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.     

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.     

Effect of lignocaine, sodium cromoglycate, and ipratropium bromide in exercise-induced asthma

Eight patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled lignocaine (estimated dose 48 mg), sodium cromoglycate (estimated dose 12 mg), and ipratropium bromide (estimated dose 120 μg). Saline was used as control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV₁) and maximal mid-expiratory flow rates (MMFR) after they had run on a treadmill for eight minutes. There was no significant change in baseline FEV₁ or MMFR before each agent was given. Saline, lignocaine, and sodium cromoglycate did not alter the mean baseline FEV₁ or MMFR significantly. Ipratropium caused bronchodilatation with an increase of 16·3% in the mean FEV₁ (p<0·001) and of 43·4% in the mean MMFR (p<0·05). After exercise the maximal percentage falls in FEV₁ (means and SEM) after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 38·1% (5·0), 34·5% (6·1), 11·3% (3·7), and 19·3% (7·4) respectively. Similarly, the mean maximal falls in MMFR after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 54·4% (5·2), 52·9% (7·7), 23·6% (6·6), and 32·1% (10·5) respectively. The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas lignocaine failed to produce an effect. These results suggest that mediator release is an important factor in exercise-induced asthma and that in some patients the effects of the mediators may be on the postsynaptic muscarinic receptors. Local anaesthesia of sensory vagal receptors, on the other hand, does not prevent exercise asthma and these receptors do not appear to have any important role in exercise-induced bronchoconstriction.     

Dose-response study of nebulised nedocromil sodium in exercise induced asthma.

Ten patients with exercise induced asthma, in whom inhaled nedocromil sodium 4 mg by metered dose inhaler attenuated the exercise fall in forced expiratory volume in one second (FEV1) by at least 40%, participated in a double blind dose response study to compare the protective effect of nedocromil sodium given 15 minutes before exercise challenge via a nebuliser (Wright) in concentrations of 0.5, 5, 10, and 20 mg/ml with that of placebo (saline). Response was assessed as the maximum fall in FEV1 after the patient had run on a treadmill for six to eight minutes. Plasma concentrations of nedocromil sodium were measured at the time of challenge. After exercise challenge the mean (SEM) maximum percentage falls in FEV1 were 30.3 (1.6) for the control run and 28.0 (4.1) after placebo. The percentage fall was attenuated by pretreatment with all concentrations of nedocromil sodium to 12.8 (2.8), 11.2 (2.1), 12.8 (2.1), and 14.1 (3.5) for the 0.5, 5, 10, and 20 mg/ml concentrations respectively (p less than 0.001). There were no significant differences between the different nedocromil concentrations. Mean plasma concentrations of nedocromil were proportional to dose. Thus concentrations of nebulised nedocromil sodium that ranged from 0.5 to 20 mg/ml gave a similar degree of protection (50-60%) against exercise induced asthma. This appears to be the maximum protection that can be achieved with nedocromil sodium and is similar to the protection obtained with 4 mg nedocromil administered by metered dose aerosol.     

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.     

Sodium cromoglycate in nocturnal asthma.

To investigate whether mast cell degranulation was important in producing nocturnal asthma, the effect of a single high dose of nebulised sodium cromoglycate on overnight bronchoconstriction, oxygen saturation, and breathing patterns in eight patients with nocturnal wheeze was examined. The study took the form of a double blind placebo controlled crossover comparison. Treatment with cromoglycate did not reduce the overnight fall in FEV1 or FVC, although it was associated with improved nocturnal oxygenation. This study suggests that mast cell degranulation may not be important in the pathogenesis of nocturnal asthma.     

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.     

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.     

Sodium cromoglycate in asthma therapy. A retrospective survey

The data obtained in a retrospective survey of the use and effectiveness of sodium cromoglycate (Lomudal; Fisons) therapy in 635 children and young adults support the findings of other long-term studies that this drug is effective and safe in the treatment of children and young adults with clear evidence of allergy contributing towards their asthma. Its administration by Spinhaler can be commenced successfully at 4 years of age or even younger and continued for as long as is required. The drug is worth a therapeutic trial in any patient with asthma requiring regular medication to control symptoms. The absence of demonstrable allergy does not entirely preclude a favourable response. Once a patient's asthma has been stabilized, sodium cromoglycate enables concomitant therapy (especially with beta 2-adrenergic stimulants and corticosteroids) to be reduced.     

Plasma cyclic nucleotide levels in exercise-induced asthma.

It is known that sympatho-adrenal control of airways is increased in asthma since beta blockade can cause severe bronchoconstriction in asthmatic individuals. It has not been established whether an altered catecholamine response to exercise plays any part in the production of the common symptom of exercise-induced asthma (EIA). We have investigated this indirectly by measuring arterial plasma cyclic nucleotide levels in 10 subjects with EIA and five normal subjects. Cyclic AMP, which in this context reflects beta stimulation, rose significantly by 25.4% in the normal subjects during exercise, while there was no significant change during or after exercise (less than 5%) in the asthmatic subjects. Cyclic GMP rose significantly after exercise in the asthmatic subjects. Six normal subjects repeated the protocol before and after inhalation of salbutamol aerosol, 1600 microgram daily for 18 days. This did not reduce the cAMP response to exercise, and we conclude that the diminished cAMP response of the asthmatic subjects was not caused by their medication. The results may indicate either impaired catecholamine production or endogenous beta receptor hyporesponsiveness in some asthmatic subjects and this may contribute to the development of EIA.     

Long term study of the effect of sodium cromoglycate on non-specific bronchial hyperresponsiveness.

A double blind, crossover study was undertaken to determine whether non-specific hyperresponsiveness in subjects with asthma was reduced by long term treatment with sodium cromoglycate and, if so, whether this was related to change in lung function. Forty four adult asthmatic subjects (41 atopic, three non-atopic) entered the one year study at intervals staggered over six months. After a baseline period to ensure that asthma control was stable subjects entered the treatment period, during which they inhaled sodium cromoglycate 20 mg four times daily or matching placebo four times daily for 16 weeks each, in random order. Response was assessed at four weekly intervals by measurement of lung function and histamine inhalation tests, from which the provocative concentration of histamine causing a 20% fall in FEV1 (PC20H) was calculated. The assessment included daily symptom score, morning and evening Airflow-meter readings and treatment; mean values for each treatment period and also for the final four weeks of each period were compared. There were no significant differences between placebo and sodium cromoglycate treatment for PC20H, FEV1, morning or evening flow meter readings, bronchodilator usage, or symptom scores for the group as a whole, for the 16 week period or for the final four weeks of each period. Thirteen subjects showed better morning and evening flow meter readings while taking sodium cromoglycate than while taking placebo and eight better readings with placebo than with sodium cromoglycate (p less than 0.05). Improvement in lung function did not correlate with baseline lung function or baseline PC20H, or with features of atopy. These results suggest that long term sodium cromoglycate treatment does not alter non-specific bronchial responsiveness in adult asthmatic subjects.     

Cholinergic blockade in the prevention of exercise-induced asthma.

The contribution of vagal mechanisms to exercise-induced asthma has been studied in 10 adult asthmatic patients using the anticholinergic drug ipratropium bromide. Exercise tests were performed for eight minutes on a cycle ergometer and each individual's tests were standardised by matching oxygen uptake. Two tests were done on each of three study days, the first being without previous medication, and the second preceded by inhalation of ipratropium bromide, 0.1, or 1 mg or saline placebo given 90 minutes beforehand. The mean falls in FEV1 and PEFR after the initial tests were very similar on the three study days. The mean falls in FEV1 after the second test were 22.3%, 19.5%, and 12.5% with placebo, 0.1 mg, and 1 mg ipratropium bromide respectively. Only the higher dose was significantly better than placebo. The results were also analysed using a protection index to compare the first and second tests each day and 1 mg ipratropium bromide was significantly better than both 0.1 mg and placebo. Similar results were obtained using PEFR. Equal bronchodilatation was produced by the two doses of drug. We conclude that conventional doses of anticholinergic drugs are not effective in preventing exercise-induced asthma, while large doses may do so in the same group of subjects.     

Plasma catecholamines during exercise-induced bronchoconstriction in bronchial asthma.

Plasma levels of adrenaline and noradrenaline during and after submaximal exercise in patients with bronchial asthma were investigated. Three groups were studied comprising 10 patients with exercise-induced bronchoconstriction (EIB), 10 asthmatic patients without EIB and four normal control subjects. Plasma catecholamines were measured at rest, at the end of exercise, and five and 15 minutes after exercise. Changes in airway resistance were assessed by measuring peak expiratory flow rate. Significant differences in catecholamine levels between reacting and non-reacting patients were found. In 10 patients developing EIB adrenaline and noradrenaline levels had risen significantly by the end of exercise and remained elevated up to the fifth minute of recovery. The rise in catecholamine levels in non-reacting asthmatics was insignificant. In control subjects noradrenaline had increased significantly by the end of exercise.