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Beta2-adrenoreceptor agonists (beta 2-agonists) are extensively used in the treatment of childhood asthma. However, there have been concerns regarding their adverse effects and safety. In 2005, the FDA commissioned a "Black Box Warning" communicating the potential for an increased risk for serious asthma exacerbations or asthma related deaths, with the regular use of LABAs. In a meta-analysis of controlled clinical trials, the incidence of severe adverse events appeared to be highest in the 4-11 year age group. Several mechanisms have been proposed regarding the risk of regular use of beta 2-agonists, such as masking patients' perception of worsening asthma, desensitization and downregulation of the beta 2-adrenoreceptor, pro-inflammatory effects of beta 2-agonists, pharmacogenetic effects of beta 2-adrenoreceptor polymorphisms and age related differences in pathophysiology of asthma. In this paper, we review beta 2-receptor pharmacology, discuss the concerns regarding treatment with beta 2-agonists in childhood asthma, and provide suggestions for clinical pediatric practice in the light of current literature. (C) 2016 Elsevier Ltd. All rights reserved.

Beta2-adrenoreceptor agonists (beta 2-agonists) are extensively used in the treatment of childhood asthma. However, there have been concerns regarding their adverse effects and safety. In 2005, the FDA commissioned a "Black Box Warning" communicating the potential for an increased risk for serious asthma exacerbations or asthma related deaths, with the regular use of LABAs. In a meta-analysis of controlled clinical trials, the incidence of severe adverse events appeared to be highest in the 4-11 year age group. Several mechanisms have been proposed regarding the risk of regular use of beta 2-agonists, such as masking patients' perception of worsening asthma, desensitization and downregulation of the beta 2-adrenoreceptor, pro-inflammatory effects of beta 2-agonists, pharmacogenetic effects of beta 2-adrenoreceptor polymorphisms and age related differences in pathophysiology of asthma.In this paper, we review beta 2-receptor pharmacology, discuss the concerns regarding treatment with beta 2-agonists in childhood asthma, and provide suggestions for clinical pediatric practice in the light of current literature. (C) 2016 Elsevier Ltd. All rights reserved.

BACKGROUND: The dose-response relationship between two dose levels of fluticasone/formoterol (flutiform®, 100/10 μg and 500/20 μg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints). METHODS: Patients aged ≥18 years with forced expiratory volume in 1 second (FEV1) ≥60% predicted and who required a dose of

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics.Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured.Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25−75% and FEV1/FVC (P = 0.008–0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01).Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

Bronchodilators are central to the management of chronic obstructive pulmonary disease (COPD). Clinical studies combining different classes of bronchodilators, in particular a long-acting muscarinic antagonist (LAMA) and a long-acting beta(2)-agonist (LABA), have demonstrated greater improvements in lung function (forced expiratory volume in 1 second, FEV1) in patients with COPD than monotherapy. FEV1 has served as an important diagnostic measurement of COPD, and the majority of clinical studies of currently available pharmacotherapies grade effectiveness of treatment regimens based on improvements in FEV1. However, FEV1 alone may not adequately reflect the overall health status of the patient. Published evidence suggests that LABA/LAMA combination therapies demonstrate greater improvements in patient-centred outcomes such as dyspnoea, symptoms, rescue medication use, and quality of life than individual drugs used alone. Evaluating patient-centred outcomes associated with COPD is likely to play an important role in future research as a measure of overall treatment effectiveness. Raising awareness of the importance of outcomes beyond lung function alone, particularly in primary care where most patients initially present themselves for medical evaluation, should form a fundamental part of a more holistic approach to COPD management. (C) 2012 Primary Care Respiratory Society UK. All rights reserved. T van der Molen and M Cazzola. Prim Care Respir J 2012; 21(1): 101-108 http://dx.doi.org/10.4104/pcrj.2011.00102

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airflow obstruction and a progressive lung function decline. Although widely used, the efficacy of inhaled corticosteroids (ICS) in the treatment of COPD remains a matter of debate.Areas covered in this review: This article reviews the evidence about the effects of inhaled corticosteroids in the treatment of CORD.What the reader will gain: Short-term treatment with ICS improves lung function and quality of life; in addition, several studies with longer follow-up have shown less decline over time in quality of life, and fewer exacerbations. By contrast, long-term studies have been unable to show substantial improvement in the decline of lung function in COPD. Based on these findings, it was concluded that the use of ICS did not influence the natural course of COPD. However, this conclusion has been challenged by two subsequent studies, TORCH and GLUCOLD, which both showed a reduction in lung-function decline over time with the use of ICS. These two studies indicate that ICS might indeed influence the natural course of the disease, at least in a subgroup of COPD patients.Take home message: Further studies are needed to identify which individuals have a favorable short- and long-term response to ICS treatment.

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airflow obstruction and a progressive lung function decline. Although widely used, the efficacy of inhaled corticosteroids (ICS) in the treatment of COPD remains a matter of debate. Areas covered in this review: This article reviews the evidence about the effects of inhaled corticosteroids in the treatment of CORD. What the reader will gain: Short-term treatment with ICS improves lung function and quality of life; in addition, several studies with longer follow-up have shown less decline over time in quality of life, and fewer exacerbations. By contrast, long-term studies have been unable to show substantial improvement in the decline of lung function in COPD. Based on these findings, it was concluded that the use of ICS did not influence the natural course of COPD. However, this conclusion has been challenged by two subsequent studies, TORCH and GLUCOLD, which both showed a reduction in lung-function decline over time with the use of ICS. These two studies indicate that ICS might indeed influence the natural course of the disease, at least in a subgroup of COPD patients. Take home message: Further studies are needed to identify which individuals have a favorable short- and long-term response to ICS treatment.

One of the major goals of bronchodilator therapy in patients with COPD is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of treatment with beta-agonists, anticholinergics, and theophyllines on dyspnea, and steady-state and incremental exercise capacity. Thirty-three, double-blind, randomized, placebo-controlled studies written in English were selected. This review shows that approximately half of the studies showed a significant effect of bronchodilator therapy on exercise capacity. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting beta(2)-mimetics have favorable effects on exercise capacity in more than two thirds of the studies; surprisingly, the situation is less clear for long-acting beta(2)-agents. The majority, of the results of the published reports on theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently, large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.

Bronchodilators are central to the management of chronic obstructive pulmonary disease (COPD). Clinical studies combining different classes of bronchodilators, in particular a long-acting muscarinic antagonist (LAMA) and a long-acting beta(2)-agonist (LABA), have demonstrated greater improvements in lung function (forced expiratory volume in 1 second, FEV1) in patients with COPD than monotherapy. FEV1 has served as an important diagnostic measurement of COPD, and the majority of clinical studies of currently available pharmacotherapies grade effectiveness of treatment regimens based on improvements in FEV1. However, FEV1 alone may not adequately reflect the overall health status of the patient. Published evidence suggests that LABA/LAMA combination therapies demonstrate greater improvements in patient-centred outcomes such as dyspnoea, symptoms, rescue medication use, and quality of life than individual drugs used alone. Evaluating patient-centred outcomes associated with COPD is likely to play an important role in future research as a measure of overall treatment effectiveness. Raising awareness of the importance of outcomes beyond lung function alone, particularly in primary care where most patients initially present themselves for medical evaluation, should form a fundamental part of a more holistic approach to COPD management. (C) 2012 Primary Care Respiratory Society UK. All rights reserved. T van der Molen and M Cazzola. Prim Care Respir J 2012; 21(1): 101-108 http://dx.doi.org/10.4104/pcrj.2011.00102

Combination therapy with inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs), or treatment with high doses of ICSs alone improves asthma control when therapy with low-dose ICSs is not sufficient. However, it is not known which of these treatment options is more effective in sustaining asthma control.To evaluate the effect of increasing the ICS dosage vs adding LABAs on the time spent with well-controlled asthma or poorly controlled asthma.Post hoc analysis of the Formoterol and Corticosteroid Establishing Therapy study, which compared a fourfold increase in the budesonide dose with and without formoterol.Time with well-controlled asthma was improved by 19% (95% confidence interval [CI], 3 to 35%; p = 0.017) by adding formoterol, 24 microg/d, to therapy with budesonide, 200 microg/d, compared to 2% (95% CI, -9 to 12%; p = 0.76) with therapy with budesonide, 800 microg/d, alone. Time with well-controlled asthma was further improved by 29% (95% CI, 13 to 47%; p0.001) by adding formoterol to therapy with budesonide, 800 microg/d. Time with poorly controlled asthma was significantly reduced using the same interventions by 43% (95% CI, 25 to 57%), 22% (95% CI, 7 to 44%), and 50% (95% CI, 30 to 64%), respectively. Adding formoterol to budesonide was significantly more effective in increasing time with well-controlled asthma when compared to increasing the budesonide dose fourfold (increase, 16%; 95% CI, 1 to 33%; p = 0.035), with a trend for a greater reduction in time with poor control (decrease, 21%; 95% CI, -5 to 42%).The addition of formoterol to therapy with low-dose budesonide increases the probability of well-controlled asthma compared to a substantial increase in the dose of an ICS.