Action of budesonide on asthmatic bronchial hyperresponsiveness. Effects on directly and indirectly acting bronchoconstrictors.

We have investigated the effects of inhaled budesonide on the bronchial responsiveness to both directly and indirectly acting spasmogens in man. Following treatment with budesonide or placebo for three weeks in a double-blind, crossover trial with a three-week washout, the response to histamine and bradykinin was determined in ten patients with mild asthma. After treatment with budesonide, the response to both inhaled histamine and bradykinin was decreased when compared with placebo. The PD35 histamine was increased by 1.95 doubling doses and PD35 bradykinin by 2.1 doubling doses. Daily (PEF) recordings were significantly increased during budesonide therapy, the morning PEF by 34.8 +/- 14.1 L/min and evening by 50.3 +/- 23.1 L/min. Baseline laboratory lung function on the study days was not altered by budesonide nor were symptom records altered significantly. Inhaled budesonide therefore inhibits to the same extent the exaggerated response to both directly acting histamine and bradykinin which acts through airway nerves.

A comparison of the effect of inhaled diuretics on airway reflexes in humans and guinea pigs.

The effects of nebulized diuretics on citric acid-induced cough and airway obstruction in guinea pigs and capsaicin-induced cough and increase in airway resistance in humans have been studied. Half-maximum inhibition of cough in the guinea pig was produced by 1.3 mM furosemide and 0.25 mM hydrochlorothiazide. Cough was inhibited by 78 +/- 9% by 3 mM furosemide (P less than 0.05) and 89 +/- 11% by 3 mM hydrochlorothiazide (P less than 0.01). At the same time, airway obstruction was inhibited by 50 +/- 9% (P less than 0.001) and 42 +/- 15% (P less than 0.05), respectively. Nebulized furosemide (3 mM) was without effect on the airway obstruction produced by inhaled histamine or acetylcholine in the guinea pigs. Intravenously administered furosemide (270 nmol/kg) did not affect citric acid-induced responses. In humans, aerosolized furosemide (9 mM) and hydrochlorothiazide (3.4 mM) reduced the percent increase in respiratory resistance from 22.1 +/- 3.7 and 15.6 +/- 3.4 to 10.5 +/- 4.9 and 9.4 +/- 3.3%, respectively (P less than 0.05), but were without effect on cough due to capsaicin. Thus both furosemide and hydrochlorothiazide inhibited airway obstruction in the guinea pig and reduced the capsaicin-induced increase in airway resistance in humans. However, whereas coughing was inhibited in the guinea pig, neither drug affected cough in humans. This difference in the action of the loop diuretic and thiazide, which interact differently with Na(+)-K(+)-Cl-transport within the airway mucosa, on the cough and airflow obstruction in guinea pig and humans supports the view that different sensory limbs are involved in these reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhaled nicotine in humans: effect on the respiratory and cardiovascular systems.

Inhalation of nicotine (0-64 mg/ml) and capsaicin (2 x 10(-6)-2.5 x 10(-4) M) in 24 healthy nonsmoking subjects produced a concentration-dependent cough response. Two subjects coughed to capsaicin but not to nicotine. The mean (95% confidence interval) nicotine concentrations causing two and five coughs were 5.5 (3.5-8.7) and 15.8 (10.0-25.1) mg/ml, respectively, and were reproducible over 3 different days. Capsaicin inhalation did not alter the response to nicotine and vice versa. Both agents increased respiratory resistance, but the response was more rapid to capsaicin. Inhalation of nicotine (0-8 mg/ml) over 5 min caused increases in heart rate and blood pressure and a decrease in skin temperature. Inhaled ipratropium bromide (0.50 mg) had an antitussive effect and also inhibited the nicotine-induced bronchoconstriction, indicating a vagally mediated effect. Sodium cromoglycate (0.20 mg) did not affect cough or airway resistance changes caused by nicotine. This study shows that inhaled nicotine produces a concentration-dependent cough and airway obstruction in healthy subjects, probably because of stimulation of afferent nerve endings in the bronchial mucosa and mediated through parasympathetic cholinergic pathways. Respiratory reflexes evoked by nicotine are similar to those produced by capsaicin, but it is unclear whether these reflexes are mediated by the same type of sensory nerves.

Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans.

To determine the site of action of opiates in humans, we have studied the effect of systemic and inhaled opiates on cough and increase in respiratory resistance (Rrs) caused by inhaled capsaicin. In 13 subjects, a range of doses of capsaicin inhaled in single breaths given in random order produced a reproducible dose-cough response. Inhalation of a dose of capsaicin that caused fewer than two coughs increased Rrs by 28% (21-35, mean 95% confidence interval). Inhaled codeine (50 mg) and morphine (10 mg) did not alter the cough response. In contrast, both drugs increased base-line Rrs by 24% (16-44) and 13% (3-23), respectively, and significantly reduced the increase in Rrs after inhaled capsaicin (P less than 0.05). Oral codeine (60 mg) significantly (P less than 0.05) reduced the number of coughs at 1 and 2 h but did not alter base-line Rrs or its increase after capsaicin. Intravenous morphine (0.15 mg/kg) significantly reduced the sensitivity of the cough response (P less than 0.05), which was reversed by naloxone. However, there was no significant drug effect on either the base-line Rrs or its increase after capsaicin. Systemic dosing of opiates is therefore required to reduce the cough reflex, whereas inhaled opiates may reduce the increase in Rrs after inhaled capsaicin.

Bronchial hyperresponsiveness in patients recovering from acute severe asthma.

Bronchial hyperresponsiveness is widely recognized as a marker of airway inflammation in asthma. The degree of bronchial hyperresponsiveness following acute severe attacks of asthma and the time course of its recovery has not previously been studied. Bronchial responsiveness to histamine was measured in 18 unselected patients admitted to hospital because of acute severe asthma, during their acute admission, and geometric mean PD20 histamine was 0.08 (range 0.02-0.32) mumol. In nine patients, further measurements were performed at 3-4 and 12 weeks following discharge. Geometric mean PD20 histamine was 0.09 mumol acutely, 0.23 mumol at 3-4 weeks (n = 9, p = 0.05 by analysis of variance) and 0.59 mumol at 12 weeks (n = 8, P = 0.04). For the eight patients studied at 12 weeks, a mean 10.3-fold increase in PD20 was shown, with no suggestion of a maximum effect having been achieved. In contrast, spirometry had returned to the normal range by 4 weeks. The dissociation between improvement in bronchial hyperresponsiveness and spirometry is of interest. The delayed reduction in hyperresponsiveness may have important clinical implications for the duration of anti-inflammatory corticosteroid treatment following acute severe asthma.

Sensitivity of the cough reflex in patients with chronic cough.

Cough may occur in association with excess bronchial secretions and may, therefore, be productive. However, in a proportion of patients the cough is non-productive and a possible association with an enhanced response of the cough reflex has been postulated. Using the irritant capsaicin, the sensitivity of the cough reflex was measured in 363 individuals. A questionnaire was used to divide subjects into three groups: Group A) non-coughing controls; Group B) subjects with non-productive cough; and Group C) subjects with productive cough. The group means (+/- 99% confidence interval (CI)) of the log capsaicin concentration causing two or more coughs (C2) for groups A, B, C were 0.98 (+/- 0.08), 0.64 (+/- 0.09) and 1.04 (+/- 0.23), respectively. The log capsaicin concentration causing five or more coughs (C5) for groups A, B, C were 1.78 (+/- 0.1), 1.16 (+/- 0.12) and 1.54 (+/- 0.25), respectively. Group B was significantly more sensitive to inhaled capsaicin than the other groups (p less than 0.01). No significant difference was observed between groups A and C. Some differences were found when subgroups were examined within groups B and C. In group B, patients with post-nasal drip were found to have a normal sensitivity of the cough reflex and were, therefore, different from the remainder of patients with non-productive cough. In group C, patients with bronchiectasis and current infection showed an increase in the sensitivity of their cough reflex. It is concluded that cough can occur in association with either excess mucus production leading to productive cough or an increase in the sensitivity of the cough reflex, possibly leading to non-productive cough.

LTD4-induced bronchoconstriction in patients with asthma: lack of a vagal reflex.

The mechanism by which leukotriene D4 (LTD4) induces bronchoconstriction in man is unclear. We have investigated this mechanism by examining the effect of nedocromil sodium and ipratropium bromide on LTD4-induced bronchoconstriction in six mild asthmatic patients. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.08 to 100 nmol) was assessed by measuring changes in respiratory resistance (Rrs) at 6 Hz by the forced oscillation method. Results were expressed as the provocative dose causing 100% increase in Rrs (PD100). Neither nedocromil (4 mg) nor ipratropium (0.8 mg) showed significant effect on LTD4-induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatics LTD4-induced bronchoconstriction is unlikely to involve vagal reflexes.

Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine.

Prostaglandins may cause hyperresponsiveness to bronchoconstrictor agents in the lung and hyperalgesia in the skin. Increased airway concentration of both prostaglandins and bradykinin has been suggested as the possible cause of the increased cough sensitivity sometimes found in patients with cough associated with taking drugs that inhibit angiotensin-converting enzyme. We have therefore investigated the effect of prostaglandin E2 (PGE2), bradykinin (BK), histamine (H), and citric acid (C) on capsaicin-induced cough and increase in respiratory resistance (Rrs). Capsaicin-induced changes in Rrs and dose-cough response were measured before and after inhaling 0.76 mumol of PGE2, BK, H, and C. All the test substances caused cough, which was subject to tachyphylaxis, but no significant change in Rrs. Neither BK, H, nor C altered the capsaicin cough or Rrs response. However, PGE2 significantly increased both responses to capsaicin, the geometric mean (95% Cl) for the dose of capsaicin causing 5 or more coughs being 16.2 (14.3 to 18.3) nmol before and 4.4 (2.4 to 7.9) nmol after PGE2 (p less than 0.05). The percent increase (95% Cl) in Rrs after capsaicin was 20 (16.5 to 23.5)% before and 37.2 (32.2 to 43.2)% after PGE2 (p less than 0.05). The results suggest that the cough reflex will be increased in the presence of PGE2 in the airway.

The effect of sulindac on the abnormal cough reflex associated with dry cough.

In order to determine the possible role of prostaglandins in the abnormal cough reflex in patients with dry cough, the effects of a cyclooxygenase inhibitor on cough symptoms were examined. This was measured by a cough symptom score and by the cough reflex sensitivity to inhaled capsaicin in a double blind, randomized, cross-over study comparing the effects of placebo with sulindac, 200 mg daily for 1 week. We studied six hypertensive patients with angiotensin converting enzyme inhibitor-associated cough and six patients with an idiopathic, dry, unproductive cough, all of whom had an increase in the sensitivity of the cough reflex. There was no change in blood pressure control in the hypertensive patients during sulindac therapy. The patients with the angiotensin converting enzyme-associated cough had a significant reduction in the cough symptom score and also a significant increase in the dose of capsaicin causing two or more coughs (threshold sensitivity) and that causing five or more coughs (near maximum response) during sulindac therapy as compared to placebo. In those patients with idiopathic, dry, unproductive cough, sulindac did not alter the symptom of cough or the cough reflex response to capsaicin. These results suggest that prostaglandins may be involved in cough associated with angiotensin converting enzyme inhibitor therapy, but are less likely to be important in the pathogenesis of more common dry coughs of unknown cause.

Modulation of capsaicin induced airway reflexes in humans: effect of monoamine oxidase inhibition.

1. In animal studies monoamine oxidase (MAO) inhibition has been shown to reduce the cough response through elevation of 5-HT in the central nervous system. In this study the effect of selective inhibition of the two subtypes of MAO (MAO-A and MAO-B) was studied on human airway reflexes. 2. Capsaicin-induced cough and reflex increase in respiratory resistance were measured in nine normal volunteers before and after MDL 72394 (MAO-A inhibitor) 16 mg or MDL 72974A (MAO-B inhibitor) 12 mg. 3. Neither inhibitor altered capsaicin-induced cough. Following treatment with MDL 72394, however, the capsaicin-induced reflex increase in resistance was enhanced, by 5.97 +/- 2.1 fold of the placebo value at 1 h. 4. Thus, neurotransmitters in the central nervous system which are substrate for MAO-A (i.e. noradrenaline, 5-HT) may be involved in the control of capsaicin-induced reflex bronchoconstriction.

The effect of altering airway tone on the sensitivity of the cough reflex in normal volunteers.

Cough is frequently the presenting symptom of bronchial asthma, although cough can result from a wide variety of other respiratory disease. Treatment of chronic cough has proved extremely difficult. It has been suggested that treatment with bronchodilators may reduce the symptom of cough. In this study the effect of altering airway tone on the sensitivity of the cough reflex was determined. Twelve normal, healthy volunteers took part. The number of coughs following inhalations of single breaths of doubling concentrations of capsaicin (1.95-500 microM) was recorded before and after doses of salbutamol, methacholine and saline which altered forced expiratory volume in one second (FEV1) by 6.2 +/- 2.6%, -8.8 +/- 3.2% and -0.18 +/- 1.38%, respectively. In a further study the cough response was recorded before and after doses of salbutamol and ipratropium bromide, both of which reduced baseline respiratory resistance and resistance measured after capsaicin. Ipratropium bromide, salbutamol and methacholine, despite having significant effects on airway tone, did not change the sensitivity of capsaicin-induced cough. Thus, if bronchodilator drugs are antitussive in non-asthmatic patients, then this is unlikely to be due to an effect on the sensitivity of the cough reflex.

Effect of nedocromil sodium on the airway response to inhaled capsaicin in normal subjects.

In six normal subjects treatment with 4 mg nedocromil sodium failed to alter the cough and bronchoconstriction induced by inhaled capsaicin. Because nedocromil has previously been shown to inhibit reflex bronchoconstriction provoked by inhaled sulphur dioxide and inhaled bradykinin, the results suggest that inhaled capsaicin acts on different nerve fibres.

Separation of cough and reflex bronchoconstriction by inhaled local anaesthetics.

Cough and airway constriction are common features of respiratory diseases. Both can be caused by stimulation of airway nerves. We have studied the effects of airway anaesthesia on these reflexes, stimulated by inhaled capsaicin, in order to determine whether they are controlled by the same sensory nerves. Ten volunteers had capsaicin cough dose responses performed before and at 10 min after inhaling placebo (ascorbic acid in saline), and the topical anaesthetics lignocaine 40 mg, and dyclonine 8 and 4 mg. The effect of the drugs on respiratory resistance (Rrs), measured using a forced oscillation technique, was measured both before and after the inhalation of a dose of capsaicin which caused less than two coughs. Lignocaine (40 mg) and dyclonine (8 mg) caused significant reports of oral anaesthesia but only lignocaine reduced the cough response to inhaled capsaicin, increasing the log dose of capsaicin causing three or more coughs by 162%. None of the treatments altered basal Rrs or its increase after inhaled capsaicin. Thus, the cough and reflex bronchoconstriction caused by inhaled capsaicin have different sensitivities to inhaled local anaesthesia, suggesting that the effect may be mediated by different sensory pathways.

The effect of 443C81, a mu opioid receptor agonist, on the response to inhaled capsaicin in healthy volunteers.

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male volunteers. Using a randomised, double-blind crossover design, each subject inhaled either saline, 1 mg ml-1 443C81 or 4 mg ml-1 443C81 for 10 min from an ultrasonic nebuliser. The cough response to a range of doses of inhaled capsaicin and the increase in Rrs caused by inhalation of a single subtussive dose of capsaicin were measured before and after each treatment. There was no evidence of an effect of either 1 or 4 mg ml-1 443C81 on cough or increase in Rrs produced by capsaicin when compared with the saline placebo. It is concluded that inhalation of this mu opioid receptor agonist had no effect on capsaicin-induced cough or reflex bronchoconstriction in healthy volunteers.

The effect of prolonged submaximal warm-up exercise on exercise-induced asthma.

The effect of a prolonged warm-up period of exercise on subjects with exercise-induced asthma (EIA) has been studied. Seven asthmatic subjects with known EIA were exercised according to two different protocols on two separate days, which were randomized. On Day A, subjects performed a standard 6-min treadmill run (S1A), which increased heart rate to 98% predicted maximum, followed 45 min later by an identical run (S2A). Refractoriness was demonstrated on the second exercise test, with a mean maximal fall in FEV1 of 29 +/- 3.1% and a PEFR of 32 +/- 2.8% after S2A, compared with a mean maximal fall in FEV1 of 46 +/- 2.6% and a PEFR of 51 +/- 4.0% after S1A. On Day B, subjects performed a 30-min treadmill run at a lower gradient (W1B), followed 21 min later by another standard 6-min treadmill test (S2B). W1B was followed by significantly less EIA (mean maximal fall in FEV1 of 17 +/- 5.4% and a PEFR of 21 +/- 6.3%) than followed S1A. Nevertheless, when subjects subsequently performed a standard 6-min run (S2B), significant refractoriness to bronchoconstriction, comparable to that observed after S2A, developed, with a mean maximal fall in FEV1 of 26 +/- 3.6% and a PEFR of 27 +/- 2.3% (p less than 0.05). We conclude that a warm-up period of exercise can induce refractoriness to EIA without itself inducing marked bronchoconstriction.

A comparative study in atopic subjects with asthma of the effects of salmeterol and salbutamol on allergen-induced bronchoconstriction, increase in airway reactivity, and increase in urinary leukotriene E4 excretion.

Salmeterol (SM) is a novel beta 2-adrenoceptor agonist with a duration of action in excess of 12 hours. Evidence from in vitro studies has also demonstrated that, unlike the short-acting beta 2-agonists, such as salbutamol (SB), it may have some anti-inflammatory properties. With a randomized, double-blind, crossover design, we have compared the inhibitory effects of SM (50 micrograms) and SB (200 micrograms) delivered by metered-dose inhaler on allergen-induced bronchoconstriction, changes in airway reactivity, and urinary leukotriene (LT) E4 excretion in 12 atopic subjects with mild asthma. The immediate bronchoconstriction to allergen was significantly reduced by both beta 2-agonists (p less than 0.005), when reduction was expressed either in terms of maximum fall in FEV1 at 15 minutes after allergen (percent fall in FEV1, mean +/- SEM: 6.2 +/- 4.9, SM; 5.7 +/- 2.5, SB; 40.4 +/- 6.3, placebo) or the area under the FEV1 time curve (AUC) for the first 120 minutes after allergen. Four hours after challenge, results in the SB-treated and placebo-treated groups were not significantly different and demonstrated a small persistent bronchoconstriction compared to bronchodilatation in the SM-treated group (percent fall in FEV1, respectively, 9.3 +/- 3.7, 14.3 +/- 7.1, and -6.3 +/- 2.7; p less than 0.005, SM versus SB; p less than 0.02, SM versus placebo). Expressed in terms of AUC, only SM significantly reduced bronchoconstriction in the period 120 to 240 minutes after allergen (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Human responses to inhaled capsaicin are not inhibited by granisetron.

Cough is a common respiratory symptom, the mechanism of which is poorly understood. In this study the role of 5-HT3 receptors was investigated. Capsaicin-induced cough and increase in airways resistance were measured in six male volunteers before and after infusion with granisetron 160 micrograms kg-1 or placebo. Neither cough nor the increase in respiratory resistance was altered by the active treatment. These results suggest that 5-HT3 receptors are not involved in these two respiratory responses to inhaled capsaicin in humans.