Effect of inhaled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma. Effect of triamcinolone acetonide aerosol upon exercise-induced asthma. Effects of single-dose fluticasone on exercise-induced asthma in asthmatic children: a pilot study. Betamethasone valerate inhalation and exercise-induced asthma in adults. Low-dose budesonide improves exercise-induced bronchospasm in schoolchildren. Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma. Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma.
It has been suggested that inhaled corticosteroids may provide greater protection against constrictor stimuli that act indirectly such as exercise than those that act directly such as histamine.
                The effects of six weeks treatment with inhaled budesonide (800 micrograms twice daily) on bronchial reactivity to histamine, exercise, and eucapnic voluntary hyperventilation of dry air were compared in a double blind, placebo controlled, non-crossover study in 40 subjects with asthma. Change in bronchial reactivity to histamine and eucapnic hyperventilation over the six weeks was measured as change in the provocative dose of histamine or dry air causing a 20% fall in FEV1 (PD20 histamine and PV20 eucapnic hyperventilation (EVH) of dry air); this was not possible for exercise because of the development of refractoriness. To enable the change in response to all three stimuli to be compared, the response (percent fall in FEV1) to a fixed dose was measured for all three challenge tests.
                After budesonide there was an increase in PD20 histamine from 0.48 to 2.81 mumol and in PV20 EVH from 364 to 639 litres, and a significant correlation between the changes in PD20 histamine and PV20 EVH (r = 0.63). The median percentage fall in FEV1 in response to eucapnic hyperventilation, exercise, and histamine was similar before budesonide (25.5%, 26.6%, and 24.5%); the reduction in the percentage fall in FEV1 with budesonide was also similar for the three challenges (18.9%, 17.5%, and 16.6%), and all differed significantly from the changes following placebo. There was a significant correlation between change in percentage fall in FEV1 after budesonide with the three stimuli (histamine v exercise: r = 0.48; histamine v eucapnic hyperventilation: r = 0.46; exercise v eucapnic hyperventilation: r = 0.63).
                The similar magnitude of change in bronchial reactivity to all three stimuli after budesonide and the within subject correlation obtained between these changes suggest that corticosteroids act by a common mechanism to protect against eucapnic hyperventilation, exercise, and histamine. The effect of triamcinolone acetonide aerosol upon exercise-induced asthma was compared with that of placebo in a double-blind, crossover study in 11 asthmatic children. Measurement of pulmonary function before and after treatment and before and after exercise disclosed inhibition of exercise-induced asthma in only three of nine children in whom exercise after inhalation of placebo caused bronchospasm. A single high dose of inhaled corticosteroid (ICS) can increase airway caliber in children with asthma attacks and laryngitis subglottica. Presumably the effect is due to the vasoconstrictive and antiedematous properties of topical steroids. Enlarged vessels have been suggested to play a role in the pathophysiology of exercise-induced bronchial obstruction (EIB). To investigate this, we evaluated the effect of a single high dose of fluticasone propionate (FP) on EIB in asthmatic children. Nine children aged 8-16 years with mild to moderate asthma were included. All children had a history of EIB, which was confirmed by an exercise test. None was taking ICS maintenance therapy. The children inhaled either a single dose of 1 mg FP or placebo on 2 separate days within 7-14 days. After inhalation, airway caliber (FEV(1)) was assessed for 4 hr before exercise. Then an exercise challenge was performed on a treadmill to assess EIB (% fall FEV(1)). A significant increase in FEV(1) was observed 1 hr after inhalation of FP compared to placebo. Response to exercise was expressed as maximal % fall in FEV(1) from baseline (% fall) and as area under the curve (AUC) of the 30-min time/response curve. The % fall FEV(1) after exercise and the AUC were significantly reduced when FP was inhaled compared to placebo inhalation (% fall 9.7% vs. 19.2%, respectively, P = 0.038 and AUC 92.0%.min vs. 205.7%.min, respectively, P = 0.03). There was considerable individual variability in reduction of EIB, with 5 out of 9 children having a clinically significant response. We conclude that a single high dose of inhaled FP has an acute protective effect on the bronchial response to exercise in a substantial proportion of asthmatic children.
                Copyright 2001 Wiley-Liss, Inc. The effect of regular inhalation of betamethasone valerate (800 microgram daily) on exercise-induced asthma has been studied in 18 adult patients. The active aerosol was compared with placebo in a double-blind cross-over study, each inhaler being used for four weeks. Exercise tests after each period of treatment were performed using a cycle ergometer, care being taken to match the oxygen uptake during exercise each time a patient was tested. Twelve patients experienced less exercise-induced fall in peak expiratory flow rate after the corticosteroid inhaler, while six did not. This effect appeared to be independent of any alteration in base-line lung function, suggesting that it was due primarily to diminution of bronchial hyperreactivity. It is suggested that this change may have been due to interference with the synthesis or release of mediator substances from mast cells. The aim of this study was to compare the clinical efficacy of low-dose inhaled budesonide (once or twice daily) and placebo, administered via Turbuhaler, on exercise-induced bronchoconstriction (EIB) in children with mild asthma. Fifty-seven steroid-naive children (7-16 years old; 41 boys, 16 girls) with EIB participated in this sub-population study according to the following inclusion criterion: a maximum fall in forced expiratory volume in 1 s (FEV1) > or = 10% after a standardized treadmill test. Mean baseline FEV1 was 100.3% of predicted, and mean maximum fall in FEV1 after the standardized exercise test was 22%. The study was a double-blind, randomized, parallel-group design. After 2 weeks of run-in, the children received inhaled budesonide 100 microg or 200 microg once daily in the morning, 100 microg twice daily, or placebo, for 12 weeks. After 12 weeks of treatment, the fall in FEV1 after the exercise test was significantly less in all three budesonide groups (7.2-7.8%) vs. placebo (16.7%). Daytime symptom scores were significantly lower in all three budesonide groups compared with placebo (p <0.02). The three budesonide groups did not differ significantly, and no significant change in lung function was found in any group. Therefore children with mild asthma, but with significant EIB, improved their exercise tolerance and symptom control after 3 months of treatment with a low dose of inhaled budesonide given once or twice daily. When treating bronchial hyperresponsiveness to so-called direct and indirect stimuli, distinct pathophysiological mechanisms might require differences in dose and duration of inhaled corticosteroid therapy. To test this hypothesis in children with asthma, we investigated the time- and dose-dependent effects of 2 doses of fluticasone propionate (FP, 100 or 250 microg bid.) in improving exercise- (EIB) and methacholine-induced bronchoconstriction during 6 months of treatment, using a placebo-controlled parallel group study design. Thirty-seven children with asthma (aged 6 to 14 years; forced expired volume in 1 sec (FEV(1)) >/=70% predicted; EIB >/=20% fall in FEV(1) from baseline; no inhaled steroids during the past 4 months) participated in a double-blind, placebo-controlled, 3-arm parallel study. Children receiving placebo were re-randomized to active treatment after 6 weeks. Standardized dry air treadmill exercise testing (EIB expressed as %fall in FEV(1) from baseline) and methacholine challenge using a dosimetric technique (expressed as PD(20)) were performed repeatedly during the study. During FP-treatment, the severity of EIB decreased significantly as compared to placebo within 3 weeks, the geometric mean % fall in FEV(1) being reduced from 34.1% to 9.9% for 100 microg FP bid, and from 35.9% to 7.6% for 250 microg FP bid (P < 0.05). These reductions in EIB did not differ between the 2 doses and were sustained throughout the treatment period. PD(20) methacholine improved significantly during the first 6 weeks as compared to placebo (P < 0.04) and steadily increased with time in both treatment limbs (P = 0.04), the difference in improvement between doses (100 microg FP bid, 1.6 dose steps; 250 microg FP bid, 3.3 dose steps) approaching significance after 24 weeks (P = 0.06). We conclude that in childhood asthma, the protection afforded by inhaled fluticasone propionate against methacholine-induced bronchoconstriction is time- and dose-dependent, whereas protection against EIB is not. This suggests different modes of action of inhaled steroids in protecting against these pharmacological and physiological stimuli. This has to be taken into account when monitoring asthma treatment.
                Copyright 2000 Wiley-Liss, Inc. A new hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) aerosol markedly increases drug delivery to the airways. Therefore, even low doses of HFA-BDP should be effective, and the present study assesses this. A randomised, double-blind, crossover study was used to compare the effect of placebo, HFA-BDP 50 microg or 100 microg given q.d. (QVAR(TM) Autohaler(TM); 3M Pharmaceuticals, St. Paul, MN, USA) on exercise-induced bronchoconstriction and exhaled nitric oxide (eNO). After a 14-day run-in, 25 children (5-14 yrs old) entered three 4-week treatment periods, separated by a 1-week washout. After each period, the fall in forced expiratory volume in one second (FEV1), after an exercise test, and eNO were measured. Significant treatment effects with no carry-over or period effects were seen for both eNO and maximum fall in FEV1 after exercise. Differences were seen between placebo (fall in FEV1=27.9%; eNO=14.4 parts per billion (ppb)) and either dose of HFA-BDP, but not between the two active doses (50 microg: fall in FEV1=20.8%, eNO=9.3 ppb; 100 microg: fall in FEV1=20.9%, eNO=8.9 ppb). In conclusion, low q.d. doses of hydrofluoroalkane-beclomethasone dipropionate reduced exhaled nitric oxide and exercise-induced bronchoconstriction. Further studies are needed to assess whether q.d. administration of beclomethasone dipropionate is as effective as b.i.d. administration. Exercise-induced bronchoconstriction occurs in a large proportion of children with asthma, limiting everyday activities important for their physical and social development.
                The purpose of this randomized, double-blind, placebo-controlled study was to compare the ability of different patterns of antiasthmatic treatment, recommended in childhood asthma, to protect patients from exercise-induced bronchoconstriction.
                Children 6 to 18 years of age with atopic asthma were randomized to a 4-week, placebo-controlled, double-blind trial. Patients were randomly allocated to receive daily 200 microg budesonide (twice daily, 100 microg per dose) + 9 microg formoterol (twice daily, 4.5 microg per dose; n = 20); 200 microg budesonide + 5 or 10 mg montelukast (once daily at bedtime; n = 20); 5 or 10 mg montelukast (n = 20); 200 microg budesonide (n = 20); or placebo (n = 20). A standardized treadmill exercise challenge was performed before and after treatment.
                Exercise-induced bronchoconstriction, reflected by area under the curve for the FEV1 values from exercise over the 20-minute period and by maximum percent fall in FEV1 after exercise, was significantly diminished after 4 weeks in all active treatment groups, and compared with placebo. Exercise-induced bronchoconstriction protection improved more significantly in the budesonide + montelukast and montelukast groups compared with other therapeutic options.
                These data indicate differences in effects on exercise-induced bronchoconstriction between therapeutic options recommended in childhood asthma. Control of childhood asthma with exercise-induced bronchoconstriction can be obtained by using regular controller treatment.
Inhaled corticosteroids used for 4 weeks or more before exercise testing significantly attenuated exercise-induced bronchoconstriction. The relative benefits of inhaled corticosteroids compared to other forms of exercise induced bronchoconstriction treatment (sodium cromoglycate, nedocromil sodium, salbutamol, and other anti-inflammatory agents) remains unclear.