Cough and airway irritation with inhaled treprostinil does not involve activation of laryngeal reflexes.

Abstract

Introduction: Cough and airway irritation are adverse effects (AEs) associated with inhaled treprostinil (TRE). The site of action causing these AEs is unknown. Aim: Nebulized TRE, at a concentration that causes cough in guinea pigs, was administered to the isolated laryngeal airway of rats and guinea pigs to determine if the actions of TRE involved activation of laryngeal reflexes. Methods: The laryngeal airway was isolated in anesthetized male Sprague Dawley rats and Dunkin Hartley guinea pigs for administration (20 sec) of either nebulized TRE (30 µg/mL), citric acid (CA), hypertonic saline (HS) or phosphate buffered saline (PBS). Pulmonary airflow and expiratory duration (TE) were measured with a pneumotachograph connected to a tracheal catheter. The apneic index (TE post-challenge/TE pre-challenge), mean arterial blood pressure (MAP), heart rate (HR), arterial oxygen saturation (SaO2) and the number of swallows were measured before and after drugs. Results: In rats, nebulized CA (0, 0.01, 0.1 and 1 M) increased the apneic index (1, 32, 90, 101, respectively), MAP and swallowing and decreased SaO2 and HR. Similar effects occurred with nebulized HS (1.5, 3, 5 and 7 %). However, nebulized TRE (30 µg/mL), like nebulized PBS had no effects. In guinea pigs, nebulized CA (0, 0.1 and 1 M) increased the apneic index (2, 3 and 15, respectively) and produced cough and swallowing. Nebulized TRE (30 µg/mL) had no effects. Conclusions: These results demonstrate that nebulization of TRE to the laryngeal airway of rats and guinea pigs does not produce cough and airway irritation and suggest that sites more distal in the tracheobronchial tree and lung are involved.