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TRPV1 Antagonism in Refractory Chronic Cough: A Double Blind Randomised Controlled Trial
Saifudin Khalid, Robert Murdoch, Amy Newlands, Kevin Smart, Angela Kelsall, Kimberley Holt, Rachel Dockry, Ashley Woodcock and Jaclyn A. Smith
Journal of Allergy and Clinical Immunology. 2014;:56-62.
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Abstract
Background: Inhalation of the extract of hot chilli peppers, capsaicin, induces coughing in both animals and humans, via activation of Transient Receptor Potential Vanilloid 1 (TRPV1) on airway sensory nerves. The TRPV1 receptor is therefore an attractive target for the development of anti-tussive agents. Objective: To assess the anti-tussive effect of TRPV1 antagonism in patients with refractory chronic cough. Methods: Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic, were recruited to a randomised, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (C5) and 24hr cough frequency were co-primary endpoints, assessed following a single dose of SB-705498 (600mg) and matched placebo. Cough severity and urge to cough were reported on visual analogue scales and cough specific quality of life also collected. Results: Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2hrs and a borderline significant improvement at 24hrs compared with placebo; adjusted mean difference of +1.3 doubling doses at 2hrs (95% CI +0.3 to +2.2), p=0.0049 and +0.7 at 24hrs (95% CI +0.0 to +1.5), p=0.0259. However, 24hr objective cough frequency was not improved compared with placebo. Patient reported cough severity, urge to cough and cough specific quality of life similarly suggested no effect of SB-705498. Conclusion: This study raises important questions about both the role of TRVP1 mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel anti-tussive agents.
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