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P11 The Role Of Gabab Receptor Mechanisms In The Human Cough Reflex
  1. H Badri1,
  2. CL Gibbard1,
  3. D Valdramidou1,
  4. BJ Canning2,
  5. LA Houghton3,
  6. A Holt4,
  7. G Wilkinson4,
  8. JA Smith1
  1. 1Centre for Respiratory and Allergy, University of Manchester, Manchester, UK
  2. 2Asthma and Allergy Centre, Johns Hopkins Medical Institutes, Baltimore, USA
  3. 3Mayo Clinic, Florida, USA
  4. 4AstraZeneca R&D, Emerging Innovations Unit, Scientific Partnering and Alliances, Cheshire, UK

Abstract

Background Chronic cough represents an important unmet clinical need. Gamma-aminobutyric acid is a major inhibitory neurotransmitter in the central nervous system (CNS). GABAB receptors have been identified peripherally, as well as centrally. Studies in guinea-pigs, have suggested that the activation of GABAB receptors in the CNS and PNS can inhibit cough. The only clinically available GABAB agonist is Baclofen, and although it has been shown to suppress cough in animals and humans, it causes drowsiness as it is centrally acting. Lesogaberan, is a novel, predominantly peripherally acting GABAB agonist.

Objective To determine whether both peripherally acting (Lesogaberan) and centrally acting (Baclofen) GABAB agonists modulate cough responses to inhaled capsaicin compared with placebo in healthy volunteers.

Methods Single centre, double-blind, double-dummy, three-way crossover trial in healthy controls of Lesogaberan (120 mg MR), Baclofen (40 mg) and placebo. Subjects were treated with single doses of each study medication with a washout period of ≥7 days between doses. Cough responses to inhaled capsaicin were assessed using a novel challenge protocol (1) measured at screening and 2 hrs post dosing (tmax) on each study day. The primary end point was the maximum number of coughs evoked at any concentration of capsaicin (Emax). The secondary end point was the concentration of capsaicin evoking 50% of the maximal response (ED50).

Results There were 15 patients enrolled onto the study with a median age of 29 years old (IQR25–44); 7 female; mean BMI was 24.6 (±3.0).

Lesogaberan treatment was associated with a small, statistically significant increase in Emax (mean 13.4 coughs, 95% CI 10.1–17.9) compared with placebo (11.8, 95% CI 8.8–15.9) (p = 0.04), but had no effect on ED50 (geometric mean 47.4 µM 95% CI 24.4–91.7 vs Placebo 37.6 95% CI 19.2–73.5 p = 0.37), see Figure 1.

In contrast, Baclofen had no significant effect on Emax (11.1, CI8.1–15.4) (p = 0.23), but, ED50 was significantly increased compared with placebo (geometric mean 75.2 µM 95% CI 37.2–151.8 p = 0.002).

Conclusion This data suggests the anti-tussive actions of GABAB agonists, against capsaicin-induced cough in healthy volunteers, occurs in the central rather than the peripheral nervous system.

References

  1. Allergy Clin Immunol. 2013 Oct;132(4):847–55

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