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EFFECT OF CENTRALLY AND PERIPHERALLY ACTING GABAB AGONISM ON THE COUGH REFLEX
  • +7
  • Huda Badri,
  • Carmen Gibbard,
  • Dimitra Denton,
  • Imran Satia,
  • Rachel Dockry,
  • Kimberley Holt,
  • Graeme Wilkinson,
  • Alison Holt,
  • Brendan Canning,
  • Jaclyn A. Smith
Huda Badri
The University of Manchester Faculty of Biology Medicine and Health
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Carmen Gibbard
The University of Manchester Faculty of Biology Medicine and Health
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Dimitra Denton
The University of Manchester Faculty of Biology Medicine and Health
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Imran Satia
The University of Manchester Faculty of Biology Medicine and Health
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Rachel Dockry
The University of Manchester Faculty of Biology Medicine and Health
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Kimberley Holt
The University of Manchester Faculty of Biology Medicine and Health
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Graeme Wilkinson
AstraZeneca Medimmune Cambridge
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Alison Holt
AstraZeneca Medimmune Cambridge
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Brendan Canning
Johns Hopkins Asthma and Allergy Center
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Jaclyn A. Smith
University of Manchester, Manchester University NHS Foundation Trust and Manchester Academic Health Science Centre
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Abstract

Background: Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABAB receptors in both the peripheral and central nervous systems inhibit cough. Objective: To compare the effect of central and peripherally acting GABAB agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. Methods: We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120mg MR), with baclofen (40mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). Results: Fifteen patients enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p=0.04], but had no effect on ED50 [geometric mean 47.4µM (95%CI 24.4-91.7) vs 37.6 µM (95%CI 19.2-73.5), p=0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p=0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2µM (95%CI 37.2-151.8), p=0.002). Conclusion: This data suggests the anti-tussive actions of GABAB agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.