Background Previous studies have shown a reduction in cough response to inhaled citric acid after blocking NK1, NK2 and also NK3 receptors in guinea pigs. NK3 receptor may be more relevant to study the role of tachykinins in cough due to their greater specificity for its agonist neurokinin B. We studied a specific NK3 receptor antagonist Talnetant to determine the effect on the human cough reflex sensitivity to citric acid in healthy individuals. Oral codeine and placebo were included as comparators.
Methods Double-blind, randomised, placebo-controlled, 4-period cross-over study in non-smoking healthy adult volunteers. A total of 28 subjects (12M, 16F) with mean age of 33 years (SD 10.5, range 22–55) were studied. Each subject received A. matched placebos; B. Talnetant 200 mg; C.Talnetant 25 mg; D. Codeine 60 mg, in a double blind double dummy manner. Subjects were randomly assigned to one of four treatment sequences (ABCD, BCDA, DCAB, BDCA). Each study period was 24 h with citric-acid challenges performed at 2, 6, 10 and 24 h post dose and a 7 day washout period between treatments.
Results There was no significant difference in logC5 Citric acid between Talnetant 25 mgs, 200 mgs and placebo at any time point (see Abstract S114 Figure 1). The ‘positive’ control codeine had a non-significant trend for improvement in logC5 compared to placebo (all confidence intervals contained unity). Talantent was adequately absorbed with sustained blood levels at time points designed to coincide with the cough challenges.
Conclusions In healthy volunteers, Talnetant had no significant effect on cough reflex sensitivity to citric acid despite an adequately powered study and sufficient systemic drug exposure. Possible explanations for this lack of efficacy are (1) NK3 receptors do not play an appreciable role in the healthy human cough reflex or (2) the role of NK3 receptors may be limited to the central nervous system where Talnetant has limited penetrance and receptor occupancy. Whilst this study suggests predominantly peripherally acting NK3 receptor antagonists do not influence the cough reflex in healthy volunteers, a significant effect in patients with a hypersensitive cough reflex cannot be excluded and this class of drugs may yet prove to have anti-tussive properties, especially with improved central activity.
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