title: Olodaterol attenuates citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs.
abstract: Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the cough reflex, the mechanism underlying the pro-tussive property of indacaterol is not known.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Respiratory Diseases Research, Biberach a. d. Riss, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wex
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Respiratory Diseases Research, Biberach a. d. Riss, Germany.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bouyssou
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage / Q000627:therapeutic use*; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D008297:Male
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000996:Antitussive Agents; D048588:Benzoxazines; D019343:Citric Acid; C549647:olodaterol