The effect of astemizole on exercise-induced asthma

Astemizole, a new oral long acting antihistamine devoid of significant central, sedative or anticholinergic effects, was studied in nine patients with exercise-induced asthma. Most patients received some protection with the active drug after 1 week of treatment (10 mg daily) and all showed less of a fall in FEV1 on exercise 1 week after stopping the drug compared with an initial placebo period (P less than 0.01). A significant reduction in histamine-induced skin reaction (weal size) was also demonstrated (P less than 0.01).     

The effect of azelastine on exercise-induced asthma

In ten young asthmatic subjects, we studied the effect of a single oral dose of 4.4 mg of azelastine hydrochloride on exercise-induced bronchoconstriction during the breathing of cold air. Exercise challenges were performed on two different days before and four hours after azelastine and placebo given in a randomized double-blind crossover fashion. Placebo had no effect on baseline pulmonary function and postexertional obstruction of the airways, in contrast to azelastine, which exerted a small but significant (p less than 0.05) bronchodilation and a significant attenuation (p less than 0.01) of exercise-induced bronchoconstriction as compared to data from before treatment and after placebo.     

The effect of sustained-release aminophylline on exercise-induced asthma

The effect of a sustained-release aminophylline on exercise-induced asthma (EIA) has been studied in nine young adult asthmatic patients, whose asthma was mild enough to be controlled with intermittent inhaled β-adrenoceptor agonists only. Exercise testing consisted of running for six minutes on a treadmill at a workload that was held constant for each individual and was sufficient to result in a pulse rate of greater than 160 beats/minute. Placebo or sustained-release aminophylline tablets were each given twice daily for one week periods in double blind random order. At the end of each week, morning and afternoon exercise tests were performed four and eight hours after the last dose of tablets, and plasma theophylline levels at these times were measured. The maximum falls in peak expiratory flow rate (PEFR) in the 20-minute period following the exercise tests were compared.On placebo the maximum fall in PEFR for the group after exercise testing was 29.6 ± 5.6% (mean ± se) in the morning and 28.5 ± 5.6% in the afternoon. On sustained-release aminophylline all subjects were found to have plasma theophylline levels greater than 7 μg/ml (range 7–17 μg/ml) with a mean of 10.8 μg/ml in the morning and 11.2 μg/ml in the afternoon. The maximum fall in PEFR following exercise was 13.3 ± 3.6% (mean ± se) in the morning and 18.6 ± 2.5% in the afternoon. The difference between the percentage falls in PEFR for the group on placebo compared to sustained-release aminophylline was significant at the 1% level for the morning tests and the 5% level for the afternoon tests. These results demonstrate that slow-release aminophylline is effective in inhibiting EIA over a prolonged period and that therapeutic levels of theophylline were present four and eight hours after the last dose of drug.     

The effect of Sch 1000 and disodium cromoglycate on exercise-induced asthma.

The effect of disodium cromoglycate and Sch 1000 on exercise-induced asthma was studied in nine patients. The exercise stimulus consisted of either treadmill running or jogging; spirometric measurements were made before and at intervals after exercise. In six patients, disodium cromoglycate and Sch 1000 were both effective in preventing exercise-induced asthma. In two patients, Sch 1000 was effective, while disodium cromoglycate gave no protection. In the remaining patient, disodium cromoglycate was more effective than Sch 1000. The findings of this study suggest that the mechanism of exercise-induced asthma may be multifactorial, and the relative importance of each factor may vary in different patients.     

Effects of inhaled budesonide alone and in combination with low-dose terbutaline in children with exercise-induced asthma

The effect of aerosolized terbutaline in a dose of 32.5 micrograms and its placebo, administered in a double-blind fashion, was studied in 14 children with exercise-induced asthma (EIA) before and during a 4-wk treatment period with aerosolized steroid (budesonide, 400 micrograms/day). Effects were assessed from the changes in peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and forced expiratory flow (FEF25-75) before and after treadmill exercise challenge. Compared with placebo there was a significant improvement in pulmonary function after terbutaline. During budesonide therapy, pulmonary function improved further, but there was no enhancement of the response to terbutaline. Terbutaline alone, budesonide plus placebo, and budesonide plus terbutaline reduced the exercise-induced fall in FEV1 by 30, 51, and 84%, respectively. The effect of budesonide on EIA was delayed during the 4 wk of treatment as compared with the improvement in resting pulmonary function. The present results suggest that 1 to 4 wk of therapy with inhaled corticosteroids decreases the severity of EIA. Further, the combined effect of inhaled corticosteroid and beta-2 agonist on pulmonary function appears to be additive.     

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.     

The effect of inhaled RS 7540, a xanthone, on exercise-induced asthma.

The effect of 71 oxo-7-thiomethoxyxanthone-2-carboxylic acid sodium salt (RS 7540) in inhibiting exercise-induced asthma was compared with that of placebo in a double-blind crossover study. Single doses of 40 mg were given by inhalation to 12 patients. Ten of these subsequently received a dose of 20 mg. RS 7540 at both dose levels had a statistically significant effect in giving total or partial protection from exercise-induced bronchospasm; however, no dose relationship was apparent.     

The effect of inhaled naloxone on resting bronchial tone and exercise-induced asthma

We wanted to determine whether 10 mg naloxone inhaled quantitatively could modulate the resting bronchial tone and respiratory response in exercise-induced asthma (EIA). In 11 asthmatic subjects, we measured specific airway conductance (SGaw) and forced expiratory flow (FEF) before and after the inhalation of naloxone or saline. In another 10 asthmatic subjects, we measured SGaw, FEF, and the ventilatory gas exchange, heart rate, and blood pressure responses produced by a treadmill exercise during 3 separate days: without any pretreatment (Day 1) or preceded by the inhalation of either 10 mg naloxone (Day 2) or saline (Day 3). We found that after 10 mg inhaled naloxone only one of 11 subjects bronchodilated, displaying an isolated, reproducible delta SGaw greater than 40% at 30 and 60 min. In the EIA protocol, the cardiopulmonary responses during exercise remained similar on all experimental days, but in seven of 10 subjects (all with %FEV1/FVC greater than or equal to 70% delta SGaw was -60 +/- 11%, + 1 +/- 40%, and -52 +/- 7% during no treatment, naloxone, and saline days, respectively (p less than 0.05). FEF changes were comparable on all days (p greater than 0.05). In conclusion: (1) consistent with the general role of endogenous opioids, these neurotransmitter/neuromodulators can modulate a stress-related bronchoconstrictor response (EIA), but only very seldom the resting bronchial tone. (2) Naloxone does not blunt EIA through a decrease in the asthmogenic stimulus (i.e., ventilation) or airway caliber change, but presumably through competition with the endogenous opioids released during exercise.     

Protective effect and duration of action of formoterol aerosol on exercise-induced asthma.

The short-term protective effect on exercise-induced asthma (EIA) and the duration of action of formoterol, given by metered dose aerosol at a dose of 24 micrograms, were compared with salbutamol (200 micrograms) and placebo in twelve asthmatic EIA-positive patients in a double-blind, placebo-controlled, three period cross-over study. On each treatment day the patients were given one of the drugs or placebo and two exercise tests were performed at the second and at the eighth hour after dosing. Using a standard procedure, exercise was performed by treadmill in well-controlled environmental conditions. In the first test at 2 h a significant difference relative to placebo (p less than 0.001) at each incremental time after exercise (i.e. 5, 10, 15, 20, 30 min) was obtained with both formoterol and salbutamol, without any significant difference between formoterol and salbutamol. After the eighth hour test formoterol still protected against EIA in comparison to both salbutamol and placebo. The effect of salbutamol at this time was not different from placebo. No adverse effects were reported in any treatment group. Formoterol has a long duration of action in protecting against EIA that persisted for eight hours, removing the need to dose with beta 2-agonist before every exercise.     

Mechanisms of exercise-induced asthma

In a previous review in this journal McFadden eloquently presented the findings which led him and his colleagues to propose that respiratory heat loss and the subsequent cooling of the airways are the initial reaction sequence leading to airway obstruction in hyperventilation and exercise-induced asthma [62]. He further concluded that: “Exercise per se is not essential and serves only as means to increase ventilation”. Our interpretation of currently available data has led us to conclude that while respiratory heat loss may play an important permissive role in initiating the bronchoconstriction which follows exercise, the weight of evidence indicates that exercise per se serves as the trigger mechanism and is not just a tool to increase ventilation. Moreover, we believe that the role of exercise in releasing chemical mediators has been established, although pathways by which the airway smooth muscle is affected are still uncertain.     

Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma.

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.     

Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma

BACKGROUND: Previous research has demonstrated that fish oil supplementation has a protective effect on exercise-induced bronchoconstriction (EIB) in elite athletes, which may be attributed to its antiinflammatory properties. Since EIB in asthma involves proinflammatory mediator release, it is feasible that fish oil supplementation may reduce the severity of EIB in asthmatic subjects. STUDY OBJECTIVES: To determine the efficacy of fish oil supplementation on severity of EIB in subjects with asthma. DESIGN: Randomized, double-blind, crossover study. SETTING: Lung function and exercise testing in a university research laboratory.Patients and measurements: Sixteen asthmatic patients with documented EIB entered the study on their normal diet and then received either fish oil capsules containing 3.2 g of eicosapentaenoic acid and 2.0 g of docohexaenoic acid (fish oil diet, n = 8) or placebo capsules (placebo diet, n = 8) daily for 3 weeks. At the beginning of the study (normal diet) and at the end of each treatment phase, the following pre-exercise and postexercise measures were assessed: (1) pulmonary function; (2) induced sputum differential cell count percentage and proinflammatory eicosanoid metabolite (leukotriene C4 [LTC4]-leukotriene E4 [LTE4] and prostaglandin D2 [PGD2]) and cytokine (interleukin [IL]-1beta and tumor necrosis factor [TNF]-alpha) concentrations; and (3) eicosanoid metabolites leukotriene B4 (LTB4) and leukotriene B5 (LTB(5)) generation from activated polymorphonuclear leukocytes (PMNLs). RESULTS: On the normal and placebo diet, subjects exhibited EIB. However, the fish oil diet improved pulmonary function to below the diagnostic EIB threshold, with a concurrent reduction in bronchodilator use. Induced sputum differential cell count percentage and concentrations of LTC4-LTE4, PGD2, IL-1beta, and TNF-alpha were significantly reduced before and following exercise on the fish oil diet compared to the normal and placebo diets. There was a significant reduction in LTB4 and a significant increase in LTB5 generation from activated PMNLs on the fish oil diet compared to the normal and placebo diets. CONCLUSION: Our data suggest that fish oil supplementation may represent a potentially beneficial nonpharmacologic intervention for asthmatic subjects with EIB.     

Acute protection against exercise-induced bronchoconstriction by formoterol, salmeterol and terbutaline.

The onset of bronchoprotection as obtained by various beta2-agonists has not been examined in a comparitive study. In this study, the onset of bronchodilation and protection against exercise-induced bronchoconstriction in asthmatics after inhalation of the long-acting beta2-agonists formoterol and salmeterol and the short-acting beta2-agonist terbutaline were measured. Twenty-five subjects with asthma and a history of exercise-induced bronchoconstriction (mean baseline forced expiratory volume in one second (FEV1): 90% predicted; mean fall in FEV1 after exercise: 31% from baseline) were enrolled in this double-blind, double-dummy, placebo-controlled, randomized, four-period crossover study. Exercise challenges were performed on 12 days at either 5, 30, or 60 min after inhalation of a single dose of formoterol (12 microg Turbuhaler), salmeterol (50 microg Diskus), terbutaline (500 microg Turbuhaler) or placebo. Exercise-induced bronchoconstriction (maximum fall in FEV1 or area under the curve) did not differ significantly between terbutaline, formorerol and salmeterol either 5, 30, or 60 min after inhalation of the study medication. In contrast, the onset of bronchodilation was slower after salmeterol compared to terbutaline and formoterol (p<0.05, each), which both showed a similar time course. At all time points between 5 and 60 min, formoterol provided significantly greater bronchodilation than salmeterol (p<0.05). These data indicate that equipotent doses of the bronchodilators salmeterol, formoterol and terbutaline were similarly effective with respect to their short-term protective potency against exercise-induced bronchoconstriction, despite the fact that the time course of bronchodilation was significantly different between the three beta2-agonists.     

Airway cooling. Stimulus for exercise-induced asthma.

Five patients were studied using a randomly assigned sequence of four inspired-air conditions during strenuous treadmill exercise for 10 min. The four inspired-air conditions were: (1) Cool, dry room air (CDA) at 23 degrees C with 3 mg of water and 7.3 cal of heat content/l, (2) over-saturated air (OSA) at room temperature containing 43 mg water and 16.3 cal/l, (3) hot, dry air (HDA) at 120 degrees C having 3 mg water and 24.4 cal/l, and (4) warm, humidified air (WHA) at 37 degrees C with 43 mg water and 34.7 cal/l. Using inspired-air CDA and OSA, all patients manifested exercise-induced asthma (EIA) while forced expiratory volume in 1 sec (FEV1) and maximal mid-expiratory flow (MMEF) decreased to an average of 81% and 63% of the baseline when breathing CDA and to 83% and 71% of the baseline when breathing OSA. With WHA, EIA was clearly prevented while the post-exercise FEV1 and MMEF were 101% and 103% of baseline, respectively. With HDA, the post-exercise FEV1 and MMEF were 95% and 86% of baseline, respectively. Analysis of variance revealed that the post-exercise pulmonary function changes had resulted solely from respiratory heat loss and not from water loss or from interaction of heat and water losses. These results indicate that exercise-induced asthma is associated with airway cooling incurred during exercise rather than airway dehydration.     

ECG changes in exercise-induced asthma

Changes in ECG during and after exercise were analyzed in 17 patients with exercise-induced asthma (EIA) and in 12 control patients (asthmatic patients without exercise-induced bronchial obstruction). The changes in ECG were compared with those in peak expiratory flow (PEF) rate and in arterial PCO2, PO2 and pH. It was found that in EIA the amplitude of the P wave increased in the inferior leads and decreased in the aVL lead during and after exercise. In addition, the amplitude of the R wave diminished and the amplitude of the S wave increased in the anterior precordial leads during bronchoconstriction. The changes in the ECG of the control patients were small and were already beginning to return to normal 4 min after exercise, whereas the changes in EIA patients persisted for 4-10 min after exercise. In EIA, a significant negative correlation was found between the PEF rate and the amplitude of the P wave in leads II, III and aVF. In addition, the PEF rate and the amplitude of the S wave in the V3 lead showed significant negative correlation. Almost no changes were observed in PO2 or PCO2 in the EIA or in the control patients. The pH decreased significantly in both groups during exercise. The PEF rate did not correlate with arterial PO2, PCO2 or pH after exercise in EIA.