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Do sympathomimetic amines prevent exercise-induced asthma by bronchodilatation alone?
Br.J.
Dis. Chest (1977) 73, 109
SYMPATHOMIMETIC AMINES PREVENT INDUCED ASTHMA BY BRONCHODILATATION DO
EXERCISEALONE?
M. R. HETZEL, J. C. BATTEN AND T. J. H. CLARK St George’s Hospital
and Brompton
Hospital,
London
Summary Seventeen patients with exercise-induced asthma were studied. Eleven patients (cases 7-17), of whom seven were atopic subjects, were given isoetharine or isoprenaline and were subsequently tested for exercise-induced asthma after bronchodilatation had ceased. In two atopic and one non-atopic patients protection was observed which could not be attributed to chance. Two of these three patients were studied again and this phenomenon was repeatable. Prevention of exercise-induced asthma 30 min after inhalation of isoetherine and sodium cromoglycate was compared in 10 patients (cases l-lo), of whom six were atopic subjects. There was no significant difference in the results and protection from isoetharine was not related to the magnitude of its bronchodilator effect. These results suggest that P-adrenergic agonists may have both bronchodilator and other actions in exercise-induced asthma. Whether these other actions are anti-allergic is unknown. INTRODUCTION
In vitro tests of antigen challenge to passively sensitized human lung show that sympathomimetic amines are more effective than sodium cromoglycate (SCG) in preventing histamine release (Assem & Schild 1969). Stimulation of cyclic AMP production to prevent mediator release may be an important factor in the control of asthma by ,& sympathomimetic drugs, but only their action as bronchodilators has been demonstrated in the intact patient. This paper attempts to separate the bronchodilator effect of isoetharine and isoprenaline from their ability to protect patients from exercise-induced asthma in two separate experiments. In the first study the magnitude of the initial increase in peak expiratory flow rate (PEFR) on inhaling isoetharine has been compared with subsequent protection from exercise 30 min later; protection from sodium cromoglycate after the same interval was also assessed. In a second experiment, the ability of isoetharine and isoprenaline to prevent exercise-induced asthma has been studied after longer periods when their bronchodilator effect has apparently ceased. Patients and Methods Seventeen constriction
patients gave
with informed
well controlled consent to
the
asthma studies.
and a history Their mean
of exercise-induced age was 16.5 years
broncho(range 7-36
110
ill. R. Hetzel, 7. C. Batten and T. J: H. Clark
years). Twelve had positive prick tests to one or more common allergens, principally house dust, house dust mite, grass pollen and animal fur. Sixteen required treatment; seven took SCG, four took sympathomimetic drugs and five took both. Identical capsules for use in a spinhaler were prepared with powders of particle size 30-60 pm containing: (a) isoetharine 350 pg, anhydrous sodium sulphate 5 mg, lactose BP 34.65 mg; (b) SCG 20 mg, lactose 20 mg; or (c) placebo lactose BP 40 mg. Isoprenaline sulphate 80 pg was given from a standard pressure-packed aerosol canister. A placebo aerosol contained propellants only. All patients performed a preliminary exercise test which was then used throughout all subsequent studies. After stopping treatment for 12 hours, peak flow rate (mean of three readings with a Wright peak flow meter) and pulse rate (by palpation at the wrist) were measured at intervals, until conditions were stable. The patient then exercised for 8 min (6 min for children) and readings were subsequently made at 1 -min intervals for 5 min and at 5-min intervals thereafter to recovery. Eleven patients ran on a treadmill at speeds of 1.6-1.8 m/set (3.5-4 mph) and gradients of 10-15x (Silverman & Anderson 1972). Five patients exercised on a flight of steps (McNeil et al. 1966). Case 4 ran in a park (Jones et al. 1963; Godfrey et al. 1973). Ten patients (Cases l-10) entered the first study. On three separate days, having obtained stable readings, they were given isoetharine, SCG or placebo in random order. PEFR and pulse rate were measured at 0, 15 and 30 minutes after inhalation. Exercise was then performed as previously described. Eleven patients (cases 7-17) took part in the second study. The method is described in detail for three of them (Cases 10-12). After stable conditions were obtained, they inhaled isoetharine and measurements were made immediately and at lo-minute intervals thereafter until the initial increase in PEFR could no longer be detected. Patients then repeated their usual exercise test. On the second day placebo powder was given and lo-minute readings were repeated for the same period as was necessary on the first day followed by the same exercise test. Case 10 repeated this study and at a later date underwent a third pair of tests using isoprenaline and placebo aerosol instead, Case 11 repeated the study following the same protocol after inhaling isoprenaline and aerosol placebo but on these last two occasions she performed an extra exercise test after 35 minutes’ rest. Similar protocols were followed for the other eight patients using isoetharine or isoprenaline and appropriate placebos. All tests were performed at the same time of day under single blind conditions. The effect of exercise was measured as the maximum fall in PEFR expressed as a percentage of the preexercise level. The bronchodilator effects of isoetharine and isoprenaline were measured as the maximum increase in PEFR after inhalation expressed as a percentage of the baseline reading.
RESULTS The individual results of the first study are shown in Table I. The mean fall in PEFR after the preliminary exercise test was 44%. Exercise 30 minutes after inhalation of SCG,
placebo and isoetharine produced mean falls in PEFR of 12x, 35% and 14% respectively. The results for isoetharine and- SCG were significantly better than placebo (0.02> P> 0.01 and 0.01 > P> 0.001 respectively) but the differences between isoetharine and SCG were not significant (0.8 > P> 0.7). The mean increase in PEFR on inhaling isoetharine was 13% and there was no significant correlation between this increase and the subsequent fall in PEFR on exercise 30 minutes later (Y= 0.38, 0.4 > P > 0.3). In the second study three patients (Cases 10-12; all children, exercised on the treadmill) were protected from exercise by isoetharine after its measurable bronchodilator effect had ceased. The results of these three patients are shown in Table II. This phenomenon was repeatable in Case 10 but a subsequent attempt to show similar prolonged protection by isoprenaline was unsuccessful. Persistent protection was seen when the study was repeated with isoprenaline in Case 11 and this drug also prevented broncho-
Sympathomimetic Table
I.
Cuse No.
Fall
Exercise alone
Drug
in peak
111
in Asthma SCG
First study. Protection by isoetharine, challenge 30 minutes later
and placebo
after exercise (%)
flow
Placebo
SCG
from
exercise
Bonchodilatation
after isoetharine (%I
Isoetharine
2 3 4 5 6 7 8 9 IO
43 82 35 35 41 63 26 37 40 33
7 20 17 9 24 5 5 14 12
16 20 13 49 65 61 18 24 30 52
25 1 c I 10 68 3 11 6 9
33 17 4 0 22 24 5 21 11 20
Mean
44
12
35
14
13
1
Table
Amines
II.
used
Isoetharine
Isoprenaline
IO
Second study. Persistent protection isoprenaline after bronchodilatation Case No.
IO 11 12 10 11
Increase PEFR
in
on inhalation (%)
from exercise-induced asthma by isoetharine has ceased seen in 3 of I I patients studied Duration increase PEFR
25 25 8 29 14 7
* Second exercise test after 35 minutes
of
Fall
in
(min)
165 125 80 165 90 35
After
in PEFR exercise
drug
8 31 11 0 69 15, 14”
and
on subsequent (%)
After
placebo 1
52 69 39 56 50 48, 49”
rest.
on a second exercise test 35 minutes later. Repeated bronchoconstriction on exercise at the same intervals was seen in the subsequent placebo study (Fig. 1). The other eight patients were not protected by isoetharine or isoprenaline after bronchodilatation had ceased and significant protection from placebo was seen in two of them.
constriction
DISCUSSION
In the first study the protection .from exercise-induced asthma afforded by isoetharine and sodium cromoglycate was similar but there was no correlation between the reduction in the fall in PEFR on exercise after inhaling isoetharine and the magnitude of its initial bronchodilator &ect. It is therefore unlikely that isoetharine reduced the effect of exercise by sustained bronchodilatation alone and a second mechanism may have contributed to this protective effect. 14
112
M. R. Hetxel, J. C. Batten and ip. J: H. Clark
0
20
40
60
Isoetharine -.Placebo capsule - -- Isoprenaline **e***. Placebo aerosol
80
100 Minutes
0 I
+
20
40
60
80 100
Medication Predicted
normal
P.E.F.R.
LB Exercise
2. Second study, Case 11. Persistent protection from exercise by (a) isoetharine powder and (b) isoprenaline aerosol after their bronchodilator effect has ceased compared with placebo. Protection by isoprenaline continues through a second exercise test 35 minutes later. (Predicted PEFR from Godfrey et al. 1970.) Fig.
In the second prolonged study three of 11 patients were protected by isoetharine after its bronchodilator effect had apparently ceased. When repetition of the study was attempted in two of them, protection could only be consistently demonstrated with isoetharine in one, but the other patient (Case 11) was similarly protected by isoprenaline. Moreover, in this patient protection persisted through a second exercise test 35 minutes later. This could not be explained by exhaustion of the exercise effect
(McNeil et al. 1966) as repeated bronchoconstriction occurred on exercise when placebo was used. In these three patients prevention of exercise-induced asthma may therefore have been effected by inhibition of mediator release and not by sustained bronchodilatation. There are no distinguishing features between these three and the other patients; in particular, like the rest of the group, they were of mixed atopic status (one non-atopic and two atopic subjects). It seems that these two effects can only occasionally be separated in time. However, our earlier observation in the first study that the magnitudes of the bronchodilator and protective effects of isoetharine were unrelated lends further support to our hypothesis that both mechanisms contributed to prevention of exercise-induced asthma. The possibility of temporal separation of these two actions is suggested also by the observation in children that protection from exercise-induced asthma two hours after inhaling isoprenaline was associated with minimal residual bronchodilatation (Sly et al. 1967). Delaying exercise until bronchodilatation has ceased shows this effect only in a minority of asthma patients, however. Our choice of isoetharine in powder form was governed by our wish to compare it
Sympathomimetic
Amines in Asthma
113
with sodium cromoglycate in the first study. It was convenient to use this preparation in the second study also but subsequent substitution of a conventional aerosol containing isoprenaline shows that the choice of sympathomimetic is not critical to demonstration of this phenomenon. The mechanism of exercise-induced asthma is unknown. Several authors have suggested that exercise provokes mediator release (McNeil et al. 1966; Cropp 1975; Godfrey 1975). Although the demonstration of sustained protection from bronchial challenge with inhaled allergens may have been a better test for our hypothesis, since mediator release is generally believed to be involved, exercise was used because repeated allergen challenge was considered unethical. Prevention of mediator release by /3 sympathomimetic drugs might explain the results of some clinical studies in which their regular use was more effective than expected. Regular treatment with isoprenaline in powder form, in comparison with sodium cromoglycate powder, cromoglycate plus isoprenaline powder and placebo powder, effectively controlled symptoms for several months in patients whose asthma was refractory to pre-trial symptomatic use of a panel of bronchodilator drugs which included conventional isoprenaline aerosol (Brompton Hospital/Northern General Hospital/MRC Collaborative Trials 1972, 1976). Of children regularly taking a placebo powder containing isoprenaline in a similar comparison with SCG 24% were well controlled for a year (Silverman et al. 1972). Symptomatic improvement after regular use of p stimulants in patients with apparently irreversible airways obstruction has also been observed (Clark 1971). Two distinct actions for sympathomimetic substances (isoetharine and isoprenaline) were only clearly demonstrated in a minority of the patients studied. However, this adds to the growing volume of evidence that prevention of mediator release might be one of the ways in which sympathomimetic agents help towards relief of extrinsic and intrinsic asthma. ACKNOWLEDGMENTS
We thank M. Horn, G. Beynon, I. Gregg and J. Evelegh for permission to study their patients and Beecham Research Laboratories for preparation of the capsules. REFERENCES E. S. K. & SCHILD, M. 0. (1969) Inhibition by sympathomimetic amines of histamine release induced by antigen in passively sensitised human lung. Nature, Lond. 224, 1028. BROMPTON HOSPITAL/MEDICAL RESEARCH COUNCIL COLLABORATIVE TRIAL (1972) Long term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults. BY. med. J. 4, 383. CLARK, T. J. H. (1971) The status of bronchodilator treatment. Postgrad. med. r. 47, Suppl. 50. Csopp, G. J. (1975) Exercise induced asthma. Pediat. Clins N. Am. 22, 63. GODFREY, S. (1975) Exercise induced asthma-Clinical, physiological and therapeutic implications. J. Allergy clin. Immunol. 56, 1. GODFREY, S., KAMBUROFF, P. L. & NAIRN, J. R. (1970) Spirometry, lung volumes and airways resistance in normal children aged 5 to 18 years. Br. J. Dis. Chest 64, 15. GODFREY, S., SILVERMAN, M. & ANDERSON, E. D. (1973) Problems of interpreting exerciseinduced asthma. j(. Allergy clin. Immunol. 52, 199. ASSEM,
114
M. R. Hetxel, J. C. Batten and T. J: H. Clark
JONES, R. S., BUSTON, M. H. &WHARTON, dilator
drugs R. S.,
in the
M. J. (1963) The place of physical exercise and bronchoassessment of the asthmatic child. Archs Dis. ChiZdh. 38, 539. J. R., MILLAR, J. S. & INGRAM, C. G. (1966) Exercise induced asthma.
MCNEIL, NAIRN, Q. Jl Med. 35, 55. NORTHERN GENERAL HOSPITAL/BROMPTON HOSPITAL/MEDICAL RESEARCH COUNCIL COLLABORATIVE TRIAL (1976) Sodium cromoglycate in chronic asthma. Br. med. J. 1, 361. SILVERMAN, M. & ANDERSON, S. D. (1972) Standardisation of exercise tests in asthmatic children. Archs Dis. Childh. 47, 882. SILVERMAN, M., CONNOLY, N. M., BALFOUR LYNN, L. & GODFREY, S. (1972) Long term trial of d&odium cromoglycate and isoprenaline in children with asthma. Br. med. J. 3, 378. SLY, R. M., HEIMLICH, E. M., BUSSER, R. J. & STRICK, C. (1967) Exercise induced bronchospasm. Evaluation of isoproterenol, phenylephrine and the combination. Awn. Allergy 25, 324.
Dis. Chest (1977) 73, 109
SYMPATHOMIMETIC AMINES PREVENT INDUCED ASTHMA BY BRONCHODILATATION DO
EXERCISEALONE?
M. R. HETZEL, J. C. BATTEN AND T. J. H. CLARK St George’s Hospital
and Brompton
Hospital,
London
Summary Seventeen patients with exercise-induced asthma were studied. Eleven patients (cases 7-17), of whom seven were atopic subjects, were given isoetharine or isoprenaline and were subsequently tested for exercise-induced asthma after bronchodilatation had ceased. In two atopic and one non-atopic patients protection was observed which could not be attributed to chance. Two of these three patients were studied again and this phenomenon was repeatable. Prevention of exercise-induced asthma 30 min after inhalation of isoetherine and sodium cromoglycate was compared in 10 patients (cases l-lo), of whom six were atopic subjects. There was no significant difference in the results and protection from isoetharine was not related to the magnitude of its bronchodilator effect. These results suggest that P-adrenergic agonists may have both bronchodilator and other actions in exercise-induced asthma. Whether these other actions are anti-allergic is unknown. INTRODUCTION
In vitro tests of antigen challenge to passively sensitized human lung show that sympathomimetic amines are more effective than sodium cromoglycate (SCG) in preventing histamine release (Assem & Schild 1969). Stimulation of cyclic AMP production to prevent mediator release may be an important factor in the control of asthma by ,& sympathomimetic drugs, but only their action as bronchodilators has been demonstrated in the intact patient. This paper attempts to separate the bronchodilator effect of isoetharine and isoprenaline from their ability to protect patients from exercise-induced asthma in two separate experiments. In the first study the magnitude of the initial increase in peak expiratory flow rate (PEFR) on inhaling isoetharine has been compared with subsequent protection from exercise 30 min later; protection from sodium cromoglycate after the same interval was also assessed. In a second experiment, the ability of isoetharine and isoprenaline to prevent exercise-induced asthma has been studied after longer periods when their bronchodilator effect has apparently ceased. Patients and Methods Seventeen constriction
patients gave
with informed
well controlled consent to
the
asthma studies.
and a history Their mean
of exercise-induced age was 16.5 years
broncho(range 7-36
110
ill. R. Hetzel, 7. C. Batten and T. J: H. Clark
years). Twelve had positive prick tests to one or more common allergens, principally house dust, house dust mite, grass pollen and animal fur. Sixteen required treatment; seven took SCG, four took sympathomimetic drugs and five took both. Identical capsules for use in a spinhaler were prepared with powders of particle size 30-60 pm containing: (a) isoetharine 350 pg, anhydrous sodium sulphate 5 mg, lactose BP 34.65 mg; (b) SCG 20 mg, lactose 20 mg; or (c) placebo lactose BP 40 mg. Isoprenaline sulphate 80 pg was given from a standard pressure-packed aerosol canister. A placebo aerosol contained propellants only. All patients performed a preliminary exercise test which was then used throughout all subsequent studies. After stopping treatment for 12 hours, peak flow rate (mean of three readings with a Wright peak flow meter) and pulse rate (by palpation at the wrist) were measured at intervals, until conditions were stable. The patient then exercised for 8 min (6 min for children) and readings were subsequently made at 1 -min intervals for 5 min and at 5-min intervals thereafter to recovery. Eleven patients ran on a treadmill at speeds of 1.6-1.8 m/set (3.5-4 mph) and gradients of 10-15x (Silverman & Anderson 1972). Five patients exercised on a flight of steps (McNeil et al. 1966). Case 4 ran in a park (Jones et al. 1963; Godfrey et al. 1973). Ten patients (Cases l-10) entered the first study. On three separate days, having obtained stable readings, they were given isoetharine, SCG or placebo in random order. PEFR and pulse rate were measured at 0, 15 and 30 minutes after inhalation. Exercise was then performed as previously described. Eleven patients (cases 7-17) took part in the second study. The method is described in detail for three of them (Cases 10-12). After stable conditions were obtained, they inhaled isoetharine and measurements were made immediately and at lo-minute intervals thereafter until the initial increase in PEFR could no longer be detected. Patients then repeated their usual exercise test. On the second day placebo powder was given and lo-minute readings were repeated for the same period as was necessary on the first day followed by the same exercise test. Case 10 repeated this study and at a later date underwent a third pair of tests using isoprenaline and placebo aerosol instead, Case 11 repeated the study following the same protocol after inhaling isoprenaline and aerosol placebo but on these last two occasions she performed an extra exercise test after 35 minutes’ rest. Similar protocols were followed for the other eight patients using isoetharine or isoprenaline and appropriate placebos. All tests were performed at the same time of day under single blind conditions. The effect of exercise was measured as the maximum fall in PEFR expressed as a percentage of the preexercise level. The bronchodilator effects of isoetharine and isoprenaline were measured as the maximum increase in PEFR after inhalation expressed as a percentage of the baseline reading.
RESULTS The individual results of the first study are shown in Table I. The mean fall in PEFR after the preliminary exercise test was 44%. Exercise 30 minutes after inhalation of SCG,
placebo and isoetharine produced mean falls in PEFR of 12x, 35% and 14% respectively. The results for isoetharine and- SCG were significantly better than placebo (0.02> P> 0.01 and 0.01 > P> 0.001 respectively) but the differences between isoetharine and SCG were not significant (0.8 > P> 0.7). The mean increase in PEFR on inhaling isoetharine was 13% and there was no significant correlation between this increase and the subsequent fall in PEFR on exercise 30 minutes later (Y= 0.38, 0.4 > P > 0.3). In the second study three patients (Cases 10-12; all children, exercised on the treadmill) were protected from exercise by isoetharine after its measurable bronchodilator effect had ceased. The results of these three patients are shown in Table II. This phenomenon was repeatable in Case 10 but a subsequent attempt to show similar prolonged protection by isoprenaline was unsuccessful. Persistent protection was seen when the study was repeated with isoprenaline in Case 11 and this drug also prevented broncho-
Sympathomimetic Table
I.
Cuse No.
Fall
Exercise alone
Drug
in peak
111
in Asthma SCG
First study. Protection by isoetharine, challenge 30 minutes later
and placebo
after exercise (%)
flow
Placebo
SCG
from
exercise
Bonchodilatation
after isoetharine (%I
Isoetharine
2 3 4 5 6 7 8 9 IO
43 82 35 35 41 63 26 37 40 33
7 20 17 9 24 5 5 14 12
16 20 13 49 65 61 18 24 30 52
25 1 c I 10 68 3 11 6 9
33 17 4 0 22 24 5 21 11 20
Mean
44
12
35
14
13
1
Table
Amines
II.
used
Isoetharine
Isoprenaline
IO
Second study. Persistent protection isoprenaline after bronchodilatation Case No.
IO 11 12 10 11
Increase PEFR
in
on inhalation (%)
from exercise-induced asthma by isoetharine has ceased seen in 3 of I I patients studied Duration increase PEFR
25 25 8 29 14 7
* Second exercise test after 35 minutes
of
Fall
in
(min)
165 125 80 165 90 35
After
in PEFR exercise
drug
8 31 11 0 69 15, 14”
and
on subsequent (%)
After
placebo 1
52 69 39 56 50 48, 49”
rest.
on a second exercise test 35 minutes later. Repeated bronchoconstriction on exercise at the same intervals was seen in the subsequent placebo study (Fig. 1). The other eight patients were not protected by isoetharine or isoprenaline after bronchodilatation had ceased and significant protection from placebo was seen in two of them.
constriction
DISCUSSION
In the first study the protection .from exercise-induced asthma afforded by isoetharine and sodium cromoglycate was similar but there was no correlation between the reduction in the fall in PEFR on exercise after inhaling isoetharine and the magnitude of its initial bronchodilator &ect. It is therefore unlikely that isoetharine reduced the effect of exercise by sustained bronchodilatation alone and a second mechanism may have contributed to this protective effect. 14
112
M. R. Hetxel, J. C. Batten and ip. J: H. Clark
0
20
40
60
Isoetharine -.Placebo capsule - -- Isoprenaline **e***. Placebo aerosol
80
100 Minutes
0 I
+
20
40
60
80 100
Medication Predicted
normal
P.E.F.R.
LB Exercise
2. Second study, Case 11. Persistent protection from exercise by (a) isoetharine powder and (b) isoprenaline aerosol after their bronchodilator effect has ceased compared with placebo. Protection by isoprenaline continues through a second exercise test 35 minutes later. (Predicted PEFR from Godfrey et al. 1970.) Fig.
In the second prolonged study three of 11 patients were protected by isoetharine after its bronchodilator effect had apparently ceased. When repetition of the study was attempted in two of them, protection could only be consistently demonstrated with isoetharine in one, but the other patient (Case 11) was similarly protected by isoprenaline. Moreover, in this patient protection persisted through a second exercise test 35 minutes later. This could not be explained by exhaustion of the exercise effect
(McNeil et al. 1966) as repeated bronchoconstriction occurred on exercise when placebo was used. In these three patients prevention of exercise-induced asthma may therefore have been effected by inhibition of mediator release and not by sustained bronchodilatation. There are no distinguishing features between these three and the other patients; in particular, like the rest of the group, they were of mixed atopic status (one non-atopic and two atopic subjects). It seems that these two effects can only occasionally be separated in time. However, our earlier observation in the first study that the magnitudes of the bronchodilator and protective effects of isoetharine were unrelated lends further support to our hypothesis that both mechanisms contributed to prevention of exercise-induced asthma. The possibility of temporal separation of these two actions is suggested also by the observation in children that protection from exercise-induced asthma two hours after inhaling isoprenaline was associated with minimal residual bronchodilatation (Sly et al. 1967). Delaying exercise until bronchodilatation has ceased shows this effect only in a minority of asthma patients, however. Our choice of isoetharine in powder form was governed by our wish to compare it
Sympathomimetic
Amines in Asthma
113
with sodium cromoglycate in the first study. It was convenient to use this preparation in the second study also but subsequent substitution of a conventional aerosol containing isoprenaline shows that the choice of sympathomimetic is not critical to demonstration of this phenomenon. The mechanism of exercise-induced asthma is unknown. Several authors have suggested that exercise provokes mediator release (McNeil et al. 1966; Cropp 1975; Godfrey 1975). Although the demonstration of sustained protection from bronchial challenge with inhaled allergens may have been a better test for our hypothesis, since mediator release is generally believed to be involved, exercise was used because repeated allergen challenge was considered unethical. Prevention of mediator release by /3 sympathomimetic drugs might explain the results of some clinical studies in which their regular use was more effective than expected. Regular treatment with isoprenaline in powder form, in comparison with sodium cromoglycate powder, cromoglycate plus isoprenaline powder and placebo powder, effectively controlled symptoms for several months in patients whose asthma was refractory to pre-trial symptomatic use of a panel of bronchodilator drugs which included conventional isoprenaline aerosol (Brompton Hospital/Northern General Hospital/MRC Collaborative Trials 1972, 1976). Of children regularly taking a placebo powder containing isoprenaline in a similar comparison with SCG 24% were well controlled for a year (Silverman et al. 1972). Symptomatic improvement after regular use of p stimulants in patients with apparently irreversible airways obstruction has also been observed (Clark 1971). Two distinct actions for sympathomimetic substances (isoetharine and isoprenaline) were only clearly demonstrated in a minority of the patients studied. However, this adds to the growing volume of evidence that prevention of mediator release might be one of the ways in which sympathomimetic agents help towards relief of extrinsic and intrinsic asthma. ACKNOWLEDGMENTS
We thank M. Horn, G. Beynon, I. Gregg and J. Evelegh for permission to study their patients and Beecham Research Laboratories for preparation of the capsules. REFERENCES E. S. K. & SCHILD, M. 0. (1969) Inhibition by sympathomimetic amines of histamine release induced by antigen in passively sensitised human lung. Nature, Lond. 224, 1028. BROMPTON HOSPITAL/MEDICAL RESEARCH COUNCIL COLLABORATIVE TRIAL (1972) Long term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults. BY. med. J. 4, 383. CLARK, T. J. H. (1971) The status of bronchodilator treatment. Postgrad. med. r. 47, Suppl. 50. Csopp, G. J. (1975) Exercise induced asthma. Pediat. Clins N. Am. 22, 63. GODFREY, S. (1975) Exercise induced asthma-Clinical, physiological and therapeutic implications. J. Allergy clin. Immunol. 56, 1. GODFREY, S., KAMBUROFF, P. L. & NAIRN, J. R. (1970) Spirometry, lung volumes and airways resistance in normal children aged 5 to 18 years. Br. J. Dis. Chest 64, 15. GODFREY, S., SILVERMAN, M. & ANDERSON, E. D. (1973) Problems of interpreting exerciseinduced asthma. j(. Allergy clin. Immunol. 52, 199. ASSEM,
114
M. R. Hetxel, J. C. Batten and T. J: H. Clark
JONES, R. S., BUSTON, M. H. &WHARTON, dilator
drugs R. S.,
in the
M. J. (1963) The place of physical exercise and bronchoassessment of the asthmatic child. Archs Dis. ChiZdh. 38, 539. J. R., MILLAR, J. S. & INGRAM, C. G. (1966) Exercise induced asthma.
MCNEIL, NAIRN, Q. Jl Med. 35, 55. NORTHERN GENERAL HOSPITAL/BROMPTON HOSPITAL/MEDICAL RESEARCH COUNCIL COLLABORATIVE TRIAL (1976) Sodium cromoglycate in chronic asthma. Br. med. J. 1, 361. SILVERMAN, M. & ANDERSON, S. D. (1972) Standardisation of exercise tests in asthmatic children. Archs Dis. Childh. 47, 882. SILVERMAN, M., CONNOLY, N. M., BALFOUR LYNN, L. & GODFREY, S. (1972) Long term trial of d&odium cromoglycate and isoprenaline in children with asthma. Br. med. J. 3, 378. SLY, R. M., HEIMLICH, E. M., BUSSER, R. J. & STRICK, C. (1967) Exercise induced bronchospasm. Evaluation of isoproterenol, phenylephrine and the combination. Awn. Allergy 25, 324.