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1.
Influence of β2-adrenoceptor 16 genotype on propranolol-induced bronchoconstriction in patients with persistent asthma.
Anderson, WJ, Short, PM, Manoharan, A, Lipworth, JL, Lipworth, BJ
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2014;(5):475-6
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2.
The effect of nebulized salbutamol or isotonic saline on exercise-induced bronchoconstriction in elite skaters following a 1,500-meter race: study protocol for a randomized controlled trial.
Driessen, JM, Gerritsma, M, Westbroek, J, ten Hacken, NH, de Jongh, FH
Trials. 2013;:204
Abstract
BACKGROUND Prevalence of exercise-induced bronchoconstriction (EIB) is high in elite athletes, especially after many years training in cold and dry air conditions. The primary treatment of EIB is inhaling a short-acting beta-2-agonist such as salbutamol. However, professional speed skaters also inhale nebulized isotonic saline or tap water before and after a race or intense training. The use of nebulized isotonic saline or tap water to prevent EIB has not been studied before, raising questions about safety and efficacy. The aim of this study is to analyze the acute effect of nebulized isotonic saline or salbutamol on EIB in elite speed skaters following a 1,500-meter race. METHODS This randomized controlled trial compares single dose treatment of 1 mg nebulized salbutamol in 4 mL of isotonic saline, or with 5 mL of isotonic saline. A minimum of 13 participants will be allocated in each treatment group. Participants should be between 18 and 35 years of age and able to skate 1,500 m in less than 2 min 10 s (women) or 2 min 05 s (men). Repeated measurements of spirometry, forced oscillation technique, and electromyography will be performed before and after an official 1,500-m race. Primary outcome of the study is the difference in fall in FEV1 after exercise in the different treatment groups. The trial is currently enrolling participants. DISCUSSION Elite athletes run the risk of pulmonary inflammation and remodeling as a consequence of their frequent exercise, and thus increased ventilation in cold and dry environments. Although inhalation of nebulized isotonic saline is commonplace, no study has ever investigated the safety or efficacy of this treatment. TRIAL REGISTRATION This trial protocol was registered with the Dutch trial registration for clinical trials under number NTR3550.
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3.
Comparison of the bronchodilator and systemic effects of AZD3199, an inhaled ultra-long-acting β₂-adrenoceptor agonist, with formoterol in patients with asthma.
Bjermer, L, Rosenborg, J, Bengtsson, T, Lötvall, J
Therapeutic advances in respiratory disease. 2013;(5):264-71
Abstract
OBJECTIVES Pharmacologically mediated bronchodilation is important in the management of asthma, and is primarily achieved with β₂-agonists. Novel compounds should preferably have a longer duration of action and a better systemic side effect profile than established alternatives at comparable peak bronchodilation. This single-dose crossover study was conducted to investigate and compare with formoterol the bronchodilatory and systemic effects, tolerability and safety of AZD3199, a novel ultra-long-acting β₂-agonist (uLABA). METHODS Patients with asthma (n = 37) were randomized to receive AZD3199 (120, 480, 1920 µg), formoterol (9, 36 µg) or placebo inhaled via a Turbuhaler™. Bronchodilation was evaluated by maximum (E(max)) and average 22-26 h (E₂₂₋₂₆) forced expiratory volume in 1 second (FEV1). Serum potassium was evaluated by minimum (E(min)) and 0-4 h average (E(av)) determined from serial measurements. AZD3199 and formoterol were compared on the basis of relative dose potency. Adverse events, clinical laboratory tests and physical examinations were markers for safety and tolerability, with plasma AZD3199 as the indicator of drug exposure. RESULTS All active treatments dose-dependently increased E(max) and AZD3199 (480 and 1920 µg) and formoterol (36 µg) significantly increased E(₂₂₋₂₆) versus placebo. Relative dose potency between AZD3199 and formoterol was 50-fold on the microgram scale with respect to E max and 11-fold with respect to E(₂₂₋₂₆). Small, dose-dependent effects on potassium, heart rate and QTc were seen after administration of AZD3199 compared with placebo. These well-known dose-related class effects of β₂-agonists were mild. Notably, serum potassium suppression was less pronounced after AZD3199 compared with formoterol at similar bronchodilation. Overall, AZD3199 was well tolerated. CONCLUSIONS AZD3199 480 µg and 1920 µg produced 24-hour bronchodilation. At comparable peak bronchodilator effect, AZD3199 was associated with a lower level of systemic side effects than formoterol. AZD3199 was well tolerated, with no safety concerns identified to preclude further investigation. ClinicalTrials.gov study identifier: NCT00736489.
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4.
Long-term safety and efficacy of indacaterol, a long-acting β₂-agonist, in subjects with COPD: a randomized, placebo-controlled study.
Chapman, KR, Rennard, SI, Dogra, A, Owen, R, Lassen, C, Kramer, B, ,
Chest. 2011;(1):68-75
Abstract
BACKGROUND Indacaterol is an inhaled, long-acting β(2)-agonist providing 24-h bronchodilation with once-daily dosing in patients with COPD. METHODS Subjects with moderate to severe COPD who completed a 26-week, randomized, double-blind study were eligible for enrollment in an extension, during which treatment with double-blind indacaterol, 150 or 300 μg once daily, or placebo was continued for a further 26 weeks. The primary objective was to evaluate the long-term safety of indacaterol. Efficacy end points included trough (24 h postdose) FEV(1) at 52 weeks, exacerbations, and health status (St. George Respiratory Questionnaire [SGRQ]). RESULTS Four hundred fifteen subjects participated in the extension. Adverse events, mostly mild or moderate, occurred in 76%, 77%, and 68% of subjects receiving indacaterol, 150 μg; indacaterol, 300 μg; and placebo, respectively. Serious adverse events occurred in 10.4%, 12.3%, and 10.5%, respectively. Indacaterol had no clinically significant effects on ECG findings (corrected QT interval) or on serum potassium or plasma glucose levels. Indacaterol increased trough FEV(1) relative to placebo throughout the study (difference of ≥ 170 mL at week 52). No tolerance to its bronchodilator effect was detected. Indacaterol treatment was accompanied by significant reductions in COPD exacerbations (rate ratios compared with placebo, 0.62-0.64; P < .05) and as-needed albuterol use (1.2-1.4 puffs/d decrease, P < .001 compared with placebo). Health status improved with indacaterol treatment, with decreases from baseline in mean total SGRQ score generally > 4 units. CONCLUSIONS During 1 year of treatment, indacaterol was well tolerated and provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00677807; URL: www.clinicaltrials.gov.
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5.
Time-effect of montelukast on protection against exercise-induced bronchoconstriction.
Peroni, DG, Pescollderungg, L, Sandri, M, Chinellato, I, Boner, AL, Piacentini, GL
Respiratory medicine. 2011;(12):1790-7
Abstract
INTRODUCTION Montelukast has been proven to assure a protective effect against exercise-induced bronchoconstriction. AIM: To verify exactly when montelukast begins protection in asthmatic children by evaluating different time intervals between dosing and challenge. METHODS In a double blind, placebo-controlled, three day doses, crossover study, patients were randomized to receive in sequence treatment with either a placebo or montelukast and assigned to one of seven groups that were tested 1, 2, 3, 4, 5, 6 and 8 h after drug administration, respectively. For each group, the exercise challenge was always performed at the same hour on the first and third days of treatment. RESULTS Sixty-nine asthmatic children took part in the study. On day 3, the mean FEV(1) % fall from baseline was 25.54 (95% CI = 21.63/29.46) and 14.89 (95% CI = 11.85/17.92) for the placebo and active drug (p < 0.05), respectively. On day 1, the mean fall of FEV(1) was 28.20 (95% CI = 24.46/31.94) and 19.01 (95% CI = 15.71/22.31) for the placebo and montelukast (p < 0.05), respectively. Clinical protection was achieved in 21 (30%) and 33 (48%) subjects by montelukast on the first and third days, respectively. CONCLUSIONS Montelukast assured protection against exercise-induced bronchoconstriction from the first through the eighth hour from the first day of treatment. However, individual susceptibility to protection was evident since some individuals were not protected at any time. We conclude that in clinical use individual responses to the drug should be carefully evaluated in the follow-up management.
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6.
Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children.
Fogel, RB, Rosario, N, Aristizabal, G, Loeys, T, Noonan, G, Gaile, S, Smugar, SS, Polos, PG
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2010;(6):511-7
Abstract
OBJECTIVES To evaluate the effect of montelukast, 5 mg, or inhaled salmeterol, 50 microg, added to inhaled fluticasone in reducing the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) after a standardized exercise challenge and response to rescue bronchodilation with albuterol in children aged 6 to 14 years with persistent asthma and exercise-induced bronchoconstriction (EIB). METHODS Randomized, double-blind, double-dummy, multicenter, 2-period, 4-week, crossover study conducted between December 22, 2005 and November 14, 2008 at 30 centers in Europe, Asia, Mexico, and South America. Patients with asthma receiving inhaled corticosteroids demonstrated an FEV1 of 70% or higher of the predicted value and EIB (defined as a decrease in FEV1 > or = 15% compared with preexercise baseline FEV1 on 2 occasions before randomization). Standardized exercise challenges were performed at baseline (prerandomization) and at the end of each active treatment period. RESULTS Of 154 patients randomized, 145 completed the study. Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), mean area under the curve for the first 20 minutes after exercise (116.0% x min vs 168.8% x min; P = .006), and median time to recovery (6.0 vs 11.1 minutes; P = .04). Response to albuterol rescue after exercise challenge was significantly greater (P < .001) with montelukast. Montelukast and salmeterol were generally well tolerated. CONCLUSIONS Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment.
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7.
Comparative effects of caffeine and albuterol on the bronchoconstrictor response to exercise in asthmatic athletes.
VanHaitsma, TA, Mickleborough, T, Stager, JM, Koceja, DM, Lindley, MR, Chapman, R
International journal of sports medicine. 2010;(4):231-6
Abstract
The main aim of this study was to evaluate the comparative and additive effects of caffeine and albuterol (short-acting beta (2)-agonist) on the severity of EIB. Ten asthmatic subjects with EIB (exercise-induced bronchoconstriction) participated in a randomized, double-blind, double-dummy crossover study. One hour before an exercise challenge, each subject was given 0, 3, 6, or 9 mg/kg of caffeine or placebo mixed in a flavored sugar drink. Fifteen minutes before the exercise bout, an inhaler containing either albuterol (180 microg) or placebo was administered to each subject. Pulmonary function tests were conducted pre- and post-exercise. Caffeine at a dose of 6 and 9 mg/kg significantly reduced (p<0.05) the mean maximum % fall in post-exercise FEV (1) to -9.0+/-9.2% and -6.8+/-6.5% respectively compared to the double-placebo (-14.3+/-11.1%) and baseline (-18.4+/-7.2%). There was no significant difference (p>0.05) in the post-exercise % fall in FEV (1) between albuterol ( PLUS CAFFEINE PLACEBO) (-4.0+/-5.2%) and the 9 mg/kg dose of caffeine (-6.8+/-6.5%). Interestingly, there was no significant difference (p>0.05) in the post-exercise % fall in FEV (1) between albuterol ( PLUS CAFFEINE PLACEBO) (-4.0+/-5.2%) and albuterol with 3, 6 or 9 mg/kg of caffeine (-4.4+/-3.8, -6.8+/-5.6, -4.4+/-6.0% respectively). Similar changes were observed for the post-exercise % fall in FVC, FEF (25-75%) and PEF. These data indicate that moderate (6 mg/kg) to high doses (9 mg/kg) of caffeine provide a significant protective effect against EIB. It is feasible that the negative effects of daily use of short-acting beta (2)-agonists by asthmatic athletes could be reduced simply by increasing caffeine consumption prior to exercise.
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8.
Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma.
Stelmach, I, Grzelewski, T, Majak, P, Jerzynska, J, Stelmach, W, Kuna, P
The Journal of allergy and clinical immunology. 2008;(2):383-9
Abstract
BACKGROUND Exercise-induced bronchoconstriction occurs in a large proportion of children with asthma, limiting everyday activities important for their physical and social development. OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.
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9.
Effect of azelastine, montelukast, and their combination on allergen-induced bronchoconstriction in asthma.
Richter, K, Grönke, L, Janicki, S, Maus, J, Jörres, RA, Magnussen, H
Pulmonary pharmacology & therapeutics. 2008;(1):61-6
Abstract
OBJECTIVES Histamine and cysteinyl leukotrienes play an important role in early (EAR) and late (LAR) allergen reactions. Although protection by anti-histamines and anti-leukotrienes has been studied extensively, little is known about the effect of their combination. We, therefore, assessed the effect of clinically recommended doses of azelastine and montelukast alone and in combination on EAR and LAR. METHODS Seventeen patients (mean age 31 years, 14 m/3 f) with asthma and proven EAR and LAR received an oral dose of 4 mg azelastine twice daily, or 10mg montelukast once daily, or both for 1 week, in a double-blind, double-dummy, cross-over fashion. FEV(1) was measured after single-dose allergen challenges during EAR (0-2h) and LAR (2-9h). RESULTS Azelastine, montelukast and their combination protected against both EAR and LAR (p<0.004, each) by 46% and 43%, 76% and 59%, and 89% and 78%, respectively. Azelastine was not as effective during EAR but equally effective to montelukast during LAR. The combination was superior to each drug alone during both EAR and LAR (p<0.05, each). CONCLUSION The combination of azelastine and montelukast in clinically recommended doses has a greater effect in suppressing early and late allergen reactions than each drug alone.
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10.
Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma.
Tecklenburg, SL, Mickleborough, TD, Fly, AD, Bai, Y, Stager, JM
Respiratory medicine. 2007;(8):1770-8
Abstract
BACKGROUND Previous research has shown that diet can modify the bronchoconstrictor response to exercise in asthmatic subjects. OBJECTIVE Determine the effect of ascorbic acid supplementation on pulmonary function and several urinary markers of airway inflammation in asthmatic subjects with exercise-induced bronchoconstriction (EIB). METHODS Eight asthmatic subjects with documented EIB participated in a randomized, placebo controlled double-blind crossover trial. Subjects entered the study on their usual diet and were placed on either 2 weeks of ascorbic acid supplementation (1500 mg/day) or placebo, followed by a 1-week washout period, before crossing over to the alternative diet. Pre- and post-exercise pulmonary function, asthma symptom scores, fraction of exhaled nitric oxide (FENO), and urinary leukotriene (LT) C4-E4 and 9alpha, 11beta-prostagladin (PG) F2] were assessed at the beginning of the trial (usual diet) and at the end of each treatment period. RESULTS The ascorbic acid diet significantly reduced (p < 0.05) the maximum fall in post-exercise FEV1 (-6.4 +/- 2.4%) compared to usual (-14.3 +/- 1.6%) and placebo diet (-12.9 +/- 2.4%). Asthma symptoms scores significantly improved (p<0.05) on the ascorbic acid diet compared to the placebo and usual diet. Post-exercise FENO, LTC4-E4 and 9alpha, 11beta-PGF2 concentration was significantly lower (p<0.05) on the ascorbic acid diet compared to the placebo and usual diet. CONCLUSION Ascorbic acid supplementation provides a protective effect against exercise-induced airway narrowing in asthmatic subjects.