The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study

Abstract

Background: Methacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholineinduced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting β 2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve. Methods: This was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV 1 ) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV 1 .

<p>Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap</p>

“…40 Blais et al showed the bronchoprotective effect of GLY in asthmatic patients. 41 Virchow and their colleagues also showed the beneficial effect of GLY on ICS/LABA in uncontrolled asthma. 42 The BUD administered in this study is an ICS retained in airway tissue for longer than other inhaled steroids, resulting in significant prolongation of the anti-inflammatory effect.…”

Methacholine challenge testing: comparative pharmacology

“…Several studies have addressed the effect of beta 2 agonists on other aspects of the methacholine dose–response curve. 22 , 39 , 40 All three studies confirm that beta agonists do not lead to a methacholine dose–response plateau, and that they may actually increase the steepness of the dose–reponse curve (ie, reactivity). 39 …”

“…Glycopyrronium bronchoprotection at 1, 24, and 48 hours was reproduced by this same group in a subsequent study. 22 Neither treatment produced clinically significant bronchodilation, possibly explained by the mild asthma study population.…”

“…The shift in methacholine PC 20 was 1.5 doubling concentrations at 1 hour post-dose and this decreased to 1 doubling concentration on subsequent testing at both 24 and 48 hours. 22 …”

Diversity of methacholine dose-response curves among asymptomatic non-asthmatics

“…This was a retrospective analysis of additional data from a previous study [4] that examined the influence of respiratory medications on the MDRC of mild asthmatics for comparison with a control non-asthmatic MDRC [approved by institution Research Ethics Board (Bio-REB 16-205) and registered on clinicaltrials.gov (NCT02953041)]. During data collection, it was found that a significant number of control participants were in fact hyperresponsive to methacholine.…”