 是美国最常见的呼吸道疾病，也是全球发病的主要原因 该项目的目标是对富含 γ 生育酚的混合生育酚 (γT-mT) 制剂进行 IIa 期研究，以治疗过敏性哮喘患者的慢性嗜酸性粒细胞炎症和中性粒细胞炎症的急性增加。 与 LPS 和 O3 激发相关的哮喘患者 (AA)。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成分。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 都是重要的哮喘诱因。在 AA 的挑战研究中，我们发现 LPS 和 O3 会诱导 AA 中中性粒细胞 (PMN) 和嗜酸性粒细胞的流入，并增强对吸入过敏原的反应。 O3 也是一种氧化剂，O3 和 LPS 都会增加气道细胞自由基的产生，营养和基因定义的抗氧化剂缺乏（例如 GSTM1 无效基因型）与污染物引起的哮喘恶化风险增加有关。在挑战研究中，我们报道了 GSTM1 无效志愿者的 LPS 和 O3 PMN 反应增加。伽玛生育酚具有已知的抗氧化和抗炎作用。我们已经证明，γT 可预防啮齿类动物过敏原、O3 和 LPS 引起的呼吸道炎症。我们对 γT-mT 进行的 I 期人体研究确定了维持 γT 及其抗炎代谢物、降低单核细胞对 LPS 的反应以及 IgE 介导的嗜碱性粒细胞对过敏原的反应的剂量。我们最初对健康志愿者进行的双盲、安慰剂对照 IIa 期研究的数据表明，γT-mT 抑制 LPS 诱导的粒细胞流入。成功完成这项 AA 的 IIa 期研究将指导开展这种低成本营养干预措施的 III 期疗效研究，以预防污染物引起的哮喘恶化。