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: 8598698
• 负责人: David B. Peden
• 金额: $ 52.61万
• 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/8598698
• 关键词: Acute; Air Pollutants; Air Pollution; Allergens; Allergic; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic A23187; Antioxidants; Arachidonate 5-Lipoxygenase; Asthma; Basophils; Biological; Biological Markers; Biomass; Breathing; Cells; Chronic; Cytokine Signaling; DNA; Data; Dehydration; Development; Dose; Double-Blind Method; Endotoxins; Enrollment; Eosinophilia; Epidemiologic Studies; Epithelial Cells; Exhalation; Extrinsic asthma; GSTM1 gene; Gene Proteins; Genotype; Goals; 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; Smoke; Source; Sputum; Stress; Supplementation; Testing; Therapeutic; Tissues; Tobacco; Tocopherols; United States; Variant; Vitamin E; airway inflammation; cost; cost effective; cytokine; design; efficacy testing; environmental intervention; eosinophil; eosinophilic inflammation; gamma-Tocopherol; granulocyte; healthy volunteer; human CCL26 protein; injured airway; monocyte; neutrophil; novel; phase 2 study; phase 3 study; placebo controlled study; pollutant; prevent; public health relevance; randomized placebo controlled trial; response; 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 (?T-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 ?T prevents allergen, O3 and LPS-induced respiratory tract inflammation in rodents. Our phase I human studies with ?T-mT established a dose which maintains ?T 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 ?T-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.

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 (?T-mT) preparation on chronic eosinophilic inflammation and acute increases in neutrophilic inflammation in allergic与LP和O3挑战相关的哮喘患者（AAS）。内毒素（脂多糖或LPS）是粗和细模式PM，生物素，烟草和生物质烟雾的组成部分。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，LP和O3都是重要的哮喘触发因素。在对AAS的挑战研究中，我们表明LP和O3诱导AAS中嗜中性粒细胞（PMN）和嗜酸性粒细胞的涌入，并增强对吸入过敏原的反应。 O3也是一种氧化剂，O3和LPS都会增加气道细胞的自由基产生，其营养和遗传定义的抗氧化剂缺乏症（例如GSTM1无效的基因型）与污染物诱导的哮喘患者的风险增加有关。在挑战研究中，我们报道了GSTM1无效志愿者中有LPS和O3 PMN的反应增加。伽玛生育酚具有已知的抗氧化剂和抗炎作用。我们已经表明，t可防止过敏原，O3和LPS诱导的啮齿动物炎症。我们使用？t-MT的I阶段研究建立了一种维持及其抗炎代谢产物的剂量，减少了对LPS的单核细胞反应，而IgE介导的bas粒对过敏原的反应。我们最初的双盲，安慰剂控制的IIA研究研究中的数据表明，T-MT抑制了LPS诱导的粒细胞涌入。在AAS中，成功完成了IIA期研究的成功完成，将指导对这种低成本的营养干预措施的III期疗效研究，以预防污染物引起的哮喘加重。