Efficacy and Safety of Beta-adrenoceptor Inverse Agonist, Nadolol in Mild Asthma

描述(申请人提供)：哮喘是一种慢性呼吸道炎症性疾病，以可逆性呼吸道阻塞和气道高反应性为特征。药理管理的目的是逆转支气管收缩和抗击慢性炎症。β2-肾上腺素能受体(β-AR)激动剂是一种有效的支气管扩张剂，在哮喘治疗的各个阶段发挥重要作用。然而，长期经常使用它们可能与有害影响有关，包括增加与哮喘相关的死亡。相反，最近的试验数据表明，某些β-受体阻滞剂的长期使用，特别是目前在哮喘中禁用的3-AR反向激动剂，如纳多洛尔，可能与轻度哮喘患者的气道高反应性减弱有关。对哮喘小鼠模型的研究表明，这种作用可能与减少呼吸道炎症和粘液化生有关。我们提出了一项三点前瞻性、随机、双盲、安慰剂对照研究，以进一步研究慢性纳多洛尔治疗哮喘的有效性和安全性。这项研究将招募60名患有轻度哮喘的受试者。年龄为18-60岁，为期24周。主要的结果衡量指标将是对乙酰甲胆碱的气道高反应性的变化(PC20一秒用力呼气量，FEV1)。次要结果将是肺功能(FEV1)和哮喘控制的测量。探索性结果将调查纳多洛尔对呼气、血液和诱导痰中呼吸道炎症指数的影响。一项子研究(n=30)将在一组受试者中使用支气管镜检查，以调查纳多洛尔对通过刷子和呼吸道活检获得的呼吸道上皮细胞中的呼吸道炎症和粘液化生的影响。将在呼吸道上皮细胞和外周淋巴细胞中检测P-AR的表达、配体结合和信号转导。其他探索性结果将包括基因分析，以确定这些因素是否会影响个体对纳多洛尔的反应。在整个研究过程中收集的安全措施包括不良事件(AEs)、因AEs而停药、严重AEs、肺功能测量、生命体征和体检。 公共卫生相关性：这项试验将调查哮喘的一个新的治疗方向，即β受体反向激动剂(阻滞剂)是否对哮喘有效。这一结果有可能显著改变人们对这种疾病中β-2肾上腺素受体的看法，并可能为哮喘的慢性治疗提供一个范式转变。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways characterized by the presence of reversible airway obstruction and airway hyperresponsiveness. Pharmacological management aims at reversing bronchoconstriction and combating chronic inflammation. Beta2-adrenoceptor (¿-AR) agonists are effective bronchodilators and play a major role in every stage of asthma management. However, their chronic regular use may be associated with detrimental effects including an increase in asthma-related deaths. Conversely, recent pilot data suggest that the chronic use of certain beta-blockers, specifically 3-AR inverse agonists such as nadolol, which are currently contraindicated in asthma, may be associated with attenuation of airway hyperresponsiveness in patients with mild asthma. Studies in the mouse model of asthma suggest that such effects may be related to decreased airway inflammation and mucous metaplasia. We propose a three site, prospective, randomized, double-blind, placebo-controlled study to further investigate the efficacy and safety of chronic nadolol in asthma. The study will enroll 60 subjects with mild asthma. 18-60 years of age, will be of 24 weeks duration. The primary outcome measure will be the change in airway hyperresponsiveness to methacholine (PC20 forced expiratory volume in one second, FEV1). Secondary outcomes will be measures of lung function (FEV1) and asthma control. Exploratory outcomes will investigate the effects of nadolol on indices of airway inflammation as measured in exhaled breath, blood, and induced sputum. A substudy (n = 30) will employ bronchoscopy in a subset of subjects to investigate the effects of nadolol on airway inflammation and mucous metaplasia measured in airway epithelial cells obtained by brushes and airway biopsies. P-AR expression, ligand binding and signaling will be measured in airway epithelial cells and peripheral lymphocytes. Other exploratory outcomes will include genetic analyses to determine if these influence individual responses to nadolol. Safety measures collected throughout the study will include adverse events (AEs), withdrawals due to AEs, serious AEs, pulmonary function measurements, vital signs, and physical examinations. PUBLIC HEALTH RELEVANCE: This trial will investigate a novel treatment direction in asthma, whether beta-receptor inverse agonists (blockers) have efficacy in asthma. The results have the potential to significantly change how view the beta-2 adrenoceptor in this disease and may provide a paradigm shift in the chronic management of asthma.