OBJECTIVE: Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). METHODS: A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods. Patients were monitored for cough for 8 hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. RESULTS: Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. CONCLUSIONS: While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough. .
OBJECTIVE: Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). METHODS: A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods. Patients were monitored for cough for 8 hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. RESULTS: Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. CONCLUSIONS: While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough. .
Authors: Philip W Rouadi; Samar A Idriss; Jean Bousquet; Tanya M Laidlaw; Cecilio R Azar; Mona S Al-Ahmad; Anahi Yañez; Maryam Ali Y Al-Nesf; Talal M Nsouli; Sami L Bahna; Eliane Abou-Jaoude; Fares H Zaitoun; Usamah M Hadi; Peter W Hellings; Glenis K Scadding; Peter K Smith; Mario Morais-Almeida; René Maximiliano Gómez; Sandra N Gonzalez Diaz; Ludger Klimek; Georges S Juvelekian; Moussa A Riachy; Giorgio Walter Canonica; David Peden; Gary W K Wong; James Sublett; Jonathan A Bernstein; Lianglu Wang; Luciana K Tanno; Manana Chikhladze; Michael Levin; Yoon-Seok Chang; Bryan L Martin; Luis Caraballo; Adnan Custovic; Jose Antonio Ortego-Martell; Olivia J Ly Lesslar; Erika Jensen-Jarolim; Motohiro Ebisawa; Alessandro Fiocchi; Ignacio J Ansotegui Journal: World Allergy Organ J Date: 2022-05-14 Impact factor: 5.516
Authors: Luis Puente-Maestu; Jesús Molina-París; Juan A Trigueros; J Tomás Gómez-Sáenz; Luis Cea-Calvo; Sabela Fernández; Marta Sánchez-Jareño; Javier Domínguez-Ortega Journal: Lung Date: 2021-09-17 Impact factor: 2.584
Authors: Kai K Lee; Paul W Davenport; Jaclyn A Smith; Richard S Irwin; Lorcan McGarvey; Stuart B Mazzone; Surinder S Birring Journal: Chest Date: 2020-09-02 Impact factor: 9.410