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

描述（由申请人提供）：哮喘是一种以可逆性气道阻塞和气道高反应性为特征的气道慢性炎症性疾病。药理学管理旨在逆转支气管收缩和对抗慢性炎症。β -肾上腺素受体激动剂是一种有效的支气管扩张剂，在哮喘治疗的每个阶段都发挥着重要作用。然而，它们的长期定期使用可能与有害影响有关，包括哮喘相关死亡的增加。相反，最近的试点数据表明，长期使用某些β受体阻滞剂，特别是3-AR逆激动剂，如纳多洛尔，目前是哮喘的禁忌症，可能与轻度哮喘患者气道高反应性的衰减有关。对哮喘小鼠模型的研究表明，这种作用可能与减少气道炎症和粘膜化生有关。我们提出了一项三点、前瞻性、随机、双盲、安慰剂对照的研究，以进一步研究慢性纳多洛尔治疗哮喘的疗效和安全性。该研究将招募60名轻度哮喘患者。18-60岁，将为期24周。主要结局指标将是气道对甲胆碱高反应性的改变（PC20 1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。探索性结果将研究纳多洛尔对呼出气体、血液和诱导痰等气道炎症指标的影响。一项亚研究（n = 30）将在一部分受试者中使用支气管镜检查，研究纳多洛尔对气道炎症和粘膜化生的影响，这些影响是通过刷子和气道活检获得的气道上皮细胞测量的。在气道上皮细胞和外周血淋巴细胞中检测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（ae）、因ae而停药、严重ae、肺功能测量、生命体征和体格检查。

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.