Beta2-agonist tolerance and exercise-induced bronchospasm. Combination drug therapy for the prevention of exercise-induced bronchoconstriction in children. Short-term regular beta 2-adrenergic agonists treatment is safe in mild asthmatics taking low doses of inhaled steroids. A comparison of regular with intermittent bronchodilators in asthma patients on inhaled steroids. Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Exercise-induced bronchoconstriction as an expression of bronchial hyperreactivity: a study of its mechanisms in children. Nedocromil, a mucosal and connective tissue mast cell stabilizer, inhibits exercise-induced asthma.
The effect of regular inhaled beta-agonist on the treatment of exercise-induced bronchoconstriction was studied. Eight subjects with exercise-induced bronchoconstriction took 1 week each of salbutamol 200 microg qid or placebo in a random-order, double-blind, crossover study. They then withheld this treatment for 8 hours before performing a dry-air, sub-maximal exercise challenge at a work-rate previously shown to induce a 15% fall in forced expiratory volume in 1 second (FEV1). Five minutes after exercise, they inhaled salbutamol 100, 100, and 200 microg at 5-minute intervals. The mean pre-exercise FEV1 was similar on both study days. However, pretreatment for 1 week with salbutamol led to a significantly greater fall in FEV1 after exercise. The FEV1 remained lower than during the placebo arm despite the administration of salbutamol after exercise. This difference persisted 25 minutes after exercise. It is concluded that regular beta-agonist treatment leads to increased exercise-induced bronchoconstriction and a suboptimal bronchodilator response to beta-agonist. The data suggest that previous regular beta-agonist treatment may lead to a failure to respond to emergency bronchodilator treatment during an acute asthma attack and support current opinion that regular short-acting beta-agonist therapy should not be used to treat asthma. Sequential administration of a beta-agonist and cromolyn or nedocromil before exercise is recommended for patients whose symptoms are not controlled by beta-agonists alone; however, this practice reduces compliance.
                To evaluate the effectiveness of a new pre-combined aerosol formulation (salbutamol and nedocromil) in preventing exercise-induced bronchoconstriction and to compare it to salbutamol alone.
                Twelve children with asthma were studied in a double-blind, double-dummy, randomized, crossover, placebo-controlled design to compare the protective effect of salbutamol and a new pre-combined salbutamol/nedocromil formulation against exercise-induced bronchoconstriction. The drugs were delivered by a metered-dose inhaler (salbutamol, 200 microg; salbutamol/nedocromil, 200 microg/4 mg; placebo, 2 puffs) 20 minutes before exercise.
                Both active drugs were significantly more protective than placebo but there was no difference between them. Complete protection was obtained in 12/12, 10/12, and 1/12 subjects for the salbutamol/nedocromil combination, salbutamol alone and placebo, respectively.
                Although inhaled beta-agonists alone are highly efficacious in preventing exercise-induced bronchoconstriction, a minority of patients exists for whom a combined treatment with salbutamol and nedocromil is advantageous. This group may represent a subpopulation of subjects who release more, or different, mediators in response to exercise. Regular treatment with beta 2-adrenergic agonists is controversial in bronchial asthma. To investigate whether beta 2-adrenergic agonists can be used safely if associated with low doses of inhaled steroids, for a short period, without a deterioration of asthma control, we have examined 24 mild asthmatics. In a parallel, double-blind, placebo-controlled study, 1 week of run-in and run-out period framed 3 weeks of treatment. All patients received inhaled beclomethasone dipropionate (BDP 250 micrograms t.i.d.); after 1 week, 12 patients inhaled 400 micrograms of broxaterol and 12 patients received placebo t.i.d. FVC, FEV1, PD20-FEV1 methacholine, morning and evening PEF, and PEF amplitude % mean were measured before, during, and after treatment. No significant changes were noted in patients receiving inhaled broxaterol. There were no differences in symptoms and the use of rescue medication (salbutamol spray). We conclude that short-term regular treatment with beta 2-adrenergic agonists is not associated with a deterioration in asthma control in mild asthmatics inhaling low doses of steroids. The aim of this study was to compare the effect of regular versus intermittent (p.r.n.) bronchodilators on bronchial reactivity and asthma control in patients on concomitant inhaled corticosteroids. We studied 12 patients with asthma in a prospective, randomised, single-blind, single-dummy, three-period crossover trial comparing placebo (2 puffs t.d.s.), salbutamol (200 micrograms t.d.s.) and oxitropium bromide (200 micrograms t.d.s.) for 28 days each. Computerised spirometry and bronchial reactivity to histamine were obtained on entry and after each treatment period. Symptom scores, use of rescue bronchodilator and peak expiratory flow rates were recorded daily. There were no significant differences in bronchial hyperreactivity between the salbutamol, oxitropium and placebo treatment periods. There were no significant differences in baseline FEV1, FEF25-75%, symptom scores, use of rescue bronchodilator or morning and evening PEFR between treatment periods. Intermittent beta agonist therapy is as effective as regular therapy in terms of asthma control and bronchial hyperreactivity in patients on concomitant inhaled corticosteroid therapy. Since intermittent therapy achieves similar results with significantly lower beta agonist consumption, the data support current recommendations that beta agonists should be taken on a p.r.n. basis in asthma patients on inhaled steroids. Tolerance to the direct bronchodilator effects of beta 2-agonists does not appear to occur in asthma. However, it is not known whether this is true for the nonbronchodilator effects of these agents, which protect the airways against bronchoconstrictive stimuli.
                We investigated whether tolerance develops to the protective effect of inhaled terbutaline on airway responsiveness to the bronchoconstrictors methacholine (which acts directly on airway smooth muscle) and AMP (which acts indirectly by stimulating the release of mediators from mast cells) during sustained treatment with terbutaline. In a randomized, double-blind, crossover study, 12 patients with mild asthma each inhaled a single dose of terbutaline (500 micrograms) or placebo before a challenge with a series of doubling doses of inhaled methacholine or AMP, before and after treatment for seven days with 500 micrograms of terbutaline four times daily or placebo.
                Before the seven days of treatment with terbutaline, a single dose of terbutaline reduced airway responsiveness to methacholine by 2.7 doubling doses (95 percent confidence interval, 1.9 to 3.5), but it had an even greater protective effect against AMP, reducing airway responsiveness by 3.8 doubling doses (95 percent confidence interval, 2.7 to 4.9; P less than 0.001). After seven days of treatment with terbutaline, the protective effect of terbutaline against methacholine decreased to 2.2 doubling doses (95 percent confidence interval, 1.3 to 3.0; P = 0.04), and that against AMP decreased even more, to 1.7 doubling doses (95 percent confidence interval, 1.1 to 2.4; P less than 0.001). By contrast, the bronchodilator response to terbutaline was unchanged during seven days of treatment with this agent.
                We observed tolerance to the nonbronchodilator actions of the inhaled beta 2-agonist terbutaline in patients with mild asthma, an effect that may be more pronounced in mast cells than in bronchial smooth muscle. This property of beta-agonists may constitute a drawback to their regular use in patients with asthma. 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. Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens. The mechanism of exercise-induced bronchoconstriction (EIB) was studied by observing the protective effects of several aerosol agents in a double-blind, randomised trial. Exercise-induced bronchoconstriction was not affected by placebo, but was reduced by each agent used (p less than 0.001). Blocking the parasympathetic system had the weakest effect, while beta 2 adrenergic stimulation produced the strongest effect which was significantly different from the parasympatholytic (p less than 0.02). The effect of the mast cell stabilizer, sodium cromoglycate (SCG) was found to be intermediate. However in some patients SCG had a stronger effect than the beta 2 adrenergic agonist. A relationship was found between EIB and bronchial hyperreactivity induced by histamine (p less than 0.05). Nedocromil, the disodium salt of a pyranoquinoline dicarboxylic acid, has a similar profile of activity to disodium cromoglycate (DSCG) but appears to be more active in stabilizing mucosal-type mast cells. In a double-blind placebo-controlled trial nedocromil (2 mg) was given by inhalation to eight asthmatic patients prior to a treadmill exercise task. There was a significant reduction in the fall in FEV1 (P less than 0.01) and FVC (P less than 0.05) after nedocromil when compared to placebo. This study indicates that nedocromil might be an effective anti-asthma agent and in addition may help define the role of the mucosal mast cell.
In a population of stable asthmatics short acting beta-agonists, mast cell stabilisers, or anticholinergics will provide a significant protective effect against exercise-induced bronchoconstriction with few adverse effects. On average, SABAs resulted in more effective attenuation than mast cell stabilisers, while mast cell stabilisers were more effective than anti-cholinergic agents. Combining SABA and mast cell stabilisers may be appropriate in selected cases. The variability in the individual degree of response to these drugs in multi arm trials suggests clinicians and patients work together to identify the most effective prophylactic therapy.