Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil.

Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved in TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS). Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously. In guinea pigs, cough with inhaled TRE (1.23 µg·kg ^-1 ) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg ^-1 ) to induce cough. TRE cough was blocked with IP and tachykinin NK ₁ receptor antagonists but not with EP ₁ , EP ₂ , EP ₃ , DP ₁ or bradykinin B ₂ antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnoea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects. The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibres in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves.
Competing Interests: Conflict of interest: R.W. Chapman is an employee of Insmed Incorporated. Conflict of interest: M.R. Corboz is an employee of Insmed Incorporated. Conflict of interest: C. Fernandez is an employee of Insmed Incorporated. Conflict of interest: E. Sullivan is an employee of Insmed Inc. Conflict of interest: A. Stautberg is an employee of Insmed Incorporated. Conflict of interest: A.J. Plaunt is an employee of Insmed Incorporated. In addition, he has patents pending or issued (patent numbers US 10,010,518, US 10,526,274, US 9,255,064 and US 9,469,600) related to treprostinil palmitil and methods of treatment via administration of treprostinil palmitil. Conflict of interest: D.M. Konicek is an employee of Insmed Incorporated. In addition, she has patents pending or issued (patent numbers US 10,010,518, US 10,526,274, US 9,255,064 and US 9,469,600) related to treprostinil palmitil and methods of treatment via administration of treprostinil palmitil. Conflict of interest: V. Malinin is an employee of Insmed Incorporated. In addition, he has patents pending or issued(patent numbers US 10,010,518, US 10,526,274, US 9,255,064 and US 9,469,600) related to treprostinil palmitil and methods of treatment via administration of treprostinil palmitil. Conflict of interest: Z. Li is an employee of Insmed Incorporated. In addition, he has patents pending or issued(patent numbers US 10,010,518, US 10,526,274, US 9,255,064 and US 9,469,600) related to treprostinil palmitil and methods of treatment via administration of treprostinil palmitil. Conflict of interest: D. Cipolla is an employee of Insmed Incorporated. Conflict of interest: W. Perkins is an employee of Insmed Incorporated. In addition, he has patents pending or issued(patent numbers US 10,010,518, US 10,526,274, US 9,255,064 and US 9,469,600) related to treprostinil palmitil and methods of treatment via administration of treprostinil palmitil.
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