ABSTRACT (250 words)
Background and Purpose : 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. This
study compares the effect of central and peripherally acting
GABAB agonists (lesogaberan and baclofen) on the cough
reflex in healthy volunteers (HV).
Experimental Approach: Single center, double-blind,
double-dummy, three-way crossover trial in HV comparing single doses of
lesogaberan, with baclofen 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).
Key Results: Fifteen HV were enrolled (median age 29 (IQR
25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan (120mg MR)
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 (40mg) 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 and Implications: This data suggests the
anti-tussive actions of GABAB agonists, in HV, occur in
the central rather than the peripheral nervous system.