Citric acid induced cough

Fig. 4 Selective activation of pulmonary C-flbers arising from the nodose ganglia with either adenosine or 2-methyl-5-hydroxytryptamine (a 5-HT3 receptor selective agonist) markedly inhibits citric acid induced coughing in anesthetized guinea pigs, while intrapulmonary RAR activation by histamine is without effect. Citric acid (0.001-2 M) was applied topically to the tracheal mucosa in 100 — pL ahquots at 1-min intervals and in ascending concentrations. Each bar represents the mean SEM cumulative number of coughs evoked by citric acid in five to six experiments...

Suppressive effect of clenbuterol on citric acid-induced cough reflex in guinea pigs. Res Commun Mol Pathol Pharmacol 88(3) 293-301... 

Another Kca that may modulate airway afferent nerve excitability is the large conductance Ca +-activated channel (BKca). An opener of this channel, NS 1619, inhibited citric acid induced cough in conscious guinea pigs and inhibited the generation of action potentials in guinea-pig fracheal A5 and C fibers in vifro (Fox et al. 1997). The effects of NS 1619 on A8 and C fibers were prevented by iberi-otoxin, a BKca channel-selective blocker. 

Danzon A, Lacroix J, Infante-Rivard C, Chicoine L (1988) A double-blind clinical trial on diphenhydramine in pertussis. Acta Paediatr Scand 77 614-615 Daoui S, Cognon C, Naline E, Emonds-Alt X, AdvenierC (1998) Involvement of tachykinin NK3 receptors in citric acid-induced cough and bronchial responses in guinea pigs. Am J Respir Crit Care Med 158 42-48... 

Moreaux B, Nemmar A, Vincke G, Halloy D, Beerens D, Advenier C, Gustin P (2000) Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs. Eur J Pharmacol 408 305-312... 

Yasumitsu R, Hirayama Y, Imai T, Miyayasu K, Hiroi J (1996) Effects of specific tachykinin receptor antagonists on citric acid-induced cough and bronchoconstriction in unanesthetized guinea pigs. Eur J Pharmacol 300 215-219... 

Morice AH, Marshall AE et al (1994) Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 49 1024-1026... 

Morice AH, Marshall AE, Higgins KS, Grattan TJ (1994) Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 49 1024-1026 Morice AH, Kastehk JA, Thompson R (2001) Cough challenge in the assessment of cough reflex. Br J Chn Pharmacol 52 365-375... 

Rostami-Hodjegan A, Abdul-Manap R, Wright CE, Tucker GT, Morice AH (2001) The placebo response to citric acid-induced cough Pharmacodynamics and gender differences. Pulm Pharmacol Ther 14 315-319... 

In healthy subjects, menthol vapor inhibits citric acid induced cough, unlike other aromatic oils which were used to act as placebos (Packman and London 1980 Morice et al. 1994). Unfortunately no properly designed clinical trials of vaporized menthol against cough seem to have been done, possibly for lack of an adequate placebo, but the basic studies suggest that it is potentially an active antitussive. 

A non-peptide NK3 receptor antagonist (SB235375), with low penetrance into the central nervous system, inhibited citric acid induced cough and airways hyperreactivity in the guinea pig (Hay et al. 2002 Daoui et al. 1998) but its development has been suspended. 

Despite being used as a component in cough remedies since the introduction of a VapoRub in 1890, there are few human trials of menthol used alone as being effective. In a citric acid-induced cough model in healthy subjects. Packman and London (1980) found that menthol was effective, although 1,8-cineole was more ef cacious. The use of an aromatic unction rather than direct inhalation may have affected the results, since the inhalation of menthol has been shown in animal models to be signi cantly more effective at cough frequency reduction (28% and 56% at 10 and 30 pg/L, respectively) when compared to 1,8-cineole (Laude et al., 1994). 

A single-blind pseudo randomized crossover trial in 42 healthy children was used to compare the effect of an inhalation of either menthol or placebo on citric acid-induced cough. It was found that cough frequency was reduced in comparison to the baseline but not to that of the placebo (Kenia et al., 2008). However, the placebo chosen was eucalyptus oil, whose main component is 1,8-cineole and known to have similar antitussive properties to menthol. 

In a randomized, placebo controlled trial of citric acid-induced cough in 20 healthy subjects, the inhalation of a combination of menthol and eucalyptus oil (75% and 25%, respectively) signi cantly decreased the cough frequency (Morice et al., 1994). 

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