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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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Treatment options for the management of exercise-induced asthma and bronchoconstriction.
Millward, DT, Tanner, LG, Brown, MA
The Physician and sportsmedicine. 2010;(4):74-80
Abstract
Treatment for exercise-induced bronchospasm and exercise-induced asthma includes both pharmacologic and nonpharmacologic options. Pharmacologic agents that have been proven to be effective for treating these conditions include short- and long-acting β2-adrenoceptor agonists, mast cell-stabilizing agents, anticholinergics, leukotriene receptor antagonists, and inhaled corticosteroids (ICS). When selecting the most appropriate medication, factors to consider include the effectiveness of each, the duration of action, frequency of administration, potential side effects, and tolerance level. Long-acting β2-adrenoceptor agonists should not be used without ICS. Nonpharmacologic treatments include physical conditioning, incorporating a warm-up before and a cool-down period after exercise, performing nasal breathing, avoiding cold weather or environmental allergens, using a face mask or other aid to warm and humidify inhaled air, and modifying dietary intake. The data to support nonpharmacologic treatments are limited; however, they are routinely recommended because of the low risk associated with their use. This article highlights the advantages and limitations of each treatment option.
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Indirect challenge tests: Airway hyperresponsiveness in asthma: its measurement and clinical significance.
Anderson, SD
Chest. 2010;(2 Suppl):25S-30S
Abstract
Indirect challenges cause the release of endogenous mediators that cause the airway smooth muscle to contract and the airways to narrow. Airway sensitivity to indirect challenges is reduced or even totally inhibited by treatment with inhaled corticosteroids (ICS), so a positive response to an indirect stimulus is believed to reflect active airway inflammation. The indirect challenges commonly used in pulmonary function laboratories include exercise, eucapnic voluntary hyperpnea, hypertonic (4.5%) saline, and mannitol. Exercise was the first test to be standardized and was used to identify exercise-induced bronchoconstriction (EIB). The inhibition of EIB in young children by sodium cromoglycate led to the concept that mast cells were important very early in the onset of asthma. All of these indirect challenges are associated with the release of mast cell mediators (eg, prostaglandins, leukotrienes, and histamine). The hypertonic saline and mannitol challenges arose from the concept that EIB was caused by an increased osmolarity of the airway surface with release of mediators. These osmotic aerosols simplified testing with indirect challenges in the laboratory, improving the potential to identify currently active asthma. Although hyperresponsiveness to indirect challenges is frequently associated with a sputum eosinophilia, it is not a prerequisite because the mast cell is the most important source of mediators. The mechanism for ICS reducing hyperresponsiveness to indirect challenges likely involves both mast cells and eosinophils. Indirect challenges are appropriate to inform further on both the pathogenesis of asthma and the role of antiinflammatory agents in its treatment.
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Exercise induced bronchoconstriction and sports.
Billen, A, Dupont, L
Postgraduate medical journal. 2008;(996):512-7
Abstract
Exercise induced bronchoconstriction (EIB) describes the acute transient airway narrowing that occurs during and most often after exercise, and is prevalent in elite athletes. Prolonged hyperventilation of dry or cold air and increased inhalation of pollutants or allergens could account for the bronchoconstrictive reaction. The subsequent airway inflammation seems to differ from typical asthma. Objective measures of lung function and provocation tests should be used for an accurate and reliable diagnosis. EIB is currently treated with inhalation of beta(2)-agonists or, as second choice, sodium cromoglycate approximately 15 min before exercise. If this proves to be insufficient then inhaled steroids should be added. Leukotriene receptor antagonists can be used in patients whose symptoms do not respond to inhaled steroids. The screening of high risk populations such as swimmers, cyclists, rowers and winter athletes is recommended by some authors. Drug doping regulations and practical recommendations for competitive athletes and their health care providers are explained.
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Airway smooth muscle as a regulator of immune responses and bronchomotor tone.
Lazaar, AL, Panettieri, RA
Clinics in chest medicine. 2006;(1):53-69, vi
Abstract
The traditional view of airway smooth muscle (ASM) in asthma, as a purely contractile tissue, seems to be inadequate. Compelling evidence now suggests that ASM plays an important role in regulating bronchomotor tone, in perpetuating airway inflammation, and in remodeling of the airways. This article reviews three distinct functions of ASM cells: the process of excitation-contraction coupling, with a particular focus on the role of cytokines in modulating calcium responses; the processes of smooth muscle cell proliferation and migration; and the synthetic and immunomodulatory function of ASM cells. This article also discusses how altered synthetic function contributes to airway remodeling.
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Dietary salt intake as a potential modifier of airway responsiveness in bronchial asthma.
Mickleborough, TD, Gotshall, RW
Journal of alternative and complementary medicine (New York, N.Y.). 2004;(4):633-42
Abstract
While pharmacologic treatment of chronic asthma is usually highly effective, medications often have significant side-effects or exhibit tachyphylaxis. Alternative and/or complementary treatments that reduce dependence on pharmacologic medications are of interest in reducing the severity of asthma. This review analyzes the literature that has evaluated dietary salt intake as a potential modifier of the severity of asthma and airway responsiveness. High dietary intakes of salt, greater than 9 g/d, are common in Western civilizations, as is asthma. The question is whether reducing dietary salt intake potentially would improve pulmonary function and airway responsiveness in individuals with asthma. This review details the existing studies in this regard and includes the studies that have evaluated dietary salt on the severity of exercise-induced asthma (exercise-induced bronchoconstriction [E1B]). From a critical analysis of the existing literature, the data that support a role for dietary salt reduction for reducing severity of asthma and airway responsiveness in individuals with asthma is considered encouraging but not clinically convincing. The existing studies have suffered from a variety of experimental and population limitations. In contrast, the data from studies that have altered dietary salt and evaluated severity of EIB in nonatopic individuals is much more convincing. In each study so far, lowering dietary salt has reduced the severity of EIB to subclinical levels. Correspondingly, the supplementing of diets to higher than normal salt intake increased EIB significantly. This review concludes that the data are sufficient to warrant a clinical trial that is properly controlled and randomized to further investigate the influence of dietary salt intake on pulmonary function, airway responsiveness, symptoms, quality of life, and medication requirements in asthma and EIB.
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Mast-cell stabilising agents to prevent exercise-induced bronchoconstriction.
Spooner, CH, Spooner, GR, Rowe, BH
The Cochrane database of systematic reviews. 2003;(4):CD002307
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Abstract
BACKGROUND Exercise-induced bronchoconstriction (or asthma) following strenuous physical exertion is common and can cause sub-optimal performance, symptoms such as cough, dyspnea, wheeze, chest tightness, and can lead people to avoid physical activity. Management focuses on prevention with pre-exercise treatment using various pharmacologic agents. Mast cell stabilizing agents are effective in attenuating exercise-induced bronchoconstriction but their effectiveness compared to bronchodilator agents is unclear. OBJECTIVES To quantitatively compare the effects of inhaling a single dose of either mast cell stabiliser - nedocromil sodium or sodium cromoglycate - to a single dose of short acting beta-agonists or anti-cholinergic agents - atropine or ipratropium bromide - prior to a strenuous exercise challenge in participants with asthma who are at least 6 years of age and suffer from reproducible exercise-induced bronchoconstriction. The review also compares the effects between a short acting beta-agonist alone to a combination of a short acting beta-agonist + mast cell stabiliser. SEARCH STRATEGY We searched the Cochrane Airways Group ASTHMA and WHEEZ* trials register, Cochrane CENTRAL, Current Contents, review articles, textbooks and reference lists of articles. We also contacted the drug manufacturer and primary authors for additional citations. SELECTION CRITERIA Randomised trials comparing a single prophylactic dose of a mast cell stabiliser to a short acting beta-agonist, anti-cholinergic agent, or a short acting beta-agonist alone to a combination of short acting beta-agonist plus a mast cell stabiliser to prevent exercise-induced bronchoconstriction in asthmatics over six years old. The exercise challenge had to conform to acceptable standards and pulmonary function (PFT) reported as percent decrease from baseline of FEV1 or peak flow. Complete protection (maximum % fall PFT <15% post-exercise) and clinical protection (50% improvement over placebo effect) measures were included. DATA COLLECTION AND ANALYSIS Trial inclusion and quality assessments were conducted independently by two reviewers using standardised forms. A second reviewer confirmed data extraction and calculations. Attempts were made to contact study authors. The pooled estimate involving continuous pulmonary function measures are reported as a weighted mean difference (WMD), dichotomous data as an odds ratio (OR), both with 95% confidence intervals (95%CI) using a random effects model. Heterogeneity tests for pooled results were performed. MAIN RESULTS Twenty-four trials (518 participants) conducted in 13 countries between 1976 and 1998 were included. All drugs were effective at attenuating the exercise-induced bronchoconstriction response but to varying degrees even within the same individual. Compared to anti-cholinergic agents, mast cell stabilisers were somewhat more effective at attenuating bronchoconstriction. On average the maximum fall on MCS was reduced to 7.1% compared to 13.8% on AC ( WMD = 6.7%; 95% CI: 3.3 to 10.0), provided more individuals with complete protection (73% vs 56%; OR = 2.2; 95% CI: 1.3 to 3.7) and clinical protection (73% vs 52%; OR = 2.7; 95% CI: 1.1 to 6.4). There were no subgroup differences based on age, severity, or study quality, and no adverse effects were reported for either agent group. When compared to short acting beta-agonists mast cell stabilisers were not as effective at preventing deterioration. On average the maximum fall on MCS was 11.2% compared to 4.3% on beta agonists ( WMD = 6.8%; 95% CI: 4.5 to 9.2). MCS provided fewer individuals with complete protection (66% vs 85%; OR = 0.3; 95% CI: 0.2 to 0.5) or clinical protection (55% vs 77%; OR = 0.4; 95% CI: 0.2 to 0.8). There were no significant subgroup differences based on age, severity, drug, delivery, or study quality. A non-significant difference in side effects was demonstrated with 11% of short acting beta-agonist patients experiencing side effects compared to 3% of those receiving mast cell stabilisers (OR = 0.2; 95% CI: 0.0 to 8.2). Combining masta-agonist patients experiencing side effects compared to 3% of those receiving mast cell stabilisers (OR = 0.2; 95% CI: 0.0 to 8.2). Combining mast cell stabilisers with a short acting beta-agonist did not produce significant advantages to pulmonary function over short acting beta-agonists alone. On average the maximum fall on SABA only was reduced to 5.3% compared to 3.5% on the combination ( WMD = 1.8%; 95% CI: -1.1 to 4.6). Beta-agonists alone provided fewer individuals with complete protection (68% vs 80%; OR = 0.5; 95% CI: 0.2 to 1.4) or clinical protection (70% vs 86%; OR=0.4; 95% CI: 0.1 to 1.2) but the difference did not reach significance (p=0.17). There were no subgroup differences. REVIEWER'S CONCLUSIONS 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.
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Nedocromil sodium for preventing exercise-induced bronchoconstriction.
Spooner, CH, Saunders, LD, Rowe, BH
The Cochrane database of systematic reviews. 2002;(1):CD001183
Abstract
BACKGROUND Exercise-induced bronchoconstriction (EIB) following strenuous physical exertion afflicts many people. It can be the cause of sub-optimal performance, symptoms such as cough, dyspnea, wheeze and chest tightness, and can lead people to avoid physical activity. Management of EIB focuses on prevention through pharmaco-therapy and alternate strategies. Single use, pre-exercise, beta-agonists and non-steroidal antiinflammatory agents are recommended. OBJECTIVES Bronchodilator medications have been commonly used to prevent narrowing of airways after exercise, but anti-inflammatory drugs such as nedocromil sodium have also been used. The objective of this review was to assess the effects of a single dose of nedocromil sodium to prevent exercise-induced bronchoconstriction. SEARCH STRATEGY We searched the Cochrane Airways Group trials register, the Cochrane Controlled Trials Register, Current Contents, review articles, textbooks and reference lists of articles. We also contacted the drug manufacturer and primary authors for additional citations. SELECTION CRITERIA Randomised trials comparing a single dose of nedocromil sodium with placebo to prevent exercise-induced bronchoconstriction in patients with EIB over six years of age. DATA COLLECTION AND ANALYSIS Trial quality assessment and data extraction were conducted independently by two reviewers. Study authors were contacted for confirmation of data. MAIN RESULTS The combined results from 20 randomised controlled trials involving 280 participants, show that 4 mg, of nedocromil sodium inhaled 15 to 60 minutes prior to exercise significantly reduce the severity and duration of EIB in both adults and children, when compared to placebo. The maximum percentage fall in FEV1 was improved significantly compared to placebo (weighted mean difference 15.5 %; 95% confidence interval:13.2 to 18.1). For the maximum percentage fall in peak expiratory flow rate (PEFR) the improvement was similar: WMD 15.0%, (95% CI 8.3 to 21.6). Nedocromil shortened the time to recover lung normal function from more than 30 minutes with placebo to less than 10 minutes with the drug. It had a greater effect on those patients with more severe exercise-induced bronchoconstriction (defined as an exercise-induced fall in lung function > 30% from baseline). There were no significant adverse effects reported with the short term use of nedocromil. A further search conducted in September 2001 did not yield any further studies. REVIEWER'S CONCLUSIONS Nedocromil sodium used before exercise reduces the severity and duration of exercise-induced bronchoconstriction. This effect appears to be more pronounced in people with severe exercise-induced bronchoconstriction.
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Montelukast: a review of its therapeutic potential in asthma in children 2 to 14 years of age.
Muijsers, RB, Noble, S
Paediatric drugs. 2002;(2):123-39
Abstract
UNLABELLED Montelukast is a cysteinyl leukotriene receptor antagonist which is used as a preventive treatment for persistent asthma in patients > or =2 years of age. In children aged 6 to 14 years montelukast (5 mg/day) treatment resulted in a significant increase in FEV(1) (forced expiratory volume in 1 second, primary clinical outcome) during an 8-week randomized, double-blind trial. Moreover, significant improvements were observed for a range of secondary endpoints assessing symptoms, exacerbation rates, beta-agonist usage and quality of life. Concomitant administration of montelukast (5 mg/day) and inhaled budesonide (200 microg twice daily) resulted in a trend towards an increase in FEV(1) (p = 0.06, primary endpoint) and a statistically significant reduction in both as-needed beta(2)-agonist usage and the percentage of days with asthma exacerbations compared with budesonide plus placebo. No significant differences were observed in asthma-related quality of life between the two groups. During clinical trials both improvements in lung function and reductions in as-needed beta(2)-agonist usage were generally observed within 1 day after initiation of therapy in children 2 to 14 years of age with persistent asthma. Data from a randomized, nonblind trial in 6- to 11-year-old children and a 6-month extension to this trial suggest that both compliance to therapy and patient satisfaction are greater for montelukast than for either inhaled sodium cromoglycate or inhaled beclomethasone. In addition, patients and parents preferred oral montelukast over sodium cromoglycate. In 2- to 5-year-old children with persistent asthma, montelukast (4 mg/day) treatment resulted in significant improvements in a range of outcomes, such as as-needed beta(2)-agonist usage, symptom scores and percentage of days with asthma symptoms, as assessed during a randomized, double-blind trial primarily designed to assess tolerability. Data from small randomized, double-blind trials suggest that montelukast reduces exercise-induced bronchoconstriction in 6- to 14-year-old children. Montelukast is generally well tolerated. The frequency of adverse events in montelukast-treated children of all ages was comparable to that in patients receiving placebo. CONCLUSION Oral montelukast has shown efficacy as a preventive treatment for asthma during clinical trials in children aged 2 to 14 years. The drug offers benefits over more standard therapies such as inhaled sodium cromoglycate and nedocromil in terms of compliance and convenience. In addition, the drug offers significant benefits when added to inhaled corticosteroids (according to secondary endpoints). Montelukast offers an effective, well tolerated and convenient treatment option for children with asthma.
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10.
[Special characteristics of bronchial smooth muscle cells].
Marthan, R, Molimard, M
Revue des maladies respiratoires. 2000;(2 Pt 2):544-8
Abstract
Airway smooth muscle is one of the main effectors of bronchial reactivity. Our understanding of the cellular mechanisms involved in the contraction of this muscle has advanced in the recent past since isolated cells in culture can now be studied. Extracellular messengers (neurotransmitters and mediators) as well as their specific membrane receptors have been analyzed in some details. Membrane transduction of extracellular messengers brings about the formation (or the increase in the concentration) of the intracellular second messenger which, in airway smooth muscle, is cytosolic calcium (Ca2+i) via activation of calcium channels which depend on surface membrane potential changes (electromechanical coupling) on one hand and mainly via mechanisms independent of surface membrane potential changes, the so called--pharmacomechanical coupling--which involves membrane phosphoinositide metabolism. Changes in Ca2+i activate contractile proteins leading the muscle to shorten and to develop force via several controlled steps such as phosphorylation of myosin or changes in the sensitivity to Ca2+ of the contractile elements. Information about the cellular physiology and pathophysiology of this muscle is of value to design new drugs for the treatment of bronchoconstriction.