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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AI095050-03S1
Application #
8858923
Study Section
Program Officer
Davidson, Wendy F
Project Start
2011-08-15
Project End
2015-07-31
Budget Start
2014-08-21
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$506,531
Indirect Cost
$139,370
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030