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

β-肾上腺素受体反向激动剂纳多洛尔治疗轻度哮喘的疗效和安全性

• 批准号: 8858923
• 负责人: NICOLA A HANANIA
• 金额: $ 50.65万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858923
• 关键词: Acute; Address; Adrenergic Receptor; Adrenergic beta-Antagonists; Adverse event; Affinity; Age-Years; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Area; Asthma; Biopsy; Blood; Bronchial Spasm; Bronchoconstriction; Bronchodilator Agents; Bronchoscopy; Cessation of life; Chronic; Clinical Trials; Data; Deterioration; Disease; Disease Management; Dose; Double-Blind Method; Drug Targeting; Drug usage; Enrollment; Epithelial Cells; Exhalation; Faculty; Forced expiratory volume function; Goals; Human; Individual; Inflammation; Inflammatory; Juniper; Knockout Mice; Ligand Binding; Light; Lymphocyte; Maintenance; Measurement; Measures; Metaplasia; Modeling; Morbidity - disease rate; Mucous body substance; Multi-Institutional Clinical Trial; Mus; Nadolol; Obstruction; Outcome; Outcome Measure; Patients; Peak Expiratory Flow Rate; Peripheral; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Physical Examination; Placebo Control; Placebos; Play; Population; Prospective Studies; Pulmonary Function Test/Forced Expiratory Volume 1; Questionnaires; Randomized; Research; Respiratory physiology; Role; Safety; Serious Adverse Event; Serum; Signal Transduction; Site; Sputum; Staging; Subgroup; Testing; Withdrawal; airway epithelium; airway hyperresponsiveness; airway inflammation; airway obstruction; attenuation; base; beta-2 Adrenergic Receptors; clinical effect; clinical research site; combat; density; experience; genetic analysis; indexing; inflammatory marker; insight; methacholine; mortality; mouse model; novel; placebo controlled study; pre-clinical; primary outcome; prospective; pulmonary function; receptor; response; secondary outcome; symptomatic improvement; therapy duration; translational clinical trial

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.

描述（由应用提供）：哮喘是气道的慢性炎症性疾病，其特征是存在可逆气道物镜和气道高反应性。药理学管理旨在逆转支气管收缩和抗击慢性炎症。 beta2-adenoceptor（�-ar）激动剂是有效的支气管扩张剂，并且在哮喘管理的每个阶段都起着重要作用。但是，它们的慢性常规使用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，特别是当前在哮喘中禁忌的纳多洛尔等3 AR反向激动剂，可能与轻度哮喘患者的气道高反应性衰减有关。在小鼠哮喘模型中的研究表明，这种作用可能与气道感染减少和粘膜化生有关。我们提出了一个三个地点，前瞻性，随机，双盲，安慰剂对照研究，以进一步研究慢性纳多尔在哮喘中的有效性和安全性。该研究将招募60名轻度哮喘受试者。 18-60岁的年龄将为24周。主要结局指标将是气道高反应对甲氧烯的变化（PC20强迫呼气量在一秒钟内，FEV1）。次要结果将是肺功能（FEV1）和哮喘控制的测量结果。探索性结果将研究Nadolol对用尽呼吸，血液和诱导的痰液测量的气道注入指数的影响。在一部分受试者中，将采用支气管镜检查（n = 30），以研究Nadolol对通过刷子和气道活检获得的气道上皮细胞中气道注射和粘液上皮的影响。 P-AR表达，配体结合和信号传导将在气道上皮细胞和周围淋巴细胞中进行测量。其他探索结果将包括遗传分析，以确定这些结果是否影响了对Nadolol的个人反应。在整个研究中收集的安全措施将包括不良事件（AES），由于AES引起的戒断，严重的AE，肺功能测量，生命体征和身体检查。