Abstract
A study was conducted with a Guinea Pig (GP) cough model to demonstrate that post-inhalation (PI) cough can be correlated and predicted with the acidity constant of the chemical stimulant. The test animals were exposed to nebulized solutions of citric acid and maleic acid. Cough responses were measured by audio, video, and respiratory flow signals via whole-body plethysmography. Nonparametric one-way ANOVA (Kruskal-Wallis) of cough counts showed statistically significant dose dependence for both citric acid (p<0.0001) and maleic acid (p<0.0001). For citric acid, post-hoc Dunn’s test indicated elevated cough response at the higher concentrations (p ≤ 0.0001 for 200 mM, and 300 mM) compared to control, i.e., isotonic saline (SL). The cough count at 100 mM citric acid was not significantly different from SL (p>0.05). Similar results were obtained for maleic acid exposures, with cough response at the higher concentrations significantly different compared to SL (p=0.0039 for 50 mM, p<0.0001 for 100 mM), while cough counts at 30 mM were not different compared to SL. The GP model is able to differentiate the cough response of maleic acid vs. citric acid, and the threshold of cough (1-2 coughs in 2 min) for maleic acid (~30 mM) is lower than that for citric acid (~100 mM). The lower threshold of cough for maleic acid as compared to citric acid is consistent with the mechanism of action mediated by protons, in a dose dependent way. A prediction of the cough response from citric acid to maleic acid was confirmed by this study. Experiments with nebulized acids confirmed expectations that the threshold of cough for citric acid in GP is at 100 mM and for maleic acid at 10- 30 mM. The lower cough threshold for maleic vs. citric acid is consistent with proton-mediated mechanism of action.
Highlights
The literature on acid-evoked cough is extensive[1,2,3,4,5,6], and the subject matter is accessible for study via animal models
The test animals were exposed to nebulized solutions of citric acid and maleic acid, relatively straightforward to prepare and aerosolize
Similar results were obtained for maleic acid exposures, with cough response at the higher concentrations significantly different compared to SL (p=0.0039 for 50 mM, p
Summary
The literature on acid-evoked cough is extensive[1,2,3,4,5,6], and the subject matter is accessible for study via animal models. It was reported that citric acid-evoked coughing observed in anesthetized guinea pigs (GP) could be mimicked by administration of hydrochloric acid but not by sodium citrate[1]. Citric acid-evoked coughing in anesthetized GPs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels[1]. Chronic cough has often been considered to be caused by gastro-oesophageal reflux, post-nasal drip, or asthma. New insights in chronic cough revealed two important mechanisms that http://www.imedpub.com/advanced-drug-delivery/
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