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A Physicochemical Assessment of Acid-induced Post-inhalation Cough in Guinea Pigs Animal Model

Blasko, Andrei and Rao, Raj and Kuehl, Philip J. and Holmes, Thomas D. and Reed, Matthew D. and Xu, Fadi and Zhuang, Jianguo (2017) A Physicochemical Assessment of Acid-induced Post-inhalation Cough in Guinea Pigs Animal Model. American Journal of Advanced Drug Delivery, 5 (4). pp. 131-138. ISSN ISSN 2321-547X

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 (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) 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 0.1 M and for maleic acid at 0.01 - 0.03 M. The lower cough threshold for maleic vs. citric acid is consistent with proton-mediated mechanism of action.

Item Type: Article
Date Deposited: 02 Jan 2018 00:45
Last Modified: 02 Jan 2018 00:45
URI: https://oak.novartis.com/id/eprint/33837

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