Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough

Jaclyn A. Smith*, Lorcan P.A. McGarvey, Huda Badri, Imran Satia, Francis Warren, Sarah Siederer, Lia Liefaard, Robert D. Murdoch, Kathryn Povey, Joanna Marks-Konczalik

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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/pla-cebo 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.

Original languageEnglish
Pages (from-to)712-719
Number of pages8
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume55
Issue number9
DOIs
Publication statusPublished - 1 Sept 2017

Keywords

  • Capsaicin challenge
  • Citric acid challenge
  • Cough
  • GSK2339345
  • Voltage-gated sodium channels

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