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: 8143915
• 负责人: NICOLA A HANANIA
• 金额: $ 141.73万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143915
• 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 Delivery Systems; 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. 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.

描述（由申请人提供）：哮喘是一种慢性气道炎症性疾病，其特征是存在可逆性气道阻塞和气道高反应性，药物治疗旨在逆转支气管收缩和对抗慢性炎症。支气管扩张剂在哮喘治疗的各个阶段都发挥着重要作用，但长期经常使用可能会带来痛苦。包括哮喘相关死亡增加在内的影响，最近的试点数据表明，长期使用某些β受体阻滞剂，特别是目前在哮喘中禁用的3-AR反向激动剂，可能与气道减弱有关。轻度哮喘患者的高反应性。对哮喘小鼠模型的研究表明，这种作用可能与气道炎症和粘膜化生的减少有关。双盲、安慰剂对照研究进一步调查纳多洛尔治疗慢性哮喘的疗效和安全性，该研究将招募 60 名 18-60 岁的轻度哮喘受试者，为期 24 周。是气道对乙酰胆碱高反应性的变化（PC20 一秒用力呼气量，FEV1）。次要结果是肺功能（FEV1）和哮喘控制的测量。将研究纳多洛尔对呼出气、血液和诱导痰中测量的气道炎症指标的影响。一项子研究（n = 30）将在一部分受试者中采用支气管镜检查，以研究纳多洛尔对气道炎症和粘膜化生的影响。通过刷子和气道活检获得的气道上皮细胞中进行测量，将在气道上皮细胞和外周细胞淋巴中测量P-AR表达、配体结合和信号传导。其他探索性结果将包括遗传分析，以确定这些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将包括不良事件 (AE)、因 AE 导致的退出、严重 AE、肺功能测量、生命体征和体检。 公共健康相关性：该试验将研究哮喘的新治疗方向，β-受体反向激动剂（阻滞剂）是否对哮喘有效。结果有可能显着改变人们对β-2肾上腺素受体在这种疾病中的看法，并可能提供帮助。哮喘长期治疗的范式转变。