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

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

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Abstract

Objective: Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibres 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 randomised, 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 analysed 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. Eight 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 two 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
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Early online date06 Jul 2017
DOIs
Publication statusEarly online date - 06 Jul 2017

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    Smith, J. A., McGarvey, L., Badri, H., Satia, I., Warren, F., Siederer , S., Liefaard , L., Murdoch, R. D., Povey , K., & Marks-Konczalik , J. (2017). Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough. International Journal of Clinical Pharmacology and Therapeutics. https://doi.org/10.5414/CP202804