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Comparable reductions in hyperpnoea-induced bronchoconstriction and markers of airway inflammation after supplementation with 6·2 and 3·1 g/d of long-chain n-3 PUFA in adults with asthma.
Williams, NC, Hunter, KA, Shaw, DE, Jackson, KG, Sharpe, GR, Johnson, MA
The British journal of nutrition. 2017;(10):1379-1389
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Abstract
Although high dose n-3 PUFA supplementation reduces exercise- and hyperpnoea-induced bronchoconstriction (EIB/HIB), there are concurrent issues with cost, compliance and gastrointestinal discomfort. It is thus pertinent to establish the efficacy of lower n-3 PUFA doses. Eight male adults with asthma and HIB and eight controls without asthma were randomly supplemented with two n-3 PUFA doses (6·2 g/d (3·7 g EPA and 2·5 g DHA) and 3·1 g/d (1·8 g EPA and 1·3 g DHA)) and a placebo, each for 21 d followed by 14 d washout. A eucapnic voluntary hyperpnoea (EVH) challenge was performed before and after treatments. Outcome measures remained unchanged in the control group. In the HIB group, the peak fall in forced expiratory volume in 1 s (FEV1) after EVH at day 0 (-1005 (sd 520) ml, -30 (sd 18) %) was unchanged after placebo. The peak fall in FEV1 was similarly reduced from day 0 to day 21 of 6·2 g/d n-3 PUFA (-1000 (sd 460) ml, -29 (sd 17) % v. -690 (sd 460) ml, -20 (sd 15) %) and 3·1 g/d n-3 PUFA (-970 (sd 480) ml, -28 (sd 18) % v. -700 (sd 420) ml, -21 (sd 15) %) (P<0·001). Baseline fraction of exhaled nitric oxide was reduced by 24 % (P=0·020) and 31 % (P=0·018) after 6·2 and 3·1 g/d n-3 PUFA, respectively. Peak increases in 9α, 11β PGF2 after EVH were reduced by 65 % (P=0·009) and 56 % (P=0·041) after 6·2 and 3·1 g/d n-3 PUFA, respectively. In conclusion, 3·1 g/d n-3 PUFA supplementation attenuated HIB and markers of airway inflammation to a similar extent as a higher dose. Lower doses of n-3 PUFA thus represent a potentially beneficial adjunct treatment for adults with asthma and EIB.
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Vitamin D and omega-3 polyunsaturated fatty acid supplementation in athletes with exercise-induced bronchoconstriction: a pilot study.
Price, OJ, Hull, JH, Howatson, G, Robson-Ansley, P, Ansley, L
Expert review of respiratory medicine. 2015;(3):369-78
Abstract
OBJECTIVE The aim of this pilot study was to determine the combined effect of vitamin D and omega-3 polyunsaturated fatty acid (PUFA) supplementation on airway function and inflammation in recreational athletes with exercise-induced bronchoconstriction (EIB). METHODS Ten recreational athletes with EIB participated in a single-blind, placebo-controlled trial over six consecutive weeks. All subjects attended the laboratory on three occasions. Each visit was separated by a period of 3 weeks: visit 1 (usual diet), visit 2 (placebo) and visit 3 (SMARTFISH® NutriFriend 2000; 30 µg vitamin D3-3000 mg eicosapentaenoic acid, 3000 mg docosahexaenoic acid) consumed once daily for a period of 3 weeks. Venous blood was collected at the beginning of each trial to determine vitamin D status. Spirometry was performed pre- and post-eucapnic voluntary hyperpnoea (EVH). RESULTS The Maximum fall in FEV1 (ΔFEV1max) post-EVH was not different between visits (usual diet: -15.9 ± 3.6%, placebo: -16.1 ± 6.1%, vitamin D + omega-3 PUFA -17.8 ± 7.2%). Serum vitamin D remained unchanged between visits. CONCLUSION Vitamin D and omega-3 PUFA supplementation does not attenuate the reduction in lung function post-EVH. This finding should be viewed as preliminary until the results of randomised controlled trials are made available.
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Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways.
Brown, RH, Reynolds, C, Brooker, A, Talalay, P, Fahey, JW
Respiratory research. 2015;(1):106
Abstract
BACKGROUND It is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients. METHODS Forty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption. RESULTS Sulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane. Moreover, in individuals in whom the FEV1 response to MCh challenge decreased after sulforaphane administration, i.e., sulforaphane was protective, the activities of Nrf2-regulated antioxidant and anti-inflammatory genes decreased. In contrast, individuals in whom sulforaphane treatment enhanced the FEV1 response to MCh, had increased expression of the activities of these genes. High resolution CT scans disclosed that in asthmatics sulforaphane treatment resulted in a significant reduction in specific airway resistance and also increased small airway luminal area and airway trapping modestly but significantly. CONCLUSION These findings suggest the potential value of blocking the bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as sulforaphane.
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Vitamins C and E for asthma and exercise-induced bronchoconstriction.
Wilkinson, M, Hart, A, Milan, SJ, Sugumar, K
The Cochrane database of systematic reviews. 2014;(6):CD010749
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Abstract
BACKGROUND The association between dietary antioxidants and asthma or exercise-induced bronchoconstriction (EIB) is not fully understood. Vitamin C and vitamin E are natural antioxidants that are predominantly present in fruits and vegetables; inadequate vitamin E intake is associated with airway inflammation. It has been postulated that the combination may be more beneficial than either single antioxidant for people with asthma and exercise-induced bronchoconstriction. OBJECTIVES To assess the effects of supplementation of vitamins C and E versus placebo (or no vitamin C and E supplementation) on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma. To also examine the potential effects of vitamins C and E on exercise-induced bronchoconstriction in people with asthma and in people without a diagnosis of asthma who experience symptoms only on exercise. SEARCH METHODS Trials were identified from the Cochrane Airways Review Group Specialised Register and from trial registry websites. Searches were conducted in September 2013. SELECTION CRITERIA We included randomised controlled trials of adults and children with a diagnosis of asthma. We separately considered trials in which participants had received a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). Trials comparing vitamin C and E supplementation versus placebo were included. We included trials in which asthma management for treatment and control groups included similar background therapy. Short-term use of vitamins C and E at the time of exacerbation or for cold symptoms in people with asthma is outside the scope of this review. DATA COLLECTION AND ANALYSIS Two review authors independently screened the titles and abstracts of potential studies and subsequently screened full-text study reports for inclusion. We used standard methods as expected by The Cochrane Collaboration. MAIN RESULTS It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind.None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis. AUTHORS' CONCLUSIONS It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies.When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.
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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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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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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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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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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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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.