Cockcroft, Donald WDavis, Beth E2017-08-212017-08-212017-072017-08-21July 2017http://hdl.handle.net/10388/8034Background: Although asthma treatments are extensively studied for their physiological effects in animal models and their safety and efficacy in humans, their effects on standard testing methods and their physiological benefits in asthmatics are often unknown. The result is a gap in knowledge on newer therapies such as long-acting muscarinic antagonists (LAMAs) and ultra- long acting β2 agonists (uLABAs); standardization guidelines for methacholine challenge testing (MCT), a common research and clinical technique, remain uninformed as to an appropriate abstinence period from these drug classes prior to testing. In addition, the mechanisms through which these drugs improve airway hyperresponsiveness, an important factor in asthma, remain unknown. These mechanisms can be elucidated through methacholine dose-response curves, which illustrate airway hyperresponsiveness in terms of airway sensitivity (position), reactivity (slope), and maximal airway narrowing response. Methods: Two single dose, double blind, double dummy, randomized clinical trials were performed; the first crossover study examined the duration and degree of bronchoprotection provided by two LAMAs, tiotropium and glycopyrronium, against methacholine-induced bronchoconstriction in mild asthmatics; the second study had a three-way crossover design for investigating the effects of glycopyrronium (LAMA) and indacaterol (uLABA), alone and in combination, on the methacholine dose-response curve of mild asthmatics. The first study entailed baseline MCT, treatment administration, and repeat MCT at 1, 24, 48, 72, 96, and 168 hours for each treatment, while the second study used a similar protocol but only followed participants for 48 hours. Results: The first study found that the two LAMAs provided clinically significant and sustained bronchoprotection for up to seven days, with the maximal degree of protection (16-fold increase in methacholine tolerance) provided at one hour post-treatment. The second study revealed that glycopyrronium and combination glycopyrronium/indacaterol each significantly reduced airway sensitivity and reactivity. The combination therapy also significantly reduced the maximal airway narrowing response to methacholine. Indacaterol alone only produced a mild and short- lived reduction in airway sensitivity. Conclusion: LAMAs should be abstained from for at least seven days prior to undergoing MCT to ensure test accuracy. The LAMA glycopyrronium and the combination glycopyrronium/indacaterol both show promising results in terms of improvements in airway sensitivity, reactivity, and maximal response characteristics of airway hyperresponsiveness and following further experimentation may become standard therapies for the treatment of poorly controlled asthma.application/pdfmethacholine challengelong-acting muscarinic antagonistultra long-acting beta-2 agonistmethacholine dose-response curveThesis2017-08-21