Sodium cromoglycate and ipratropium bromide in exercise-induced asthma.

In thirteen patients with extrinsic asthma the effects of placebo, sodium cromoglycate, ipratropium bromide, and ipratropium bromide plus sodium cromoglycate were studied in a random double-blind fashion to assess their inhibitory action in exercise-induced asthma (EIA). Exercise testing consisted of steady state running on an inclined treadmill for up to eight minutes. In eight of the 13 patients studied the baseline ratio of expiratory flow at 50% vital capacity (VC) breathing helium-oxygen (V50He) to V50air was over 1.20 and they were called responders; the remaining five patients were called non-responders. There was a significantly lower baseline maximum mid-expiratory flow rate (MMEF) in non-responders (P less than 0.02) as compared to responders but no difference in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). Sodium cromoglycate (P less than 0.02), ipratropium bromide (P less than 0.01), and ipratropium bromide plus spdium cromoglycate (P less than 0.01) all significantly inhibited the percentage fall in FEV1 after exercise in the responders. Ipratropium bromide had no preventive action on non-responders, unlike sodium cromoglycate (P less than 0.05) and ipratropium bromide plus sodium cromoglycate (P less than 0.02). It is postulated that mediator release is an important factor in development of EIA in most extrinsic asthmatics, whereas cholinergic mechanisms are relevant only in those patients in whom the main site of airflow obstruction is in the large central airways.     

Dose-response study of sodium cromoglycate in exercise-induced asthma.

Ten patients with exercise-induced asthma participated in a single-blind dose-response study comparing the protective effect of inhaled sodium cromoglycate in increasing concentrations from 2 to 40 mg/ml. Saline was used as a control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) after the patients had run on a treadmill for eight minutes. There was slight bronchodilation evident from the increase in baseline FEV1 after inhalation of sodium cromoglycate, the difference reaching statistical significance with the highest concentration (5.7%, p less than 0.05). After exercise the maximal percentage falls in FEV1 (means and SEM) after saline and after sodium cromoglycate at 2, 10, 20, and 40 mg/ml were 37.3 +/- 4.7, 17.3 +/- 4.1, 10 +/- 3.3, 7.6 +/- 2.4, and 12 +/- 2.9. Sodium cromoglycate inhibited the exercise-induced fall in FEV1 at all the concentrations used in the study (p less than 0.001) and its inhibitory effect increased from 2 to 20 mg/ml. The mean FEV1 returned to baseline values within 15 minutes at higher concentrations of sodium cromoglycate (20 and 40 mg/ml) and a small bronchodilator effect was noted at 30 minutes. The findings suggest that the protective effect of sodium cromoglycate in exercise asthma is dose related. At higher concentration the drug suppresses chemical mediator release from the lung mast cells and may also modify the bronchial reactivity to release mediators.     

Effect of oral sodium cromoglycate and ketotifen in fish-induced bronchial asthma.

The effects of sodium cromoglycate and ketotifen were studied in a group of 20 patients in whom fish repeatedly provoked an attack of wheezing and dyspnoea within one hour of its being eaten. Fish ingestion resulted in a fall in forced expiratory volume in one second (FEV1) of at least 15%. All patients had a weal greater than 4 mm in response to fish antigen in the skinprick test and most had blood eosinophilia and raised serum IgE levels. Administration of drugs and placebos was carried out under double-blind conditions, in a randomised fashion, on different days. Cromoglycate blocked the fall in FEV1 either completely or significantly in 16 patients. Ketotifen did not appear to have any significant effect in the group as a whole.     

Controlled-analysis of the effects of inhaled lignocaine in exercise-induced asthma.

To determine whether anaesthesia of the intrathoracic airways would attenuate the development of exercise-induced asthma, we studied eight symptomless asthmatic patients by cycle ergometry after saline or lignocaine pretreatment while they were breathing air at 24 degrees C with 9.1 mg of H2O/l. Pulmonary mechanics were measured before and after the administration of each agent, and again five minutes after cessation of exercise. Sufficient lignocaine was administered to abolish the gag reflex and the cough response to aerosols of citric acid. Before exercise there were no significant differences for any lung function variable between the saline and lignocaine results. Equally, there were no significant differences between these agents for minute ventilation (VE) during exercise (VE lignocaine = 71.0 +/- 7.4 (SEM) l/min; VE saline 67.2 +/- 8.1 l/min;), or in the severity of the subsequent bronchospastic response (for example, the FEV1 with saline was 22.6 +/- 2.9% decrease, and with lignocaine 23.6 +/- 8.5%). Thus these results do not support the idea that there are thermally sensitive neural receptors in intrathoracic airways that play a role in the pathogenesis of exercise-induced asthma.     

Relative efficacy of nebulised ipratropium bromide and fenoterol in acute severe asthma

In a double-blind, randomised, controlled clinical trial of 145 patients with acute asthma, the efficacy of nebulised 4-hourly ipratropium bromide plus 4-hourly fenoterol (group I, 50 patients), 2-hourly fenoterol (group II, 50 patients) and 4-hourly fenoterol (group III, 45 patients) was assessed. All patients received an optimal infusion of aminophylline and 81 patients (27 in each group) received hydrocortisone for clinical indications. It was found that cholinergic side-effects in group I were not more common than in group II. Tremor was more common in group II. Assessment of bronchodilator efficacy was confined to the 81 patients whose therapy included hydrocortisone. Peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity were expressed as a percentage of predicted for each individual and the mean values for each group plotted. It was found that the response rate, as assessed by the area under the curve, was significantly more rapid in group I compared with both group II (P less than 0.001) and group III (P less than 0.005). These findings were consistent for all three lung function measurements. However, there was no significant difference in the responses between group II and group III. It is concluded that adding ipratropium bromide to conventional regimens is likely to benefit patients with acute asthma.     

Effect of verapamil and sodium cromoglycate on leukotriene D4 induced bronchoconstriction in patients with asthma.

Leukotriene D4 (LTD4) may be an important mediator in asthma. The effect of verapamil and sodium cromoglycate on LTD4 induced bronchoconstriction has been examined in seven patients with asthma. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.0032-50 micrograms/ml) was assessed by measuring changes in FEV1, specific airways conductance, and flow rate at 30% of vital capacity (V30(p)). Results were expressed as the provocation concentration (PC) producing a 10% fall in FEV1 (PC10FEV1), a 35% fall in specific airways conductance (PC35SGaw), and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Neither verapamil nor cromoglycate inhibited LTD4 induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatic patients LTD4 induced bronchoconstriction is not mediated via verapamil or cromoglycate sensitive mechanisms.     

Bronchial responsiveness to hyperventilation in children with asthma: inhibition by ipratropium bromide.

Isocapnic hyperventilation dose response curves were constructed for 11 asthmatic children before and after pretreatment with placebo or ipratropium bromide, 40-1500 micrograms given by inhalation, on three separate days. The response before and after placebo was highly reproducible (within subject coefficient of variation 7.5%, 18%, and 22% for intervals of two hours, within two weeks, and over two weeks). It was independent of baseline lung function. Complete protection against hyperventilation induced asthma was achieved by ipratropium bromide 40 micrograms in six children and by 200 micrograms or more in a further four. The remaining child was unaffected by any dose of ipratropium up to 1500 micrograms. The dose of ipratropium required for protection was better related to the subjects' requirement for regular medication than to their sensitivity to hyperventilation or baseline lung function.     

Failure of ipratropium bromide to modify the diurnal variation of asthma in asthmatic children.

Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind, randomised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity. Subjects measured peak expiratory flow rate approximately eight hourly, before and after inhaled salbutamol, for four week periods. Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol. Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20% fall in FEV1 (geometric mean PD20 = 0.78 v 0.49 mg/ml, p less than 0.05), despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge. It did not, however, diminish the diurnal variation in airway calibre (mean amplitude = 12.7 v 10.1) or in bronchodilator responsiveness (mean amplitude = 62.4 v 63.5). There was no improvement in the clinical state of subjects while they were taking ipratropium bromide.     

Dose-response effect of sodium cromoglycate pressurised aerosol in exercise induced asthma.

The effects of 2, 10, and 20 mg of sodium cromoglycate delivered by aerosol were compared with those of placebo in a double blind study in 11 patients with extrinsic and exercise induced asthma. The effect of nebulised sodium cromoglycate delivered through a Wright nebuliser (estimated dose 12 mg) was also studied. Patients exercised on a treadmill for six to eight minutes at submaximal work loads on five days, 30 minutes after inhaling placebo or sodium cromoglycate. The FEV1 was recorded before treatment, before exercise, and up to 30 minutes after exercise. Mean baseline values of FEV1 before and after placebo or sodium cromoglycate did not differ significantly on the five days. After exercise the mean (SEM) maximal percentage fall in FEV1 after placebo; 12 mg sodium cromoglycate nebuliser solution; and 2, 10, and 20 mg sodium cromoglycate aerosol were 31.1 (3.8); 9.4 (2.1); and 19.4 (4.6), 13.7 (3.5), and 9.4 (1.9). Sodium cromoglycate inhibited exercise induced asthma at all doses used; the protective effect of the aerosol increased from 2 to 20 mg. The protective effect of 20 mg sodium cromoglycate aerosol was similar to that seen with 12 mg nebulised solution. Our results suggest that the effect of sodium cromoglycate aerosol in exercise induced asthma is dose related.     

Site of action of ipratropium bromide and clinical and physiological determinants of response in patients with asthma.

It has been suggested that in normal subjects inhaled anticholinergic agents have a preferential dilating effect on large central airways. We therefore studied 21 patients with asthma to see if response to inhaled ipratropium bromide was related to the initial central or peripheral site of major airway narrowing. Fourteen out of 21 patients with asthma increased their Vmax more than 10% after ipratropium but when assessed by air and helium/oxygen (He/O2) flow-volume curves, responders and non-responders to He/O2 breathing were divided equally between those who benefited from the drug, and those who did not. There were no significant differences in percentage improvement in Vmax between initial responders, and initial non-responders to He/O2 breathing. Furthermore the results from air and He/O2 flow-volume curves suggest that, contrary to some previous reports (not in asthmatics), inhaled ipratropium has a generalised action throughout the airways. There were no differences in severity of airflow obstruction, nor in age, sex, smoking history, or atopic status between those who benefited from ipratropium and those who did not. However, those improving after the drug had a significantly longer history of asthma than those who did not.     

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.     

Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis.

The bronchodilating responses to 400 micrograms salbutamol and 80 micrograms ipratropium bromide were studied in 188 patients with chronic bronchitis (n = 113) or asthma (n = 75) and mild to moderate airflow obstruction (forced expiratory volume in one second (FEV1) above 50% but below 2 SD of predicted value) in a crossover study on two days a week apart. Both the patients with asthma and the patients with chronic bronchitis varied considerably in their responses to the salbutamol and the ipratropium bromide. The mean increase in FEV1 in the subjects with asthma was higher after salbutamol (0.371 or 18% of the prebronchodilator value) than after ipratropium bromide (0.26 1 or 13%). In chronic bronchitis there was no difference between the increase in FEV1 after salbutamol (0.161 or 7%) and after ipratropium bromide (0.191 or 8%). When patients were categorised into those with a better response to salbutamol 400 micrograms and those with a better response to ipratropium bromide 80 micrograms, patients with chronic bronchitis responded better in general to ipratropium bromide whereas asthmatic patients responded better to salbutamol. The response pattern was also related to allergy and age, allergic patients and patients under 60 being more likely to respond better to salbutamol 400 micrograms than non-allergic patients and older patients, who benefited more from ipratropium bromide 80 micrograms. The response pattern was not related to sex, smoking habits, lung function, bronchial reactivity, respiratory symptoms, or number of exacerbations during the preceding year.     

Effect of ipratropium bromide aerosol on respiratory function in patients under ventilator treatment

Twenty patients, 36-78 years old, with a history of chronic obstructive lung disease, and immediately after operation mostly for cardiac disease, were treated with ipratropium bromide (IB, 15 cases) or placebo (5 cases). A metered dose inhaler with a new adapter was used during postoperative ventilator treatment. In the IB group the heart rate did not change, but the inspiratory resistance decreased and the arterial oxygen tension increased. This is considered to indicate an effect not only on large but also on small airways, or an improvement of the ventilation/perfusion relationship. The investigation also demonstrated the practical usefulness of the new adapter.     

Synergism between ipratropium and theophylline in asthma

Ipratropium bromide is a bronchodilator whose effect has been compared with beta agonists but not with theophylline. Twelve asthmatics were given four two-week courses of the different combinations of ipratropium (40 micrograms in two puffs), theophylline capsules, and their corresponding placebos in a random, double-blind fashion. There was a significant increase in FEV1 and MMFR 60 minutes after theophylline was administered (p less than 0.05) when measured after one and two weeks of therapy. FEV1 and MMFR were significantly increased (p less than 0.05) 30 and 60 minutes after ipratropium inhalation and this increase was significantly greater when the patient had also been taking theophylline compared with placebo capsules (p less than 0.05). There was no toxicity associated with this combination. The synergism demonstrated may be related to the time sequence of drug administration, mechanical or cellular factors.     

Ketotifen in atopic asthma and exercise-induced asthma.

The efficacy of ketotifen, a tricyclic benzocycloheptathiophene derivative, was assessed in an outpatient clinical trial and in a group of 12 asthmatic subjects with exercise-induced asthma. Subjects in the outpatient trial had mild asthma and consisted of two groups: a group of 24 atopic asthmatics with at least one positive skin test reaction and with an associated history of bronchial reactivity to at least one allergen; and a group of eight asthmatics with one or more positive skin prick tests but not bronchial reactivity to an allergen. Both groups took four weeks medication of ketotifen 1 mg bd and placebo in a randomised double-blind crossover study. There was no difference between ketotifen and placebo for any measurement made during the study and consequently no evidence of drug efficacy. The exercise study followed a standardised protocol and each subject took in random double-blind order, placebo, 1 mg, 2 mg, and 4 mg ketotifen two hours before exercise. There was no difference in the mean decreases in lung function from pre-exercise baseline values after three doses of ketotifen than with placebo. Drug levels suggested ketotifen was well absorbed. It would appear that if given for a period of only four weeks ketotifen had no beneficial effects in the management of mild asthma, and that a single dose before exercise does not modify exercise-induced asthma.