Yumie Kamio

Female gender as a determinant of cough threshold to inhaled capsaicin

Chronic, nonproductive cough and cough associated with the use of angiotensin converting enzyme inhibitors, are more frequently observed in females as compared to males. To examine the influence of sex, age, height, weight and pulmonary function on airway cough sensitivity, cough threshold to inhaled capsaicin, an index of the airway cough sensitivity, was measured in 160 nonsmoking, nonatopic healthy subjects. Forty young males (aged 24 +/- 2 yrs) 40 young females (aged 22 +/- 2 yrs) 40 middle-aged males (aged 48 +/- 5 yrs) and 40 middle-aged females (aged 50 +/- 7 yrs) were studied. The cough threshold was defined as the lowest concentration of inhaled capsaicin causing five or more coughs. The cough threshold was 3-5 fold lower in females than in males both in young (p<0.001) and middle-aged (p<0.005) subjects. Cough threshold was weakly but significantly correlated to height, weight, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) when all subjects were considered together but not when each group was considered separately. Multiple regression analysis revealed that sex difference was the significant predictive factor for the cough threshold in either age group. These results confirm that cough sensitivity is heightened in females and suggest that influence of height and pulmonary function on the cough threshold may have resulted from sex difference.

Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid.

BACKGROUND: The direct effect of bronchoconstriction on cough receptor sensitivity is unknown, and the antitussive effect of beta 2 adrenergic agonists in man has been controversial. This study was designed to throw light on these questions. METHODS: The threshold of the cough response to inhaled capsaicin, a stimulant acting on C fibre endings, and tartaric acid, a chemostimulant, was measured before and 10 minutes after inhalation of methacholine, which caused a nearly 20% fall in forced expiratory volume in one second (FEV1), in 14 normal subjects (study 1), and also before and 30 minutes after inhalation of procaterol (30 micrograms), placebo, and saline in eight normal subjects (study 2). Progressively increasing concentrations of capsaicin and tartaric acid solutions were inhaled for 15 seconds by mouth tidal breathing at one minute intervals and cough threshold was defined as the lowest concentration of capsaicin and tartaric acid that elicited five or more coughs. RESULTS: In study 1 the geometric mean values of the cough threshold of response to capsaicin and tartaric acid before methacholine callenge, 2.98 (GSE 1.30) micrograms/ml and 46.6 (1.22) mg/ml, were not significantly different from those of the response to methacholine inhalation, 3.45 (1.33) micrograms/ml and 32.9 (1.37) mg/ml. In study 2 the geometric mean value of the cough threshold of response to capsaicin before inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml) was not different from that after inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml), which had significant bronchodilator effects. The cough threshold was not altered by placebo or saline. CONCLUSIONS: These findings suggest that muscarinic receptor stimulation, bronchoconstriction, beta 2 receptor stimulation, or bronchodilation might have no direct effect on the sensitivity of the cough receptors in normal subjects.

Effect of a leukotriene antagonist, ONO-1078, on bronchial hyperresponsiveness in patients with asthma

To evaluate the involvement of sulphidopeptide leukotrienes on bronchial hyperresponsiveness in asthma, we examined the effects of a specific orally active leukotriene antagonist (ONO-1078) on bronchial responsiveness to methacholine in stable asthmatic subjects by a double-blinded, randomized, two-phase crossover study. Eleven asthmatic subjects received ONO-1078 (225 mg twice a day) or placebo. After 1 week administration of ONO-1078 or placebo, the subjects underwent methacholine challenge test. Test drug administrations were then discontinued for 1 week, and the subjects were then crossed over to the alternative treatment regimen. After 1 week of the alternate regimen, the subjects underwent a second methacholine challenge. Mean baseline values of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) and geometric mean value of provocative concentration of methacholine causing a 20% fall in FEV1 (PC20-FEV1) were equal between the first and the second methacholine test. The geometric mean value of PC20-FEV1 after the administration of ONO-1078 was 0.48 (geometric SEM, 1.48) mg ml-1, which was significantly (P < 0.01) greater than the value after the placebo administration (0.30 geometric SEM, 1.41 mg ml-1), but the baseline values of FVC and FEV1 were not altered by ONO-1078. We conclude that sulphidopeptide leukotrienes are significantly involved in the development of bronchial hyperresponsiveness in asthma but the degree of the involvement may be small.

Cough Receptor Sensitivity and Bronchial Responsiveness in Patients with Only Chronic Nonproductive Cough: In View of Effect of Bronchodilator Therapy

Twenty-two patients with only chronic nonproductive cough lasting for more than 2 months were prospectively examined to determine whether airway cough receptor sensitivity and bronchial responsiveness relate to the efficacy of bronchodilator therapy on the cough. Clenbuterol (10 micrograms, 4 times a day for 1 week) was effective on the cough in 10 patients (group 2) but not in the other 12 patients (group 1). Cough threshold to inhaled capsaicin was significantly less in group 1 than in group 2 at the first visit but not after the therapy when the cough stopped. Bronchial responsiveness to methacholine (PC20-FEV1) was not heightened in group 1, while that in group 2 was hyperreactive. These findings suggest that nonproductive cough is elicited based on two different mechanisms: (1) heightened airway cough receptor sensitivity in bronchodilator-resistant cough and (2) bronchoconstriction in bronchodilator-responsive cough such as cough-variant asthma.

Sex difference in the inhaled tartaric acid cough threshold in non-atopic healthy subjects.

The threshold for cough induced by inhaled tartaric acid was measured in 71 non-atopic healthy volunteers. The cough threshold was lower in women than in men, which may be relevant to previous reports that angiotensin converting enzyme inhibitors induce cough more frequently in women than in men.

Detection of eosinophils in hypertonic saline-induced sputum in patients with chronic nonproductive cough

This study was conducted to examine (1) whether an appropriate sputum can be obtained by inducing with inhalation of hypertonic saline in patients with chronic nonproductive cough and (2) whether eosinophils can be detected in the induced sputum. Appropriate samples were obtained by the induction in 25 of 31 patients with bronchial asthma (BA), 12 of 17 patients with cough-variant asthma (CVA), 17 of 20 patients with bronchodilator-resistant cough associated with atopy (atopic cough, AC), and 23 of 25 healthy subjects. Eosinophils were detected in the successfully induced sputum in 100%, 66.6%, and 88.2% of the patients with BA, CVA, and AC, respectively. Detection of eosinophils in induced sputum may be the initial diagnostic procedure for nonproductive cough of allergic nature.

Airway cough sensitivity to inhaled capsaicin and bronchial responsiveness to methacholine in asthmatic and bronchitic subjects

Abstract The objective of this study was to evaluate the effect of chronic airway inflammation on airway cough sensitivity and non‐specific bronchial responsiveness, and the relationship between them. The capsaicin cough threshold, defined as the lowest concentration of capsaicin causing five or more coughs, and non‐specific bronchial responsiveness, defined as the methacholine concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1) (PC20‐FEV1)were measured in 18 asthmatic, 13 bronchitic (sinobronchial syndrome) and 28 healthy non‐atopic subjects. All subjects were non‐smoking men. The geometric mean values (μmol) of the cough threshold were 18.9 (GSEM 1.29), 8.69 (GSEM 1.29) and 27.6 (GSEM 1.31) in asthmatic, bronchitic and normal subjects, respectively. The value in bronchitic subjects was significantly lower (P“0.02) than that in normal subjects. The geometric mean value of PC20‐FEV1 in asthmatic subjects (0.48mg/ml (GSEM 1.38)) was significantly lower than that in bronchitic subjects (18.5mg/ml (GSEM 1.75)) (P“0.001). There was no correlation between cough threshold and PC20‐FEV1 values (correlation coefficient (r)= 0.155). These results indicate that cough sensitivity is potentiated by chronic airway inflammation in bronchitis but not in asthma, and suggest that cough sensitivity and bronchial responsiveness may be independently potentiated by different mechanisms resulting from chronic airway inflammation.

Atopy in cough sensitivity to capsaicin and bronchial responsiveness in young females

We have shown previously that female sex is a determinant of cough sensitivity to inhaled capsaicin, but the relationship between atopy and the cough sensitivity has not been examined. The capsaicin cough threshold, defined as the lowest concentration of capsaicin causing five or more coughs, nonspecific bronchial responsiveness, defined as the provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20), total immunoglobulin E (IgE) and specific IgEs to eight common aeroallergens (house dust 1, 2 and 6, Dermatophagoides pteronyssinus and D. farinae, Japanese cedar, ragweed and orchard grass) in the serum were measured in 71 nonsmoking, healthy young women aged 20.6+/-0.1 yrs (mean+/-EM). A structured interviewer-led questionnaire on allergic diseases revealed that one and six subjects had mild current and past asthma, respectively. These seven subjects were excluded from the data analysis. PC20 was significantly lower in 42 subjects showing a positive specific IgE than in 22 subjects showing a negative specific IgE to any of the eight allergens (p<0.05), while the capsaicin cough threshold was not significantly different between the subgroups. PC20 was significantly lower in subjects with positive specific IgE to Dermatophagoides and house dust, but not to the three kinds of pollen examined. It was confirmed that atopy indicated by specific immunoglobulin E to mite-related antigens, but not to pollen antigens, is associated with nonspecific bronchial responsiveness, and it is suggested that atopy is not a determinant of airway cough sensitivity in healthy, nonasthmatic subjects.

Effect of inhaled procaterol on cough receptor sensitivity to capsaicin in patients with asthma or chronic bronchitis and in normal subjects.

BACKGROUND--To evaluate the effect of inhaled beta 2 adrenergic agonists on the sensitivity of airway cough receptors, the effect of inhaled procaterol on cough induced by aerosolised capsaicin, a stimulant of C fibres, was studied in patients with asthma or chronic bronchitis and in normal subjects. METHOD--Eleven patients with asthma and 10 with chronic bronchitis and 14 normal subjects participated. Increasing concentrations of capsaicin solution were inhaled for 15 seconds by tidal breathing through the mouth at one minute intervals until five or more coughs were elicited, before and 30 minutes after inhalation of 20 micrograms procaterol or placebo (freon gas alone) through a metered dose inhaler. Cough threshold was defined as the lowest concentration of capsaicin that elicited five or more coughs. To evaluate the bronchodilator effect of procaterol and the bronchoconstrictor effect of inhaled capsaicin, forced expiratory volume in one second (FEV1) was measured before and one minute after a capsaicin provocation test. This test was carried out both before and 30 minutes after treatment with procaterol or placebo. RESULTS--The geometric mean value of cough threshold to capsaicin was significantly increased by procaterol and placebo in both groups of patients but not in the control subjects. The increment in the cough threshold was not significantly different between the treatments with procaterol and placebo in each group. FEV1 was significantly increased by procaterol but not by placebo in all three groups. CONCLUSIONS--Inhaled procaterol has no effect on airway cough receptor sensitivity to capsaicin. The attenuation of the cough sensitivity seen after inhalation of procaterol in patients with asthma and bronchitis may result from tachyphylaxis to capsaicin.

Effect of oral mexiletine on the cough response to capsaicin and tartaric acid

BACKGROUND The effect of the orally active local anaesthetic mexiletine on the cough response to two different tussive agents, a C-fibre ending stimulator capsaicin and a chemostimulant tartaric acid, was examined in normal subjects. METHODS The cough threshold, defined as the lowest concentration of capsaicin (C5-CP) or tartaric acid (C5-TA) causing five or more coughs, and histamine induced bronchoconstriction were measured three hours after a single oral dose of 300 mg mexiletine or placebo in 14 normal subjects. RESULTS Mexiletene in a mean (SE) serum concentration of 0.99 (0.04) μg/ml significantly increased C5-TA from a geometric mean (SE) of 32.0 (1.27) mg/ml with placebo to 49.9 (1.34) mg/ml, but C5-CP did not differ significantly between treatment with mexiletine (12.2 (1.33) μM) and placebo (14.9 (1.23) μM). CONCLUSIONS These results suggest that the cough response to capsaicin and tartaric acid may be mediated in part via different neural pathways.