Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

Abstract

a b s t r a c tLong-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min). Aclidinium 4 mg/mL and tiotropium 200 mg/mL inhaled in 1 min proved to have similar protective effect on methacholine-induced bronchoconstriction in anesthetized animals. The total dosage employed for aclidinium and tiotropium was 4 mg and 200 mg, respectively. In awake animals, similar reductions in the cough number were observed following 10-min inhalation of each drug with a slight, not significant tendency to higher antitussive effects for aclidinium. In anesthetized animals, 1-min inhalation of each drug caused similar depressant effects on cough responses induced by both mechanical and chemical stimulation. A complete suppression of cough responses to mechanical stimuli was seen in some preparations. The results strongly suggest that the LAMA-induced downregulation of cough may be mediated not only by transient receptor potential vanilloid type 1 channels, as already reported, but also by acid-sensing ion channels and mechanoreceptors. The route of administration along with the more rapid hydrolysis of aclidinium into inactive metabolites minimize potential systemic side effects and give to this drug a very favorable safety profile.

Effect of aclidinium bromide on cough and sputum symptoms in moderate-to-severe COPD in three phase III trials

“…For example, there is evidence that muscarinic antagonists reduce experimental cough,40 and that tiotropium and ipratropium act on TRPV1 to reduce the cough response in preclinical models 41. In addition, a 2016 preclinical study in rabbits showed that, further to their anticholinergic activity and any action on TRPV1 receptors, aclidinium and tiotropium may also have antitussive actions involving mechanoreceptors and acid-sensing ion channels 42. These studies provide preclinical evidence of LAMA antitussive activity; however, it is not yet clear how this may translate into clinical practice.…”

Brainstem mechanisms underlying the cough reflex and its regulation

“…Nevertheless, investigations on the basic neural mechanisms subserving the cough reflex performed on healthy preparations can provide useful hints for the development of antitussive or protussive strategies (see e.g. Cinelli et al, 2016;Mutolo et al, 2016).…”

The evidence on tiotropium bromide in asthma: from the rationale to the bedside

“…Birrell and colleagues [121] showed that tiotropium, but not glycopyrronium, was able to modulate the cough reflex through the transient-potential vanilloid receptor type-1 (TRPV1) with mechanisms not related to its anticholinergic activity, but rather interacting with another binding site on the channel or by acting indirectly as a modulator of the TRPV1 channel [121]. Further insight was given by Mutolo and coworkers that suggested that the down-regulation of cough promoted by tiotropium implied also the involvement of acid-sensing ion channels and mechanoreceptors [122]. …”