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

描述(由申请人提供)：过敏性哮喘(AA)是美国最常见的呼吸系统疾病，也是全球发病率的主要原因。该项目的目标是进行IIa期研究，研究一种富含生育酚的混合生育酚(？T-MT)制剂对慢性嗜酸性炎症和过敏性哮喘(AAs)患者中性粒细胞炎症的急性增加与脂多糖和臭氧的挑战。内毒素(脂多糖或内毒素)是粗细模式PM、生物气溶胶、烟草和生物质烟雾的一种成分。臭氧(臭氧)是美国最常见的环境空气污染物。流行病学研究表明，内毒素和臭氧都是重要的哮喘诱因。在对AAS的攻击性研究中，我们发现，内毒素和臭氧可诱导AAS内中性粒细胞(PMN)和嗜酸性粒细胞的内流，并增强对吸入性变应原的反应。臭氧也是一种氧化剂，臭氧和脂多糖都会增加呼吸道细胞的自由基产生，营养和基因定义的抗氧化剂缺陷(如GSTM1零基因)都与污染物诱导的哮喘恶化的风险增加有关。在挑战研究中，我们已经报道了在GSTM1缺失的志愿者中，内毒素和臭氧的PMN反应增加。生育酚具有已知的抗氧化和抗炎作用。我们已经证明？T可以预防过敏原、臭氧和脂多糖诱导的啮齿动物呼吸道炎症。我们用T-MT进行的I期人体试验确定了维持T及其抗炎代谢物、降低单核细胞对内毒素的反应和IgE介导的嗜碱性细胞对变应原的反应的剂量。我们最初在健康志愿者中进行的双盲、安慰剂对照IIa期研究的数据表明，？T-MT抑制了内毒素诱导的粒细胞内流。在AAs中成功完成这项IIa期研究将指导开展这一低成本营养干预措施预防污染物引起的哮喘加重的III期疗效研究。

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.