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

Abstract

Long-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 μg/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 μg, 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.

Introduction

Cough is a very important airway defensive reflex [1], [2], [3], [4] and is the most common symptom for which patients seek medical advice. Despite considerable efforts in the last decades to find appropriate therapies, a safe and effective cough remedy is still lacking [5], [6], [7], [8], [9], [10], [11].

Inhaled bronchodilator therapies with long-acting muscarinic receptor antagonists (LAMAs) are of crucial importance for chronic obstructive pulmonary disease (COPD) management and cause an improvement in symptoms including cough ([12], [13], [14], [15], [16] also for further Refs.). Tiotropium was the first LAMA, reaching the market in 2002 [17]. Dicpinigaitis et al. [18] reported that tiotropium (1 h after its inhalation) inhibits cough induced by capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) agonist, in patients with upper respiratory tract infections. Furthermore, tiotropium inhalation has been shown to improve cough and other symptoms in patients with chronic pulmonary disease due to sulphur mustard lung injury [19]. More recently, it has been shown that inhaled tiotropium attenuates after 1 h cough induced by capsaicin in the guinea pig and that this effect is mediated by TRPV1 receptors through a mechanism unrelated to its anticholinergic activity [17]. However, Clay et al. [7] have reported that, in contrast to the guinea pig, the ozone-induced hypertussive responses to citric acid are not inhibited by tiotropium in the rabbit.

Aclidinium bromide is a LAMA that has recently been approved as a maintenance bronchodilator treatment for patients with COPD and asthma [14], [20], [21]. In clinical studies, aclidinium provides greater improvements in COPD symptoms, including cough, than tiotropium and is well tolerated, with a similar safety profile [12], [13]. A recent study in the guinea pig chronically exposed to cigarette smoke (an experimental model of COPD) indicates that aclidinium, in addition to beneficial effects on lung structure and function, shows a trend toward fewer cough episodes [22]. A comparative study on the antitussive effects of aclidinium and tiotropium in animal models is lacking.

The present study was undertaken to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex in the rabbit. The two drugs were administered by inhalation, whilst the cough reflex was evoked by citric acid inhalation in awake animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals [8], [9], [10], [11], [23], [24], [25], [26], [27], [28].