Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism. Salmeterol compared with slow‐release terbutaline in nocturnal asthma A multicenter, randomized, double‐blind, double‐dummy, sequential clinical trial Blood eosinophil numbers and activity during 24 hours: effects of treatment with budesonide and bambuterol. Effects of budesonide and formoterol on NF-kappaB, adhesion molecules, and cytokines in asthma. Comparison between formoterol 12 microg b.i.d. and on-demand salbutamol in moderate persistent asthma. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial). Effect of salmeterol compared with beclomethasone on allergen-induced asthmatic and inflammatory responses. Formoterol, a new long acting beta 2 agonist for inhalation twice daily, compared with salbutamol in the treatment of asthma. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma. Formoterol, a new long-acting beta 2 agonist, inhaled twice daily, in stable asthmatic subjects. Effects of montelukast on surrogate inflammatory markers in corticosteroid-treated patients with asthma. Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. The Dutch Asthma Study Group. Serum potassium levels, CPK-MB and ECG in children suffering asthma treated with beclomethasone or beclomethasone-salmeterol. Addition of inhaled salmeterol to inhaled corticosteroids in patients with poorly controlled nocturnal asthma. Onset of bronchodilation of budesonide/formoterol vs. salmeterol/fluticasone in single inhalers. Salmeterol reduces the need for inhaled corticosteroid in steroid-dependent asthmatics. Effect of long term treatment with salmeterol on asthma control: a double blind, randomised crossover study Effect of Salmeterol Is Independent of Previously Inhaled Salbutamol: A Clinical Controlled Study [Contribution of salmeterol in ambulatory practice to the improvement of asthma and quality of life in childhood]. Salmeterol in paediatric asthma. Comparison of second controller medications in addition to inhaled corticosteroid in patients with moderate asthma. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. A twelve month comparison of salmeterol with salbutamol in asthmatic patients. European Study Group. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Protection against cold air and exercise-induced bronchoconstriction while on regular treatment with Oxis. Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction. Sputum cellular and cytokine responses to inhaled endothelin‐1 in asthma Inhaled salmeterol and albuterol in asthmatic patients receiving high-dose inhaled corticosteroids. Formoterol compared with beclomethasone and placebo on allergen-induced asthmatic responses. Addition of salmeterol to low-dose fluticasone versus higher-dose fluticasone: an analysis of asthma exacerbations. Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge. Effects of once-daily formoterol and budesonide given alone or in combination on surrogate inflammatory markers in asthmatic adults. Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Effects of treatment with formoterol on bronchoprotection against methacholine. Effect of formoterol on clinical parameters and lung functions in patients with bronchial asthma: a randomised controlled trial The protective effect of salbutamol inhaled using different devices on methacholine bronchoconstriction. Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study Salmeterol xinafoate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. UK Study Group. A dose-response study with formoterol Turbuhaler as maintenance therapy in asthmatic patients. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Changes in methacholine induced bronchoconstriction with the long acting beta 2 agonist salmeterol in mild to moderate asthmatic patients. Airway inflammatory response to ozone in subjects with different asthma severity. Fluticasone alone or in combination with salmeterol vs triamcinolone in asthma. Validation of an asthma quality of life diary in a clinical trial. Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma in vivo Asthma quality of life during 1 year of treatment with budesonide with or without formoterol. Salmeterol/fluticasone propionate (50/250 microg) combination is superior to double dose fluticasone (500 microg) for the treatment of symptomatic moderate asthma. A bolus of inhaled budesonide rapidly reverses airway subsensitivity and beta2-adrenoceptor down-regulation after regular inhaled formoterol. An antiinflammatory effect of salmeterol, a long-acting beta(2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. Salmeterol improves quality of life in patients with asthma requiring inhaled corticosteroids. Salmeterol Quality of Life Study Group. Airway tissue mast cells in persistent asthma: predictor of treatment failure when patients discontinue inhaled corticosteroids. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid Salmeterol/fluticasone propionate (50/100 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in children with asthma. Effects of fluticasone plus salmeterol versus twice the dose of fluticasone in asthmatic patients Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. Anti-inflammatory effects of salmeterol compared with beclomethasone in eosinophilic mild exacerbations of asthma: a randomized, placebo controlled trial. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Is the increase in bronchial responsiveness or FEV1 shortly after cessation of beta2-agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting beta2-agonists. Low-density areas on high-resolution computed tomograms in chronic pediatric asthma. Initial treatment of symptomatic mild to moderate bronchial asthma with the salmeterol/fluticasone propionate (50/250 microg) combination product (SAS 40023). Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) maintains pulmonary function and symptoms of asthmatic children previously receiving inhaled corticosteroids. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled beta 2 agonist. Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma. Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. Efficacy of salmeterol xinafoate powder in children with chronic persistent asthma. The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics. A placebo-controlled, crossover comparison of salmeterol and salbutamol in patients with asthma. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group. Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. European Respiratory Study Group. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Concomitant bitolterol mesylate aerosol and theophylline for asthma therapy, with 24 hr electrocardiographic monitoring. [Long-term effect of inhaled budesonide in patients with mild to moderate chronic obstructive lung disease. The Osterbro Study]. A randomized, double‐blind trial of the effect of glucocorticoid, antileukotriene and bβ‐agonist treatment on IL‐10 serum levels in children with asthma Discriminative aspects of two generic and two asthma-specific instruments: relation with symptoms, bronchodilator use and lung function in patients with mild asthma Salmeterol xinafoate in the treatment of mild to moderate asthma in primary care. UK Study Group. Cost-effectiveness of eformoterol Turbohaler versus salmeterol Accuhaler in children with symptomatic asthma. Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Safety of formoterol by Turbuhaler® as reliever medication compared with terbutaline in moderate asthma Comparison of fluticasone propionate-salmeterol combination therapy and montelukast in patients who are symptomatic on short-acting beta(2)-agonists alone. Fluticasone propionate, salmeterol xinafoate, and their combination in the treatment of nocturnal asthma. A randomised controlled trial of short term growth and collagen turnover in asthmatics treated with inhaled formoterol and budesonide Clinical evaluation of CFC-free metered dose inhalers. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma Salmeterol in two different doses in the treatment of nocturnal bronchial asthma poorly controlled by other therapies Long-term circadian effects of salmeterol in asthmatic children treated with inhaled corticosteroids. A randomized clinical trial of nebulized magnesium sulfate in addition to albuterol in the treatment of acute mild-to-moderate asthma exacerbations in adults. Salmeterol/fluticasone propionate combination therapy 50/250 microg twice daily is more effective than budesonide 800 microg twice daily in treating moderate to severe asthma. In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma. Asthma therapy modulates priming-associated blood eosinophil responsiveness in allergic asthmatics. Nocturnal asthma: effect of treatment with oral sustained-release terbutaline, inhaled budesonide, and the two in combination. Combination Therapy with Single Inhaler Budesonide/Formoterol Compared with High Dose of Fluticasone Propionate Alone in Patients with Moderate Persistent Asthma Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Regular formoterol treatment in mild asthma. Effect on bronchial responsiveness during and after treatment. Effect of salmeterol and salmeterol plus beclomethasone on saliva flow and IgA in patients with moderate-persistent chronic asthma. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Improved Ability to Perform Strenuous Activities After Treatment with Fluticasone Propionate/Salmeterol Combination in Patients with Persistent Asthma A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma. Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis. Clinical equivalence of salmeterol/fluticasone propionate in combination (50/100 microg twice daily) when administered via a chlorofluorocarbon-free metered dose inhaler or dry powder inhaler to patients with mild-to-moderate asthma. Influence of budesonide on the response to inhaled terbutaline in children with mild asthma. Antitussive Effect of the Leukotriene Receptor Antagonist Zafirlukast in Subjects with Cough-Variant Asthma* Need for theophylline in severe steroid‐requiring asthmatics A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma. Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide. Formoterol and beclomethasone versus higher dose beclomethasone as maintenance therapy in adult asthma. Additive effects of salmeterol and fluticasone or theophylline in COPD. Salmeterol and fluticasone propionate given as a combination Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. [Salmeterol improves the control of disease in patients with moderate asthma. A comparative study of inhaled salmeterol 50 mg and salbutamol depot tablets 8 mg, both administered twice daily]. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Comparison of salmeterol with beclomethasone in adult patients with mild persistent asthma who are already on low-dose inhaled steroids. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. Effects of fluticasone vs. fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in mild persistent asthma. Dose-related effects of formoterol on airway responsiveness to adenosine 5′‐monophosphate and histamine Efficacy and safety of formoterol Turbuhaler when added to inhaled corticosteroid treatment in children with asthma. Effect of anti-asthmatic drugs on the response to inhaled endotoxin. Step-down therapy with low-dose fluticasone-salmeterol combination or medium-dose hydrofluoroalkane 134a-beclomethasone alone. Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Salmeterol added to inhaled corticosteroid therapy is superior to doubling the dose of inhaled corticosteroids: a randomized clinical trial. Comparison of the effects of salmeterol and formoterol in patients with severe asthma. Comparison of anti-inflammatory and clinical effects of beclomethasone dipropionate and salmeterol in moderate asthma Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. A Health-Related Quality-of-Life Comparison of Formoterol (Oxis®) Turbuhaler® plus Budesonide (Pulmicort®) Turbuhaler® with Budesonide Turbuhaler® Alone and Noncorticosteroid Treatment in Asthma: A Randomized Clinical Study in Russia Possibilities of formoterol to enhance the peripheral lung deposition of the inhaled liposome corticosteroids. Short-term effects of budesonide, nedocromil sodium and salmeterol on bronchial hyperresponsiveness in childhood asthma. Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Formoterol (OXIS) Turbuhaler as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma. The effect of anti‐allergic mattress encasings on house dust mite‐induced early‐ and late‐airway reactions in asthmatic patients. A double‐blind, placebo‐controlled study A cost-effectiveness study comparing the as-needed use of formoterol (Oxis) and terbutaline (Bricanyl) in patients with moderate to severe asthma. A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma. One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Salmeterol and fluticasone propionate (50/250 microg) administered via combination Diskus inhaler: as effective as when given via separate Diskus inhalers. Quality of life during formoterol treatment: comparison between asthma-specific and generic questionnaires. Canadian and the Dutch Formoterol Investigators. Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma. One-year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler) for the treatment of asthma. Pilgrim's progress: the effect of salmeterol in older children with chronic severe asthma. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma Potential masking effects of salmeterol on airway inflammation in asthma. Effectiveness and safety of salmeterol in nonspecialist practice settings. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Long-acting bronchodilators in premenstrual exacerbation of asthma. The inflammatory marker serum eosinophil cationic protein (ECP) compared with PEF as a tool to decide inhaled corticosteroid dose in asthmatic patients. Fluticasone propionate/salmeterol combination compared with montelukast for the treatment of persistent asthma. Influence of fluticasone and salmeterol on airway effects of inhaled organic dust;an in vivo and ex vivo study Salmeterol/Fluticasone Combination Inhaler Effect of inhaled fluticasone with and without salmeterol on airway inflammation in asthma. Comparison of intramuscular betamethasone and oral prednisone in the prevention of relapse of acute asthma. A proof of concept study to evaluate putative benefits of montelukast in moderate persistent asthmatics. Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Nocturnal asthma: effect of salmeterol on quality of life and clinical outcomes. [Salmeterol improves control in asthmatic patients treated in general practice. A comparative study of salmeterol (Serevent) and salbutamol (Ventoline) in patients with mild to moderate asthma].
BACKGROUND Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors , with formoterol being a full agonist . The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40 % of patients and is known to predispose to agonist-induced downregulation and desensitization . OBJECTIVES To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction ( the primary end point ) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism . METHODS Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were r and omized to completion ( mean [ SEM ] age , 35.8 [ 3.2 ] years ; mean FEV(1 ) , 76.9 [ 2 . 5]% predicted ) . Patients received three different treatments for 1 week in r and omized , double-blind , crossover fashion , with a 1-week washout period between treatments : formoterol , 12 microg bid ; salmeterol , 50 microg bid ; and placebo . For each of the r and omized treatment periods , there were three separate methacholine challenges : baseline after washout , 12 h after the first dose , and 12 h after the last dose . RESULTS Both salmeterol and formoterol exhibited significantly ( p < 0.05 ) greater bronchoprotection than placebo for their effects after single or repeated dosing , although there was no significant difference between the two drugs . The geometric mean fold protection vs placebo ( 95 % confidence interval [ CI ] ) for the first dose was 1.6-fold ( 95 % CI , 1.1 to 2.2 ) for salmeterol and 1.9-fold ( 95 % CI , 1.1 to 3.2 ) for formoterol , and for last dose was 1.6-fold ( 95 % CI , 1.2 to 2.3 ) for salmeterol and 1 . 9-fold ( 95 % CI , 1.2 to 2.8 ) for formoterol . Salmeterol and formoterol produced significant ( p < 0.05 ) increases in FEV(1 ) and forced expiratory flow after 25 to 75 % of vital capacity has been expelled , after the first but not the last dose compared to placebo , while there were significant ( p < 0.05 ) improvements in domiciliary peak flows during treatment with both drugs . CONCLUSION Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype . There was a significant residual degree of bronchoprotection after 1 week of treatment , which was not significantly different compared to the first-dose effect Brambilla C , Chastang C , Georges D , Bertin L. Salmeterol compared with slow‐release terbutaline in  nocturnal asthma .  A multicenter , r and omized , double‐blind , double‐dummy , sequential clinical trial The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers , serum levels of eosinophil cationic protein ( ECP ) , serum eosinophil chemotactic activity ( ECA ) , and serum neutrophil chemotactic activity ( NCA ) were studied in two groups of patients with allergic asthma . Group 1 ( n = 8) had a circadian variation of peak expiratory flow ( PEF ) 15 % or greater , and group 2 ( n = 9 ) had a circadian PEF variation less than 15 % . Both groups were r and omized and crossover treated for 4 weeks with ( A ) 0.4 mg budesonide at 8 AM and 8 PM , ( B ) 20 mg bambuterol at 8 PM , and ( C ) placebo . At the end of each period blood eosinophil numbers , ECP , ECA , and NCA were measured during 24 hours at 4-hour intervals . No significant differences in the inflammatory parameters could be observed between the groups , although eosinophil numbers tended to be higher in group 1 than in group 2 . Highest eosinophil numbers were observed at night . Budesonide reduced both eosinophil numbers and ECP levels , especially at night ; bambuterol had no effect on both variables . No circadian variation or treatment effects were observed for ECA and NCA . This study suggests a role for the eosinophil in the nocturnal worsening of asthma , and it demonstrates that budesonide produces , in contrast to bambuterol , a reduction of ( nocturnal ) eosinophil numbers and activity The asthmatic inflammatory response can be attenuated by corticosteroids and in part by beta(2)-agonists . We investigated if these effects are accompanied by a downregulation in nuclear factor kappa B ( NF-kappaB ) , a transcription factor regulating many of the cytokine and adhesion molecule genes expressed in allergic inflammation . Bronchial biopsies were taken before and after 8 wk treatment with formoterol , budesonide , or placebo from atopic asthmatics . Biopsies were processed into glycol methacrylate and stained immunohistochemically for eosinophils ( as an index of inflammation ) , activated and total NF-kappaB , adhesion molecules , and cytokines . After budesonide treatment there was a significant decrease in the number of submucosal cells staining for total NF-kappaB , granulocyte macrophage colony-stimulating factor ( GM-CSF ) and tumor necrosis factor-alpha ( TNF-alpha ) , accompanied by a significant decrease in mucosal eosinophils and expression of vascular cell adhesion molecule-1 ( VCAM-1 ) in the endothelium and interleukin-8 ( IL-8 ) in the epithelium . After formoterol treatment there was a significant decrease in eosinophils and the epithelial expression of activated NF-kappaB , but these changes were not accompanied by reduced immunoreactivity for adhesion molecules or cytokines . We conclude that at least some of the therapeutic efficacy of inhaled corticosteroids is mediated through inhibition of NF-kappaB-regulated gene expression , whereas the reduction in airway eosinophilia by long-acting beta(2)-agonists probably operates through alternative pathways Inhalation of on-dem and salbutamol ( ODS ) several times daily is sometimes the only beta2-agonist prescribed in moderate persistent asthma , whereas a long-acting beta2-agonist should be added . This trial aim ed to compare the efficacy of formoterol dry-powder capsule 12 microg b.i.d . ( Foradil ) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids , in the conditions of real practice . Two hundred and fifty-nine patients were r and omized ( formoterol ; 130 ; ODS : 129 ) in this open , parallel-group trial . The mean increases in morning peak expiratory flow ( PEF primary variable ) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol : + 25.7 and + 24.1 l min(-1 ) , respectively vs. + 4.5 and + 0.5 l min(-1 ) respectively with ODS . The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3 . Formoterol  reduced the use of salbutamol as rescue medication by two-thirds . The percentages of symptom-free days and nights statistically significantly increased with formoterol ( + 20 % and + 33 % respectively ) , but did not significantly change with ODS  .  Clinical ly relevant and statistically significant improvement in the mean total score of the St George 's Hospital Respiratory Question naire was observed in the formoterol group . Adverse events were similar in the two groups . The results show that treatment with formoterol has significant advantages over ODS  in patients with moderate persistent asthma Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone . Design and setting A 52 week , two period , double blind , multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were r and omised to add montelukast or salmeterol .  Participants Patients ( 15 - 72 years ; n = 1490 ) had a clinical history of chronic asthma for ≥ 1 year , a baseline forced expiratory volume in one second ( FEV 1 ) value 50 - 90 % predicted , and a β agonist improvement of ≥ 12 % in FEV 1 . Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation . Results 20.1 % of the patients in the group receiving montelukast and fluticasone  had an asthma exacerbation compared with 19.1 % in the group receiving salmeterol and fluticasone ; the difference was 1 % ( 95 % confidence interval -3.1 % to 5.0 % ) . With a risk ratio ( montelukast-fluticasone/salmeterol-fluticasone ) of 1.05 ( 0.86 to 1.29 ) , treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone . Salmeterol and fluticasone  significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone ( P ≤ 0.001 ) , whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups . Montelukast and fluticasone significantly ( P = 0.011 ) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone . Both treatments were generally well tolerated . Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol BACKGROUND The greatest prevalence of asthma is in preschool children ; however , the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index , long-term tolerability , and frequency and /or difficulty of administration .  Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma , although very young patients may have difficulty using inhalers , and dose delivery can be variable . Moreover , reduced compliance with inhaled therapy relative to orally administered therapy has been reported . One potential advantage of montelukast is the ease of administering a once-daily chewable tablet ; additionally , no tachyphylaxis or change in the safety profile has been evidence d after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years , respectively . To our knowledge , this represents the first large , multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma , as well as one of the few asthma studies that incorporated end points vali date d for use in preschool children . OBJECTIVE Our primary objective was to determine the safety profile of montelukast , an oral leukotriene receptor antagonist , in preschool children with persistent asthma . Secondarily , the effect of montelukast on exploratory measures of asthma control was also studied . DESIGN AND STATISTICAL ANALYSIS : We conducted a double-blind , multicenter , multinational study at 93 centers worldwide : including 56 in the United States , and 21 in countries in Africa , Australia , Europe , North America , and South America . In this study , we r and omly assigned 689 patients ( aged 2 - 5 years ) to 12 weeks of treatment with placebo ( 228 patients ) or 4 mg of montelukast as a chewable tablet ( 461 patients ) after a 2-week placebo baseline period . Patients had a history of physician-diagnosed asthma requiring use of beta-agonist and a predefined level of daytime asthma symptoms . Caregivers answered questions twice daily on a vali date d , asthma-specific diary card and , at specified times during the study , completed a vali date d asthma-specific quality -of-life question naire . Physicians and caregivers completed a global evaluation of asthma control at the end of the study . Efficacy end points included : daytime and overnight asthma symptoms , daily use of beta-agonist , days without asthma , frequency of asthma attacks , number of patients discontinued because of asthma , need for rescue medication , physician and caregiver global evaluations of change , asthma-specific caregiver quality of life , and peripheral blood eosinophil counts . Although exploratory , the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding . At screening and at study completion , a complete physical examination was performed . Routine laboratory tests were drawn at screening and weeks 6 and 12 , and su bmi tted to a central laboratory for analysis . Adverse effects were collected from caregivers at each clinic visit . An intention-to-treat approach , including all patients with a baseline measurement and at least 1 postr and omization measurement , was performed for all efficacy end points . An analysis -of-variance model with terms for treatment , study center and stratum ( inhaled/nebulized corticosteroid use , cromolyn use , or none ) was used to estimate treatment group means and between-group differences and to construct 95 % confidence intervals . Treatment-by-age , -sex , -race , -radioallergosorbent test , -stratum , and - study center interactions were evaluated by including each term separately . Fisher 's exact test was used for between-group comparisons of the frequency of asthma attacks , discontinuations from the study because of worsening asthma , need for rescue medication , and the frequencies of adverse effects . Because of an imbalance in baseline values for eosinophil counts for the 2 treatment groups , an analysis of covariance was performed on the eosinophil change from baseline with the patient 's baseline as covariate . STUDY PARTICIPANTS Of the 689 patients enrolled , approximately 60 % were boys and 60 % were white . Patients were relatively evenly divided by age : 21 % , 24 % , 30 % , and 23 % were aged 2 , 3 , 4 , and 5 years , respectively . For 77 % of the patients , asthma symptoms first developed during the first 3 years of life . During the placebo baseline period , patients had asthma symptoms on 6.1 days/week and used beta-agonist on 6.0 days/week . RESULTS In over 12 weeks of treatment of patients aged 2 to 5 years , montelukast administered as a 4-mg chewable tablet produced significant improvements compared with placebo in multiple parameters of asthma control including : daytime asthma symptoms ( cough , wheeze , trouble breathing , and activity limitation ) ; overnight asthma symptoms ( cough ) ; the percentage of days with asthma symptoms ; the percentage of days without asthma ; the need for beta-agonist or oral corticosteroids ; physician global evaluations ; and peripheral blood eosinophils . The clinical benefit of montelukast was evident within 1 day of starting therapy . Improvements in asthma control were consistent across age , sex , race , and study center , and whether or not patients had a positive radioallergosorbent test . Montelukast demonstrated a consistent effect regardless of concomitant use of inhaled/nebulized corticosteroid or cromolyn therapy . Caregiver global evaluations , the percentage of patients experiencing asthma attacks , and improvements in quality -of-life scores favored montelukast , but were not significantly different from placebo . There were no clinical ly meaningful differences between treatment groups in overall frequency of adverse effects or of individual adverse effects , with the exception of asthma , which occurred significantly more frequently in the placebo group . There were no significant differences between treatment groups in the frequency of laboratory adverse effects or in the frequency of elevated serum transaminase levels .  Approximately 90 % of the patients completed the study . CONCLUSIONS Oral montelukast ( 4-mg chewable tablet ) administered once daily is effective therapy for asthma in children aged 2 to 5 years and is generally well tolerated without clinical ly important adverse effects . Similarly , in adults and children aged 6 to 14 years , montelukast improves multiple parameters of asthma control . Thus , this study confirms and extends the benefit of montelukast to younger children with persistent asthma Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids  represent a management challenge . Leukotrienes play a key role in asthma pathophysiology , and since pro-inflammatory leukotrienes are poorly suppressed by corticosteroids it seems rational to add a leukotriene receptor antagonist ( LTRA ) when a low to moderate dose of inhaled corticosteroids does not provide sufficient disease control . Long acting beta2-agonist ( LABA ) treatment represents an alternative to LTRAs and both treatment modalities have been shown to provide additional disease control when added to corticosteroid treatment . To compare the relative clinical benefits of adding either a LTRA or a LABA to asthma patients inadequately controlled by inhaled corticosteroids , a r and omized , double-blind , multi-centre , 48-week study will be initiated at approximately 120 centres throughout Europe , Latin America , Middle East , Africa and the Asia-Pacific region in early 2000 . The study will compare the oral LTRA montelukast with the inhaled LABA salmeterol , each administered on a background of inhaled fluticasone , on asthma attacks , quality of life , lung function , eosinophil levels , healthcare utilization , and safety , in approximately 1200 adult asthmatic patients . The requirements for study enrollment include a history of asthma , FEV1 or PEFR values between 50 % and 90 % of the predicted value together with > or = 12 % improvement in FEV1 after beta-agonist administration , a minimum pre-determined level of asthma symptoms and daily beta-agonist medication . The study will include a 4-week run-in period , during which patients previously taking inhaled corticosteroids are switched to open-label fluticasone ( 200 microg daily ) , followed by a 48-week double-blind , treatment period in which patients continuing to experience abnormal pulmonary function and daytime symptoms are r and omized to receive montelukast ( 10 mg once daily ) and salmeterol placebo , or inhaled salmeterol ( 100 microg daily ) and montelukast placebo . All patients will continue with inhaled fluticasone ( 200 microg daily ) . During the study , asthma attacks , overnight asthma symptoms , and morning peak expiratory flow rate will be assessed using patient diary cards ; quality of life will also be assessed using an asthma-specific quality -of life question naire . The results of this study are expected to provide physicians with important clinical evidence to help them make a rational and logical treatment choice for asthmatic patients experiencing breakthrough symptoms on inhaled corticosteroids Salmeterol is a selective long-acting beta 2-agonist bronchodilator considered to have added anti-inflammatory effects , but this is controversial . We investigated the effects of a single dose of salmeterol , 100 micrograms , on the physiological and inflammatory responses to inhaled allergen and compared these with the effects of a single dose of beclomethasone , 500 micrograms , and of placebo .  Eight atopic adults with mild stable asthma , treated only with inhaled short-acting beta 2-agonist when needed , attended the laboratory sequentially for screening tests , two single-blind control inhalation tests preceded 30 min by placebo or salmeterol and three allergen inhalation tests preceded by placebo , salmeterol or beclomethasone double-blind in r and om order . Airway responsiveness to methacholine ( assessed as the provocative concentration of methacholine producing 20 % fall in forced expiratory volume in one second ( PC20 ) ) , induced sputum eosinophils , blood eosinophils and serum eosinophil cationic protein ( ECP ) were examined before and 7 - 48 h after treatment . The statistical power to detect twofold changes in blood and sputum parameters was > or = 90 % . Salmeterol inhaled before allergen challenge completely prevented the early asthmatic response , late asthmatic response and fall in methacholine PC20 at 24 h , and produced additional bronchodilatation . These effects were similar to those obtained by the inhalation of a single dose of salmeterol before the control inhalation test , and significantly better than those observed after a single dose of beclomethasone inhaled before the allergen test . Beclomethasone had no effect on the early asthmatic response or on the fall in methacholine PC20 at 24 h but partially inhibited the late asthmatic response . Neither salmeterol nor beclomethasone had any significant effect on sputum or blood inflammatory changes 7 - 48 h after allergen inhalation . In conclusion , whilst salmeterol had no demonstrable anti-inflammatory action in sputum after allergen challenge in asthma , neither did a single dose of the positive anti-inflammatory control , beclomethasone . The latter result excludes a more positive judgement on the possible anti-inflammatory action of salmeterol . However , the results do indicate that potent functional effects of a single dose of salmeterol can mask the airway inflammatory cell influx caused by inhaled allergen Sixteen patients with stable chronic asthma participated in a double blind crossover study comparing the new inhaled long acting beta 2 agonist formoterol with salbutamol . Inhaled ( n = 15 ) and oral steroid ( n = 1 ) treatment were maintained at the same daily dose throughout the study . For four weeks the patients received either formoterol 24 micrograms twice daily or salbutamol 400 micrograms twice daily , plus additional puffs ( with the same drug ) when needed . Asthma symptoms , additional puffs of beta 2 agonist , peak expiratory flow ( PEF ) , and side effects were recorded daily . During treatment with formoterol the patients used fewer additional puffs of beta 2 agonist , had better symptom scores , less disturbed sleep , more days without additional aerosol , and higher PEF both morning and evening than during salbutamol treatment . Thus formoterol 24 micrograms twice daily gave long lasting bronchodilatation and asthma symptoms were well controlled with regular twice daily administration The development of tolerance to the bronchodilator effects of beta2-agonists used in asthma therapy has been the subject of debate . We conducted two placebo-controlled crossover studies to assess the bronchodilator response to a short-acting beta2-agonist before and after chronic therapy with salmeterol .  Patients in one study were corticosteroid-naive ; patients in the other study were using inhaled corticosteroids .  Changes in FEV1 after cumulative doubling doses of inhaled albuterol were assessed after a 2-wk beta-agonist washout period , before administering study medication on Day 1 , and again after 28 d of therapy . Ipratropium bromide was provided as rapid-relief treatment for asthma , and use of any beta2-agonist except the study treatment was prohibited . On both assessment days for salmeterol , and during placebo administration periods , significant increases from predose FEV1 values were observed beginning with the lowest dose of albuterol and continuing throughout the dose-response assessment ( p < /= 0.001 ) . These increases in FEV1 were maintained for 6 h after the last dose of albuterol ( p < 0.05 ) . There were no statistically significant differences in the albuterol dose response following salmeterol or placebo . These studies indicate that irrespective of concurrent corticosteroid treatment , chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol The relationship between asthma medication and the perception of asthma symptoms is of interest for daily practice . Poor perception of asthma symptoms might influence patients ' health care behavior and subsequently might lead to undertreatment and deterioration of their disease . This study investigated the influence of the chronic use of short-acting and long-acting beta(2)-agonists , compared with the additional use of inhaled corticosteroids on the perception of histamine-induced bronchoconstriction . Patients with asthma ( 33 male and 31 female , mean age 35 + /- 11 yr , FEV(1 ) 87 + /- 14 % of the reference value , PC(20 ) geometric mean 1.08 mg/ml ( 95 % CI : 0.76 - 1.52 ) were selected and r and omly allocated to the use of either a short-acting beta(2)-agonists ( salbutamol , n = 22 ) or a long-acting beta(2)-agonists ( formoterol , n = 22 ) or placebo ( n = 20 ) , which has been used for 12 wk . This medication treatment was repeated exactly 1 yr later , with patients receiving the same medication plus an inhaled corticosteroid .  Perception of histamine-induced bronchoconstriction was measured at the start of each treatment period and every 4 wk thereafter . Subjects quantified their sensation of respiratory discomfort during the challenge tests on a modified Borg scale . The perceptive " sensitivity " for changes in FEV(1 ) was analyzed by the linear regression slope ( alpha ) " Borg versus percentage fall in FEV(1 ) . " The " absolute perceptual magnitude " was determined by the perception score at the 20 % fall in FEV(1 ) ( PS(20 ) ) . The additional use of inhaled corticosteroids during the second year result ed in an improved perception of histamine-induced bronchoconstriction ( slope alpha ) compared with the first year for only the long-acting beta(2)-agonists group ( p value 0.036 ) . This improvement was not observed for the " absolute perceptual magnitude " ( PS(20 ) ) . The additional use of inhaled corticosteroids during chronic use of long-acting beta(2)-agonists improves the perceptive " sensitivity " for changes in FEV(1 ) during histamine-induced bronchoconstriction , which was not observed for short-acting bronchodilators . This result might indicate that the positive effects on perception of airway obstruction might be another reason ( besides the beneficial effects on the clinical condition ) for prescribing a combination of long-acting beta(2)-agonists and inhaled steroids STUDY OBJECTIVE To determine whether formoterol , a new beta 2 agonist with experimentally documented long duration , is clinical ly more effective than salbutamol in the maintenance treatment of chronic asthma . DESIGN R and omized double-blind between-patient comparison between treatment with formoterol and with salbutamol during four weeks . SETTING Asthma/allergy department in a university hospital . PATIENTS Thirty-seven patients with chronic stable asthma , who during a two-week run-in period with inhaled salbutamol , 4 x 100 micrograms twice a day , used at least four additional doses ( 100 micrograms each ) daily , were r and omly assigned to use either formoterol or salbutamol .  Thirty-five patients were evaluated for efficacy . One early withdrawal and one dropout were found in the salbutamol group . The groups were similar with respect to demographic data and baseline lung function . INTERVENTIONS During the four-week study period , the patients used either formoterol ( 4 x 6 micrograms twice a day and as necessary , n = 19 ) or salbutamol ( 4 x 100 micrograms twice a day and as necessary , n = 16 ) . Inhaled steroids and orally administered theophylline were allowed if doses were kept constant . MEASUREMENTS AND MAIN RESULTS The median number of additional doses per 24 h ( median of two weeks ) of the test aerosols was 0 ( range , 0 to 6 ) for formoterol and 4 ( range , 0 to 14 ) for salbutamol ( p less than 0.01 ) . Morning and evening PEFRs were 422 ( SEM = 31 ) and 443 ( SEM = 30 ) , respectively , for formoterol , and 335 ( SEM = 30 ) and 360 ( SEM = 26 ) , respectively , for salbutamol ( p = 0.05 for both ) . Formoterol was superior ( p less than 0.05 ) to salbutamol with respect to control of asthma symptoms , estimated duration of action and patient preference . Side effects did not differ . CONCLUSIONS Inhaled formoterol administered twice a day and as necessary was clinical ly more effective than the same regimen of salbutamol We evaluated whether montelukast conferred additive effects in patients with asthma receiving fluticasone/salmeterol ( FP/SM ) combination and FP alone . Twenty-two patients with mild to moderate asthma completed a double-blind , placebo-controlled study . After a 2-week run-in using FP 250 microg/SM 50 microg 1 puff twice daily , patients entered a r and omized crossover period to receive additional montelukast 10 mg daily or placebo for 3 weeks each . For the first 2 weeks , they received FP/SM 1 puff BID , and then they received FP 250 microg 1 puff BID for the 3rd week . The primary outcome was adenosine monophosphate challenge threshold and recovery time ; secondary outcomes included surrogate inflammatory markers and lung function . Compared with FP/SM run-in , adding montelukast to FP/SM was better ( p < 0.05 ) than placebo for inflammatory markers but not for lung function . For adenosine monophosphate threshold , recovery , exhaled nitric oxide , and blood eosinophils , there were 1.4 ( 95 % confidence interval , 1.1 - 1.8 ) geometric mean fold , 10 minutes ( 3 - 17 minutes ) , 2.1 parts per billion ( 0.2 - 3.9 parts per billion ) , and 88 ( 34 - 172 ) x 10(6)/L differences , respectively . The combination of FP plus montelukast was superior to FP/SM for inflammatory markers but was inferior for lung function . Thus , in patients taking FP/SM or FP , montelukast conferred complimentary effects on surrogate inflammatory markers , which were dissociated from lung function . Further studies are required to evaluate whether these effects of montelukast translate into clinical benefits Studies in adults revealed that addition of salmeterol to a moderate dose of inhaled corticosteroid result ed in better symptom control and higher PEF compared with doubling the dose of inhaled corticosteroid . The aim of this three group study was to compare the effects of a moderate dose of beclomethasone , the same dose of beclomethasone with salmeterol , and a doubling dose of beclomethasone on lung function and symptoms in children with moderate asthma . A total of 177 children already treated with inhaled corticosteroids , were r and omized in a double-blind parallel study either to salmeterol 50 microg twice daily ( BDP400+salm ) , beclomethasone 200 microg twice daily ( BDP800 ) , or placebo ( BDP400 ) in addition to beclomethasone 200 microg twice daily . No significant differences between groups were found in FEV1 , PD20 methacholine , symptom scores , and exacerbation rates after 1 yr . Salmeterol result ed in slightly better PEF in the first months of treatment . FEV1 , and PD20 methacholine significantly improved in all groups . After 1 yr mean changes in FEV1 , percent predicted were 4.3 % ( 95 % CI 1.3 ; 7.2 ) , 5.8 % ( 95 % CI 2.9 ; 8.7 ) , and 4.3 % ( 95 % CI 2.1 ; 6.5 ) for BDP400+salm , BDP800 , and BDP400 , respectively . Changes in airway responsiveness were 0.60 ( 95 % CI 0.05 ; 1.14 ) , 1.30 ( 95 % CI 0.73 ; 1 . 87 ) , and 0.80 ( 95 % CI 0.33 ; 1.27 ) doubling doses . Growth was significantly slower in the BDP800 group . We conclude that no additional benefit was found of adding either salmeterol or more beclomethasone to a daily dose of 400 microg beclomethasone in this group of children with excellent compliance of medication Asthma morbidity and mortality has increased . One of the possible causes is the excessive use of beta agonists . The aim of this study is to compare the effects of six week treatment with beclomethasone alone ( Ibec ) or the combination of beclomethasone-salmeterol ( Ibe + Isal ) on serum potassium ( K ) , CPK-MB and ECG in children suffering asthma . It was a prospect i ve , r and omised , open cross-over trial . Patients received either Ib2 ( 2 puff/12 hr , 100 micrograms per puff ) or Ibe + Isal ( B 2 puff/12 hr , 100 micrograms per puff and S 2 puff/12 hr , 25 micrograms per puff ) with dose meter inhaler by 6 weeks , with a four-week wash-out period between the treatments . K , CPK-MB and ECG were assessed at baseline , and after each treatment period . There were 9 girls and 20 boys , aged 11 + /- 2.18 ( mean + /- SD ) years , baseline K was 4.57 + /- 0.43 mEq/l , after B K 4.38 + /- 0.39 IU and after BS K 4.38 + /- 0.40 . The CPK-MB level were baseline 14.75 + /- 4.5 , after B 20.10 + /- 6.9 and after BS 21 + /- 8.05 ( p < 0.05 ) . Baseline QTc was 0.416 + /- 0.02 msec , after B 0.425 + /- 0.027 , and after BS 0.415 + /- 0.029 . We conclude that the treatment of children with asthma with 400 micrograms per day of Ibec or concomitantly with 100 micrograms of Isal for 6 weeks does not alter the serum K+ or the QTc . However , the CPK-MB has a significant increment with both treatments but without clinical and /or ECG changes . We ca n't affirm that Ibec or Ibec plus Isal have a cardiotoxic side-effect by the only presence of high levels of CPK-MB . We agree that it is necessary a close follow up of these apparently asymptomatic patients not induce important cardiovascular changes although CPK-MB was increased The effect of adding inhaled salmeterol to inhaled corticosteroids was studied in patients with poorly controlled nocturnal asthma . In a double-blind , cross-over study , 20 patients were r and omized to receive either salmeterol 50 micrograms twice daily or placebo via a Diskhaler after a 1-week run-in period . After 4 weeks of treatment , patients were subsequently crossed over to receive the other treatment for a further 4 weeks with a 2-week wash-out period in between . The response to treatment was assessed by peak expiratory flow rates ( PEF ) measured in the morning and evening , symptom scores of asthma , number of bronchodilators used , forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) at regular intervals . Patients ' preference for the Diskhaler or metered-dose inhaler was assessed at the last visit . The results showed that morning PEF was significantly higher while on salmeterol than on placebo ( 296.9 + /- 70.2 vs 274.6 + /- 77.4 L/min ) . Evening PEF showed a trend towards a higher value while on salmeterol than on placebo ( 321.1 + /- 73.4 vs 288.7 + /- 79.4 L/min ) , but the difference was not significant . There was no statistically significant improvement in symptom scores , number of rescue bronchodilators used and FEV1 or FVC between the two treatment groups . The occurrence of side effects in terms of tremors and palpitations between treatment and placebo were similar . There were more patients who preferred Diskhaler to metered-dose inhaler ( 70 % vs 30 % ) . We conclude that salmeterol 50 micrograms twice daily produces significant improvement in morning PEF and is well tolerated in patients with nocturnal asthma . Diskhaler is a device which is easy to use and preferred to a metered-dose inhaler Combinations of inhaled glucocorticoids and long-acting beta2-agonists in the same inhaler device have become available in recent years . In this double-blind , r and omized , placebo-controlled and crossover study we have evaluated the onset of action of budesonide and formoterol in a single inhaler ( Symbicort Turbuhaler ) and that of the fixed combination of salmeterol and fluticasone ( Seretide Diskus ) . Thirty patients with a mean FEV1 of 2.54 l ( range : 1.48 - 4.28 ) and a mean inclusion reversibility in FEV1 of 19.1 % were included . Single doses of budesonide/formoterol 160/4.5 microg and 2x ( 160/4.5 ) microg , salmeterol/fluticasone 50/250 microg , or placebo were given . Serial measurements of FEV1 were performed over 3 h. The combination of one or two inhalations of budesonide/formoterol showed a faster onset of action than salmeterol/fluticasone , both evaluated as mean FEV1 at 3 min ( 2.74 , 2.75 and 2.56 l respectively P<0.001 for both doses of budesonide/formoterol ) , or as average FEV1 from 0 to 15 min ( 2.80 , 2.83 and 2.67 l respectively P<0.001 for both doses of budesonide/formoterol ) . For placebo , mean FEV1 at 3 min was 2.46 l , and the average FEV1 at 0 - 15 min was 2.50 l. Furthermore , budesonide/formoterol at both doses result ed in higher FEV1 than salmeterol/fluticasone at 3 h. We conclude that the combination of budesonide/formoterol has a faster onset of action than salmeterol/fluticasone Previous results have demonstrated addition of long-acting beta2-adrenergic agonists to be beneficial in asthma patients already receiving inhaled corticosteroid . The purpose of this study was to determine , qualitatively as well as quantitatively , the steroid-sparing properties of salmeterol in stable asthma patients receiving maintenance inhaled corticosteroids ( 800 - 1600 microg day(-1 ) ) . In these patients , the daily dose of beclomethasone dipropionate was reduced by 200 microg each week until asthma deteriorated , with the minimal acceptable dose ( MAD ) being defined as the dose one step above deterioration ( sensitivity period ) . Following this , patients received three times the MAD for 2 weeks . Patients were r and omized to receive either salmeterol 50 microg twice daily or placebo and the MAD was again determined ( treatment period ) . Forced expiratory volume in 1 sec ( FEV1 ) was measured each week . Morning and evening peak expiratory flow ( PEF ) , symptom score and use of bronchodilator were recorded each day . Fifteen patients received salmeterol and 19 placebo .  The MAD was significantly lower in the salmeterol group compared with placebo during the treatment period ( P<0.01 ) . A 50 % reduction of the MAD was achieved by more patients treated with salmeterol than placebo ( P = 0.001 ) . Salmeterol caused a significantly greater reduction in daytime symptom score and use of as-needed beta2-agoinist therapy between sensitivity and treatment periods compared with placebo ( P<0.05 for both ) . The results demonstrate , that the addition of salmeterol to corticosteroid treatment offers a clinical ly relevant potential for reduction of inhaled corticosteroid dose in steroid sensitive asthmatics Abstract Objectives : To determine the effect of adding salmeterol 50 μg twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan . Design : A double blind , r and omised crossover study . Setting : Nottingham . Subjects : 101 subjects with mild or moderate asthma taking at least 200 μg twice daily of beclomethasone dipropionate or budesonide .  Interventions : Salmeterol 50 μg twice daily and placebo for six months each , with a one month washout . Subjects adjusted inhaled steroid dose according to guidelines . Main outcome measure : Reduction in inhaled steroid use , exacerbations of asthma , and use of oral steroids . Results : Data were available for 87 subjects . When compared with placebo salmeterol treatment was associated with a 17 % reduction in inhaled steroid use ( 95 % confidence interval 12 % to 22 % ) with no significant difference in the number of subjects who had an exacerbation ( placebo 25 % , salmeterol 16 % ) or use of oral steroids . For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second ; a reduction in symptoms , bronchodilator use , and airway responsiveness to methacholine ; and no effect on serum potassium concentration , 24 hour heart rate , or the final forced expiratory volume in one second achieved during a salbutamol dose-response study . Conclusions : In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 μg twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control . Key messages One hundred and one subjects with mild or moderate asthma  took salmeterol 50 μg and placebo for six months each in a crossover study Subjects adjusted their inhaled steroid dose according to a management plan based on peak flow recordings and symptoms The dose of inhaled steroids was reduced by 17 % with salmeterol , with no change in exacerbations or use of oral steroids Despite the reduction in inhaled steroid dose , salmeterol was associated with bronchodilatation and a reduction in symptoms The efficacy of salmeterol was maintained over the six Abstract . The objective of this study was to examine the bronchodilating effect of an inhaled long acting β2-agonist ( salmeterol ) after a high dose of an inhaled short acting β2-agonist ( salbutamol ) in asthma patients . We used a r and omized double-blind , placebo-controlled , crossover design , study ing seven subjects with moderate asthma , treated with inhaled steroids and highly reversible to salbutamol and salmeterol . 1.5 h after salmeterol inhalation , the mean difference in FEV1 between salbutamol and placebo pretreatment days was 6.31 % and ranged from 0.02 to 1.05 % , 2.5–10.5 h after salmeterol inhalation . We concluded that the effect measured as the duration of bronchodilation of salmeterol is not decreased by previously inhaled salbutamol . We only found a trend toward an additive effect of combining salbutamol and salmeterol , probably because the high dose of salbutamol did not give room for further improvement in FEV1 . In accordance with other clinical studies we were unable to demonstrate any clinical implication s of the salmeterol partial β2-antagonism known from animal and in vitro studies International guidelines on asthma recommend to add inhaled long-acting b2-agonists in patients insufficiently controlled with an inhaled corticosteroid alone . A multicentre prospect i ve study was carried out in 250 children ( age 8.4 + /- 2.7 years ) whose asthma remained symptomatic with impaired lung function despite a treatment with 400 - 1000 micrograms/day of beclomethasone or equivalent . Salmeterol 100 micrograms/day was added to the previous dose of inhaled corticosteroid for 2 months . PEFR was improved as soon as the first month of treatment ( 67.2 + /- 44.4 L/min , p < 0.001 ) and at month 2 ( 75.0 + /- 44.1 L/min , p < 0.001 ) . The percentage of symptomatic patients , the number of days and nights with symptoms , the number of days with prn bronchodilator use were significantly reduced ( p < 0.001 ) . The decrease in the distress and severity scores of the Childhood Asthma Question naire indicated an improvement in quality of life due to better asthma control . This study showed that lung function and symptoms were significantly improved as soon as the first month of treatment , improvement maintained thereafter , with a better quality of life and a good tolerability BACKGROUND The addition of long acting inhaled beta(2 ) agonists is recommended at step 3 of the British guidelines on asthma management but a recent study suggested no additional benefit in children with asthma . METHODS The aim of this study was to compare , in a double blind , three way , crossover study , the effects of the addition of salmeterol 50 microg bd , salmeterol 100 microg bd , and salbutamol 200 microg qds in asthmatic children who were symptomatic despite treatment with inhaled corticosteroids in a dose of at least 400 microg/day over a one month period .  Symptom scores , morning and evening peak expiratory flow ( PEF ) rates , use of rescue medication , spirometric indices , and histamine challenge were measured . RESULTS Forty five children aged 5 - 14 years were enrolled . All three treatments improved asthma control , morning and evening PEF rates , and spirometric indices with no change in bronchial hyperreactivity . Mean morning PEF was significantly better during the salmeterol treatment periods than with salbutamol treatment ( p<0.05 ) . The analysis of mean morning PEF gave an estimated treatment difference of 9.6 l/min for salmeterol 50 microg bd versus salbutamol 200 microg qds ( 95 % confidence interval ( CI ) 2.1 to 17.1 ) , and an estimated treatment difference of 13.8 l/min for salmeterol 100 microg bd versus salbutamol 200 microg qds ( 95 % CI 6.0 to 21.5 ) . There were no significant differences between the two doses of salmeterol and all treatments were well tolerated . CONCLUSIONS In this population of moderate to severe asthmatic children on inhaled corticosteroids , salmeterol in a dose of either 50 microg bd or 100 microg bd is significantly more effective at increasing the morning PEF rate over a one month period than salbutamol 200 microg qds . The data provided no significant evidence of a difference in efficacy between the two doses of salmeterol , 50 microg and 100 microg . A trial of salmeterol 100 microg bd may be worth considering in those still symptomatic on the lower dose The objective of this study was to compare the efficacy and safety of the second controller medications ( long-acting beta2-agonist , leukotriene receptor antagonist and sustained-release theophylline ) used in addition to inhaler corticosteroid treatment in moderate persistent asthma . A total of 64 patients with asthma , in the moderate persistent asthma category , were divided into three groups . Patients , all of whom were concurrently using inhaled corticosteroid ( Budesonide 400 microg twice daily ) , were treated for 3 months with either inhaled formoterol 9 microg twice daily ( first group ) , oral zafirlukast 20 mg twice daily ( second group ) , or sustained-release theophylline 400 mg once daily ( third group ) . All of the patients were subjected to assessment s on the subject of peak expiratory flow ( PEF ) variability , forced expiratory volume in 1 sec ( FEV1 ) , asthma symptom scores ( daytime and night-time ) , supplemental terbutalin use , asthma exacerbations and adverse events . Over the 3-month treatment period . In all of the three groups , significant improvements were recorded in the lung function , asthma symptom scores and supplemental terbutalin use criteria , as a result oftreatments applied . Formoterol treatment result ed in significantly greater and earlier improvements compared with the other two groups in several criteria : PEF variability ( 17.9 + /- 2.5 ; 21.9 + /- 3.2 ; 23.7 + /- 3.3 ; P < 0.001 ) ; asthma symptom score ( daytime ) ( 1.6 + /- 0.5 ; 1 + /- 0.5 ; 2.0 + /- 0,5 ; P < 0.05 ) ; asthma symptom score ( night-time ) ( 1.2 + /- 0.4 ; 2.2 + /- 0.5 ; 16 + /- 0.6 ; P < 0001 ) ; and supplement alter butalin  use ( 1.2 + /- 0.3 ; 1.8 + /- 0.5 ; 1.7 + /- 0.5 ; P < 0.05 ) . However , at the end of the treatment , in all of the three groups studied , improvements were attained in overall asthma control and there was no statistical difference among the groups . Although there were no side effects which required the discontinuation of the treatment , it was observed that the maximum side effect was in the second group ( 20 % , 31.6 % and 20 % , respectively ) . In conclusion , in patients who still have symptoms on treatment with inhaled corticosteroids , the addition of a long-acting beta2-agonist , leukotriene antagonists or sustained-release theophylline to the treatment is a logical approach , and , in addition to inhaled corticosteroids , any one of these second controller medications may be chosen in patients with moderate asthma BACKGROUND Asthma is a disease of chronic inflammation and bronchoconstriction . Inhaled corticosteroids ( ICSs ) provide important anti-inflammatory treatment but may not provide optimal control of asthma when taken alone . Two therapeutic alternatives for enhanced asthma control are to substitute the combination of fluticasone propionate ( FP ) and salmeterol ( FP/Salm Combo ) through the Diskus inhaler or to add montelukast to existing ICS therapy . OBJECTIVE We compared the efficacy and safety of FP/Salm Combo through the Diskus inhaler versus montelukast added to FP ( FP + montelukast ) in patients whose symptoms were suboptimally controlled with ICS therapy . METHODS We performed a multicenter , double-blind , double-dummy , parallel-group , 12-week study in 447 patients with asthma who were symptomatic at baseline while receiving low-dose FP .  Patients were treated for 12 weeks with one of the following : ( 1 ) combination of FP 100 microg plus salmeterol 50 microg twice daily through the Diskus inhaler , or ( 2 ) FP 100 microg twice daily through the Diskus inhaler plus oral montelukast 10 mg once daily . RESULTS FP/Salm Combo treatment provided better overall asthma control than FP + montelukast with significantly greater improvements in morning peak expiratory flow ( + 24.9 L/min vs + 13.0 L/min , P < .001 ) , evening peak expiratory flow ( + 18.9 L/min vs + 9.6 L/min , P < .001 ) , and forced expiratory volume in 1 second ( + 0.34 L vs + 0.20 L , P < .001 ) , as well as a change in the percentage of days with no albuterol use ( + 26.3 % vs + 19.1 % , P = .032 ) and the shortness of breath symptom score ( -0.56 vs -0.40 , P = .017 ) . The groups had comparable improvements in chest tightness , wheeze , and overall symptom scores . Asthma exacerbation rates were significantly lower ( P = .031 ) in the FP/Salm Combo group ( 4 patients , 2 % ) than in the FP + montelukast group ( 13 patients , 6 % ) . Adverse event profiles were comparable . CONCLUSION Symptomatic patients on low-dose ICS therapy had significantly greater improvement in asthma control when switched to the FP/Salm Combo than when montelukast was added to ICS therapy The efficacy and tolerability of salmeterol , 50 micrograms b.i.d . was compared for three months with salbutamol , 200 micrograms q.i.d . , administered from metered-dose inhaler . For the following nine months , safety and clinic lung function was monitored on salmeterol , 50 micrograms b.i.d . , compared with salbutamol , 200 micrograms b.i.d . This comparison was made in a multicentre , double-blind , parallel-group study of 667 moderate asthmatics , who had a forced expiratory volume in one second ( FEV1 ) or peak expiratory flow rate ( PEFR ) > 50 % predicted , a 15 % reversibility to inhaled salbutamol and who were experiencing symptoms . Throughout the first three month treatment period , both morning and evening PEFR were significantly higher on treatment with salmeterol than salbutamol ( mean differences between the treatments 30 l.min-1 for morning , p < 0.001 , and 11 l.min-1 for evening , p < 0.01 ) . In addition , the diurnal variation in PEFR , nocturnal and daytime symptoms and use of additional  salbutamol were significantly lower in the salmeterol treated group . This improvement was also apparent in the separate sub population s of patients taking no concurrent glucocorticosteroid or concurrent inhaled and /or oral glucocorticosteroids . Both treatments were well-tolerated throughout the 12 months of treatment . There was a lower incidence of asthma and related events during salmeterol treatment compared to salbutamol treatment subgroups . The results of the study clearly demonstrate that salmeterol , 50 micrograms b.i.d . , is well-tolerated and more effective than salbutamol , 200 micrograms q.i.d . , in the treatment of moderate asthma OBJECTIVES The long-acting beta2-adrenergic agonist salmeterol prevents exercise-induced asthma , but tolerance may develop to its bronchoprotective effect . We wanted to ascertain if the development of tolerance could be prevented by using a low-dose treatment regimen of 50 microg once daily , instead of the usual dose of 50 microg twice daily , in adolescents receiving regular glucocorticoid inhalations . Methods . In a r and omized , double-blind , 2x28-day crossover study , we administered salmeterol ( 50 microg ) or placebo once daily via a metered-dose inhaler and Nebulizer Chronolog device to monitor compliance . Exercise challenge tests were performed 1 and 9 hours after salmeterol or placebo inhalation on the 1st and 28th day of each treatment period . The primary outcome variable was the maximum decrease in percent predicted FEV1 postexercise . RESULTS Fourteen subjects with a mean age of 13.1 years completed the study . The first dose of salmeterol had an excellent bronchoprotective effect against exercise-induced asthma at 1 and 9 hours . After the 28th consecutive daily dose of salmeterol , the bronchoprotective effect was significantly greater than that of placebo at 1 hour , but not at 9 hours . CONCLUSIONS We conclude that a single 50-microg dose of salmeterol has an excellent protective effect against exercise-induced asthma for at least 9 hours , but that this effect may wane during regular once-daily salmeterol treatment , despite the reduced frequency of dosing and despite concomitant use of inhaled glucocorticoids BACKGROUND --There is controversy as to the role of long acting beta 2 agonists such as eformoterol and , in particular , whether bronchodilator tolerance occurs during continuous therapy . The purpose of this study was to extend previous observations of bronchodilator subsensitivity with metered dose eformoterol aerosol in order to assess whether tolerance also occurs with a dry powder formulation of the same drug . METHODS --Sixteen asthmatic patients of mean age 33 ( range 18 - 53 ) years and FEV1 ( % predicted ) of 64 (3)% , of whom 13 were receiving inhaled corticosteroids  , received regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily ( without beta 2 agonists ) given concurrently for four weeks in a r and omised double blind cross-over design . An initial two week run-in was used when beta 2 agonists were withdrawn and substituted with ipratropium bromide . Dose-response curves to eformoterol ( cumulative dose 6 - 102 micrograms ) for airways and systemic beta 2 responses were constructed at the end of each treatment period . RESULTS --Baseline values for airways and systemic responses were similar . The peak delta FEV1 response from the dose-response curve ( as change from baseline ) and the delta response for FEV1 and FEF25 - 75 at six hours after the last dose were attenuated after eformoterol compared with placebo :  peak delta FEV1 response 1.001 with placebo v 0.841 with eformoterol ( 95 % CI 0.04 to 0.28 ) ; at six hours 0.931 with placebo v 0.581 with eformoterol ( 95 % CI 0.20 to 0.50 ) ; and for delta FEF25 - 75 at six hours 1.29 1/s with placebo v 0.87 1/s with eformoterol ( 95 % CI 0.15 to 0.69 ) . Morning peak expiratory flow rate was significantly improved during treatment with eformoterol ( 451 1/min ) compared with placebo ( 399 1/min ) ( 95 % CI 21 to 82 ) . Systemic beta 2 responses were blunted after eformoterol , together with a reduction in lymphocyte beta 2 receptor binding density . CONCLUSIONS --Regular twice daily eformoterol dry powder may produce bronchodilator subsensitivity in terms of both peak and duration of response to cumulative repeated doses of eformoterol . Systemic beta 2-mediated adverse effects also showed tolerance , which was mirrored by downregulation of lymphocyte beta 2 adrenoceptors This study aim ed to compare the duration of protection against exercise-induced bronchoconstriction ( EIB ) after inhalation of formoterol ( Oxis ) Turbuhaler with that of terbutaline Turbuhaler and placebo Turbuhaler in asthmatic patients treated regularly with formoterol Turbuhaler 9 microg b.i.d . and inhaled steroids .  The study . performed at three centres ( Göteborg and Lund , Sweden , and Trondheim , Norway ) , consisted of an open-label part with formoterol Turbuhaler 9 microg b.i.d . and a r and omized , double-blind , cross-over part with a single dose ( on top of the regular treatment ) of either formoterol Turbuhaler 9 microg , terbutaline Turbuhaler 0.5 mg or placebo Turbuhaler . The patients attended the clinic six times : twice for screening visits , three times for r and omized treatment and once for a follow-up visit . Patients received regular b.i.d . treatment with formoterol 9 microg for a mean period of 16 days . Formoterol gave a post-exercise fall of 12 , 10 , 15 and 17 % in forced expiratory volume in 1 sec ( FEV1 ) 15 min , 4 , 8 and 12 h after inhalation . The differences compared with placebo ( falls of 26 , 22 , 23 and 22 % ) and terbutaline ( falls of 17 , 18 , 22 and 22 % ) were all statistically significant ( P<0.05 for all comparisons ) . Patients on regular treatment with formoterol Turbuhaler 9 microg b.i.d . have a significant protection against EIB up to 12 h after inhalation of formoterol 9 microg . The protection was also significantly better than that of terbutaline Turbuhaler 0.5 mg BACKGROUND Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations . However , the influence of asthma medication on the ability to perceive symptoms is still to be documented . This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction ( MIB ) in subjects with mild asthma , using inhaled salbutamol on an " as required " basis ( n=15 ) , and in subjects with moderate asthma , using daily inhaled beclomethasone ( mean daily dose , 640 microg ; n=15 ) in addition to salbutamol to control their asthma . METHODS Methacholine challenges ( MC ) were performed at entry into the study , and then before , 1 , and 12 h following inhalation of 50 microg of salmeterol or a placebo , after a 15-day baseline period ; and after 4 weeks of twice daily use of those treatments . The measurements were then repeated with the alternate treatment after a 15-day washout period . Finally , a last MC was performed after another 15-day washout period . For each MC , the perception score of bronchoconstriction-associated breathlessness at 20 % fall in FEV1 ( PS20 ) was evaluated on a modified Borg scale from 0 to 10 . RESULTS Subjects using regular beclomethasone had a higher baseline PS20 than those using only salbutamol ( means : 3.06 0.06 and 2.01+/-0.07 , p=0.0001 ) . Short- and long-term use of salmeterol did not change significantly the PS20 compared with placebo ( p>0.05 ) in either group ( with or without corticosteroid ) . Although there were some intraindividual variations , mean PS20 did not vary significantly throughout the study . CONCLUSION These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol . Patients using inhaled corticosteroids show a greater perception of MIB Endothelin (ET)‐1 is a 21‐amino acid peptide which has potent bronchoconstrictor activity . Animal studies show elevation of ET‐1 during experimental airway inflammation , and inhibition of inflammation by endothelin‐antagonists , suggesting pro‐inflammatory activity for ET‐1 Salmeterol may be useful in the treatment of asthmatic patients requiring high-dose inhaled steroids , and there have been debates about its anti-inflammatory action . We have compared the efficacy and effects on serum inflammatory markers , including soluble interleukin 2R ( sIL-2R ) , eosinophil cationic protein ( ECP ) , and tryptase of salmeterol and albuterol in 20 patients with moderate to severe asthma who were all receiving high-dose inhaled corticosteroids and inhaled beta 2-agonist on dem and .  After a 2-week run-in period , they received , in a r and omized , crossover , double-blind and placebo-controlled manner , either salmeterol , 50 micrograms twice a day , or albuterol 400 micrograms , four times a day , from a powder inhaler during two 2-week treatment periods , separated by a 2-week washout . Compared with albuterol , salmeterol treatment was associated with better morning and mean peak expiratory flow ( p = 0.013 and 0.016 , respectively ) , less daytime and nocturnal symptoms ( p = 0.008 and 0.01 , respectively ) , reduced requirement of rescue albuterol ( p = 0.04 ) , and better efficacy rating by patients ( p = 0.04 ) . However , serum concentration of sIL-2R was significantly higher during regular albuterol treatment ( p = 0.014 ) but no differences were seen in the concentrations of ECP and tryptase between the two treatment periods . We conclude that inhaled salmeterol , 50 micrograms twice daily , confers a better control of asthma than albuterol , 400 micrograms four times daily , in patients with moderate to severe disease , and the latter treatment may be associated with increased T-lymphocyte activation Formoterol is a new long-acting beta 2-agonist . We compared the protective effect of 24 micrograms formoterol with 200 micrograms beclomethasone and placebo on inhaled allergen-induced asthmatic responses in mild stable asthmatic subjects . We measured airflow rates , histamine airway responsiveness , cell counts from sputum and peripheral blood , and markers of lymphocyte and eosinophil activation . Adjustments were made for the confounding effect of bronchodilatation produced by formoterol in comparisons using a control inhalation of normal saline . Formoterol caused bronchodilation and inhibition of histamine airway responsiveness for at least 24 h. It completely inhibited the early asthmatic responses when beclomethasone had no effect . Control comparisons of the effect of formoterol and beclomethasone on the allergen-induced late asthmatic response and increase in histamine responsiveness showed each to be equally effective but not to inhibit the responses completely . Formoterol caused bronchodilation in addition to preventing bronchoconstriction . Both drugs inhibited the rise in serum eosinophil cationic protein 24 h after allergen , but neither inhibited the allergen-induced increases in sputum or blood eosinophils or CD25 + lymphocytes . These results suggest that formoterol modifies allergen-induced airway responses through functional antagonism rather than the inhibition of inflammatory cell infiltration BACKGROUND Adding salmeterol to low-dose fluticasone propionate ( FP ) produces greater improvements in pulmonary function and symptom control than increasing the dose of FP in patients who remain symptomatic with low-dose FP .  OBJECTIVE We sought to compare the rates and characteristics of asthma exacerbations in patients after adding salmeterol to low-dose FP with the rates and characteristics of exacerbations in patients receiving higher dose FP . METHODS In 2 multicenter , double-blind studies , 925 patients 12 years of age and older receiving 88 microg twice daily FP r and omly received either 42 microg of salmeterol and 88 microg of FP or an increased dose of FP ( 220 microg ) twice daily for 24 weeks . Exacerbation rates and clinical measures of asthma worsening were assessed for all patients who experienced an asthma exacerbation . RESULTS The addition of salmeterol result ed in a significantly lower rate and number of exacerbations compared with higher dose FP . A total of 41 ( 8.8 % ) patients experienced 47 exacerbations with the addition of salmeterol compared with 63 ( 13.8 % ) patients with 75 exacerbations in the group receiving increased-dose FP ( P = .017 ) . Salmeterol plus low-dose FP was significantly more protective than increased-dose FP in preventing asthma exacerbations , as assessed by the time to first exacerbation ( P < .05 ) . In both groups clinical indicators of worsening asthma showed parallel changes before asthma exacerbation , and greater improvements were observed after exacerbation with salmeterol compared with higher dose FP . CONCLUSION Salmeterol plus low-dose FP was more effective than higher dose FP alone in reducing asthma exacerbations in patients with persistent asthma . The ability to detect deteriorating asthma and the severity of exacerbation was similar between groups STUDY OBJECTIVE One week of regular treatment with salmeterol can induce tolerance to the protective effect of a beta2-agonist on early airway response to allergen ( EAR ) . The objective was to assess whether inhaled corticosteroids revert tolerance to salmeterol . STUDY DESIGN The study had a r and omized , double-blind , placebo-controlled design . PATIENTS AND METHODS Twelve subjects with mild allergic asthma and positive result of specific bronchial provocation test ( sBPT ) to allergen underwent three sBPTs , separated by 1 week . sBPT was done in all subjects after a single dose ( T1 ) and after 1 week of regular treatment with inhaled salmeterol ( 50 microg bid ) ( T2 ) in order to induce tolerance . Subjects were then r and omized to receive either the same dose of salmeterol + beclomethasone dipropionate ( BDP , 500 microg bid ) ( group 1 , n = 6 ) or placebo + BDP ( group 2 , n = 6 ) for 1 week before sBPT ( T3 ) . RESULTS After a single dose of salmeterol ( T1 ) , all subjects were protected against EAR , whereas after 1 week of regular treatment , the protective effect of salmeterol was totally or partially lost ( T2 ) . Maximum FEV1 percent fall ( MaxdeltaFEV1 % ) after allergen inhalation was significantly higher at T2 than at T1 . All subjects except one of group 1 were protected against EAR after salmeterol + BDP ( T3 ) , and MaxdeltaFEV1 % at T3 ( median , 12 % ; range , 4 to 6 % ) was significantly lower than T2 ( median , 22 % ; range , 12 to 43 % ; p < 0.05 by Wilcoxon test ) . Subjects of group 2 did not show any significant protection against EAR after placebo + BDP treatment ( T3 ) MaxdeltaFEV1 % at T2 ( median , 31 % ; range , 9 to 40 % ) and T3 ( median , 31 % ; range , 3 to 42 % ; not significant ) . CONCLUSIONS In conclusion , the addition of inhaled BDP partially restored the bronchoprotective effect of salmeterol on allergen challenge that was lost after 1 week of regular treatment with salmeterol alone . This ability of BDP in reverting tolerance can not be ascribed to a direct effect of corticosteroids per se on allergen challenge in this group of asthmatics OBJECTIVES We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers . METHODS Fifteen patients with atopic persistent asthma were evaluated ( mean age , 32.4 years ; FEV(1 ) , 75.2 % predicted ) in a r and omized , double-blind , double-dummy , placebo-controlled crossover study with a 1-week placebo washout period , comparing the following once-daily nighttime treatments : ( 1 ) formoterol ( FM ) , 12 microg , for 2 weeks and FM , 24 microg , for 2 weeks ; or ( 2 ) budesonide ( BUD ) , 400 microg , for 2 weeks and BUD , 800 microg , for 2 weeks ; or ( 3 ) FM , 12 microg , plus BUD , 400 microg , for 2 weeks and FM , 24 microg , plus BUD , 800 microg , for 2 weeks . Adenosine monophosphate ( AMP ) bronchial challenge , exhaled nitric oxide ( NO ) , and serum eosinophilic cationic protein ( ECP ) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment . RESULTS The results of AMP challenge ( provocative concentration causing a 20 % fall in FEV(1 ) ) at 4 weeks showed significant ( p<0.05 ) improvements after patients had received all active treatments compared to placebo ( 20 mg/mL ) , with FM plus BUD , 261 mg/mL , being superior ( p<0.05 ) to FM alone , 82 mg/mL , but not to BUD , 201 mg/mL. NO and ECP showed significant ( p<0.05 ) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone . Combination therapy was associated with optimal patient preference ( rank order , FM plus BUD > FM > BUD ; p<0.0005 ) , highest domiciliary peak expiratory flow , and lowest rescue inhaler usage . All three treatments produced equivalent improvements in spirometry . CONCLUSIONS Patients preferred once-daily combination therapy , but this had no greater effect on inflammatory markers than therapy with BUD alone . FM alone had no anti-inflammatory activity but exhibited bronchoprotection . This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist STUDY OBJECTIVES To determine the effect of long-term salmeterol aerosol therapy on  airway hyperresponsiveness  measured by methacholine challenge . DESIGN R and omized , double-blind , placebo-controlled , multicenter study . SETTING Thirty-one clinical centers in the United States . PATIENTS Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70 % of predicted values . Patients were not using inhaled corticosteroids . INTERVENTIONS Twice-daily salmeterol aerosol , 42 microg , or placebo via metered-dose inhaler for 24 weeks . Backup albuterol was available . MEASUREMENTS AND RESULTS Pulmonary function tests were performed before , during , and after treatment . Subjects recorded asthma-related symptoms , morning and evening peak expiratory flow ( PEF ) levels , and use of supplemental albuterol daily on diary cards .  Methacholine challenges were performed 10 to 14 h postdose at weeks 4 , 12 , and 24 , and 3 and 7 days posttreatment . Over 24 weeks of treatment , salmeterol provided significant ( p < 0.001 ) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection . A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy . Salmeterol treatment result ed in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo ( p < 0.001 ) . The use of salmeterol significantly reduced combined daytime asthma symptoms by 20 % when compared to placebo ( p = 0.005 ) . A total of 34 and 48 exacerbations , respectively , were reported in the Salmeterol and placebo groups , and no evidence was present for a difference in the severity of asthma exacerbations between groups . Adverse event profiles were similar for the salmeterol and placebo groups . CONCLUSIONS Regular long-term use of salmeterol aerosol result ed in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period . There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy . There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment . Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks The aim of this study was to compare the effects of salmeterol and beclomethasone on lung function and symptoms in children with mild to moderate asthma . Sixty-seven children not treated with inhaled corticosteroids were r and omized in a double-blind parallel study either to salmeterol 50 micrograms b.i.d . or beclomethasone 200 micrograms b.i.d . After one year , FEV1 significantly increased in the beclomethasone group , whereas in the salmeterol group there was a small reduction . Differences between groups were 14.2 % predicted ( p < 0.0001 ) and 7.0 % predicted ( p = 0.007 ) for pre- and postbronchodilator FEV1 values , respectively . PD20 methacholine decreased by 0.73 DD ( p = 0.05 ) in the salmeterol group and increased by 2.02 DD ( p < 0.0001 ) in the beclomethasone group . Morning and evening PEF and symptom scores improved in both groups , although more in the beclomethasone group . Asthma exacerbations , for which prednisolone was needed , were more frequent in the salmeterol group ( 17 versus two ) , as were the number of withdrawals due to exacerbations ( six versus one ) . However , growth was significantly slower in the beclomethasone group ( -0.28 SDS ) compared with that in the salmeterol group ( -0.03 SDS ) ( p = 0.001 ) . We conclude that treatment with a moderate dose of beclomethasone is superior to salmeterol in children with mild to moderate asthma and recommend that salmeterol should not be used as monotherapy It has been shown that asthmatics have nocturnal symptoms associated with impaired cognitive performance . We explored more carefully different therapeutic approaches on this performance in relation to lung function in 46 atopics with mild to moderate asthma and with a circadian variation in peak expiratory flow ( PEF ) > or = 15 % . In a double-blind , parallel study they inhaled salmeterol 50 microg or fluticasone 250 microg or a combination of both twice daily for 6 wk . The psychometric tests used informed about focused attention , mental flexibility , concentration , and attention . The results of the psychometric tests were compared with those in healthy control subjects . The PASAT score and the finishing time of the color-word chart subtest were significantly lower in these asthmatics than in the control subjects . Circadian PEF variation was the only independent factor significantly associated with impaired cognitive performance before the treatment period . The three treatment groups were equally effective in reducing circadian PEF variation below 10 % and in improving FEV1 and bronchial hyperresponsiveness to methacholine ( MCh ) both day and night . After 6 wk of therapy , the daytime cognitive performance was improved to levels comparable to those of the healthy control subjects no matter which drug was inhaled . We conclude that a high level of circadian PEF variation ( > or = 20 % ) has been associated with lower daytime cognitive performance in asthmatics . Reduction of circadian PEF variation to below 10 % is an important goal of treatment in asthmatics PURPOSE In addition to their bronchodilatory effects , beta(2)-agonists protect against bronchoconstriction , such as that caused by methacholine challenge . However , tachyphylaxis to this beneficial effect develops after chronic use of beta(2)-agonists . We studied whether the frequency or dose of treatment with a long-acting beta(2)-agonist ( formoterol ) affects the degree of bronchoprotection afforded against methacholine challenge and to compare this with the effects of a short-acting beta(2)-agonist ( terbutaline ) . PATIENTS AND METHODS In a r and omized , parallel group , double-blind study at two centers , patients with stable asthma of mild to moderate severity who were treated with inhaled corticosteroids were treated with formoterol 6 micrograms twice daily , 24 micrograms twice daily , 12 micrograms once daily ; terbutaline 500 micrograms four times daily ; or placebo . Treatments were given by dry powder inhaler for a period of 2 weeks . Of the 72 patients who were enrolled , 67 completed the study . Methacholine challenge was performed to calculate the provocative dose that caused a 20 % fall in forced expiratory volume in 1 second at baseline ( unprotected ) after an initial 1-week run-in without beta(2)-agonists , 1 hour after the first dose of study treatment , and again 1 hour after 7 and 14 days of study treatment . RESULTS Each of the four active treatments exhibited significant tachyphylaxis ( P < 0.05 ) to protection against methacholine challenge when comparing first/last dose ( as geometric mean protection ratio versus baseline ) : formoterol 24 micrograms twice daily ( 9.6-fold/1.6-fold ) , 12 micrograms once daily ( 7.1-fold/2.2-fold ) , 6 micrograms twice daily ( 6.2-fold/2.3-fold ) , and terbutaline 500 micrograms four times daily ( 2.9-fold/2.0-fold ) . There were no significant differences among treatments after 2 weeks in bronchoprotection against methacholine challenge . For all formoterol regimens , the bronchodilator response 1 hour after inhalation was maintained over the 2-week treatment period . Diurnal control of morning and evening peak flow was significantly better with formoterol 24 micrograms twice daily than with terbutaline . CONCLUSIONS Tachyphylaxis to bronchoprotection against methacholine challenge develops after 2 weeks of therapy with formoterol , a long-acting beta(2)-agonist , at all three dosage regimens that were tested . In contrast , the bronchodilator effects of formoterol were maintained during the 2 weeks of treatment AIMS To determine the role of formoterol in the treatment of children with bronchial asthma who are symptomatic despite regular use of inhaled corticosteroids . METHODS A r and omised , double blind , parallel group , placebo controlled study to investigate the effects of inhaled formoterol ( 12 μg twice a day ) in 32 children with moderate to severe bronchial asthma . The study consisted of two week run in periods and six week treatment periods , during both of which the patients continued their regular anti-inflammatory drugs . The efficacy parameters were symptom scores , bronchodilator use , daily peak expiratory flow rates ( PEFR ) , methacholine hyper-reactivity , forced expiratory volume in one second ( FEV1 ) , lung volumes , and airway conductance . RESULTS Formoterol treatment for six weeks decreased symptom scores , PEFR variability , and the number of rescue salbutamol doses , and increased morning and evening PEFR significantly . No adverse reactions were seen . CONCLUSION These findings suggest that inhaled formoterol is effective in controlling chronic asthma symptoms in children who are symptomatic despite regular use of inhaled corticosteroids STUDY OBJECTIVE To determine the protective effect of salbutamol , 100 microg , inhaled by different devices ( pressurized metered-dose inhaler [ pMDI ; Ventolin ; GlaxoWellcome ; Greenford , UK ] , pMDI + spacer [ Volumatic ; GlaxoWellcome ] , or breath-activated pMDI [ Autohaler ; 3 M Pharmaceuticals ; St. Paul , MN ] ) on bronchoconstriction induced by methacholine . DESIGN R and omized , double-blind , cross-over , placebo-controlled study . PATIENTS Eighteen subjects with stable , moderate asthma , asymptomatic , receiving regular treatment with salmeterol , 50 microg bid , and inhaled beclomethasone dipropionate , 250 microg bid , in the last 6 months , with high hyperreactivity to methacholine ( baseline provocative dose of methacholine causing a 20 % fall in FEV(1 ) [ PD(20 ) ] geometric mean [ GM ] , 0.071 mg ) . Subjects were classified into two groups : subjects with incorrect ( n = 5 ) pMDI inhalation technique , and subjects with correct ( n = 13 ) inhalation technique . METHODS AND MEASUREMENTS After cessation of therapy for 3 days , all subjects underwent four methacholine challenge tests , each test 1 week apart , each time 15 min after inhalation of salbutamol , 100 microg ( via pMDI , pMDI + spacer , or Autohaler ) , or placebo . The protective effect on methacholine challenge test was evaluated as the change in the PD(20 ) , and expressed in terms of doubling doses of methacholine in comparison with placebo treatment . RESULTS The PD(20 ) was significantly higher after salbutamol inhalation than after placebo inhalation , but no significant difference was observed among the three different inhalation techniques . Only when salbutamol was inhaled via pMDI + spacer , PD(20 ) was slightly but not significantly higher ( pMDI GM , 0.454 mg ; pMDI + spacer GM , 0.559 mg ; and Autohaler GM , 0.372 mg ; not significant [ NS ] ) than other inhalation techniques . Similar results ( mean + /-SEM ) were obtained with doubling doses of methacholine ( pMDI , 2 + /- 0.47 ; pMDI + spacer , 3 + /- 0.35 ; and Autohaler , 2.4 + /- 0.40 ; NS ) . No significant difference was found among techniques when subjects with correct or incorrect inhalation technique were separately considered . CONCLUSIONS Our data show that the protective effect of salbutamol , 100 microg , on methacholine-induced bronchoconstriction is not affected by the different inhalation techniques , although inhalation via pMDI + spacer tends to improve the bronchoprotective ability of salbutamol . These data confirm the clinical efficacy of salbutamol , whatever the device , and the patient 's inhalation technique Although the anti-inflammatory effects of inhaled corticosteroids in the treatment of asthma are established , the effects of long-acting β2-adrenergic receptor agonists on inflammation are the subject of debate . The aim of the present study was to determine the effect of salmeterol on the numbers of inflammatory cells in biopsy sample s of distinct immunophenotype and those expressing the genes for interleukin-4 and -5 , regulatory cytokines particularly relevant to asthma . Twenty patients ( aged 18–55 yrs ) with mild stable asthma were r and omised in a three-way crossover study to 6 weeks of treatment with : 1 ) salmeterol ( 50 µg b.d . ; SM50 ) ; 2 ) fluticasone propionate ( 250 µg b.d . ; FP250 ) , or 3 ) placebo . Compared with placebo , SM50 significantly reduced the numbers of neutrophils in bronchial biopsy sample s and the concentrations of myeloperoxidase and soluble E-selectin in serum , each of which reflect neutrophil involvement . Compared with FP250 , SM50 reduced neutrophil number and human neutrophil lipocalin level in bronchial lavage fluid and intercellular adhesion molecule-1 level in bronchoalveolar lavage fluid . Compared with placebo , FP250 significantly reduced the numbers of ( CD3 + ) T-lymphocytes , ( CD4 + ) T-helper cells , ( CD45RO+ ) activated T-helper cells and eosinophils in the biopsy sample s ; it also reduced the percentage of eosinophils and soluble intercellular adhesion molecule-1 in serum . The percentage of symptom-free days and nights and airways hyperresponsiveness improved significantly after SM50 compared to both placebo and FP250 . In conclusion , a novel antineutrophilic effect of the inhaled long-acting β2-adrenergic receptor agonist , salmeterol , in mild asthma is reported In severe chronic asthma , long-term oral steroids may be necessary to control symptoms . In patients in whom such treatment was under consideration , the efficacy and safety of salmeterol xinafoate 100 micrograms b.i.d . was investigated in a r and omized , double-blind , placebo-controlled parallel-group , multicentre study . One hundred and nineteen chronic symptomatic asthmatics were r and omized to receive either salmeterol , 100 micrograms b.i.d . ( n = 55 ; baseline % predicted morning peak expiratory flow ( PEF ) 59 % ; forced expiratory volume in one second ( FEV1 ) 66 % ) or placebo ( n = 64 ; baseline % predicted morning PEF 63 % ; FEV1 66 % ) both via the Diskhaler . Morning and evening PEF and asthma symptoms were recorded in daily record booklets by the patient over a 12 week period . A significant improvement in morning PEF was achieved after 1 month in the salmeterol treated group ; this persisted throughout the treatment period ( estimated treatment difference 22 L.min-1 ) . There was a significant increase in the proportion of symptom-free nights experienced by the salmeterol treated group ( 33 ( SD 32 ) % ) compared with placebo ( 13 ( 26 ) % ) , and a significant decrease in daily use of relief medication ( mean decrease 5.1 ( 4.7 ) doses per day with salmeterol , 2.5 ( 4.0 ) doses with placebo ) . Both treatments were well-tolerated , with no evidence of any difference in the side-effects associated with beta 2-agonists . In conclusion , the addition of salmeterol ( 100 micrograms daily ) to the existing treatment of chronic asthmatics under consideration for maintenance oral corticosteroid therapy is well-tolerated , improves lung function and provides additional symptom control The aim of this r and omized , double-blind , parallel group study was to determine the lowest effective dose of 6 , 12 and 24 microg formoterol fumarate dihydrate Turbuhaler b.i.d . compared with placebo . The 4 week treatment was preceded by a 1 week run-in period . Morning peak expiratory flow ( PEF ) before intake of the study drug was the primary variable . Patients recorded PEF , prior to and 15 min after intake of the study drug ( immediate response ) , asthma symptoms , and use of rescue medication morning and evening . Of 221 patients ( 71 females and 150 males ) , 194 were included in the efficacy per protocol ( PP ) analysis ; mean age 47 yrs , mean forced expiratory volume in one second ( FEV1 ) 2.01 L ( 58 % of predicted ) , mean FEV1 reversibility 27 % at entry . Ninety percent used inhaled steroids .  Compared with placebo , 6 microg formoterol b.i.d was found to be the lowest effective dose in the morning ( p=0.008 ) and evening p=0.0041 ) PEF . The mean increases in PEF were 22 and 23 L x min-1 respectively , compared with placebo . After 6 microg formoterol , the mean immediate increase in morning PEF was 42 L x min-1 compared to an increase of only 9 L x min-1 after placebo ( < 0.0001 ) . All doses produced a statistically significant decrease in asthma symptoms , day and night , and the need for rescue medication at night . All doses were well-tolerated . In conclusion , the lowest effective dose in this study was formoterol Turbuhaler 6 microg b.i.d STUDY OBJECTIVES Comparison of inhaled salmeterol powder vs oral montelukast treatment in patients with persistent asthma who remained symptomatic while receiving inhaled corticosteroids . DESIGN R and omized , double-blind , double-dummy , parallel-group , multicenter trials of 12-week duration . SETTING Out patients in private and university-affiliated clinics . PATIENTS Male and female patients > or = 15 years of age with a diagnosis of asthma ( baseline FEV(1 ) of 50 to 80 % of predicted ) and symptomatic despite receiving inhaled corticosteroids . INTERVENTIONS Inhaled salmeterol xinafoate powder , 50 microg bid , or oral montelukast , 10 mg qd . MEASUREMENTS AND RESULTS Treatment with salmeterol powder result ed in significantly greater improvements from baseline compared with montelukast for most efficacy measurements , including morning peak expiratory flow ( 35.0 L/min vs 21.7 L/min ; p < 0.001 ) , percentage of symptom-free days ( 24 % vs 16 % ; p < 0.001 ) , and the percentage of rescue-free days ( 27 % vs 20 % ; p = 0.002 ) . Total supplemental albuterol use was decreased significantly more in the salmeterol group compared with the montelukast group ( - 1.90 puffs per day vs - 1.66 puffs per day ; p = 0.004 ) and nighttime awakenings per week decreased significantly more with salmeterol than with montelukast ( - 1.42 vs - 1.32 ; p = 0.015 ) . Patients treated with inhaled salmeterol were significantly more satisfied with their treatment regimen and how well , how fast , and how long it worked than were patients who were treated with oral montelukast . The safety profiles for the two treatments were similar . CONCLUSION In patients with persistent asthma who remain symptomatic while receiving inhaled corticosteroids , adding inhaled salmeterol powder provided significantly greater improvement in lung function and asthma symptoms and was preferred by patients over oral montelukast Budesonide/formoterol in a single inhaler was compared with budesonide alone , and with concurrent administration of budesonide and formoterol from separate inhalers , in patients with asthma , not controlled with inhaled glucocorticosteroids alone . In this 12-week , double-blind , r and omized , double-dummy study , 362 adult asthmatics ( forced expiratory volume in one second 73.8 % of predicted , inhaled glucocorticosteroid dose 960 microg x day(-1 ) ) received single inhaler budesonide/formoterol ( Symbicort Turbuhaler ) 160/4.5 microg , two inhalations b.i.d . , or corresponding treatment with budesonide , or budesonide plus formoterol via separate inhalers . There was a greater increase in morning peak expiratory flow ( PEF ) with single-inhaler ( 35.7 L x min(-1 ) ) and separate-inhaler ( 32.0 L x min(-1 ) ) budesonide and formoterol , compared with budesonide alone ( 0.2 L x min(-1 ) ; p<0.001 , both comparisons ) ; the effect was apparent after 1 day ( p<0.001 versus budesonide , both comparisons ) . Similarly , evening PEF , use of rescue medication , total asthma symptom scores and percentage of symptom-free days improved more with both single inhaler and separate inhaler therapy than with budesonide alone , as did asthma control days ( approximately 15 % more , p<0.001 versus budesonide , both comparisons , with a marked increase in the first week ) . All treatments were well tolerated and the adverse event profile was similar in all three treatment groups . It is concluded that single inhaler therapy with budesonide and formoterol is a clinical ly effective and well-tolerated treatment for patients with asthma that is not fully controlled by inhaled glucocorticosteroids alone BACKGROUND --Beta-2 agonists protect against non-specific bronchoconstricting agents such as methacholine , but it has been suggested that the protection afforded by long acting beta 2 agonists wanes rapidly with regular treatment . METHODS --The changes in airway responsiveness were investigated during and after eight weeks of regular treatment with salmeterol 50 micrograms twice daily in 26 adult asthmatic patients , 19 of whom were receiving maintenance inhaled corticosteroids . The study was of a r and omised , placebo controlled , double blind design . Airway responsiveness to methacholine  was measured as PD20 by a st and ardised dosimeter technique 12 hours after the first dose , at four weeks and eight weeks during treatment ( 12 hours after the last dose of test medication ) , and at 60 hours , one week and two weeks after stopping treatment . RESULTS --There were no significant differences between the baseline characteristics of the two groups . A significant improvement in PD20 was seen at all points during treatment with salmeterol compared with the placebo group , with no significant fall off with time . PD20 measurements returned to baseline values after cessation of treatment with no significant difference from the placebo group . CONCLUSIONS --Salmeterol gave significant protection against methacholine induced bronchoconstriction 12 hours after administration . This protection was of small magnitude , but there was no significant attenuation with eight weeks of regular use and no rebound increase in airway responsiveness on stopping treatment in a group of moderate asthmatic patients , the majority of whom were receiving inhaled corticosteroids The aim of this study was to evaluate whether ozone exposure induces a similar airway inflammatory response in subjects with different degrees of asthma severity . Two groups of asthmatic subjects were studied : seven with intermittent mild asthma not requiring regular treatment ( group A ) ; and seven with persistent mild asthma requiring regular treatment with inhaled corticosteroids and long-acting beta2-agonists ( group B ) . All subjects were exposed , in a r and omized cross-over design , to air or O3 ( 0.26 parts per million ( ppm ) for 2 h with intermittent exercise ) ; subjects in group B withdrew from regular treatment 72 h before each exposure . Before the exposure , and 1 and 2 h after the beginning of the exposure they performed a pulmonary function test , and a question naire was completed to obtain a total symptom score ( TSS ) . Six hours after the end of the exposure , hypertonic saline ( HS ) sputum induction was conducted . Sputum cell percentages , eosinophil cationic protein ( ECP ) and interleukin (IL)-8 concentrations in the sputum supernatant were measured . TSS significantly increased and forced vital capacity ( FVC ) and forced expiratory volume in one second ( FEV1 ) significantly decreased after O3 exposure in comparison with air exposure in group A , whereas no changes were observed in group B except for a significant decrement of FEV1 2 h after the beginning of O3 exposure . Sputum neutrophil percentage was significantly higher after O3 exposure than after air exposure in both groups ( Group A : 70.2 % ( 28 - 87 ) versus 26.6 % ( 8.6 - 73.2 ) ; Group B : 62.1 % ( 25 - 82.4 ) versus 27.9 % ( 14.4 - 54 ) ) . IL-8 was higher in sputum supernatant collected 6 h after O3 exposure than after air , only in group A. No change due to O3 has been found in sputum eosinophil percentage and ECP concentration in both groups . In conclusion , the degree of airway response to a short-term exposure to ozone is different in subjects with asthma of different severity . The available data do not allow elucidation of whether this difference depends on the severity of the disease or on the regular anti-inflammatory treatment OBJECTIVES To compare the efficacies of medium-dose fluticasone propionate ( FP ) , medium-dose triamcinolone acetonide ( TAA ) , and combined low-dose FP plus salmeterol ( SL ) . DESIGN R and omized , double-blind , triple-dummy , multicenter , 12-week clinical trial . SETTING Allergy/respiratory care clinics . PATIENTS Six hundred eighty patients with asthma previously uncontrolled with low-dose inhaled corticosteroids . INTERVENTIONS FP , 220 microg bid ; TAA , 600 microg bid ; or FP , 88 microg plus SL , 42 microg bid . MEASUREMENTS AND RESULTS Outcome measures included FEV1 , peak expiratory flow ( PEF ) , supplemental albuterol use , nighttime awakenings , asthma symptoms , and physician global assessment . Compared with TAA , 600 microg bid , treatment with FP 220 , microg bid , significantly increased FEV1 , morning and evening PEF , and percent symptom-free days , and significantly reduced rescue albuterol use , number of nighttime awakenings , and overall asthma symptom scores ( p < or = 0.035 ) . Improvements with low-dose FP , 88 microg , plus SL , 42 microg bid , were significantly ( p < or = 0.004 ) greater than TAA , 600 microg bid , in all the aforementioned efficacy measures as well as percent of rescue-free days . Combined low-dose FP , 88 microg , plus SL , 42 microg bid , also significantly increased FEV1 and percent of rescue-free days , and significantly reduced albuterol use compared with medium-dose FP , 220 microg bid ( p < or = 0.018 ) . At endpoint , both FP , 220 microg bid , and FP , 88 microg , plus SL , 42 microg bid , significantly increased FEV1 by 0.48 L and 0.58 L , respectively , compared with 0.34 L with TAA , 600 microg bid . CONCLUSION In patients who are symptomatic while taking low-dose inhaled corticosteroids , medium-dose FP ( 440 microg/d ) and combination treatment with low-dose FP ( 176 microg/d ) plus SL ( 84 microg/d ) are both more effective than medium-dose TAA ( 1200 microg/d ) in improving pulmonary function and asthma symptom control BACKGROUND -- Quality of life ( QOL ) is commonly measured in asthma clinical trials by a question naire given before and after treatment . A structured asthma QOL daily diary provides more restricted information but on a daily basis . The validity and use of such a QOL diary was examined in a clinical trial in which two asthma treatments were compared . METHODS --The effects of low dose inhaled steroid ( 400 micrograms beclomethasone dipropionate , BDP ) combined with the long acting beta 2 agonist salmeterol ( 100 micrograms ) ( n = 220 ) was compared with high dose inhaled steroid ( 1000 micrograms BDP ) ( n = 206 ) in asthmatic out patients in a double blind , parallel group study . Outcome measures consisted of a combined diary for peak expiratory flow ( PEF ) rate , symptoms , and problems , and an asthma-specific QOL question naire , the Living with Asthma Question naire . RESULTS --The QOL diary correlated with the QOL question naire for both cross sectional and longitudinal assessment s. Cross sectional correlations with PEF were higher for the QOL question naire than the QOL diary , but longitudinal correlations with PEF were higher for the diary than the question naire . Treatment with low dose steroid/salmeterol compared with high dose steroid produced better lung function , better QOL as measured by diary , and reduced night time wakenings , but treatment differences were not obtained with the QOL question naire nor for daytime symptoms . Diary assessed QOL was a better predictor of low PEF than diary assessed symptoms . Compliance with diary completion was good but there were floor or ceiling effects in the QOL diary records of about 25 % of patients . CONCLUSIONS --Structured QOL diaries are valid instruments that appear to be more responsive to longitudinal change in clinical trials than a QOL question naire , but QOL question naires provide a more sensitive cross sectional measure of disease severity . Floor and ceiling effects are found in some patients ' QOL diaries which limit their usefulness . QOL diary problem events occur during the troughs of a peak flow graph , while symptoms are more widely distributed with respect to peak flow In-vitro data suggest that long-acting β2-agonists may have a neutrophil-stabilising effect . A reduction in airway wall eosinophil number following introduction of salmeterol in persistent asthma has previously been described . There is currently interest in the “ neutrophil system ” in asthma , and thus the aim of the present study was to investigate the effect of salmeterol on interleukin (IL)-8 , neutrophils and myeloperoxidase ( MPO ) in persistent asthma . In the same 12-week double-blind parallel-group placebo-controlled study as described previously , the effects on bronchoalveolar lavage fluid ( BALF ) IL-8 , neutrophils and MPO of introducing salmeterol ( 50 µg b.i.d . ) or giving additional inhaled corticosteroid ( fluticasone 100 µg b.i.d . ) in 45 subjects with persistent asthma already on low/moderate doses of inhaled corticosteroids were further investigated . At baseline , BALF IL-8 but not neutrophil or MPO levels were significantly raised in the asthmatic subjects compared to normal controls . MPO levels correlated strongly with IL-8 levels , and weakly with BALF neutrophil numbers in the asthmatics . Fluticasone treatment result ed in significantly elevated neutrophil numbers , but not MPO or IL-8 levels . In contrast , introducing salmeterol significantly reduced IL-8 and MPO levels , but did not affect BALF neutrophil numbers . Interestingly , salmeterol and fluticasone showed significantly contrasting effects on MPO and neutrophils , and there was a divergent effect on IL-8 levels that almost reached significance . Excessive interleukin-8 levels may be relevant to asthma pathogenesis , even in the setting of moderate-dose inhaled corticosteroid therapy . Reduction in interleukin-8 production and possibly stabilisation of airway neutrophil numbers may explain the greater clinical benefit of adding a long-acting β2-agonist rather than merely increasing inhaled corticosteroid doses . Indeed , high-dose inhaled corticosteroid therapy alone may promote airway neutrophilia The Formoterol and Corticosteroids Establishing Therapy ( FACET ) study has provided the first opportunity to examine the long-term effects of inhaled steroids and long-acting beta2-agonists on asthma-specific quality of life . The objectives of the present study were to : evaluate the effects of long-term ( 1 yr ) formoterol and increasing doses of budesonide on asthma quality of life ; 2 ) to determine whether initial improvements in quality of life are sustained when improvements in clinical indices persist ; and 3 ) to evaluate the long-term relationship between changes in clinical indices and changes in quality of life . Of the 852 asthmatic adults enrolled , 470 from five countries participated in this quality of life evaluation . After a 4-week run-in on 1,600 microg budesonide , patients were r and omized to either 200 microg ( Bud200 ) or 800 microg budesonide ( Bud800 ) in combination with either 24 microg formoterol ( F ) or placebo daily for 1 yr . The Asthma Quality of Life Question naire ( AQLQ ) was completed and conventional clinical indices measured at enrolment and r and omization and on seven occasions during the following 12 months . During the run-in , there was an improvement in AQLQ score ( changes ( delta ) in overall score approximately 0.50 ; p<0.0001 ) . After r and omization , there was a further improvement in the Bud800+F group ( delta=0.21 ; p=0.028 ) . One month post-r and omization , improvements in all groups stabilized and were sustained throughout the 12 months in a pattern very similar to that observed for the conventional clinical indices . The correlation of individual patient changes in clinical indices and changes in AQLQ score during the 12-month r and omized period were weak to moderate ( maximum r=0.51 ) . Improvements in quality of life , which were greatest in the 800 microg budesonide plus 24 microg formoterol group , were sustained throughout the 12 months in a similar manner to the clinical indices . Long-term changes in conventional clinical indices can not be used to predict the effect of treatment on individual patient experience QUESTIONS UNDER STUDY if patients with asthma remain symptomatic in spite of chronic treatment with inhaled corticosteroids ( ICS ) , increasing the ICS dosage or adding another drug to the treatment regimen are possible therapeutic alternatives . We compared the efficacy and safety of combined salmeterol fluticasone therapy ( SFC , 50/250 microg twice daily ) with twice the dose of fluticasone propionate ( FP , 500 microg b.i.d . ) in symptomatic asthmatics . METHODS this prospect i ve , double-blind study was conducted in 76 study centres . 365 symptomatic patients with moderate asthma aged > 18 years and receiving ICS in a dose equivalent to 1000 microg beclomethasone propionate per day were r and omly assigned to receive either salmeterol xinafoate ( 50 microg ) and fluticasone propionate ( 250 microg ) in a single dry powder inhaler ( Diskus ) or 500 microg FP twice daily . The primary efficacy endpoint was morning peak expiratory flow rate ( PEFR ) . Secondary measurements included forced expiratory volume in 1 second ( FEV1 ) , asthma symptom scores , and use of rescue medication . RESULTS combined salmeterol fluticasone therapy result ed in significantly greater improvements in PEFR and symptom control than doubling the dose of FP . At week 12 , morning PEFR had increased by 52 L/min from baseline in patients on SFC and by 36 L/min in subjects receiving FP . The adjusted difference between groups was 16.6 L/min ( 95 % confidence interval , 1.1 to 32.0 L/min ) . In the SFC group , the percentage of symptom-free days increased from baseline by 49 % of days as compared with 38 % of days after FP ( adjusted difference : 12.6 % of days , 95 % CI 4.0 to 20.7 ) . Quality of life improved to a greater degree after SFC therapy , and patients regarded study drugs as superior to their previous asthma medication . Adverse event profiles were similar between groups . CONCLUSIONS the combination of salmeterol 50 microg and fluticasone 250 microg in a single dry powder inhaler was superior to twice the dose of FP ( 500 microg ) . It seems justified to add salmeterol rather than increasing the ICS dose if symptomatic asthmatics require supplementary therapy BACKGROUND Subsensitivity of airway beta2-adrenoceptors develops readily in asthmatics receiving regular long-acting beta2-agonists . This subsensitivity may be rapidly reversed by using systemic corticosteroids . The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid . METHODS Ten subjects with stable mild-to-moderate asthma , with a mean age of 27 years , mean ( + /- SD ) FEV1 of 2.95 L ( 0.94 L ) , 81 % ( 15 % ) of predicted , all receiving inhaled corticosteroids , reactive to adenosine monophosphate ( AMP ) with a provocative concentration producing a 20 % fall in FEV1 ( PC20 ) < 200 mg/mL , were recruited into a r and omized double-blind crossover study . The subjects received two separate 1-week treatment periods with formoterol dry powder , 24 microg bid , with an initial 1-week run-in and a 1-week washout period between the treatments . A single dose of placebo or budesonide turbuhaler , 1,600 microg , was taken in conjunction with the last dose of both treatment periods . AMP challenge was performed 2 h after the first and last dose of formoterol . Blood for lymphocyte beta2-adrenoceptor density ( Bmax ) was also measured before and after treatment with formoterol . RESULTS There was no significant difference in the geometric mean PC20 after the first dose of formoterol comparing the two treatment periods : 362 mg/mL vs 391 mg/mL. The PC20 after the last dose of formoterol was significantly higher ( p < 0.05 ) in conjunction with budesonide than with placebo : 427 mg/mL vs 99 mg/mL , amounting to a 4.3-fold difference ( 95 % confidence interval [ CI ] , 1.1 to 16.6 ) . For comparison within each treatment period , there was significant subsensitivity ( p < 0.05 ) between the first and last dose of formoterol when the latter was given with placebo : 391 mg/mL vs 99 mg/mL , a 3.9-fold fall ( 95 % CI , 1.0 to 15.2 ) , but not when the latter was given with budesonide : 362 mg/mL vs 427 mg/mL , a 1.2-fold rise ( 95 % CI , 0.5 to 2.8 ) . Lymphocyte 02-adrenoceptor density ( geometric mean Bmax : fmol/10(6 ) cells ) also showed significant down-regulation ( p < 0.05 ) by formoterol given with placebo : preformoterol 2.53 vs postformoterol 1.91 , but not by formoterol given with budesonide : preformoterol 2.43 vs postformoterol 2.67 . The Bmax was significantly higher ( p < 0.05 ) with formoterol + budesonide as compared to formoterol + placebo , amounting to a 1.40-fold difference ( 95 % CI , 1.09 to 1.80 ) . CONCLUSION We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated beta2-adrenoceptor down-regulation in asthmatics taking regular formoterol . Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with beta2-agonists during an acute episode of bronchoconstriction The addition of long-acting beta(2 ) agonists to inhaled corticosteroid ( ICS ) therapy in symptomatic patients with asthma improves clinical status more than increasing the dose of ICS . It has been suggested that these benefits could be at the cost of an increase in airway inflammation , but few histopathological studies have been performed in the relevant group . In a double-blind , parallel-group , placebo-controlled study , we r and omly assigned 50 symptomatic patients with asthma who were receiving ICS ( range , 100 -500 microgram/d ) to 12 wk of supplementary treatment with salmeterol ( 50 microgram twice daily ) or fluticasone ( 100 microgram twice daily ) or placebo . Bronchial biopsies and BAL were obtained from 45 patients before and after treatment and analyzed . After treatment with salmeterol there was no deterioration of airway inflammation as assessed by mast cells , lymphocytes , or macrophages in BAL or biopsies , but rather a significant fall in EG1-positive eosinophils in the lamina propria ( from a median 18.3 to 7.6 cells/mm , p = 0.01 ) , which was not seen after treatment with fluticasone . The only cellular effect of added fluticasone was a decrease in BAL lymphocyte activation . There was a concurrent improvement in clinical status , more marked with salmeterol than with increased ICS . Thus , adding salmeterol to ICS is not associated with increased " allergic " airway inflammation , but conversely with a complementary antieosinophil effect BACKGROUND Traditional clinical outcomes have demonstrated that salmeterol improves pulmonary function and reduces asthma symptoms . However , they do not evaluate how patients perceive the effect of therapeutic intervention on day-to-day functioning and well-being . OBJECTIVE We sought to evaluate the impact of salmeterol on disease-specific quality of life with the Asthma Quality -of-Life Question naire , as well as the efficacy and safety of salmeterol in patients with stable asthma who were symptomatic despite daily use of inhaled corticosteroids . METHODS This was a r and omized , double-blind , placebo-controlled , parallel-group study of 506 patients . Patients were treated with 42 microg salmeterol or placebo twice daily for 12 weeks delivered through a metered dose inhaler . RESULTS Mean change from baseline in asthma quality -of-life scores was significantly greater ( p < or = 0.006 ) after 12 weeks of treatment with salmeterol compared with placebo ( " as-needed " albuterol ) in global scores ( 1.08 vs 0.61 ) and individual domains ( activity limitations , 0.91 vs 0.54 ; asthma symptoms , 1.28 vs 0.71 ; emotional function , 1.17 vs 0.65 ; and environmental exposure , 0.84 vs 0.47 ) . Patients treated with salmeterol experienced significantly greater improvements from baseline to week 12 compared with placebo in FEV1 ( 0.42 L vs 0.15 L , p < 0.001 ) , morning peak expiratory flow ( 47 L/min vs 14 L/min , p < 0.001 ) , evening peak expiratory flow ( 29 L/min vs 11 L/min , p < 0.001 ) , and asthma symptom scores ( daytime scores reduced by 0.55 vs 0.30 , p < 0.001 ) . Patients treated with salmeterol used significantly less supplemental albuterol ( reduced by 3 puffs/day vs 1 puff/day , p < 0.001 ) . CONCLUSION Salmeterol provided significantly greater improvement in quality -of-life outcomes in patients whose asthma symptoms are not well controlled with inhaled corticosteroids . These results demonstrate that the benefits of salmeterol are not limited to conventional clinical measures of efficacy STUDY OBJECTIVES To determine if persistent airway tissue mast cells are associated with treatment failure when patients discontinue inhaled corticosteroids ( ICS ) . DESIGN Double-blind , r and omized , placebo-controlled trial . SETTING Multicenter , tertiary referral centers . PATIENTS OR PARTICIPANTS Forty-five subjects with asthma recruited from six medical centers in the United States . INTERVENTIONS The Asthma Clinical Research Network undertook a 28-week , r and omized , multicenter , double-blind , placebo-controlled trial of 164 subjects with clinical ly stable , persistent asthma . A subset of subjects ( n = 45 ) underwent bronchoscopy with endobronchial biopsy and BAL at the end of a 6-week run-in period , during which all subjects received triamcinolone acetonide ( TAA ) , 400 microg bid . Airway tissue mast cells , eosinophils , neutrophils , macrophages , and T cells were quantified morphometrically along with determination of BAL tryptase . At the end of the run-in period , subjects were then r and omized to receive salmeterol ( 42 micro g bid ) , placebo , or continue TAA for 16 weeks followed by a second bronchoscopy . MEASUREMENTS AND RESULTS Outcome variables included airway tissue mast cells , eosinophils , neutrophils , macrophages , and T cells that were quantified morphometrically and BAL tryptase . Thirty-five subjects completed the treatment phase ; an additional 10 subjects , who were r and omized to either salmeterol or placebo after the run-in , had treatment failure . When the bronchoscopy results performed at the end of the run-in , prior to r and omization , were analyzed , the treatment failure group demonstrated significantly more tissue mast cells as compared to the nontreatment failure group despite 6 weeks of therapy with TAA ( p = 0.04 ) . BAL tryptase was also significantly higher in the treatment failure group ( p < 0.0001 ) . Of those subjects who completed the study , tissue mast cells and BAL tryptase did not change significantly within any of the treatment groups during the treatment phase ( p > 0.05 ) . CONCLUSIONS Persistent elevations in airway tissue mast cells and BAL tryptase after treatment with TAA predict treatment failure in patients for whom discontinuation of ICS is being considered Guidelines on asthma management recommend that in patients who still have symptoms on treatment with low-dose inhaled corticosteroids the first step should be an increase in inhaled corticosteroid dose . The addition of long-acting inhaled beta 2-adrenoceptor agonists is another option . We have compared these two strategies in a r and omised , double-blind , parallel-group trial . We studied 429 adult asthmatic patients who still had symptoms despite maintenance treatment with 200 micrograms twice daily inhaled beclomethasone dipropionate ( BDP ) .  3 did not provide verifiable data . Of the others , 220 were assigned salmeterol xinafoate ( 50 micrograms twice daily ) plus BDP and 206 were assigned higher-dose BDP ( 500 micrograms twice daily ) for 6 months . The mean morning peak expiratory flow increased from baseline in both groups , but the increase was greater in the salmeterol/BDP group than in the higher-dose BDP group at all time points ( differences 16 - 21 L/min , p < 0.05 ) . Mean evening PEF also increased with salmeterol/BDP but not with higher-dose BDP . There were significant differences in favour of salmeterol/BDP in diurnal variation of PEF ( all time points ) and in use of rescue bronchodilator ( salbutamol ) and daytime and night-time symptoms ( some time points ) . There was no significant difference between the groups in adverse effects or exacerbations of asthma , indicating that in this group of patients regular beta 2-agonist therapy was not associated with any risk of deteriorating asthma control over 6 months . This study suggests a need for a flexible approach to asthma management The aim of this study was to compare the efficacy and safety in children of salmeterol ( 50 microg twice daily ) plus fluticasone propionate ( 100 microg twice daily ) when delivered together via a single Diskus inhaler ( Seretide ; combination therapy ) or concurrently using two separate Diskus inhalers ( concurrent therapy ) . In a multicenter , r and omized , double-blind , double-dummy , parallel-group study , 257 children with reversible airways obstruction who remained symptomatic on inhaled corticosteroids ( 200 - 500 microg daily ) alone were r and omized to combination or concurrent therapy for 12 weeks . Efficacy was assessed by measuring daily peak expiratory flow ( PEF ) , symptom scores , and rescue salbutamol use . In addition , lung function tests were performed at each clinic visit . Safety assessment s included monitoring of adverse events and morning serum cortisol concentrations . The primary efficacy parameter ( mean morning PEF ) increased during treatment in both groups ; adjusted mean changes were 33 and 28 L/min for the combination and concurrent therapies , respectively . The 90 % confidence interval for the difference in mean morning PEF between treatment groups was within the + 15 L/min criterion for clinical equivalence . Similarly , there were improvements in pulmonary function , symptom score , and rescue salbutamol use during treatment in both groups , with no significant differences between the combination and concurrent therapy groups for any of these secondary efficacy parameters . Both treatment regimens were well-tolerated and had comparable adverse event profiles . Mean morning serum cortisol levels increased similarly in both groups during the study . In conclusion , salmeterol and fluticasone propionate therapy given as a new combination product is as safe and effective in children with asthma as the same drugs given concurrently via separate inhalers Objective Current guidelines advocate adding a long acting β2-agonist ( LABA ) to an inhaled corticosteroid as an alternative to increasing the dose of the latter . Since it is unclear how this translates into effects on surrogate inflammatory markers , we evaluated the anti-inflammatory activity of fluticasone plus salmeterol in combination versus twice the dose of fluticasone alone . Methods Fifteen mild-to-moderate asthmatics ( mean FEV1 80 % predicted ) uncontrolled on inhaled corticosteroids ( mean dose 470 μg ) were r and omised in a single-blind crossover fashion to receive 2 weeks each of fluticasone 250 µg plus salmeterol 50 µg in combination ( FP+SM ) , 1 puff b.i.d . , and fluticasone 500 µg ( FP ) , 1 puff b.i.d . Prior to each r and omised treatment , there was a 2-week run-in and washout period during which patients used their usual inhaled corticosteroid therapy . Measurements were made before and after r and omised treatment periods . The primary outcome was airway hyper-responsiveness to adenosine monophosphate ( AMP PC20 ) , while secondary endpoints were exhaled tidal nitric oxide ( NO ) , forced expiratory volume in 1 second ( FEV1 ) and forced mid-expiratory flow ( FEF25–75 ) . Results For AMP PC20 , FP alone but not FP+SM conferred a significant ( P<0.05 ) improvement amounting to 3.27 ( 95 % CI 1.46–7.32 ) and 1.44 ( 95 % CI 0.64–3.23 ) geometric mean fold shifts , respectively , from baseline , while the difference between treatments was significantly ( P<0.05 ) greater with FP alone : a 2.26-fold ( 95 % CI 1.01–5.07 ) difference . Both FP alone and FP+SM conferred significant ( P<0.05 ) falls in NO from baseline : 2.33 ( 95 % CI 1.71–3.19 ) and 1.49 ( 95 % CI 1.09–2.03 ) geometric mean fold changes , respectively , while between treatments the reduction was significantly ( P<0.05 ) greater with FP alone : a 1.57-fold ( 95 % CI 1.15–2.14 ) difference . Neither treatment significantly improved FEV1 or FEF25–75 . Conclusion Double the dose of FP alone relative to FP+SM conferred superior effects on surrogate inflammatory markers but not on lung function . Long-term studies are required to evaluate whether these improvements on surrogate inflammatory markers translate into commensurate reductions in airway remodelling and exacerbations OBJECTIVE We have previously found that beta2-adrenoceptor downregulation and bronchodilator desensitization to albuterol occurred at 36 hours after stopping regular treatment with twice daily salmeterol . In this study we have evaluated these same effects with formoterol given once or twice daily on a regular basis . METHODS In a r and omized , placebo-controlled , double-blind , double-dummy crossover study , 16 subjects with mild-to-moderate stable asthma ( mean [ SD ] age , 32.5 [ 15.3 ] years ; mean [ SD ] FEV1 , 73.2 [ 12.1 ] percent predicted ) receiving regular inhaled corticosteroid therapy received 1 week of treatment with formoterol dry powder ( 24 microg twice daily [ 8 AM/8 PM ] ) , formoterol ( 24 microg once daily [ 8 PM ] ) , or identical placebo .  Lymphocyte beta2-adrenoceptor parameters and a dose-response curve to inhaled albuterol ( 200 to 1600 microg ) were evaluated at 36 hours after the last dose of each treatment period . RESULTS There were no significant differences in the mean values for albuterol dose-response effects among the three treatment regimens . Comparison of maximal bronchodilator responses between treatments ( mean and SEM as change from baseline ) revealed no significant differences between treatments for FEV1 ( 0.47 L [ 0.06 L ] for placebo vs 0.48 L [ 0.07 L ] for 24 microg once daily formoterol vs 0.51 L [ 0.08 L ] for 24 microg twice daily formoterol ) or for forced expiratory flow , mid-expiratory phase ( FEF25 - 75 ) ( 0.80 L/sec [ 0.12 L/sec ] for placebo vs 0.80 L/sec [ 0.16 L/sec ] for 24 microg once daily formoterol vs 0.89 L/sec [ 0.14 L/sec ] for 24 microg twice daily formoterol ) . Formoterol also had no significant effect on mean lymphocyte beta2-adrenoceptor density . However , in five of seven patients with the homozygous Gly-16 polymorphism  , beta2-adrenoceptor density was downregulated by twice daily formoterol , whereas only two such cases exhibited a reduction in maximal FEV1 response to albuterol . CONCLUSIONS The results of this study showed that for patients taking inhaled corticosteroids , overall beta2-adrenoceptor regulation and associated bronchodilator sensitivity to inhaled albuterol were unaltered at 36 hours after stopping regular treatment with formoterol . However , in a subset of patients who were Gly-16 homozygous , there was a tendency towards downregulation but not desensitization . Further studies in subjects with more severe asthma are required to assess the clinical relevance of these findings BACKGROUND Salmeterol is a potent long acting beta-agonist that is effective in relieving the symptoms and airflow limitation of asthma .  OBJECTIVE To determine whether the effect of salmeterol on clinical parameters in a mild eosinophilic exacerbation of asthma was similar to that of beclomethasone dipropionate ( BDP ) and , thus , is due to an anti-inflammatory property . PATIENTS AND METHODS Thirty-four asthmatics with a persistent increase in symptoms for at least two weeks and an increase of sputum eosinophils of 4 % or more were r and omized in a double-blind fashion to one of three groups that received daily treatment with 100 mg salmeterol , 1 mg BDP or placebo in divided doses using identical pressurized inhalers . Patients were treated with study medications for three weeks , followed by one week of open label BDP ( 500 mg bid ) . Patients were seen at weekly intervals , and sputum and blood were obtained on each visit . The primary outcome measure was a change in sputum eosinophils , and secondary outcomes were changes in blood eosinophils , eosinophilic cationic protein ( ECP ) and clinical parameters . Three patients ( one in each group ) could not produce any sputum after r and omization and were excluded from the analysis . RESULTS Twelve patients received salmeterol , 10 received BDP and nine received placebo . Salmeterol treatment had no effect on sputum eosinophils geometric mean , ( from 35.5 [ 24.9 ] to 26.9 % [ 25.8 ] ) , blood eosinophils ( from 7.6 [ 4.8 ] to 7.2 % [ 3.9 ] ) or ECP ( from 33.1 [ 18.1 ] to 27.8 [ 16.3 ] mg/L ) but improved morning peak expiratory flow ( PEF ) and diurnal variation of PEF , and decreased the use of rescue medication more than placebo ( P<0.05 for all comparisons ) . In contrast , BDP improved both inflammatory indexes ( sputum eosinophils from 22.5 [ 17.9 ] to 5.7 % [ 6.8 ] , blood eosinophils from 9.0 [ 5.5 ] to 2.1 % 1.0 , and serum ECP from 36.5 [ 22.0 ] to 16.1 [ 10.1 ] mg/L ) as well as clinical parameters . CONCLUSIONS These results show that salmeterol improves the symptoms and airway function of patients with asthma , but has no effect on eosinophilic airway infiltration . These findings support current asthma guidelines , which recommend the initial use of  inhaled steroid  to maximize clinical improvement .  While salmeterol also produces clinical improvement , it does not suppress sputum eosinophilia . The analysis of induced or spontaneous sputum for inflammatory indexes may be a valuable clinical test to guide the use of inhaled steroid and /or a long acting beta-agonist BACKGROUND An effective , long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs . We compared a new long-acting , inhaled beta 2-adrenoceptor agonist , salmeterol , with a short-acting beta 2-agonist , albuterol , in the treatment of mild-to-moderate asthma . METHODS We r and omly assigned 234 patients ( 150 male and 84 female patients 12 to 73 years old ) to one of three treatment groups : one group received 42 micrograms of salmeterol twice daily , one received 180 micrograms of albuterol four times daily , and one received placebo . Treatment was assigned in a double-blind fashion , and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period . RESULTS Measurements of the forced expiratory volume in one second , performed hourly for 12 consecutive hours , showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart ( 6.3 vs. 4.9 liter.hr , P < 0.05 ) . The difference was significant on day 1 and at week 4 of the study , but not at week 8 or 12 . Salmeterol was also more effective than albuterol or placebo ( with albuterol taken as needed ) in increasing the morning peak expiratory flow rate : salmeterol induced a mean increase of 24 liters per minute over the pretreatment values , as compared with a decrease of 6 liters per minute with albuterol ( P < 0.001 ) and an increase of 1 liter per minute with placebo ( P = 0.002 ) . The mean overall symptom score was improved most by salmeterol treatment ( P < 0.05 ) , with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent , respectively ; there were no differences in results between albuterol treatment and placebo administration . We found no evidence of tolerance to the bronchodilating effects of salmeterol , and adverse reactions to all the treatments were infrequent and mild . CONCLUSIONS For the management of mild-to-moderate asthma , salmeterol given twice daily is superior to albuterol given either four times daily or as needed This study was design ed to determine whether the benefit of adding salmeterol was superior to doubling the dose of fluticasone propionate ( FP ) over 6 months , compared to a control group who remained on a lower dose of FP . The multi-centre , double-blind , parallel group study involved 496 symptomatic asthmatic patients with a history of exacerbations on 500 - 800 micrograms ( microg ) inhaled corticosteroids ( ICS ) twice daily ( b.d . ) in a broadly representative group of 100 hospitals and general practice s in six countries . Two doses of FP--250 microg b.d . ( FP250 ) or 500 microg b.d . (FP500)--were compared with the lower dose of FP plus a long-acting beta2-agonist , salmeterol 50 microg b.d . ( SM/FP250 ) . Patients symptomatic on the run-in dose of FP250 alone formed the control group in the treatment period . Over 6 months , SM/FP250 significantly improved mean morning peak expiratory flow rates ( amPEF ) by 42.1 l/min , more than twice the improvement achieved with either dose of FP alone . SM/FP250 also result ed in more symptom-free days and nights ( P < 0.002 ) and days and nights with no relief medication ( P < 0.001 ) . The number of severe exacerbations was low : 3 , 6 and 8 % in the SM/FP250 , low- and high-dose FP groups , respectively . This study confirms that adding salmeterol to low-dose inhaled FP offers greater improvements than either maintaining or doubling the dose of FP . Significant benefit was gained from adding salmeterol in a group of patients who appeared to have been at the top of their steroid dose-response curve receiving FP250 . There was no evidence of tolerance and a low incidence of exacerbations in all treatment groups Regular use of beta2-agonists might result in increased bronchial hyper-responsiveness ( BHR ) and decreased forced expiratory volume in 1 sec ( FEV1 ) . It has been suggested that these possible detrimental effects are not a real deterioration of the disease , but that it might be only a transient ( rebound ) effect shortly after discontinuing this regular use . Moreover , these effects are thought to occur especially during short-acting and not during long-acting beta2-agonists use . The aim of this study was to invest gate whether a rebound effect ( a pharmacological deterioration effect diminishing after several hours ) in FEV1 and PC20 ( concentration of histamine causing a 20 % fall in FEV1 with regard to baseline ) occurred after cessation of regular use of beta2-agonists , and whether this occurred both after short-acting and long-acting beta2-agonists . Allergic asthmatic patients ( n = 134 ) were r and omly allocated to the use of a short-acting ( salbutamol ) , a long-acting beta2-agonist ( formoterol ) or placebo for 12 weeks ( double-blind , double-dummy ) . No other asthma medication was allowed , including inhaled corticosteroids . At the start and every 4 weeks later FEV and PC20 were measured , each time at least 12 h after the last doses of study medication , which is in the possible rebound period . To investigate whether a ( transient ) rebound effect occurred , parameters were additionally measured at least 72 h later after discontinuation of the study medication . After 12 weeks of short-acting beta2-agonist use , a drop was seen in FEV1 from 85.6 ( + /- 2.21)% predicted to 78.8 ( + /- 2.9)% predicted , measured 15 h ( median ) after the last doses of medication . This was significantly different compared to placebo . When measured 168 h ( median ) later FEV1 recovered to 85.5 ( + /- 2.4)% predicted , comparable to baseline . PC20 decreased with -1.17 ( + /- 0.44 ) doubling dose after 12 weeks of short-acting beta2-agonist use , measured 15 h after the last doses of medication , which was significantly different compared to placebo . However , 168 h later PC20 recovered slightly with + 0.55 ( + /- 0.34 ) doubling dose , but this value was still lower compared to placebo . In contrast , during long-acting beta2-agonist and placebo use no significant changes were seen . In conclusion , the use of short-acting beta2-agonists result ed in a transient ( rebound ) effect in FEV while the effects on PC20 may point to a real deterioration of the disease . Long-acting beta2-agonist and placebo use showed no changes . We conclude that a mono-therapy of short-acting and not of long-acting beta2-agonists might have deleterious effects in asthma OBJECTIVE In children with chronic persistent asthma , we evaluated whether the presence of increased residual volume ( RV ) after anti-inflammatory treatment correlates with the detection of low-density areas on high-resolution computed tomography ( H RCT ) , similar to those in emphysema . METHODS Children with a confirmed diagnosis of asthma ( n = 32 ) were enrolled in a prospect i ve study . All patients had reduction of airflow  in the peripheral airways , increased RV , and increased serum eosinophil cationic protein ( ECP ) values indicating airway inflammation . All the children were treated with salmeterol ( 50 microg twice daily ) and fluticasone ( 250 microg twice daily ) for a 3-month period . RESULTS At the end of treatment , peripheral eosinophil counts , serum ECP , forced expiratory volume in 1 second ( FEV(1 ) ) , mean forced expiratory flow during the middle half of forced vital capacity ( FEF(25 - 75 ) ) , RV , and total lung capacity values improved in all the patients . H RCT was normal in 22 children ( 68.8 % ) ; in the remaining 10 subjects , low-density areas were found despite normalization of FEV(1 ) , FEF(25 - 75 ) , and significant reduction in ECP . A significant correlation was found between persistence of RV values > 150 % predicted and the presence of low-density areas on H RCT ( r = 0.84 , P < .0001 ) . CONCLUSIONS Structural changes similar to emphysema are also present in asthmatic children . Our findings suggest that the persistence of increased RV may be used to identify subjects with low-density areas on H RCT BACKGROUND Chronic controller therapy , particularly with inhaled corticosteroids , is required in patients with persistent bronchial asthma . Long-acting beta agonists provide prolonged bronchodilatation , improve symptoms and reduce exacerbations . A powder inhaler containing both fluticasone propionate and salmeterol xinafoate combines anti-inflammatory treatment and bronchodilatation in a single user-friendly device ( Diskus ) . OBJECTIVE The goal of the present study was to evaluate the efficacy and safety of salmeterol/ fluticasone ( 50/250 microg twice daily ) as initial treatment for symptomatic patients with mild to moderate bronchial asthma who had not previously received appropriate anti-asthma medication . METHODS This prospect i ve study was conducted in 17 study centres located predominantly in private practice s. 127 patients with mild to moderate asthma ( FEV(1 ) > 60 % of predicted ) aged 12 years and older were recruited into a one-week screening phase . If they used rescue medication on > or =3 of 7 days or had a total asthma symptom score of > or = 5 points , they were admitted to the treatment phase and received salmeterol xinafoate ( 50 microg ) and fluticasone propionate ( 250 microg ) in a single dry powder inhaler ( Diskus ) for four weeks . RESULTS Combined salmeterol/fluticasone therapy improved morning and evening peak expiratory flow rates ( PEFR ) as measured by patients and reported in asthma diaries within the first week of treatment ( by 35 and 28 L/min , respectively ) . At week 4 , morning PEFR had increased by 57 L/min or 13.0 % predicted compared to baseline , and forced expiratory volume in one second ( FEV1 ) had improved by 12.5 % of predicted ( p<0.001 ) . Use of rescue medication declined by 1.9 puffs per day . Both patients and physicians regarded treatment as a major benefit : two thirds assessed treatment as " excellent " . The combination was well tolerated . CONCLUSIONS The combined inhalation of salmeterol and fluticasone from a single dry powder inhaler ( DiskuS ) was an effective initial treatment for patients with mild to moderate asthma . Improvements of symptoms and lung function were documented by the first week of treatment . This combination provides rapid and effective asthma control that is highly acceptable to both the patient and physician BACKGROUND The incidence of pediatric asthma has increased dramatically over the past few decades , with approximately 5 % of American children affected by the disease . OBJECTIVES To compare the efficacy and safety of once-daily budesonide Turbuhaler with placebo in asthmatic children previously treated with orally inhaled corticosteroids . METHODS This r and omized , double-blind , placebo-controlled , multicenter ( 17 centers ) study included 274 male and female children ( aged 6 to 17 years ) with a history of asthma for at least the previous 6 months . Patients received placebo or budesonide Turbuhaler ( 200 microg or 400 microg ) once daily for 12 weeks . Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second ( FEV1 ) , AM and PM peak expiratory flow rates ( PEFRs ) , nighttime and daytime asthma symptom severity scores , patient discontinuations , use of beta2-agonists as breakthrough medication , forced vital capacity ( FVC ) , and midexpiratory flow rate between 25 % and 75 % of FVC ( FEF25%-75 % ) . Safety was evaluated by adverse events , physical examinations , vital signs , and laboratory tests . RESULTS Baseline characteristics were comparable among treatment groups . Percentage of predicted FEV1 at baseline was 76.6 + /- 6.9 for placebo , 77.5 + /- 7.1 , and 77.0 + /- 7.8 for the budesonide Turbuhaler 200 microg and 400 microg groups , respectively . Significantly ( P < or = 0.024 ) more placebo patients ( 24 % ) discontinued treatment because of disease deterioration or no improvement than budesonide Turbuhaler 200 microg ( 11 % ) or 400 microg patients ( 10 % ) . Patients receiving budesonide Turbuhaler experienced significant improvements in FEV1 compared with patients receiving placebo ( P < or = 0.015 ) . Significant ( P < or = 0.041 ) improvements over placebo also were observed in AM and PM PEFRs , FVC , FEF25%-75 % , nighttime and daytime asthma symptoms , and amount of beta2-agonist used in both budesonide Turbuhaler groups . Adverse events were generally mild or moderate in intensity and similar among treatment groups . CONCLUSIONS Once-daily budesonide Turbuhaler is effective and safe in children with persistent asthma previously maintained on at least twice-daily dosing regimens of inhaled corticosteroids BACKGROUND An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children . The role of long-acting beta2-adrenergic-receptor agonists , such as salmeterol , needs to be defined . METHODS We conducted a r and omized , double-blind , placebo-controlled , parallel-group , one-year study of 241 children ( mean [ + /-SD ] age , 9.3+/-2.4 years ) with clinical ly stable asthma and less than one month of prior glucocorticoid use . We compared inhaled beclomethasone dipropionate ( 200 microg twice daily ) with salmeterol xinafoate ( 50 microg twice daily ) and placebo ( lactose ) . The primary outcome measure , airway responsiveness ( as assessed with a methacholine challenge ) was evaluated before treatment ; after 3 , 6 , 9 , and 12 months of treatment ( 12 and 36 hours after study medications had been withheld ) ; and 2 weeks after the end of treatment . Spirometry , symptoms , use of rescue medication ( 200 microg of albuterol inhaled as needed ) , and adverse effects were also assessed . RESULTS During months 1 through 12 overall , beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol ( P= 0.003 ) or placebo ( P<0.001 ) . This effect was lost two weeks after treatment had been stopped . As compared with placebo , beclomethasone was associated with less variability between morning and evening in the peak expiratory flow ( P=0.002 ) , as was salmeterol ( P=0.02 ) . Beclomethasone was also associated with a reduced need for albuterol as rescue therapy ( P<0.001 ) and fewer withdrawals because of asthma exacerbations ( P=0.03 ) , but salmeterol was not ( P=0.09 and 0.55 , respectively ) . During months 1 through 12 , linear growth was 3.96 cm in the children receiving beclomethasone , as compared with 5.40 cm in the salmeterol group ( P=0.004 ) and 5.04 cm in the placebo group ( P=0.018 ) . Height was not measured after treatment ended . CONCLUSIONS Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma , but it was associated with decreased linear growth . Salmeterol was not as effective as beclomethasone in reducing airway hyperresponsiveness or in controlling symptoms ; however , it was an effective bronchodilator and was not associated with rebound airway hyperresponsiveness , masking of symptoms , or adverse effects OBJECTIVE --To determine whether inhaled salmeterol , a new long acting inhaled beta adrenergic agonist , reduces nocturnal bronchoconstriction and improves sleep quality in patients with nocturnal asthma . DESIGN --R and omised , double blind , placebo controlled crossover study . SETTING --Hospital outpatient clinics in Edinburgh . SUBJECTS -- Twenty clinical ly stable patients ( 13 women , seven men ) with nocturnal asthma , median age 39 ( range 18 - 60 ) years . INTERVENTIONS --Salmeterol 50 micrograms and 100 micrograms and placebo taken each morning and evening by metered dose inhaler . Rescue salbutamol inhalers were provided throughout the run in and study periods . MAIN OUTCOME MEASURES --Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography . RESULTS --Salmeterol improved the lowest overnight peak flow rate at both 50 micrograms ( difference in median values ( 95 % confidence interval for difference in medians ) 69 ( 18 to 88 ) l/min ) and 100 micrograms ( 72 ( 23 to 61 ) l/min ) doses twice daily . While taking salmeterol 50 micrograms twice daily patients had an objective improvement in sleep quality , spending less time awake or in light sleep ( -9 ( -4 to -44 ) min ) and more time in stage 4 sleep ( 26 ( 6 - 34 ) min ) . CONCLUSIONS --Salmeterol is an effective long acting inhaled bronchodilator for patients with nocturnal asthma and at a dose of 50 micrograms twice daily improves objective sleep quality Patients with moderate persistent asthma ( n = 523 ; mean FEV1 77.4 % ) not fully controlled with inhaled corticosteroids ( ICS ; 400 - 1000 microg/day ) were r and omized to receive either once-daily budesonide/formoterol ( 160/4.5 microg , two inhalations ) ; or twice-daily budesonide/formoterol ( 160/4.5 microg , one inhalation ) ; or budesonide ( 400 microg ) once-daily for 12 weeks . Once-daily dosing was administered in the evening and twice-daily dosing was administered in the morning and evening . All patients received twice-daily budesonide ( 200 microg ) during a 2-week run-in . Compared with budesonide alone , change in mean morning and evening peak expiratory flow was greater in the once-daily budesonide/formoterol group ( 27 and 171 min(-1 ) , respectively ; P < 0.001 ) and twice-daily budesonide/formoterol group ( 23 and 24 l min(-1 ) , respectively ; P < 0.001 ) . Night awakenings , symptom-free days , reliever-use-free days and asthma-control days were all improved during once-daily budesonide/formoterol therapy vs. budesonide ( P < or = 0.05 ) . Similar improvements were also seen with twice-daily budesonide/formoterol ( P < or = 0.05 ) . The risk of a mild exacerbation was reduced after once- and twice-daily budesonide/formoterol vs. budesonide ( 38 % and 35 % , respectively ; P < 0.002 ) . All treatments were well tolerated . Budesonide/formoterol , once- or twice-daily , in a single inhaler improved asthma symptoms and exacerbations compared with budesonide . In the majority of patients with moderate persistent asthma requiring ICS and long-acting beta-agonists , once-daily formoterol/budesonide provided sustained efficacy over 24 h , similar to twice-daily dosing BACKGROUND In-vitro studies have suggested that polymorphisms of the beta 2-adrenoceptor may influence the desensitisation induced by beta 2-agonists . We investigated the influence of beta 2-AR polymorphism on the development of bronchodilator desensitisation in asthma patients . METHODS We carried out an analysis of 22 moderately severe stable asthmatics , mean age 38 years , FEV1 63 % of predicted and FEF25 - 75 38 % of predicted , who received a median inhaled corticosteroid dose of 1000 micrograms/day . Patients were r and omly assigned inhaled placebo or inhaled formoterol 24 micrograms bid for 4 weeks each in a crossover study . Bronchodilator dose-response curves were made at the end of each treatment period by use of cumulative doses of formoterol ( 6 - 108 micrograms ) with FEV1 and FEF25 - 75 measured 30 min after each dose , and up to 6 h after the last dose . We calculated the degree of bronchodilator desensitisation by comparing the dose-response ( for maximum and 6 h ) after placebo with that after formoterol , and expressed this degree as a percentage of placebo response . Patients were divided into groups according to genotype at codon 16 : homozygous Arg 16 ( n = 4 ) , heterozygous Arg 16/Gly 16 ( n = 8) , and homozygous Gly 16 ( n = 10 ) . At codon 27 : homozygous Gln 27 ( n = 5 ) , heterozygous Gln 27/Glu 27 ( n = 11 ) , and homozygous Glu 27 ( n = 6 ) . FINDINGS We found a significantly ( p < 0.05 ) greater degree of bronchodilator desensitisation with homozygous Gly 16 than with homozygous Arg 16 for maximal FEV1 response : -8 % ( Arg 16 ) vs 46 % ( Gly 16 ) ; and for maximal FEF25 - 75 response : -32 % ( Arg 16 ) vs 74 % ( Gly 16 ; 95 % CI 15 - 92 % and 49 - 164 % , respectively ) . Bronchodilator responses at 6 h were also significantly ( p < 0.05 ) different for FEV1 and FEF25 - 75 when Arg 16 and Gly 16 were compared and values for heterozygous Arg 16/Gly 16 were intermediate . There was significantly greater desensitisation with Glu 27 than with Gln 27 for maximal FEF25 - 75 response : -7 % ( Gln 27 ) vs 68 % ( Glu 27 ) , p = 0.05 ; and for 6 h FEF25 - 75 response : 43 % ( Gln 27 ) vs 93 % ( Glu 27 ) , p < 0.05 ( 95 % CI 2 - 147 % and 5 - 94 % , respectively ) . All patients who were homozygous Glu 27 were also homozygous Gly 16 . INTERPRETATION We have found preliminary evidence that beta 2-adrenoceptor polymorphism is associated with altered beta 2-adrenoceptor expression in asthma patients . The homozygous Gly-16 form was significantly more prone to bronchodilator desensitisation than Arg 16 , with the influence of Gly 16 dominating over any putative protective effects of Glu 27 CONTEXT Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid ( ICS ) therapy . OBJECTIVE To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen . DESIGN AND SETTING A 24-week r and omized , controlled , blinded , double-dummy , parallel-group trial conducted at 6 National Institutes of Health-sponsored , university-based ambulatory care centers from February 1997 through January 1999 . PARTICIPANTS One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide ( 400 microg twice per day ) . INTERVENTION Patients continued triamcinolone therapy and were r and omly assigned to receive add-on therapy with either placebo ( placebo-minus group , n = 21 ) or salmeterol xinafoate , 42 microg twice per day ( n = 154 ) for 2 weeks . The entire placebo-minus group was assigned and half of the salmeterol group ( salmeterol-minus group ) was r and omly assigned to reduce by 50 % ( for 8 weeks ) then eliminate ( for 8 weeks ) triamcinolone treatment . The other half of the salmeterol group ( salmeterol-plus group ) was r and omly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks ( active control group ) . MAIN OUTCOME MEASURE Time to asthma treatment failure in patients receiving salmeterol . RESULTS Treatment failure occurred in 8.3 % ( 95 % confidence interval [ CI ] , 2%-15 % ) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8 % ( 95 % CI , 0%-7 % ) of the salmeterol-plus group during the same period . Treatment failure occurred in 46.3 % ( 95 % CI , 34%-59 % ) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7 % ( 95 % CI , 5%-22 % ) of the salmeterol-plus group . The relative risk ( 95 % CI ) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 ( 2.0 - 9.2 ) compared with the salmeterol-plus group ( P<.001 ) . CONCLUSIONS Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol , a substantial reduction ( 50 % ) in triamcinolone dose can occur without a significant loss of asthma control . However , total elimination of triamcinolone therapy results in a significant deterioration in asthma control and , therefore , can not be recommended BACKGROUND The efficacy and safety of salmeterol powder have not previously been evaluated in children with asthma in the United States . OBJECTIVE The efficacy and safety of salmeterol powder versus placebo were compared in children between the ages of 4 and 11 years with chronic persistent asthma . METHODS A r and omized , double-blind , placebo-controlled , parallel group trial was performed at 11 clinical centers . Two hundred seven patients were r and omly assigned to receive 50 microg salmeterol powder or placebo ( and albuterol as needed ) twice daily via a breath-actuated device for 12 weeks . Twelve-hour serial pulmonary function assessment s were conducted on day 1 and at week 12 . Daily recordings of morning and evening peak expiratory flow ( PEF ) , supplemental albuterol use , asthma symptoms , and nocturnal awakenings were assessed . RESULTS On day 1 and at week 12 , weighted mean percent of predicted PEF ( P < .001 , day 1 and P=.008 , week 12 ) and weighted mean forced expiratory volume in one second ( P < .001 , day 1 and week 12 ) were significantly higher at all timepoints evaluated over the 12-hour postdosing period in patients treated with salmeterol powder compared with placebo . Overall reductions in supplemental albuterol use and mean asthma symptom scores were also significantly greater in children administered salmeterol compared with placebo ( P=.004 and P=.006 , respectively ) . The frequency of adverse events was similar in the two treatment groups . CONCLUSION Salmeterol powder ( 50 microg twice daily ) is effective and safe in producing bronchodilation and relieving symptoms in children with chronic persistent asthma during 12 weeks of treatment In a recent placebo-controlled study in mild atopic asthmatics , we observed a significant decrease in eosinophils in the bronchial submucosa , after 2 months oftreatment with inhaled formoterol and budesonide . Biopsy material from each treatment group ; formoterol ( 24 microg bid ) , budesonide ( 400 microg b. i. d. ) and placebo has been further assessed to investigatethe role of Th-2 cytokines by immunohistochemistry using Mabs to eosinophils as an index of inflammation , IL-4 and IL-5 . Treatment with formoterol significantly reduced the number of eosinophils ( EG2 + ) in the submucosa and epithelium , but this was not paralleled by changes in cytokine immunoreactivity In contrast , treatment with budesonide significantly reduced both the number of eosinophils ( EG2 + ) and immunoreactivity for IL-4 and IL-5 in the submucosa . Thus , while budesonide has effects on cytokines involved in eosinophil recruitmentthis explanation does not apply tothe eosinopaenia observed with the long-acting beta2 adrenoreceptor agonist formoterol We compared the effects of salmeterol ( Sm ) ( 50 micrograms twice daily ) with that of salbutamol ( Sb ) ( 200 micrograms four times daily ) and placebo ( P ) in patients with mild-to-moderate asthma with asthma symptoms and related the effectiveness of these therapies between patients who used concurrent inhaled corticosteroids ( ICS ) and those who did not . The study was a 12-wk , multicenter , double-blind , placebo-controlled crossover trial with 367 adult asthmatics r and omized to each trial medication for 4 wk . Inhaled Sb was provided as rescue medication to all patients throughout the trial . Only 80 % of patients , albeit the majority , were receiving maintenance treatment with ICS throughout this trial ; this reflects practice current in early 1990 . Each study day , patients recorded their morning and evening peak expiratory flows ( PEF ) , assessment of asthma symptoms , and use of rescue medication . Both morning and evening PEF were greater during treatment with Sm than with Sb ( mean differences between the treatments of 29.8 and 14.3 L/min , respectively ) or P ( 27.7 and 20.3 L/min , respectively ) ( p < 0.0001 ) . Sm was also more effective than Sb or P in lowering diurnal variation in PEF and increasing the percentage of symptom-free days and rescue-free days and nights with no sleep disturbance ( p < or = 0.0004 ) . Sb was more effective than P in increasing evening PEF and the percentage of symptom-free days ( p < 0.05 ) and rescue-free days ( p < 0.0001 ) . The same clinical superiority of Sm compared with Sb and P was observed in those patients using ICS ( p < 0.001 for all treatment comparisons ) , and to a greater extent than in those patients not using ICS ( i.e. , Sm was more effective than Sb and P in just six of the 20 treatment comparisons ; p < 0.05 ) . In conclusion , Sm 50 micrograms twice daily is effective in the management of mild-to-moderate asthma and it further improves asthma control in patients already using ICS Adding inhaled long-acting beta(2)-agonists to a low dose of inhaled corticosteroids ( ICS ) , results in better clinical asthma control than increasing the dose of ICS . However , this approach may mask underlying airway inflammation . In a double-blind parallel-group study , we evaluated the effect of adding formoterol to a low dose of budesonide , compared with a higher dose of budesonide , on the composition of induced sputum . After a 4-wk run-in period of treatment with budesonide ( 800 microg , twice daily ) , 60 patients with moderate asthma were r and omly assigned to a 1-yr treatment with 400 microg of budesonide plus placebo , twice daily ( BUD800 ) , or 100 microg of budesonide plus 12 microg of formoterol , twice daily ( BUD200+F ) . All drugs were administered via Turbuhaler . Budesonide ( 800 microg , twice daily ) during run-in significantly reduced median sputum eosinophils from 4.5 to 0.68 % . No significant changes in the proportion of eosinophils , EG2(+ ) cells , other inflammatory cells , or ECP levels in sputum were observed over the ensuing 1-yr treatment with BUD200+F or BUD800 . Clinical asthma control was not significantly different between both groups . In conclusion , no significant differences in sputum markers of airway inflammation were observed during a 1-yr treatment with a low dose of inhaled budesonide plus formoterol compared with a higher dose of budesonide BACKGROUND Beta2-adrenergic agonists are frequently used for the prevention and relief of bronchospasm in patients with reversible obstructive airway disease .  Formoterol and salmeterol are long-acting beta2-agonists . In addition to its long duration of action , formoterol has been reported to have an onset of action similar to that of albuterol . OBJECTIVE This study compared the effects on lung function of regular twice-daily inhalation of formoterol or salmeterol in adults with moderate to moderately severe persistent asthma who were receiving daily inhaled corticosteroids . METHODS In this 6-month , multicenter , open-label , parallel-group study , patients with moderate or moderately severe asthma were r and omized to receive either formoterol 12 microg BID or salmeterol 50 microg BID . The primary end point was mean morning peak expiratory flow ( PEF ) measured 5 minutes after dosing and entered in a patient diary each day during the first 4 weeks of treatment . Secondary end points included mean morning and evening predose PEF and number of episode-free days recorded in the patient diaries during the first 4 weeks of treatment , use and time of rescue medication , symptom scores , and overall mean morning predose PEF ( spirometric measurements made by the physician during scheduled visits ) for the entire treatment period . Safety assessment s included spontaneously reported adverse events and vital signs . RESULTS A total of 528 patients were r and omized to study treatment , 262 to formoterol and 266 to salmeterol .  There were no significant differences in demographic or baseline characteristics between treatment groups , except in the proportion of current smokers in the formoterol group ( 4.6 % ) compared with the salmeterol group ( 1.5 % ; P = 0.039 ) . Based on the information recorded in patients ' diaries , those receiving formoterol showed significant improvement in mean morning PEF measured 5 minutes after dosing ( P < 0.001 ) , reduced use of rescue medication ( P < 0.03 ) , and an increased number of episode-free days ( P < 0.04 ) compared with patients receiving salmeterol .  Mean predose morning and evening PEF and symptom scores based on diary data and mean morning predose PEF based on measurements obtained during office visits were comparable between the 2 treatment groups throughout the study . CONCLUSIONS In this open-label trial , patients r and omized to formoterol treatment had greater improvement in mean PEF 5 minutes after dosing , required significantly less rescue medication ( fewer actuations of albuterol ) , and experienced more episode-free days compared with patients receiving salmeterol . Thus , although both formoterol and salmeterol are long-acting beta2-agonists , formoterol had a more rapid onset of action BACKGROUND Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate ( FP ) as the cornerstone of anti-inflammatory therapy for asthma . OBJECTIVE The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP  as compared with increasing the dose of FP . METHODS In a multicenter , double-blind study conducted over 24-weeks , 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were r and omly assigned to receive either salmeterol ( 42 microg twice daily ) or FP 220 microg twice daily . The primary efficacy endpoint was morning peak expiratory flow . Secondary measures included FEV1 , symptom scores , nighttime awakenings , and supplemental albuterol use . Safety was assessed by reported adverse events and asthma exacerbations . RESULTS The addition of salmeterol result ed in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP . Over weeks 1 to 24 , morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily ( P < .001 ) while the percent of symptom-free days increased from baseline by 26 % of days as compared with 10 % of days ( P < .001 ) . The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment . CONCLUSIONS The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinical ly and statistically superior to increasing the dose of FP The aim of this study was to assess the efficacy and safety of inhaled salmeterol 100 micrograms b.d . ( SM ) versus inhaled salbutamol 400 micrograms q.d.s . ( SB ) , both via the Diskhaler , when added to concurrent treatment , in asthmatic patients who were not controlled on high doses of inhaled steroids ( > or = 1,500 micrograms beclomethasone dipropionate ( BDP ) or equivalent daily ) . This was a multicentre , parallel group , double-blind study in which 190 patients with a forced expiratory volume in one second ( FEV1 ) or peak expiratory flow rate ( PEFR ) of 30 - 75 % predicted and 15 % reversibility to inhaled bronchodilator were r and omized to treatment for 6 weeks . In the SM group , morning PEFR increased from 281 to 315 L-min-1 during treatment and in the SB group from 311 to 315 L.min-1 ( p < 0.001 ) . The SM group showed significantly better reduction in diurnal variation , from 39 to 22 L.min-1 during treatment , than the SB group ( 34 to 37 L.min-1 ) ( p < 0.001 ) . There was a significantly greater improvement in FEV1 in the SM group ( from 1.63 to 1.85 L ) than in the SB group ( from 1.79 to 1.84 L ) . The SM group had significantly more symptom-free nights than the SB group ( p < 0.001 ) , and also more " rescue-free " nights ( p = 0.04 ) . The adverse event profile was similar in both groups . This study indicates that in asthmatic patients , not controlled on high-dose inhaled steroids , inhaled salmeterol 100 micrograms b.d . significantly improves lung function and reduces asthma symptoms The aim of this study was to evaluate the efficacy ( expressed as effect on lung function ) and tolerability of Symbicort ( budesonide/formoterol in a single inhaler ) in children with asthma . This was a double-blind , double-dummy , r and omized , parallel-group , multicenter trial . After a 2 - 4-week run-in period , 286 asthmatic children ( 177 boys , 109 girls ; mean age , 11 years ; mean forced expiratory volume in 1 sec ( FEV(1 ) ) , 75 % predicted normal ) , previously treated with inhaled corticosteroids ( average dose 548 microg/day ) , were r and omized to 12 weeks ' treatment with either budesonide/formoterol 80/4.5 microg , two inhalations twice daily ( n = 148 ) , or an equivalent dose of budesonide 100 microg , two inhalations twice daily ( n = 138 ) . Efficacy variables included morning and evening peak expiratory flow ( PEF ) , spirometery , asthma symptoms , and use of rescue medication ( beta(2)-agonists ) . Serial FEV(1 ) assessment s were carried out on a subgroup of children ( budesonide/formoterol , n = 41 ; budesonide , n = 40 ) at r and omization and at week 12 . Relative to baseline , morning PEF ( primary variable ) increased to a significantly greater extent with budesonide/formoterol than with budesonide alone ( 7.22 % predicted normal vs 3.45 % predicted normal ; P < 0.001 ) . Evening PEF also increased significantly with budesonide/formoterol ( 6.13 % predicted normal vs. 2.73 % predicted normal ; P < 0.001 ) , as did mean FEV(1 ) and serial FEV(1 ) measured over 12 hr ( both P < 0.05 ) . Similar improvements in asthma symptoms and rescue medication use were observed in both groups . The two treatment groups were similar in terms of their adverse-event profile and rates of discontinuation . Budesonide/formoterol in a single inhaler provided rapid improvements in PEF and FEV(1 ) compared to inhaled budesonide alone . These improvements were sustained throughout the study period . Budesonide/formoterol was well-tolerated in children with moderate persistent asthma A higher incidence of fatal asthma after increased use of combined inhaled beta 2-agonists and theophylline has been attributed to additive cardiac toxicity of these agents . This study had three major objectives : first , to evaluate the efficacy and safety of a new long-acting beta 2-agonist , bitolterol mesylate , given as metered-dose aerosol in a regular " round-the-clock " asthma medication regimen ; second , to compare the efficacy and safety of bitolterol with those of sustained-release theophylline alone and of the combination of bitolterol and theophylline ; third , to use 24 hr Holter monitoring to evaluate cardiac toxicity of the three medication regimens . This was a 6 wk double-blind study of regular , daily medication in 36 young non-steroid-dependent and 37 older steroid-dependent stable asthmatic patients . All patients had two 24 hr Holter ECG monitorings  during the 2 wk baseline period when all patients received theophylline only and four further 24 hr Holter monitorings during the double-blind period . All Holter recordings from the study groups showed no significant abnormalities in any treatment group . Pulmonary function studies were performed on 4 study days in the 6 wk double-blind period . The largest increase in bronchodilator effect was obtained with combined medication and the smallest with theophylline alone . Mean duration of action was markedly longer in the combined treatment group ( greater than 7 hr ) than with bitolterol mesylate aerosol or theophylline alone ( greater than 5 and greater than 4 hr , respectively ) in the non-steroid-dependent patients .  Degree of bronchodilation and duration of action was less in the steroid-dependent patients in all treatment groups . There is no evidence from cardiac monitoring that therapeutic doses of bitolterol mesylate or theophylline alone or in combination have cardiotoxic effects We compared the effect of inhaled budesonide with placebo on decline in lung function and respiratory symptoms in a three-year study of patients with chronic obstructive pulmonary disease ( COPD ) . We used a parallel-group , r and omized , double-blind , placebo-controlled design , nested in an ongoing epidemiological survey . Patients were non-asthmatic subjects with a decreased ratio between forced expiratory volume in one second ( FEV1 ) and vital capacity ( VC ) ; i.e. , FEV1/VC < or = 0.7 . All included patients had an FEV1 which was irreversible to both inhaled terbutaline and prednisolone .  Two hundred and ninety patients were r and omized to receive either budesonide , 1200 mcg . daily for six months followed by 800 mcg . daily for 30 months , or placebo for 36 months . Patients had a mean age of 59 years and their mean FEV1 was 2.37 liters or 86 % of predicted .  Crude FEV1 declines were 41.8 ml/year in the placebo group and 45.1 ml/year in the budesonide group . Using a regression model in the intention-to-treat population , patients in the placebo group had an FEV1 decline of 49.1 ml/year in contrast to 46.0 ml/year in the budesonide group ; the estimated difference 3.1 ml/year ( 95 % confidence interval--12.8 - 19.0 ) was statistically insignificant , p = 0.70 . No effect of inhaled budesonide was seen on respiratory symptoms or number of exacerbations . These findings question the role of longterm inhaled corticosteroids in the treatment of mild-moderate COPD Background Levels of an immunoregulatory and anti‐inflammatory cytokine IL‐10 are reduced in asthmatic airways , potentially contributing to more intense inflammation . Triamcinolone has anti‐inflammatory properties and the anti‐inflammatory effects of montelukast and formoterol have been discussed The objective of this study was to compare the two most frequently used asthma-specific quality of life ( QOL ) question naires and two generic QOL question naires with clinical data in order to establish their ability to discriminate in asthma severity , also referred to as cross-sectional construct validity . We conducted a multicentre , r and omized , placebo-controlled study investigating the long-term effects of the long-acting ß2-agonist formoterol in asthma patients using inhaled corticosteroids and short-acting ß2-agonists .  Before r and omization , the peak expiratory flow ( PEF ) and use of ß2-agonists for relief of symptoms were recorded twice daily for 1 month . At the end of the run-in period , the forced expiratory volume in 1s ( FEV1 ) , airway hyper-responsiveness ( PC20 methacholine ) and QOL were measured , using two asthma-specific question naires , the Asthma Quality of Life Question naire ( AQLQ ) and the Living with Asthma Quality of Life Question naire ( LWAQ ) , as well as two generic question naires , the Short Form 36 ( SF-36 ) and the Psychological General Well Being ( PGWB ) index . The quality of life of the patients ( n=110 ) was only mildly impaired . The mean symptom score was 3.6 on a scale of 0 - 21 and the mean FEV1 was 65 % of that predicted . The correlations between the QOL parameters and objective measures of asthma severity , such as the FEV1 , PEF and PC20 , were low ( 0.01 - 0.37 ) . The correlations between the QOL parameters and subjective measures of asthma severity , such as symptom scores ( range 0.26 - 0.65 ) and ß2-agonist use for the relief of symptoms ( 0.09 - 0.39 ) , were higher . The correlations of the activity and symptoms domains of the AQLQ with diary-obtained symptom scores were r=0.50 ( p[lessthan]0.0001 ) and r=0.65 ( p[lessthan]0.0001 ) , respectively . The correlation between the physical construct of the LWAQ and symptom scores was r=0.42 ( p[lessthan]0.001 ) and that between the physical sumscore of the SF-36 and symptom scores was r=0.50 ( p[lessthan]0.001 ) . The correlation between the PGWB and symptom scores was r=0.41 ( p[lessthan]0.001 ) . The relation between the FEV1 , PEF and PC20 and QOL was very low . The QOL measurements related well to the symptom scores . The AQLQ had a better cross-sectional construct validity than the LWAQ . The cross-sectional construct validity of the SF-36 was surprisingly high for this group of patients and the SF-36 performed better than the PGWB and LWAQ BACKGROUND -- Clinical studies of inhaled salmeterol xinafoate have been conducted mainly in moderately to severely affected asthmatic subjects in hospital setting s. This study was conducted to investigate the effectiveness of this drug in patients with milder asthma in primary care . METHODS --A multicentre , double blind , r and omised , parallel group comparison of salmeterol xinafoate in a dose of 50 micrograms twice daily with placebo , both administered from a four-place dry powder inhaler ( Diskhaler ) , was performed over six weeks in United Kingdom general practice s. RESULTS --A total of 427 asthmatic patients aged 18 years or older were r and omised to receive salmeterol or placebo in a 2:1 ratio . Of the total r and omised population , 247 patients were previously on short acting bronchodilators alone whilst 180 patients were concurrently receiving up to 400 micrograms inhaled corticosteroid .  Mean morning peak expiratory flow rose more in the salmeterol group than in the placebo group ( treatment difference 17 l/min , 95 % confidence interval 9 to 26 l/min ) but there was a smaller , non-significant difference in mean evening peak expiratory flow . Improvements occurred in the salmeterol-treated group compared with placebo for wheeze , shortness of breath , undisturbed nights , and relief medication use , irrespective of concomitant inhaled corticosteroid use . In addition , improvement in activity restriction was seen in the salmeterol group compared with placebo in the subgroup receiving only bronchodilator . CONCLUSIONS --Salmeterol is effective and well tolerated in the short term in mildly asthmatic adult patients irrespective of concomitant use of inhaled corticosteroid therapy We conducted an economic evaluation in a UK setting based on a 12-week prospect i ve r and omized open-label parallel-group comparison of eformoterol Turbohaler 12 microg b. i.d . with salmeterol Accuhaler 50 microg b. i.d . in children aged 6 - 17 with symptomatic asthma receiving inhaled corticosteroids and short-acting beta2-agonists .  The principal effectiveness measure was percentage of symptom-free days with no short-acting beta2-agonist use during the study period . Asthma-related medication , unscheduled physician contacts and hospitalizations were collected prospect ively and cost to the UK NHS calculated using year 2,000 prices . The economic evaluation included 73 patients in the eformoterol group and 72 patients in the salmeterol group . The mean age of patients was 11.6 years ( eformoterol ) and 11.8 years ( salmeterol ) . The mean percentage of symptom-free days with no short-acting beta2-agonist use was 39 % in the eformoterol group and 30 % in the salmeterol group . Mean per patient daily cost was 1.15 pounds in the eformoterol group and 1.39 pounds in the salmeterol group . Both cost and effectiveness differences favoured eformoterol ( P < 0.05 ; one-sided ) . Sensitivity analysis confirmed the results to be robust to changes in effectiveness , price and re source utilisation parameters . Eformoterol delivered by Turbohaler was found to be significantly more effective and less expensive than salmeterol Accuhaler in this study OBJECTIVE To assess the addition of a leukotriene receptor antagonist and a long-acting beta(2)-agonist as second-line therapy in asthma . DESIGN Placebo-controlled , double-dummy , crossover study . SETTING Outpatient clinic . PATIENTS Twenty patients with persistent asthma not controlled with inhaled corticosteroid therapy . INTERVENTIONS Montelukast 10 mg once daily , or salmeterol , 50 microg bid , each for 2 weeks with 1-week run-in and washout placebo periods . MEASUREMENTS AND RESULTS Adenosine monophosphate ( AMP ) bronchial challenge , blood eosinophil count ( EOS ) , exhaled nitric oxide , and lung function after both placebo periods and after the first and last doses of each active treatment . Patients recorded their domiciliary peak expiratory flow ( PEF ) , asthma symptoms , and rescue bronchodilator requirement ( RES ) twice daily throughout the study . For the primary end point of the provocative concentration of AMP causing a 20 % fall in FEV(1 ) , compared to placebo ( 47.5 + /- 13.0 mg/mL ) , there were significant differences with the first ( 114.1 + /- 36.9 mg/mL ) and last ( 94.2 + /- 30.4 mg/mL ) doses of montelukast as well as the first ( 160.1 + /- 64.5 mg/mL ) but not the last ( 70.1 + /- 23.7 mg/mL ) dose of salmeterol . Only montelukast produced significant suppression of the EOS . Neither drug affected exhaled nitric oxide levels . There were significant improvements with the first doses of salmeterol for all parameters of lung function . After 2 weeks of treatment , there were significant improvements with both drugs for RES and morning PEF . There were no significant differences between drugs for any end points except EOS . CONCLUSIONS Montelukast and salmeterol exhibited significant improvements in asthma control when given as second-line therapy . Montelukast also produced significant effects on AMP challenge and EOS suggesting anti-inflammatory activity There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli . Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists . In a double-blind placebo-controlled crossover study in 12 patients with mild asthma , we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol ( 200 micrograms ) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol .  Patients were r and omized to be treated for 3 wk with inhaled budesonide ( 800 micrograms twice a day ) or placebo ; salmeterol ( 50 micrograms twice a day ) was added during the third week . Airway responsiveness to methacholine was measured 15 min after albuterol , both before and exactly 12 h [ corrected ] after the last salmeterol dose . Mean FEV1 increased significantly after 2 wk of budesonide ( p < 0.05 ) and increased further after salmeterol ( p < 0.05 ) compared with placebo . After 2 wk , the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo ( 3.4 versus 2.4 doubling dilutions ; p < 0.05 ) , consistent with an improvement in airway hyperresponsiveness with budesonide therapy . However , regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge , both with budesonide and with placebo ( -1.1 + /- 0.42 and -1.41 + /- 0.30 doubling dilutions , respectively ) . There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods . Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy The present study compared the safety of 4.5 µg formoterol with 0.5 mg terbutaline , both by Turbuhaler ® and used as needed , in addition to regular formoterol in moderate asthma . In this double-blind parallel-group study , 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline ( 2–5 inhalations·day−1 during run-in ) were r and omised to either formoterol or terbutaline as needed in addition to formoterol 9 µg b.i.d . over 12 weeks . Adverse events , serum potassium levels , electrocardiogram , vital signs and lung function were assessed monthly ; peak expiratory flow and severe asthma exacerbations were recorded daily . Patients used 2.16 ( range 0.0–6.3 ) formoterol and 2.34 ( range 0.1–7.5 ) terbutaline relief inhalations·day−1 . No clinical ly significant differences in safety variables were found between treatments . Statistically greater increases in cardiac frequency ( 2.6 beats·min−1 , p=0.03 ) were found on terbutaline . There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline , respectively , with no significant difference in time to first exacerbation . There was also no difference between treatments for other efficacy measures ( peak expiratory flow , forced expiratory volume in one second and morning/evening symptom scores ) . Formoterol 4.5 µg as needed was at least as safe , well tolerated and effective as terbutaline 0.5 mg in stable patients ( requiring up to 6 relief inhalations·day−1 ) taking formoterol plus inhaled corticosteroids regularly over 12 weeks The objective of this study was to determine whether initial maintenance therapy for the treatment of inflammation and bronchoconstriction associated with persistent asthma is more effective with a combination product ( 100 microg of fluticasone propionate and 50 microg of salmeterol [ FSC ] ) administered twice daily through the Diskus device ( GlaxoWellcome , Research Triangle Park , NC ) or with montelukast at 10 mg once daily . A 12-wk , r and omized , double-blind , double-dummy , multicenter study was conducted with 423 patients 15 yr of age and older with asthma and who were symptomatic while receiving short-acting beta(2)-agonists alone . At end point , FSC result ed in significantly greater increases in morning predose FEV(1 ) ( 0.54 + /- 0.03 vs. 0.27 + /- 0.03 L ) , morning peak expiratory flow ( PEF ) ( 89.9 + /- 6.7 vs. 34.2 + /- 4.7 L/min ) , evening PEF ( 69.9 + /- 5.8 vs. 31.1 + /- 4.5 L/min ) , the percentage of symptom-free days ( 48.9 + /- 2.9 vs. 21.7 + /- 2.5 % ) , the percentage of rescue-free days ( 53.0 + /- 2.8 vs. 26.2 + /- 2.5 % ) , and the percentage of nights with no awakenings ( 23.0 + /- 2.5 vs. 15.5+/-2.4 % ) compared with montelukast ( p < or = 0.001 , all comparisons ) . FSC significantly reduced asthma symptom scores ( -1.0 + /- 0.1 vs. -0.6 + /- 0.1 ) , rescue albuterol use ( -3.3 + /- 0.2 vs. -1.9 + /- 0.2 puffs/d ) , and the number of exacerbations ( 0 vs. 11 ) compared with montelukast ( p < 0.001 ) . Both treatments were well tolerated . In summary , treatment of the two main components of asthma ( inflammation and bronchoconstriction ) with fluticasone propionate and salmeterol in a combination product was a more effective initial maintenance treatment strategy than treatment with montelukast , a single-mediator antagonist Inhaled corticosteroids have been shown to effectively reduce large circadian fluctuations in peak expiratory flow ( PEF ) .  Salmeterol xinafoate ( SLM ) , a new long-acting beta2-agonist being used in the treatment of nocturnal airway obstruction , has proved to be very effective in this respect as well . However , it is yet unknown whether using SLM alone or in combination with fluticasone propionate ( FP ) constitutes the best treatment . We studied , in a r and omized , double-blind , parallel manner , 46 asthmatics with increased circadian variation in PEF ( > or = 15 % ) for 6 wk to compare FP 250 microg , SLM 50 microg , and a combination of them , all given twice a day . These three treatment protocol s were equally effective in improving the generally used clinical outcome parameters , i.e. , the circadian variation in PEF and FEV1 and bronchial hyperresponsiveness ( BHR ) to methacholine ( MCh ) during the day and at night . FEV1 increased more at 4:00 A.M. than at 4:00 P.M. ( FEV1 at both time points > 90 % predicted ) . BHR to MCh improved with at least 1.5 doubling concentrations , thereby reducing the significant nocturnal decline in the SLM and FP group , but not in combination . The improvement in BHR to adenosine 5'monophosphate was greater ( p = 0.05 ) when FP was combined with SLM but not when FP or SLM were used alone . Our data support the clinical view that FP , with its anti-inflammatory capacity , has greater beneficial effects as monotherapy than does SLM . However , this was detectable only by using the " indirect " stimulus adenosine 5'monophosphate , which is more specific in assessing changes in different components of airway wall inflammation than is MCh AIMS To determine effects on short term growth and collagen turnover of adding formoterol ( Eformoterol ) to half the glucocorticoid dose in children with asthma , treated with inhaled budesonide ( Pulmicort Turbuhaler ) . DESIGN A r and omised double blind , placebo controlled crossover study with two six-week periods . SETTING Outpatient clinic in secondary referral centre . SUBJECTS A total of 27 prepubertal children aged 6–13 years . INTERVENTIONS Formoterol 12 μg and dry powder budesonide 100 μg twice daily in one period ; placebo and dry powder budesonide 200 μg twice daily in the other . OUTCOME MEASURES Primary outcome measures were lower leg growth rate , and serum and urine markers of type I and type III collagen turnover . Secondary outcome measures were inflammation markers in serum , and parameters of asthma control . RESULTS During budesonide 200 μg twice daily treatment , mean lower leg growth rate was 0.14 mm/week ( p = 0.02 ) lower than during the formoterol and budesonide period . Similar statistically significant effects on markers of collagen turnover were found , whereas inflammation markers and asthma control did not vary statistically significantly between the two periods . CONCLUSIONS In children treated with inhaled glucocorticoids  , halving the dose and adding formoterol is associated with faster short term growth and an increase in markers of collagen turnover , with no loss of asthma control Current metered dose inhalers ( MDIs ) contain chlorofluorocarbon ( CFC ) propellants . A new propellant HFA134a , with no effect on ozone , may be a suitable alternative . Four asthma medications , salbutamol , salmeterol , fluticasone propionate ( FP ) and beclomethasone dipropionate ( BDP ) , currently containing st and ard CFC propellants , were formulated with HFA134a for investigation . Single doses of salbutamol ( 200 micrograms ) and salmeterol ( 50 micrograms , 100 micrograms ) provided equivalent protection against bronchial provocation , after histamine and methacholine respectively , compared with the current preparation . A double-blind 4 week study comparing the two formulations of salbutamol , used as required in mild to moderate asthma , showed similar effects on morning peak expiratory flow rates ( PEFR ) and inhaler use .  Salmeterol ( 50 micrograms ) twice daily was compared with the current formulation in a 4 week trial . Improvement in morning PEFR was similar for both formulations . A double-blind study compared the two formulations of FP ( 250 micrograms ) twice daily in moderate asthmatics previously taking 400 - 1,000 micrograms of inhaled corticosteroid daily . Morning PEFR improved in both groups . Safety and tolerability of the HFA134a product were similar to current formulations . The HFA134a formulations of salbutamol , salmeterol and FP provide equivalent efficacy with a similar safety profile to the existing formulations at equivalent doses BACKGROUND The objective of this multicentre , r and omised , double blind , parallel group study was to compare the efficacy and safety of the addition of salmeterol with that of doubling the dose of fluticasone propionate in asthmatic patients not controlled by a low or intermediate dose of inhaled corticosteroids . METHODS After a four week run in period of treatment with fluticasone propionate ( 100 μg twice daily if pre-trial dose was 400–600 μg inhaled corticosteroids or 250 μg twice daily if pre-trial dose was 800–1200 μg inhaled corticosteroids ) , 274 patients were r and omised to treatment for 12 weeks with either salmeterol 50 μg twice daily plus the run in dose of fluticasone propionate or twice the run in dose of fluticasone propionate ( 200 or 500 μg twice daily ) . Outcome measures were daily records of peak expiratory flow ( PEF ) , symptom scores , and clinic lung function . RESULTS The improvements in both the morning and evening PEF were better in the salmeterol than in the fluticasone propionate group , the mean increase in morning PEF being 19 l/min higher ( 95 % CI 11.0 to 26.1 ) and in evening PEF being 16 l/min ( 95 % CI 18.4 to 24.0 ) higher in the salmeterol group . The increase in forced expiratory volume in one second ( FEV1 ) was 0.09 l greater in the salmeterol group than in the fluticasone propionate group after four weeks of treatment ( 95 % CI 0.01 to 0.18 ) , but not after 12 weeks . Both regimens showed an increase in symptom free days and a reduction in the need for rescue salbutamol both during the day and the night , but these improvements were greater in the salmeterol group . There were no significant differences between the groups in adverse effects or in the number of rescue courses of oral corticosteroids . CONCLUSIONS In this group of patients still symptomatic despite 100 or 250 μg fluticasone propionate twice daily , the addition of salmeterol caused a greater improvement in lung function and symptom control than doubling the dose of fluticasone propionate This study compared the efficacy of inhaled salmeterol ( SM ) 50 μmg twice a day with SM 100 μmg once a day ( at night ) and placebo in patients with poorly controlled nocturnal asthma despite treatment with corticosteroids , oral long‐acting bronchodilators , or both . This was a two‐center , double‐blind , r and omized , crossover study with three treatment periods , each of 3 weeks ’ duration . The first treatment period was preceded by two 1‐week run‐in periods , and the last treatment period was followed by a 2‐week follow‐up period . In the three treatment periods , patients received either SM 50 μmg twice a day , SM 100 μmg nightly , or placebo , in r and omized order . Salbutamol metered‐dose inhaler was given as relief medication . Of the 41 r and omized patients , 38 were evaluable for more than one treatment period . Efficacy and safety were determined by daily record card data : morning and evening peak expiratory flow rates ( PEFR ) , daytime and nighttime asthma symptom scores , and rescue salbutamol use . At clinic visits , FEV1 and FVC were measured , and the physicians ’ and the patients ’ respective assessment s of the study mediation were noted . The study showed that the two doses , SM 50 μmg twice a day and SM 100 μmg nightly , were equally effective in controlling nocturnal asthma symptoms and were significantly better than placebo . SM was well tolerated , and no unexpected problems were revealed . The adverse events reported during this study were related either to the patient 's underlying disease or to an intercurrent respiratory infection The present study was set up to investigate whether salmeterol in children with asthma already treated with inhaled corticosteroids ( ICS )  leads to a sustained bronchodilator effect and decreased bronchial responsiveness , both during the day and night . Furthermore , we investigated whether cessation of salmeterol leads to a rebound increase in bronchial responsiveness .  Forty children with asthma ( aged 7 - 15 yrs ) using ICS participated in a r and omized , double-blind , parallel study . They received either twice daily 50 micrograms salmeterol or placebo .  FEV1 and provocative concentration of methacholine that caused a 20 % fall in FEV1 ( PC20 ) were measured at 4:00 P.M. and 4:00 A.M. at baseline and after 16 wk . The same measurements were performed at 4:00 P.M. at 8 h after the first dose , and after 1 and 8 wk . After cessation of the study drug , FEV1 and PC20 were measured at 12 and 20 h and after 1 wk . Overall mean FEV1 from 1 to 16 wk of treatment was significantly higher in the salmeterol group than in the placebo group ( difference , 4.9 + /- 2.0 % , p = 0.01 ) . Evolution in time of FEV1 did not differ significantly between the two groups ( p = 0.09 ) . Overall mean PC20 from 1 to 16 wk of treatment was not significantly higher with salmeterol than with placebo ( difference , 0.7 + /- 0.4 doubling dose [ DD ] p = 0.07 ) ; evolution in time of PC20 did not differ significantly between the two groups ( p = 0.58 ) . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVE We sought to compare the efficacy and safety of nebulized magnesium sulfate ( MgSO(4 ) ) plus albuterol with that of albuterol alone in adult patients with mild-to-moderate acute asthma exacerbations . METHODS Patients were r and omized to receive nebulized MgSO(4 ) ( 384 mg in 6 mL of sterile water ) or an equal volume of placebo ( normal saline solution ) in a double-blind fashion after each dose of nebulized albuterol administered ( 2.5 mg/3 mL ) every 20 minutes for the first hour of the study . Spirometry was performed at baseline and every 20 minutes for 2 hours . Monitoring for safety included vital signs , pulse oximetry , and serum magnesium levels . Improvement in percent predicted forced expiratory volume in 1 second was chosen as a primary efficacy end point . RESULTS Among 74 patients enrolled , 37 were r and omized to each of 2 study groups . There were no statistically or clinical ly significant differences between the 2 study groups in percent predicted forced expiratory volume in 1 second at any point during the trial or overall . There were no significant differences in vital signs , pulse oximetry , or serum magnesium levels at any point during the study . CONCLUSION The combination of nebulized MgSO(4 ) and albuterol provides no benefit in addition to that provided by therapy with albuterol in adult patients with mild-to-moderate asthma exacerbations . The efficacy of nebulized MgSO(4 ) in patients with severe asthma exacerbations remains unknown Three hundred and fifty-three asthmatic patients who remained symptomatic despite treatment with budesonide 800 - 1200 microg day(-1 ) ( or equivalent ) were r and omized to a new combination therapy comprising salmeterol 50 microg and fluticasone propionate 250 microg ( Seretide , Advair , Viani 50/250 microg ) twice daily or budesonide 800 microg twice daily for 24 weeks . Patients kept daily records of their morning and evening peak expiratory flow ( PEF ) , daytime and night-time symptom scores and daytime and night-time use of rescue salbutamol . Mean morning PEF increased by 451 min(-1 ) ( baseline 361 l min(-1 ) ) in the salmeterol/fluticasone propionate combination ( SFC ) group and by 19 l min(-1 ) ( baseline 358 l min(-1 ) ) in the budesonide group over the 24 weeks . The adjusted mean morning PEF over weeks 1 to 24 was significantly greater in the SFC group , despite the > three-fold lower corticosteroid dose ( 406 vs. 380 l min(-1 ) ; P < 0.001 ) . A significantly greater improvement in evening PEF was also seen in the SFC group ( adjusted mean 416 vs. 398 l min(-1 ) ; P<0.001 ) . SFC also provided significantly better control of daytime symptoms and a significantly greater reduction in the requirement for rescue salbutamol compared with budesonide . These results demonstrate that SFC 50/250 microg twice daily is superior to budesonide 800 microg twice daily in the management of patients with moderate to severe asthma who are symptomatic on their existing dose of corticosteroid BACKGROUND It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the relaxant effect of albuterol in carbachol-contracted human bronchi . OBJECTIVES The primary aim of this study was to evaluate whether there is a potential in vivo interaction between long- and short-acting beta2-agonists in the presence of increased airway tone induced by methacholine . In addition , a post hoc analysis was made to evaluate the effects of beta2-adrenoceptor polymorphisms . METHODS Sixteen asthmatic subjects ( mean age [ + /-SD ] , 39 [ 13 ] years ; FEV1 , 81 % [ 17 % ] of predicted value ) , all taking inhaled corticosteroids and having methacholine PD20 values of less than 500 micrograms , were r and omized in double-blind , double-dummy , cross-over fashion to receive single doses of inhaled placebo , inhaled formoterol 12 micrograms , or inhaled salmeterol 50 micrograms followed 12 hours later by a single dose of inhaled albuterol 400 micrograms ( low dose ) or 1600 micrograms ( high dose ) . Methacholine challenges were performed on each of 6 separate occasions 1 hour after albuterol . RESULTS There was a greater numerical difference in geometric mean PD20 values between low- and high-dose albuterol after placebo dosing ( 671 micrograms vs 1080 micrograms , a 1.61-fold difference ; P < .05 ) compared with low- and high-dose albuterol after formoterol dosing ( 660 micrograms vs 799 micrograms , a 1 . 21-fold difference ; P = .4 ) , or after salmeterol dosing ( 568 micrograms vs 847 micrograms , a 1.49-fold difference ; P = .055 ) . PD20 values with high-dose albuterol in combination with formoterol or salmeterol were numerically lower than those found with high-dose albuterol in combination with placebo , but they were not significantly different . There was a significant difference between PD20 values with low-dose albuterol after dosing with formoterol ( PD20 = 660 micrograms , a 1 . 6-fold difference ; P < .05 ) or with salmeterol ( PD20 = 568 micrograms , a 1.9-fold difference ; P < .05 ) compared with PD20 with high-dose albuterol after placebo dosing ( PD20 = 1080 micrograms ) . Post hoc polymorphism analysis for pooled pretreatment with formoterol and salmeterol ( excluding placebo pretreatment ) showed significantly ( P < .05 ) lower PD20 values with homozygous glycine-16 compared with heterozygous glycine/arginine-16 and significantly ( P < .05 ) lower PD20 values with homozygous glutamate-27 compared with either heterozygous glutamate/glutamine-27 or homozygous glutamine-27 . CONCLUSION Compared with placebo , both salmeterol and formoterol caused a significant degree of antagonism of albuterol-induced bronchorelaxation in methacholine-contracted bronchi in vivo . This interaction could be caused by prolonged occupancy of airway beta2-adrenoceptors by long-acting beta2-agonists or by early tachyphylaxis 12 hours after a single-dose exposure . The degree of albuterol protection was also related to beta2-adrenoceptor polymorphism Lung mucociliary clearance is impaired in stable asthma . The long-acting beta2-agonist salmeterol has been shown in vitro to cause a significant increase in ciliary beat frequency . It seemed possible therefore that salmeterol may also have a favourable effect on lung mucociliary transport in asthmatic patients . Fourteen patients with asthma participated in a double-blind , placebo-controlled , crossover study to assess the effect of 2 weeks of treatment with salmeterol MDI ( 50 microg b.d . ) on lung mucociliary clearance .  The 11 patients who completed the study ( seven males , four females ) had a mean + /- SE age of 50 + /- 4 years , % predicted FEV1 of 74 + /- 8 % and a tobacco consumption history of 13 + /- 7 pack-years ( seven non-smokers , four exsmokers ) .  Lung mucociliary transport was measured by a radioaerosol technique . Pulmonary function indices ( FEV1 , FVC , and PEF ) were significantly improved on salmeterol relative to placebo . The main radioaerosol finding was a significant increase in the penetration of radioaerosol into the lung with 24-h radioaerosol rising from 40 + /- 5 % on placebo to 49 + /- 4 % ( P < 0.01 ) on salmeterol . Despite this increased penetration , a slight favourable change occurred in tracheobronchial aerosol clearance . This study demonstrates that 2 weeks salmeterol treatment influences deposition of particles within the lung by increasing airway patency and indicates a beneficial effect of MDI salmeterol on lung mucociliary clearance Eosinophils play an important role in the pathogenesis of asthma . Several pro-inflammatory responses of eosinophils are primed in vivo in this disease . The aim of the present study was to investigate whether regular antiasthma treatment could modulate priming-sensitive cytotoxic mechanisms of human eosinophils . In a r and omized , two-centre , double-blind parallel group study , the effect of 8 weeks of treatment with salmeterol xinafoate 50 microg b.i.d . , beclomethasone dipropionate 400 microg b.i.d . or both on pulmonary function and the activation of priming-sensitive cytotoxic mechanisms of eosinophils , i.e. degranulation of eosinophil cationic protein ( ECP ) in serum , and activation of isolated eosinophils in the context of induction of the respiratory burst and release of platelet-activating factor ( PAF ) were tested . These effects were evaluated in 40 allergic asthmatics before and 24 h after allergen inhalation challenge . Whereas baseline forced expiratory volume in one second ( FEV1 ) improved in all treatment groups , only treatment with a combination of salmeterol and beclomethasone significantly inhibited the allergen-induced increase in serum ECP , and ( primed/unprimed ) PAF-release , suggesting inhibition of eosinophil priming after allergen challenge . In contrast to the combination therapy , monotherapy with beclomethasone had no influence on allergen-induced PAF-release , suggesting an additional anti-inflammatory effect of salmeterol during combination therapy . Monotherapy with beclomethasone inhibited the prechallenge serum-treated zymosan ( STZ ) ( 0.1 mg mL(-1))-induced respiratory burst and the allergen-induced increase in serum ECP levels , reflecting pre- and postchallenge anti-inflammatory effects . During monotherapy with salmeterol , an allergen-induced increase in serum ECP concentration and STZ ( 0.1 mg x mL(-1))-induced respiratory burst was observed , suggesting that treatment with salmeterol alone had no effect on priming-sensitive eosinophil cytotoxic mechanisms . In conclusion , this study shows that st and ard asthma therapy leads to inhibition of eosinophil priming of cytotoxic mechanisms in vivo The purpose of this study was to compare effect of treatment with an oral long-acting beta 2-agonist ( sustained-release terbutaline , Bricanyl depot ) , an inhaled steroid ( budesonide , Pulmicort ) , and the combined treatment in patients with nocturnal asthma . Thirty-seven patients completed the study . During a 1-week run-in period with inhaled terbutaline monotherapy , the mean nocturnal asthma score was 1.0 ( + /- 0.1 ) ( corresponding to one awakening every night ) , and the mean overnight fall in peak expiratory flow rate was 27.7 % ( + /- 2.0 ) . The patients were r and omly entered into double-blind , crossover periods of 3 weeks each : ( 1 ) sustained-release terbutaline , 10 mg twice daily ( b.i.d . ) , ( 2 ) sustained-release terbutaline , 10 mg b.i.d . , and two puffs ( 400 micrograms ) of budesonide , b.i.d . , and ( 3 ) two puffs ( 400 micrograms ) of budesonide , b.i.d . The combined treatment result ed in significantly lower overnight fall in peak expiratory flow rate ( 6.9 % + /- 1.4 compared to 9.4 % + /- 2.0 during sustained-release terbutaline and 10.4 % + /- 1.9 during budesonide ) and less nocturnal awakenings ( nocturnal asthma score 0.15 + /- 0.05 , 0.43 + /- 0.09 , and 0.26 + /- 0.06 , respectively ) than either single treatment alone ( p less than 0.05 ) . The differences between the single treatments were not significant . We thus found that an inhaled steroid is as effective as a long-acting oral beta 2-agonist in controlling nocturnal asthma and that the combination is better . The observed differences were , however , small , and other studies would be required to evaluate the clinical significance of the present finding Background The efficacy and safety of Symbicort ® 1 ( budesonide and formoterol in a single inhaler ) were compared with those of a high dose of the commonly used corticosteroid fluticasone propionate in patients with moderate persistent asthma . Methods This r and omized , double-blind , double-dummy , parallel-group study involved 373 patients with asthma ( mean age 42 years ; FEV1 78 % of predicted ; reversibility 21 % ) . After a 2-week run-in period , during which patients received budesonide 200μg twice daily , they were r and omly assigned to treatment with either Symbicort ® Turbuhaler ® ( budesonide/formoterol 160/4.5μg , one inhalation twice daily ) or Flovent ® /Flixotide ® Diskus ™ ( fluticasone propionate 250μg twice daily ) for 12 weeks . Results Significantly greater increases in morning PEF , the primary efficacy variable , were observed in patients treated with budesonide/formoterol compared with fluticasone propionate ( 27.4 L/min vs 7.7 L/min ; p < 0.001 ) . Evening PEF and clinic FEV1 also favored budesonide/formoterol compared with fluticasone propionate ( p < 0.001 ) , as did use of reliever medication ( p = 0.04 ) and the proportion of reliever-free days ( p < 0.001 ) . There were also numerical improvements in symptom-free days ( 60.4 % vs 55.5 % ) , night-time awakenings ( 7.9 % vs 9.6 % ) and asthma-control days ( 57.8 % vs 52.4 % ) in favor of budesonide/formoterol . The risk of an exacerbation was reduced by 32 % in the budesonide/formoterol group compared with the fluticasone propionate group ( p < 0.05 ) . Both treatments were well tolerated . ConclusionS ymbicort ® ( budesonide/formoterol in a single inhaler ) was more effective than a high dose of fluticasone propionate  in improving lung function , reducing use of reliever medication and improving control of moderate persistent asthma The optimal treatment for mild asthma is uncertain . We assessed the effects of adding a long-acting inhaled beta-agonist , formoterol , to low doses of an inhaled corticosteroid , budesonide , for 1 yr in subjects with mild asthma , receiving no or only a small dose of inhaled corticosteroid . The 698 corticosteroid free patients ( Group A ) were assigned to twice daily treatment with 100 microg budesonide , 100 microg budesonide plus 4.5 microg formoterol , or placebo .  The 1,272 corticosteroid-treated patients ( Group B ) were assigned to twice daily treatment with 100 microg budesonide , 100 microg budesonide plus 4.5 microg formoterol , 200 microg budesonide , or 200 microg budesonide plus 4.5 microg formoterol . The main outcome variables were time to the first severe asthma exacerbation and poorly controlled asthma days . In Group A , budesonide alone reduced the risk for severe exacerbations by 60 % and poorly controlled days by 48 % ; adding formoterol increased lung function with no change in other end points . By contrast , in Group B , adding formoterol reduced the risk for the first severe exacerbation and for poorly controlled days by 43 and 30 % , respectively . Thus , in corticosteroid-free patients , low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control , and in patients already receiving inhaled corticosteroid , adding formoterol was more effective than doubling the corticosteroid dose Regular beta 2-adrenoceptor agonist therapy may lead to a rebound increase in bronchial responsiveness on discontinuation of therapy and a reduction in bronchoprotective effects .  Formoterol , a long-acting beta 2-agonist , is effective in single doses in the prevention of methacholine-induced bronchoconstriction . In a double-blind , placebo-controlled cross-over study , we examined the effect of an inhaled long-acting beta 2-adrenoceptor agonist , formoterol ( 24 micrograms twice a day ) for 2 wk on airway function and responsiveness in 17 subjects with mild asthma ( mean age , 26.3 + /- 1.4 yr ) who were not taking inhaled glucocorticosteroids .  FEV1 and the provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) were measured at 36 , 60 , and 108 h and at 2 wk after the last dose of regular treatment . In addition , PC20 was measured 12 h after the first and the last dose of formoterol and placebo . PC20 values at 36 , 60 , and 108 h and at 2 wk after formoterol treatment cessation were not significantly different from those after placebo . Mean FEV1 was 3.44 + /- 0.18 L after placebo compared with 3.79 + /- 0.20 L after formoterol ( p < 0.001 ) 12 h after the first dose , and mean PC20 was 0.53 ( GSEM 1.4 ) mg/ml after placebo compared with 2.0 ( GSEM 1.4 ) mg/ml after formoterol ( p < 0.001 ) . After 2 wk of regular treatment , mean FEV1 at 12 h after the final dose of formoterol fell to 3.51 + /- 0.23 L compared with 3.41 + /- 0.18 L after the final dose of placebo ( p = 0.03 ) . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND The use of short-acting beta2-agonists is associated with oral mucosa injuries that are probably provoked by decreased saliva flow and decreased concentrations of immunoglobulin (Ig)A in saliva . OBJECTIVES To explore the effect of salmeterol , alone or combined with beclomethasone , on the health of oral mucosa , as well as its effect on saliva flow and IgA concentration in saliva . METHODS Patients ranging in age from 6 to 15 years with moderate-persistent chronic asthma were enrolled . Patients received two 6-week treatments , one with salmeterol plus beclomethasone and the other with only salmeterol , with a 1-week washout period between treatments . Patients had oral cavity examinations and assessment s of saliva flow , IgA in saliva , and total protein in saliva before the beginning and at the end of each treatment RESULTS The results of the baseline oral examinations were normal in all patients . The postsalmetrol ( PS ) examinations detected 13 patients with gingivitis and the postbeclomethasone-salmeterol ( PBS ) examinations disclosed 10 patients with gingivitis and 1 with lower-lip ulceration . Baseline saliva flow was 16.25 + /- 7.04 mm/minute ( confidence interval [ CI ] 95 % 13.67 ; 18.89 ) , PS was 13.53 + /- 5.93 mm/minute ( CI 95 % 11.33 ; 15.73 ) , and PBS was 16.57 + /- 5.54 mm/minute ( CI 95 % 14.51 ; 18.62 ) . No statistical differences between the different assessment s were found . Mean saliva IgA at baseline was 4.99 + /- 1.96 mg/dL ( CI 95 % 4.26 ; 5.71 ) , PS IgA was 6.53 + /- 3.02 mg/dL ( CI 95 % 5.41 ; 7.65 ) , and PBS IgA was 4.82 + /- 1.98 mg/dL ( CI 95 % 4.08 ; 5.56 ) . PS IgA was significantly higher than the other two determinations ( P < 0.05 by Bonferroni and Tukey tests ) . Baseline saliva IgA-to-protein ratio was 0.72 + /- 0.24 ( 95 % CI 0.64 ; 0.80 ) , PS IgA : protein ratio was 1.02 + /- 0.38 ( 95 % CI 0.88 ; 1.16 ) , and PBS IgA : protein ratio was 0.72 + /- 0.25 ( 95 % CI 0.62 ; 0.82 ) . PS IgA : protein ratio was significantly higher than the other two determinations ( P < 0.05 by Bonferroni and Tukey tests ) . CONCLUSIONS In the present study it was demonstrated that salmeterol alone or in combination with beclomethasone induced injuries in the oral mucosa , but only salmeterol alone induced increases in the total and protein-adjusted IgA in saliva BACKGROUND The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12 - 14 hours . However , the precise role of formoterol in the maintenance treatment of asthma is still under debate . A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma . METHODS In a multicentre double blind , placebo controlled , parallel group study 239 subjects with mild to moderate asthma were r and omly assigned to treatment with either inhaled formoterol 24 micrograms twice daily ( n = 125 ) or placebo ( n = 114 ) during eight months . The study consisted of a four week run in period , a 24 week treatment period , and a four week washout period . All subjects were using regular inhaled corticosteroids ( 100 - 3200 micrograms daily ) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief . The study was performed in 10 outpatient clinics in Canada , and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherl and s. Twice daily self-reported peak expiratory flow ( PEF ) measurements , symptom scores , and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures . Spirometric values were measured at entry , at the start of treatment , after four , 12 and 24 weeks of treatment , and after four weeks washout . RESULTS One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo .  Baseline FEV1 was 67.1 % predicted and mean bronchodilator reversibility was 26 % . The mean total asthma symptom score was 3.6 ( maximum possible 21 ) . A significant decrease in symptoms in favour of formoterol ( difference from placebo -0.64 , 95 % CI -0.04 to -1.23 , p = 0.04 ) was observed . Compared with placebo , morning PEF increased ( difference from placebo 28 l/min , 95 % CI 18.3 to 37.7 , p = 0.0001 ) and the use of short acting beta 1 agonists decreased ( daytime difference from placebo -1.1 inhalation , 95 % CI -1.4 to -0.7 , p = 0.0001 ) in the formoterol group . PEF returned to baseline following discontinuation of formoterol , as did asthma symptom scores . Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study ( 58 and 55 courses , respectively ) . CONCLUSIONS Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF , and decreasing the use of rescue beta 2 agonists . There was no apparent loss of asthma control during 24 weeks of treatment with formoterol Patients with asthma experience disruptions in usual activities that can impair their quality of life , and in patients whose daily routine involves an active lifestyle , these disruptions can be severe . We assessed the patient-perceived effect of treatment with fluticasone propionate/salmeterol combination ( FSC ) , compared with fluticasone propionate ( FP ) or salmeterol ( SAL ) alone , on activity limitations , particularly strenuous physical activities . The Asthma Quality of Life Question naire ( AQLQ ) was administered in two 12-week , r and omized , double-blind , placebo-controlled trials comparing FSC 100/50 or 250/50 µg twice daily vs. the individual components alone in 686 adults and adolescents with asthma . In one study , patients were stratified by prior treatment [ low to medium doses of inhaled corticosteroids ( ICS ) or SAL ] , and in the other study , all patients were previously treated with medium to high doses of ICS . Patients prospect ively identified five activities they performed regularly and were asked how these activities were limited by their asthma . The effect of r and omized treatment on strenuous activities ( e.g. , aerobics , cycling , hiking , and basketball ) was assessed . In both studies , treatment with FSC result ed in clinical ly meaningful improvements ( i.e. , change in AQLQ of ≥0.5 ) and was statistically significantly better than SAL in both studies and FP in one study . Treatment of the two main components of asthma — inflammation and bronchoconstriction — with FSC results in clinical ly meaningful improvements in the ability of  patients with persistent asthma to perform not only their usual activities but also strenuous activities STUDY OBJECTIVES To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma . DESIGN A prospect i ve , double-blind , r and omized placebo-controlled trial . SETTING Medical wards of a large university-based hospital . PATIENTS Forty-three patients admitted for an acute exacerbation of asthma . INTERVENTIONS Salmeterol ( 42 microg ) or two puffs of placebo every 12 h in addition to st and ard therapy ( short-acting beta-agonists , corticosteroids , and anticholinergic agents ) . RESULTS No clinical ly adverse effects were seen with the addition of salmeterol to conventional therapy . After salmeterol , there was no difference in pulse , respiratory rate , oxygen saturation by pulse oximetry , severity of symptoms , or dyspnea score . Patients receiving salmeterol had greater FEV(1 ) percent improvements than the placebo group at 12 , 24 , 36 , and 48 h. These findings were not statistically significant . By paired Student 's t tests , there were significant improvements in FEV(1 ) ( p = 0.03 ) and FVC ( p = 0.03 ) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group . In a subgroup analysis of patients with an initial FEV(1 ) < or = 1.5 L , the absolute FEV(1 ) percent improvement for salmeterol vs placebo was 51 % vs 16 % at 24 h and 54 % vs 40 % at 48 h. The relative FEV(1 ) percent improvement for salmeterol vs placebo was 17 % vs 8 % at 24 h and 18 % vs 14 % at 48 h. CONCLUSION The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma . Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma Salmeterol ( SM ) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients . In the present study , evaluating efficacy and possible development of tachyphylaxis after SM , 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15 % to 200 micrograms salbutamol ( SB ) or 20 % to 500 micrograms SB . At inclusion all patients were receiving treatment with inhaled beta 2-agonists , and 11 of the 12 patients were also receiving inhaled corticosteroids .  The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day , following a double-blind , double-dummy , r and omized design . The treatment periods were separated by a washout period of 1 wk . Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period . On each of these days , basal FEV1 , tremor , heart rate , and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve . During the treatment periods , as well as during the washout week after each treatment , the patients recorded their morning and evening peak expiratory flow ( PEF ) each day before the inhalation of the study drug . Subjective asthma symptoms were monitored by a visual analog scale after each treatment period . The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments , but significant increases in basal FEV1 and FVC were seen after the SM period ( p less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS This multi-centre , r and omized , double-blind , double-dummy , parallel-group study was design ed to investigate the hypothesis of equivalent efficacy and comparable safety of two inhaled presentations of salmeterol/fluticasone propionate combination product ( SALM/FP ) 50/100 microg administered twice daily to patients with mild-to-moderate asthma for 12 weeks . The delivery systems were a 25/50 microg strength hydrofluoroalkane ( HFA ) metered-dose inhaler ( MDI ) and a Diskus inhaler ( 50/100 microg strength ) . A third group received FP 100 microg twice daily via a chlorofluorocarbon MDI ( 50 microg strength ) . A total of 497 patients aged 11 - 79 years with reversible airways obstruction who were symptomatic on inhaled corticosteroid ( ICS ) therapy and had room for improvement in lung function were r and omized to treatment in a double-blind , parallel-group design ( SALM/FP MDI : n=165 ; SALM/FP Diskus : n=167 ; FP MDI : n=165 ) for 12 weeks . A total of 383 patients completed the study according to the protocol . According to the primary efficacy variable , increase in mean morning PEF over weeks 1 - 12 , the two inhaled presentations of SALM/FP were clinical ly equivalent ( adjusted mean increases 43 and 46 l min(-1 ) ; treatment difference 3 l min(-1 ) ; 95 % confidence interval : -6 to 11 l min(-1 ) ) . Equivalence was also demonstrated by all secondary efficacy measures . The SALM/FP MDI was significantly superior to the FP MDI for increase in mean morning PEF ( treatment difference 19 l min(-1 ) ; P<0.001 ) and for all secondary measures except FEV1 and symptom-free nights . There was no significant difference between the groups with respect to adverse events and serum cortisol levels . These results demonstrate that the SALM/FP 25/50 microg HFA MDI ( two inhalations twice daily ) is clinical ly equivalent to the SALM/FP 50/100 microg Diskus ( one inhalation twice daily ) . Patients switching to SALM/FP from other MDI-based asthma treatments may now do so without a change of delivery device The aim of this study was to evaluate if continuous treatment with budesonide or salmeterol influences the bronchodilator response to terbutaline in children with asthma ; 23 children , aged 7 to 16 years ( mean = 11 years ) , with mild asthma were treated with inhaled budesonide 100 micrograms b.i.d . and placebo for three weeks in a r and omized , double blind crossover study . These treatments were followed by treatment with inhaled salmeterol 50 micrograms b.i.d . for 3 weeks . On the last day of each period a cumulative dose-response experiment with terbutaline in the doses 50 , 100 , 250 and 500 micrograms ( cumulative dose 900 micrograms ) was performed . Lung function was measured before and 20 min after each terbutaline inhalation . Baseline pulmonary functions after budesonide treatment were significantly higher than the baseline measured after the two other treatments ( p < 0.05 ) . After budesonide treatment , the dose-response curve was shifted vertically upwards but otherwise parallel to the dose-response curve after placebo . The increase from baseline after the first cumulative dose of terbutaline  was significantly lower after salmeterol treatment than after the two other treatments ( p < 0.01 ) . Maximal lung functions after 900 micrograms terbutaline also differed significantly between the three dose-response days ; budesonide being significantly higher and salmeterol significantly lower than placebo ( p = 0.02 and p < 0.001 , respectively ) . It is concluded that budesonide treatment does not enhance the brochodilator response to terbutaline . Further studies are needed to assess if long-term continuous salmeterol treatment reduces the response to terbutaline Cough-variant asthma ( CVA ) occurs in a subgroup of asthmatics whose sole or predominant respiratory symptom is cough . Although bronchodilators are often sufficient to treat CVA , refractory cough may require therapy with inhaled or systemic corticosteroids . In a r and omized , double-blind , placebo-controlled , crossover study , we examined the effect of a 14-day course of the leukotriene receptor antagonist zafirlukast on subjective cough score and cough-reflex sensitivity to inhaled capsaicin in eight subjects with CVA refractory to inhaled beta agonists , and in five subjects refractory to inhaled corticosteroids . Seven of eight subjects experienced significant subjective and objective improvement in cough after treatment with zafirlukast . Mean ( ± SEM ) cough score improved from 7.75 ± 0.56 to 3.25 ± 0.84 ( p = 0.0006 ) . Cough sensitivity to capsaicin was suppressed by zafirlukast in all subjects . Patients with CVA may represent a distinct subgroup of asthmatics whose afferent cough receptors within the respiratory epithelium are hypersensitive relative to those of patients with the typical form of asthma . Zafirlukast appears to be particularly effective in treating CVA by inhibiting the sensitivity of these receptors . Leukotriene receptor antagonists may offer an alternative to corticosteroids for the treatment of CVA refractory to inhaled bronchodilators Concern about side‐effects of theophylline prompted us to investigate whether this drug could be eliminated from the multi‐medication regimen of severe asthmatics . We studied patients with a demonstrated requirement for systemic steroids who were taking most other available anti‐asthma medications in an attempt to reduce systemic steroids while maintaining clinical stability . Five in‐ patients , 12–15 years old , completed a double‐blind , cross‐over trial of theophylline vs placebo . All were stable for 4 weeks prior to the study with normal spirometry and mildly elevated lung volumes . Regular medications consisted of long‐acting theophylline with levels between 12 mcg/ml and 16 mcg/ml , and prednisone 10–30 mg on alternate days . In addition , they were all taking inhaled metaproterenol , cromolyn sodium , atropine sulphate , and beclomethasone dipropionate four times daily ( qid ) . Patients received either theophylline or placebo during two drug periods . All other medications were unchanged . Parameters measured were symptom score , number of extra respiratory treatments ( prn RTs ) , increase in steroid dosage , and daily spirometry . During the placebo period , all five patients required increased steroids , daily spirometry decreased and three patients developed severe exacerbations unrelated to viral infection . A marked increase in symptom score occurred within 48 hr of discontinuing theophylline in all . These findings emphasize that theophylline is beneficial in a subset of severe asthmatics who can not be controlled with all other available bronchodilators , cromolyn , and inhaled and systemic steroids BACKGROUND Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma . It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens . Moreover , it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists . METHODS Asthmatic patients ( n = 145 ) allergic to house dust mite ( HDM ) were r and omly allocated to monotherapy with a short-acting beta(2)-agonist ( SA ; n = 48 ) , a long-acting beta(2)-agonist ( LA ; n = 50 ) , or placebo ( n = 47 ) , double blind , double dummy . The study covered three periods : ( 1 ) a 4-week run-in period , in which no changes took place ; followed by ( 2 ) cessation of treatment with asthma medication including inhaled corticosteroids , introduction of allergen avoidance measures ( active/placebo treatment ) to lower HDM exposure in the active group , and an 8-week washout period to adjust patients to these changes ; followed by ( 3 ) a 12-week study medication period . At the start of the 12-week medication period , and every 4 weeks thereafter , spirometric measurements ( FEV(1 ) and provocative concentration of histamine causing a 20 % fall in FEV(1 ) [ PC(20 ) ] ) were performed . Peak flow and asthma symptoms were recorded daily . Additionally , at the start and every 6 weeks thereafter , dust sample s were collected from mattresses and living room and bedroom floors to assess HDM ( der p 1 ) concentrations . Effects on FEV(1 ) , PC(20 ) , peak flow , and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens . RESULTS There were no significant differences among the three medication groups after 12 weeks for FEV(1 ) . However , a significant decrease in mean FEV(1 ) percent predicted ( 95 % confidence interval [ CI ] ) was observed within the SA group : - 6.6 ( - 10.4 to - 2.8 ) ( p = 0.0002 ) . A decrease in geometric mean PC(20 ) ( 95 % CI ) of - 1.2 ( - 1.96 to - 0.44 ) doubling concentration was observed within the SA group ( p = 0.05 ) . No significant changes in FEV(1 ) and PC(20 ) were observed > 12 weeks within the LA group or the placebo group . There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups . Moreover , none of the parameters showed interactive effects with allergen exposure . CONCLUSION There were no significant differences among the three medication groups for FEV(1 ) and PC(20 ) . The within-treatment group comparison showed a significant small decline in FEV(1 ) for the SA group ( but not for the LA group ) , which could indicate that monotherapy with SAs might have negative effects on FEV(1 ) . This was not seen during regular use of LAS : No clear pathophysiologic mechanism can explain these findings at the moment . Relatively high or low exposure to allergens did not alter these findings BACKGROUND Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control . OBJECTIVE Our purpose was to compare the efficacy and safety of salmeterol 50 microg combined with fluticasone 100 microg ( in a combination dry powder product ) with that of placebo , fluticasone , or salmeterol alone . METHODS A 12-week r and omized , double-blind , multicenter study was conducted in 356 patients aged 12 years or older with asthma . After a 14-day screening period , patients were r and omized to treatment with salmeterol 50 microg combined with fluticasone 100 microg ( combination product ) , salmeterol 50 microg , fluticasone 100 microg , or placebo administered in the Diskus dry powder inhaler ( GlaxoWellcome , UK ) twice daily . RESULTS Mean change in FEV(1 ) at end point was significantly ( P < or = .003 ) greater with the combination product ( 0.51 L ) compared with placebo ( 0.01 L ) , salmeterol ( 0.11 L ) , and fluticasone ( 0.28 L ) . The combination product significantly increased ( P < or = .013 ) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo , salmeterol , and fluticasone at week 1 and week 12 . Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups ( P < or = .020 ) . The combination product significantly increased ( P < or = .012 ) morning PEF ( combination , 52.5 L/min ; placebo , -23.7 L/min ; salmeterol , -1.7 L/min ; fluticasone , 17.3 L/min ) and evening PEF at end point compared with the other groups . The combination product significantly ( P < or = .025 ) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol . All treatments were equally well tolerated . CONCLUSION Salmeterol 50 microg and fluticasone 100 microg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling , such as the increased subepithelial airway vascularity in patients with asthma . We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids ( ICS ) ( range 200 - 500 microg twice a day ) and 28 normal subjects without asthma as a control population . Subjects underwent bronchoscopy with airway biopsy  and subjects with asthma were then r and omized to receive supplementary inhaled salmeterol 50 microg twice a day , fluticasone propionate 100 microg twice a day , or placebo for 3 mo in addition to their baseline ICS . Biopsy of the airway was then repeated . The biopsies were analyzed for vascular structures in the subepithelial lamina propria . Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects . We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects ( 524 + /- 137 vessels/mm2 , n = 34 versus 425 + /- 130 vessels/mm2 , n = 28 ; p = 0.004 ) . There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline ( before , 535 + /- 153 vessels/mm2 versus after , 400 + /- 142 vessels/mm2 ; n = 12 ; p = 0.04 ) . There was no significant change within the fluticasone ( n = 11 ) or placebo ( n = 11 ) treatment groups , but also no significant differences between the groups . Notably , no treatment was associated with increased airway wall vascularity . The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study , which is complementary to the action of ICS on airway vascularity BACKGROUND We evaluated the efficacy and safety of low-dose budesonide/formoterol , 80 micro g/4.5 micro g , bid in a single inhaler ( Symbicort Turbuhaler ; AstraZeneca ; Lund , Sweden ) compared with an increased dose of budesonide , 200 micro g bid , in adult patients with mild-to-moderate asthma not fully controlled on low doses of inhaled corticosteroid alone . METHODS All patients received budesonide , 100 micro g bid , during a 2-week run-in period . At the end of the run-in phase , 467 patients with a mean FEV(1 ) of 82 % predicted received 12 weeks of treatment with budesonide/formoterol in a single inhaler or budesonide alone in a higher dose . Patients kept daily records of their morning and evening peak expiratory flow ( PEF ) , nighttime and daytime symptom scores , and use of reliever medication . RESULTS The increase in mean morning PEF-the primary efficacy measure-was significantly higher for budesonide/formoterol compared with budesonide alone ( 16.5 L/min vs 7.3 L/min , p = 0.002 ) . Similarly , evening PEF was significantly greater in the budesonide/formoterol group ( p < 0.001 ) . In addition , the percentage of symptom-free days and asthma-control days ( p = 0.007 and p = 0.002 , respectively ) were significantly improved in the budesonide/formoterol group . Budesonide/formoterol decreased the relative risk of an asthma exacerbation by 26 % ( p = 0.02 ) compared with budesonide alone . Adverse events were comparable between the two treatment groups . CONCLUSION This study shows that in adult patients whose mild-to-moderate asthma is not fully controlled on low doses of inhaled corticosteroids , single-inhaler therapy with budesonide and formoterol provides greater improvements in asthma control than increasing the maintenance dose of inhaled corticosteroid BACKGROUND Inhaled , long-acting beta2-agonists or antileukotrienes are alternatives as add-on therapy for asthmatic children taking regular inhaled steroids . Any complementary effects would be relevant to the choice between these alternatives . Exhaled nitric oxide ( FeNO ) may reflect these effects . OBJECTIVE To compare the control of FeNO provided by salmeterol or montelukast add-on therapy in asthmatic children undergoing regular maintenance treatment with a daily dose of 400 microg of budesonide .  METHODS The study included children with increased FeNO despite regular treatment with budesonide , 400 microg/d , and normal lung function .  Montelukast , 5 mg/d , salmeterol , 50 microg twice daily , or placebo was compared as add-on therapy to budesonide , 400 microg , in a r and omized , double-blind , double-dummy , crossover study . RESULTS Twenty-two children completed the trial . The geometric mean FeNO level was 20 ppb ( 95 % confidence interval [ CI ] , 15 - 27 ppb ) after salmeterol , which was significantly higher than after montelukast ( mean , 15 ppb ; 95 % CI , 11 - 18 ppb ; P = 0.002 ) and placebo ( mean , 15 ppb ; 95 % CI , 10 - 21 ppb ; P = 0.03 ) . There was no difference in FeNO between the montelukast and placebo groups . Mean forced expiratory volume in 1 second ( FEV1 ) was significantly increased after salmeterol ( mean , 2.63 L ; 95 % CI , 2.34 - 2.91 L ) compared with placebo ( mean , 2.48 L ; 95 % CI , 2.19 - 2.77 L ) . Montelukast ( mean , 2.57 L ; 95 % CI , 2.33 - 2.80 L ) was no different than placebo . CONCLUSIONS The FeNO levels were significantly higher after salmeterol add-on treatment compared with both placebo and montelukast add-on treatment . Salmeterol significantly improved lung function ( FEV1 ) compared with placebo and nonsignificantly compared with montelukast . Montelukast failed to reduce FeNO and improve lung function compared with placebo in this group of children taking regular budesonide , 400 microg A total of 132 adult asthmatics who were symptomatic on 500 microg x day(-1 ) inhaled beclomethasone dipropionate ( BDP )  were studied in an open-label r and omized , parallel group , 12 week , clinical trial . The addition of 12 microg formoterol fumarate solution aerosol ( pressurized metered dose inhaler ) b.i.d . to BDP at a dose of 500 microg x day(-1 ) was compared with a higher dose of 1,000 microg x day(-1 ) BDP .  Mean morning premedication peak expiratory flow rate ( PEF ) during the final week of treatment ( primary end-point ) increased in both groups compared to baseline . The estimated treatment difference of 20.4 L x min(-1 ) ( 95 % confidence interval 3.2 - 37.6 ) after 12 weeks of treatment was statistically significant ( p<0.05 ) in favour of the formoterol/BDP group . The overall mean morning premedication PEF for the entire treatment period was higher in the formotero/BDP group ( p=0.002 ) . The overall number of puffs of rescue medication and asthma symptom scores were less in the formotero/BDP group ( p<0.01 ) . Safety and tolerability evaluations were satisfactory in both groups . In conclusion , the results suggest that the addition of formoterol fumarate to the existing dose of an inhaled corticosteroid should be considered as an alternative to increasing the dose of inhaled corticosteroid in the inadequately controlled asthmatic BACKGROUND ss(2)-Agonists and corticosteroids or theophylline can interact to produce beneficial effects on airway function in asthma , but this has not been established in COPD . METHODS Eighty patients with well-controlled COPD were r and omized to receive 3 months of treatment in one of four treatment groups : ( 1 ) salmeterol , 50 microg bid ; ( 2 ) salmeterol , 50 microg , plus fluticasone propionate , 250 microg bid ; ( 3 ) salmeterol , 50 microg , plus fluticasone propionate , 500 microg bid ; and ( 4 ) salmeterol , 50 microg , plus titrated theophylline bid . At each visit , a dose-response curve to inhaled salbutamol was constructed using a total cumulative dose of 800 microg . RESULTS A gradual increase in FEV(1 ) was observed with each of the four treatments . Maximum significant increases in FEV(1 ) over baseline values that were observed after 3 months of treatment were as follows : salmeterol , 50 microg bid , 0.163 L ( 95 % confidence interval [ CI ] , 0.080 to 0.245 L ) ; salmeterol , 50 microg , plus fluticasone propionate , 250 microg bid , 0.188 L ( 95 % CI , 0.089 to 0 . 287 L ) ; salmeterol , 50 microg , plus fluticasone propionate , 500 microg bid , 0.239 L ( 95 % CI , 0.183 to 0.296 L ) ; and salmeterol , 50 microg , plus titrated theophylline bid , 0.157 L ( 95 % CI , 0.027 to 0 . 288 L ) . Salbutamol always caused a significant dose-dependent increase in FEV(1 ) ( p < 0.001 ) , although the 800-microg dose never induced further significant benefit when compared with the 400-microg dose . The mean differences between the highest salbutamol FEV(1 ) after salmeterol , 50 microg , plus fluticasone propionate , 500 microg bid , and that after salmeterol , 50 microg , plus titrated theophylline bid or salmeterol , 50 microg bid , were statistically significant ( p < 0.05 ) . CONCLUSION These data show that both long-acting ss(2)-agonists and inhaled corticosteroids have a role in COPD . The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone . Moreover , it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol , although regular salmeterol is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect . In any case , patients must be treated for at least 3 months before a real improvement in lung function is achieved Abstract Objective : To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects . Methods : Twenty-eight healthy subjects received salmeterol 100 µg , salmeterol 100 µg/fluticasone propionate 500 µg and fluticasone propionate 500 µg via a Diskus dry powder inhaler twice daily for 11 days according to a r and omised , double-blind , placebo-controlled , crossover design . Subjects in the placebo group also received a single dose of salmeterol 100 µg on the morning of day 10 . On day 10 , the systemic effects of salmeterol  [ on pulse rate , blood pressure , corrected QT ( QTc ) interval and serum potassium and glucose levels ] and fluticasone propionate  ( on 24-h urinary cortisol and morning plasma cortisol levels ) were assessed . Maximal number and affinity of lymphocyte β2-adrenoceptors and β2-adrenoceptor polymorphism at loci 16 and 27 were also determined . Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10 . Dosing continued on the evening of day 10 and on day 11 , and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol ( up to a total dosage of 3200 µg ) was evaluated . Results : All treatments were safe and well tolerated . With the exception of a higher pulse rate after repeat administration of salmeterol [ 66.2 beats per minute ( bpm ) versus 63.6 bpm ] , there were no significant differences between the single-dose and repeat-dose salmeterol groups . The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate . Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol ; however , co-administration of fluticasone propionate did not affect the response to salbutamol . Fluticasone propionate reduced 24-h urinary cortisol excretion ( 22.4 µg compared with 48.6 µg with placebo ) , but this was unaffected by the co-administration of salmeterol . Morning plasma cortisol levels were not reduced compared with placebo . There was no significant treatment effect on lymphocyte β2-adrenoceptors and no correlation of β2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis . Salmeterol plasma concentrations were measurable only during the first half-hour after dosing . Co-administration of fluticasone propionate did not affect the peak plasma concentration ( Cmax ) of salmeterol . For fluticasone propionate , there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax , plasma concentration at the end of the dosing interval ( Ct ) , terminal elimination half-life ( t1/2 ) or time to Cmax ( tmax ) . The area under the concentration – time curve within a dosing interval ( AUCt ) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher ( about 8 % ) than after inhalation of fluticasone propionate alone ( P=0.0135 ) . However , the 90 % confidence intervals ( CIs ) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence ( 1.03 , 1.13 and 0.97 , 1.12 , respectively ) . Conclusion : These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination Using BAL , we studied the effects of 8 wk of treatment with salmeterol on airway inflammation in nine asthmatic subjects in a double-blind crossover placebo-controlled protocol . The study patients were all receiving regular inhaled corticosteroid therapy ( 400 to 1,000 micrograms beclomethasone dipropionate per day ) and inhaled albuterol for symptomatic relief , i.e. , subjects who might be considered suitable for treatment with salmeterol . The asthmatic group had significant differences in numbers of epithelial cells and eosinophils in BAL compared with a group of 15 normal control subjects ( p < 0.01 ) . During salmeterol treatment mean morning and evening peak flow rates were increased ( p < 0.05 ) . There was no significant change in BAL cell profile and no change in percentages of CD4 and CD8 lymphocytes or proportion of lymphocytes expressing HLA-DR after salmeterol . In conclusion , we were unable to demonstrate any significant anti-inflammatory effect of regular salmeterol therapy on airway inflammation using BAL in these asthmatic patients . At the same time , there was equally no evidence of a deterioration in the underlying inflammatory disease process BACKGROUND The role of long-acting , inhaled beta2-agonists in treating asthma is uncertain . In a double-blind study , we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide . METHODS After a four-week run-in period of treatment with budesonide ( 800 microg twice daily ) , 852 patients being treated with glucocorticoids  were r and omly assigned to one of four treatments given twice daily by means of a dry-powder inhaler ( Turbuhaler ) : 100 microg of budesonide plus placebo , 100 microg of budesonide plus 12 microg of formoterol , 400 microg of budesonide plus placebo , or 400 microg of budesonide plus 12 microg of formoterol . Terbutaline was permitted as needed . Treatment continued for one year ; we compared the frequency of exacerbations of asthma , symptoms , and lung function in the four groups . A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days . RESULTS The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent , respectively , when formoterol was added to the lower dose of budesonide . The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent , respectively . Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent , respectively . Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide , but the improvements with formoterol were greater . CONCLUSIONS In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids , the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial . The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma In a r and omized , double-blind , double-dummy , cross-over study the efficacy and safety of inhaled salmeterol 50 mcg ( b.i.d . ) was compared with oral salbutamol controlled release 8 mg ( b.i.d . ) . Fifty-nine patients with moderate asthma were r and omized to two four-week periods of treatment with a two-week washout period . During the study period the patients were allowed to use inhaled Salbutamol on a prn . basis . Inhaled steroids , if any , were continued . On diary cards patients recorded peak expiratory flow rate ( PEFR ) morning and evening before medication , asthma symptom score , and use of inhaled salbutamol .  Salmeterol was more effective than salbutamol CR in decreasing daily symptoms ( p = 0.001 ) and increasing morning-PEFR ( p = 0.004 ) . Salmeterol result ed in significantly more days without symptoms ( p = 0.0004 ) and days and nights without need for rescue medication ( p = 0.01 and p = 0.01 ) . Salmeterol was better tolerated than salbutamol CR The identification , prevention , and prompt treatment of exacerbations are major objectives of asthma management . We looked at change in PEF , symptoms , and use of rescue beta-agonists  during the 425 severe exacerbations that occurred during a 12-mo parallel group study ( FACET ) in which low and high doses of budesonide with and without formoterol were compared in patients with asthma .  Oral corticosteroids were prescribed for severe exacerbations , the main study end point , defined as the need for a course of oral corticosteroids  ( n = 311 ) or a reduction in morning PEF of > 30 % on two consecutive days . PEF , symptoms , and bronchodilator use over the 14 d before and after the exacerbation were obtained from diary cards . Exacerbations were characterized by a gradual fall in PEF over several days , followed by more rapid changes over 2 to 3 d ; an increase in symptoms and rescue beta-agonist use occurred in parallel , and both the severity and time course of the changes were similar in all treatment groups . Exacerbations identified by the need for oral corticosteroids were associated with more symptoms and smaller changes in PEF than those identified on the basis of PEF criteria . Female sex was the main patient characteristic associated with an increased risk of having a severe exacerbation . Exacerbations may be characterized predominantly by change in symptoms or change in PEF , but the pattern was not affected by the dose of inhaled corticosteroid or by whether the patient was taking formoterol Current guidelines on asthma management recommend the early use of inhaled corticosteroids . Recent studies of patients with moderate to severe asthma show that the addition of salmeterol is superior to a further increase of the steroids . In this study with adult , mild persistent asthma patients , we compared the effects of adding salmeterol 50 microg b.i.d . versus beclomethasone dipropionate ( BDP ) 200 microg b.i.d . ( both via Diskhaler dry powder inhaler ) to the low-dose inhaled steroids . A double-blind , r and omized , parallel-group study was conducted with a run-in period of 2 weeks and a treatment period of 12 weeks . Patients ( n = 233 ) were r and omized with a peak expiratory flow ( PEF ) reversibility of 22 + /- 10 % ( mean + /- SD ) in the run-in period . The morning PEF was 84 + /- 17 % predicted and the age was 42 + /- 14 years ( 45 % males ) . The average pre study inhaled steroid dose was 361 microg daily . Within a week of salmeterol treatment the daily PEF recordings reached maximal levels . At the end of the treatment period the evening PEF remained significantly better in the salmeterol group than in the BDP group ( p = 0.036 ) . The PEFs , measured at the general practitioners ' ( GPs ' ) office , were at least 95 % of the predicted values and the post-salbutamol values at the end of both treatments . However , the salmeterol group had already obtained this level after 2 weeks and differed significantly from the beclomethasone group ( p = 0.003 for percent predicted and p = 0.0007 for post-salbutamol PEF values ) . The symptom scores and the use of rescue medication showed a similar profile . Quality of life improved with both treatments , but without significant statistical differences between the groups . The frequency of adverse events , typical for beta2-agonists , was low and showed no differences between the groups . These results showed that the addition of salmeterol is at least as effective as adding beclomethasone in normalizing peak flows and improving asthma control in mild persistent asthma patients . Furthermore , salmeterol has a much faster onset of action BACKGROUND Salmeterol , a long-acting beta2 -agonist , and zafirlukast , a leukotriene receptor antagonist , are both indicated for the treatment of asthma in adolescent and adult patients . OBJECTIVE We sought to compare the effect of 4 weeks of treatment with inhaled salmeterol xinafoate versus oral zafirlukast in the treatment of persistent asthma . METHODS This was a r and omized , double-blind , double-dummy , parallel-group , multicenter clinical trial . Patients , over 80 % of whom were on a concurrent inhaled corticosteroid regimen , were treated for 4 weeks with either inhaled salmeterol xinafoate 42 microgram twice daily administered by means of a metered-dose inhaler or oral zafirlukast 20 mg twice daily . The primary efficacy measure was morning peak expiratory flow ( PEF ) ; secondary efficacy measures included evening PEF , asthma symptom scores , supplemental albuterol use , nighttime awakenings , sleep symptoms , asthma exacerbations , and FEV1 . RESULTS Both inhaled salmeterol and oral zafirlukast result ed in within-group improvements from baseline in measures of pulmonary function , asthma symptoms , and supplemental albuterol use . Salmeterol treatment result ed in significantly greater improvements from baseline compared with zafirlukast for most efficacy measurements , including morning PEF ( 29.6 vs 13.0 L/min ; P < /= .001 ) , percentage of symptom-free days ( 22.4 % vs 8.8 % ; P < /= .001 ) , and percentage of days and nights with no supplemental albuterol use ( 30.5 % vs 11.3 % ; P < /= .001 ) . There were no differences in safety profiles as assessed by adverse event monitoring . CONCLUSION In patients with persistent asthma , most of whom were concurrently using inhaled corticosteroids , treatment with inhaled salmeterol provided significantly greater improvement than oral zafirlukast in overall asthma control over the 4-week treatment period AIMS Inhaled corticosteroids alone or in combination with long acting beta2-agonists are indicated for use in mild persistent asthmatics . We set out to evaluate effects on airway hyperresponsiveness ( AHR ) and airway calibre using hydrofluoroalkane fluticasone/salmeterol ( FP/SM ) vs. double the dose of fluticasone alone ( FP ) . METHODS Fourteen mild persistent asthmatics completed a r and omized double-blind crossover study with 1-week run-in and washout periods prior to treatments . Subjects received 3 weeks of FP 250 microg or FP 125 microg/SM 25 microg as 1 puff twice daily .  Methacholine PD20 and lung function were measured after both baseline and treatment periods . RESULTS There were no significant differences in baseline values prior to r and omized treatments . Compared with pooled baseline , FP/SM and FP conferred improvements ( P < 0.05 ) on methacholine PD20 : 2.5 ( 95 % confidence interval 1.7 , 3.2 ) and 1.6 ( 0.8 - 2.3 ) doubling dose improvements , respectively ; between FP/SM vs. FP there was a 0.9 ( 0.4 , 1.4 ) doubling dose difference ( P < 0.05 ) . For forced expiratory volume in 1 s ( FEV1 ) , forced mid-expiratory flow ( FEF25 - 75 ) and morning peak expiratory flow ( PEF ) , FP/SM but not FP conferred improvements ( P < 0.05 ) compared with pooled baseline , with FP/SM being greater than FP ( P < 0.05 ) : differences in FEV1 of 7.2 % ( 3.8 , 10.6 ) predicted , FEF25 - 75 of 11.2 % ( 6.3 , 16.1 ) predicted , and morning PEF of 17 L x min(-1)(1 - 32 ) . CONCLUSIONS FP/SM conferred improvements on AHR and airway calibre , while twice the dose of FP improved only AHR in patients with mild asthma . The differential effects of FP/SM and FP suggest separate but complementary actions of the two moieties on airway inflammation and smooth muscle stabilization . This may explain the beneficial effects of combination inhalers on exacerbations Inhaled short-acting β2‐agonists provide greater protection against airway responsiveness ( AR ) to the mast-cell stimulus , adenosine 5′‐monophosphate ( AMP ) , than to histamine , a direct spasmogen . Both terbutaline and albuterol exhibit this mast-cell stabilizing property in a dose-dependent manner . A single dose of the long-acting β2‐agonist formoterol has also been reported to have a mast cell-stabilizing effect , whereas salmeterol has not . To explore the dose-related actions of the long-acting β2‐agonist formoterol on AR , the authors compared the acute effects of three doses of formoterol and terbutaline on AR to AMP and histamine . In a double-blind , r and omized , placebo-controlled , cross-over study , 25 mild , steroid naive , asthmatic subjects attended on 10 occasions . At each visit , subjects inhaled either a single dose of terbutaline ( 500 µg ) , formoterol ( 6 , 12 or 24 µg ) or a matched placebo , administered via Turbuhaler ® , 30 min prior to challenge with both AMP and histamine . Each dose of β2‐agonist reduced AR to AMP and histamine . The bronchoprotective effects of formoterol ( 6 µg ) and terbutaline ( 500 µg ) were similar in magnitude in reducing AR to histamine ( mean±sd : 3.6±0.3 and 3.1±0.3 doubling doses ( DD ) ) and AR to AMP ( 3.5±0.5 and 3.3±0.4 DD , respectively ) . Overall , formoterol reduced AR to both spasmogens in a dose-dependent manner . In addition , formoterol ( 12 and 24 µg ) provided a significantly greater protective effect against AMP than against histamine challenge . It decreased AR by 5.7±0.6 and 6.3±0.7 DD against AMP and 4.3±0.4 and 4.8±0.43 DD against histamine , respectively . The results of this study indirectly demonstrated an in vivo dose-dependent mast-cell stabilizing effect of formoterol , in addition to functional antagonism on airway smooth muscle . This property of β2‐agonists may have clinical benefits in asthma management This double-blind , placebo-controlled , r and omized , parallel-group , multicenter study was conducted in 302 children aged 6 - 11 years with asthma not optimally treated with inhaled corticosteroids alone . Patients continued with their existing dose of inhaled corticosteroids and in addition received placebo , formoterol 4.5 microg or formoterol 9 microg b.i.d . , for 12 weeks ( all delivered via Turbuhaler ) . Terbutaline was available as reliever medication . The primary efficacy variable was change from baseline in morning peak expiratory flow ( PEF ) ; secondary efficacy variables included forced expiratory volume in 1 sec ( FEV(1 ) ) , serial PEF measured over 12 hr , evening PEF , asthma symptom score , and quality of life . Compared with placebo , formoterol 4.5 microg and 9 microg improved morning PEF by 8 l/min ( P = 0.035 ) and 11 l/min ( P = 0.0045 ) , respectively . Evening PEF and FEV(1 ) were also significantly increased compared with placebo , with no statistically significant difference between formoterol doses . Lung-function improvements compared with placebo were greater in the middle of the day . Twelve-hour average serial PEF after 3 months increased by 24 l/min ( 95 % CI , 9 , 39 l/min ) in the formoterol 9-microg group , and by 14 l/min ( 95 % CI , 0 , 29 l/min ) in the formoterol 4.5-microg group . The incidence of severe exacerbations in both formoterol groups was numerically lower than in the placebo group , indicating that formoterol may have the potential to improve exacerbation control in children . Both formoterol doses were well-tolerated , and tolerance to the drug 's bronchodilator effect was not observed . Formoterol provided sustained improvements in lung function and was well-tolerated in children with asthma suboptimally treated with inhaled corticosteroids alone BACKGROUND Endotoxin is a pro-inflammatory agent contaminating the dust that has been associated with the risk to develop pulmonary diseases . There is no data on the protective efficacy of anti-asthmatic drugs on the response induced by inhaled endotoxin in human . METHODS Twelve mildly asthmatic subjects were su bmi tted weekly to bronchial challenge tests with 20 microg endotoxin . The response was evaluated by the changes in FEV1 , blood cells count , neutrophils activation ( measured with the luminol-enhanced chemiluminescence ) and blood concentration in the acute phase proteins , C-reactive protein ( CRP ) and haptoglobin . In a double-blind r and omized cross-over placebo-controlled design , a single dose each of 500 microg beclomethasone dipropionate , 200 microg salbutamol , and 50 microg salmeterol were administered 30 minutes before the endotoxin challenge test . RESULTS The 20-microg endotoxin challenge test induced a significant decrease in FEV1 and luminol-enhanced chemiluminescence ( P < .001 and < .05 , respectively ) . There was an increase in the blood neutrophils count ( P < .05 ) , in CRP ( P < .02 ) and in haptoglobin ( P < .03 ) concentrations . Pretreatment with beclomethasone dipropionate did not have any significant effect on the response to inhaled endotoxin . Salbutamol and salmeterol completely prevent the FEV1 decline due to their potent bronchodilatation activity . Salmeterol and salbutamol did not have any significant effect on the blood inflammation induced by endotoxin inhalation . CONCLUSION The bronchodilating properties of beta2-agonists prevent the lung function response to inhaled endotoxin . When given in a single dose , an inhaled corticosteroid does not have protective activity on the endotoxin-induced blood inflammation BACKGROUND Options for step-down therapy include use of inhaled corticosteroids alone or in combination with a long-acting beta2-agonist . OBJECTIVE We sought to evaluate step-down therapy with a fluticasone propionate-salmeterol ( FP-SM ) combination administered through a dry powder inhaler ( DPI ; Advair Diskus ) versus a medium dose of hydrofluoroalkane 143a-beclomethasone dipropionate ( HFA-BDP ) administered through a breath-actuated pressurized metered-dose inhaler ( QVAR Autohaler ) . METHODS Thirty-nine patients with uncontrolled moderate-to-severe asthma were treated with 1000 microg of DPI-administered BDP twice daily ( DPI-BDP ) for 4 weeks and then r and omized to 200 microg of HFA-BDP twice daily ( n = 20 ) or 100 microg of FP and 50 microg of SM twice daily ( FM-SM ; n = 19 ) for 8 weeks in a double-blind , double-dummy , parallel-group design . We measured the provocative dose of methacholine producing a 20 % fall in FEV1 ( methacholine PD20 ) as the primary outcome , with secondary outcomes being lung function , surrogate inflammatory markers , diary card responses , quality of life , and safety . RESULTS There was a 0.9 ( 95 % confidence interval , 0.5 - 1.2 ) doubling dose improvement in methacholine PD20 comparing asthma before versus after DPI-BDP . HFA-BDP maintained this improvement , whereas FP-SM produced a further significant improvement , amounting to a 1.1 ( 95 % confidence interval , 0.2 - 2.1 ) doubling dose difference at 8 weeks for FP-SM versus HFA-BDP . Effects on FEV1 , peak expiratory flow , and quality of life ( symptoms and emotions ) were similar to those on methacholine PD20 , with a significant difference between FP-SM and HFA-BDP . Suppression of plasma and urinary cortisol and serum osteocalcin levels occurred with DPI-BDP , but values returned to baseline levels within 1 month of HFA-BDP or FP-SM administration . CONCLUSION After high-dose inhaled corticosteroid , stepping down with the combination inhaler conferred further improvements in bronchoprotection , bronchodilatation , and clinical control , but not inflammatory markers , compared with that seen with a medium dose of inhaled corticosteroid This multicentre double-blind , double-dummy study compared the safety and efficacy of a new combination Diskus inhaler containing both salmeterol 50 microg and fluticasone propionate 500 microg ( Seretide , GlaxoWellcome , France ) with the same doses of the two drugs delivered via separate Diskus inhalers and with the same dose of fluticasone propionate alone .  Patients were eligible for study entry if they had received an inhaled corticosteroid continuously for 12 weeks prior to run-in , and had received treatment with  beclomethasone dipropionate or budesonide 1500 - 2000 microg day(-1 ) or fluticasone propionate 750 - 1000 microg day(-1 ) for at least 4 weeks prior to run-in . In total , 503 patients receiving inhaled corticosteroids were r and omized to 28 weeks ' treatment with either salmeterol/fluticasone propionate ( 50/500 microg ) via a single Diskus inhaler ( combination ) and placebo , or salmeterol 50 microg and fluticasone propionate 500 microg administered via separate Diskus inhalers ( concurrent ) , or fluticasone propionate 500 microg and placebo . All treatments were administered twice daily , mean morning peak expiratory flow rate ( PEFR ) and asthma symptoms were measured for the first 12 weeks and safety data were collected throughout the 28-week study . Over weeks 1 to 12 , improvement in adjusted mean morning PEFR was 35 and 33 l min(-1 ) , respectively , in the combination and concurrent therapy treatment groups ( 12 and 10 % increase from baseline , respectively ) . The mean difference between treatments was -3 l min(-1 ) ( 90 % confidence interval -10.4 l min(-1 ) ) which was within the criteria for clinical equivalence . However , the combination therapy was statistically significantly superior to fluticasone propionate alone for mean morning PEFR ( P<0.001 ) and other measures of lung function , whilst clinical equivalence of the combination and concurrent therapies was observed . All three treatments were well tolerated . In addition , there were no differences between the three treatments in either the c.hange in serum cortisol or urinary cortisol concentrations , which , for each treatment group , were no significantly different from baseline at the end of the treatment period . Thus , the combination of salmeterol and fluticasone propionate in a single inhaler is as well tolerated and effective in achieving asthma control in steroid-dependent patients as the separate administration of the two drugs , and both combination and concurrent therapy are superior to administration of the same dose of corticosteroid alone This r and omized , double-blind , double-dummy , parallel group clinical trial compared the efficacy and safety of adding salmeterol xinafoate to concurrent inhaled beclomethasone dipropionate therapy with doubling the dose of beclomethasone dipropionate in patients experiencing symptoms on low-dose beclomethasone .  Salmeterol added to low-dose beclomethasone was superior ( p < or = 0.05 ) to doubling the dose of beclomethasone in improving peak expiratory flow ( PEF ) and forced expiratory volume in 1 sec ( FEV1 ) , and in reducing symptoms of asthma , sleep loss , nighttime awakenings , and use of albuterol . Both treatment regimens had comparable safety profiles . In asthma patients inadequately controlled despite the use of low-dose inhaled corticosteroids ( i.e. , less than 400 microg per day ) , the addition of salmeterol may be a more effective treatment option than doubling the dose of inhaled corticosteroids STUDY OBJECTIVE Several studies have demonstrated the superiority of salmeterol and formoterol to either regular treatment with albuterol or placebo . However , to date there have been no trials comparing the efficacy of salmeterol and formoterol in patients with severe asthma . DESIGN We undertook a r and omized , placebo-controlled , crossover study to compare 4 weeks of treatment with inhaled formoterol ( 12 microg twice daily ) or salmeterol ( 50 microg twice daily ) in patients with severe asthma whose conditions were not being adequately controlled by therapy with high doses of inhaled corticosteroids ( i.e. , > or = 1,500 microg daily ) or with regular oral corticosteroid treatment .  Morning pretreatment peak expiratory flow ( PEF ) during the last 14 days of the treatment period was the primary outcome variable . Patients recorded morning and evening pretreatment PEF , daytime and nighttime symptom scores , and any use of rescue medication . Spirometry and bronchial reversibility were performed after each treatment . RESULTS Forty-two nonsmoking patients ( 29 women ; mean age , 45 + /- 2 years ; mean [ + /- SEM ] FEV(1 ) , 61.8 + /- 3.4 % of predicted ) took part in the trial , and 27 patients completed the trial . The mean morning PEF was greater in patients receiving formoterol ( mean increase , 14.4 L/min ; 95 % confidence interval [ CI ] . 0.2 to 28.6 ) or salmeterol ( mean increase , 14.8 L/min ; 95 % CI , 0.5 to 29.1 ) compared with those receiving placebo , but there was no difference between these treatments . There were no significant treatment effects for any of the secondary outcome variables ( i.e. , FEV(1 , ) FVC , mean evening PEF , mean daytime symptom score , or nighttime symptom score ) . CONCLUSION We conclude that the long-acting beta(2)-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma , but that there is no difference in efficacy between the two drugs Inhaled corticosteroids and long-acting β2‐agonists effectively control asthma symptoms and improve airway function . The effects of beclomethasone were compared with those of salmeterol on markers of eosinophilic inflammation in induced sputum in steroid-naïve asthmatic subjects with moderate asthma . Fifteen moderate asthmatics were treated with either beclomethasone dipropionate ( 500 µg b.i.d ) or salmeterol ( 50 µg b.i.d ) for 4 weeks , according to a r and omised , double-blind , parallel-group study design . All patients underwent spirometry , methacholine test , sputum induction , and blood sampling before and after 2 and 4 weeks of treatment . They also recorded daily symptoms and peak expiratory flow ( PEF ) . Sputum eosinophils , eosinophil cationic protein ( ECP ) and eosinophil protein X ( EPX ) , and blood eosinophils , as well as the forced expiratory volume in one second ( FEV1 ) and morning PEF , significantly improved after beclomethasone but not after salmeterol . PEF variability , the symptom score and rescue β2‐agonist use significantly improved after both treatments , although the improvement in the symptom score tended to be greater after beclomethasone . After 2 and 4 weeks of beclomethasone  treatment , both serum ECP and EPX decreased . With salmeterol , only serum EPX decreased , after 4 weeks . Bronchial hyperresponsiveness to methacholine did not change after either treatment . The authors conclude that beclomethasone , but not salmeterol , substantially improves airway inflammation in asthma . Beclomethasone also had an overall greater clinical effect , although the improvement in symptoms and peak expiratory flow variability was similar after both treatments Salmeterol inhaled twice-daily is now being used more frequently as additional treatment in asthma insufficiently controlled by inhaled corticosteroids . We compared oral bambuterol in a dose of 20 mg taken once daily in the evening with inhaled salmeterol at 50 microgram taken twice daily in 126 asthmatic patients ( 60 bambuterol , 66 salmeterol ) aged 18 to 74 yr who were treated for at least 4 wk with inhaled corticosteroids at a constant dose of 400 to 2,000 microgram/d or with oral corticosteroids at < /= 20 mg/d . The patients were able to use a pressurized metered dose inhaler ( pMDI ) efficiently , and had an  FEV1  of 40 to 85 % of the predicted normal value . During a run-in period , patients had to show at least one nocturnal or early awakening caused by asthma symptoms that required rescue medication , and a > /= 15 % overnight decrease in peak expiratory flow ( PEF ) on 3 of the preceding 7 d , in order to be r and omized into this double-blind , double dummy , multicenter parallel group study ( 2-wk run-in period and 6 wk of treatment ) . There was no significant difference between bambuterol and salmeterol in morning change from baseline in PEF ( p = 0.53 ) . The median increases in morning PEF were 50 L/min for bambuterol and 55 L/min for salmeterol . Other variables ( evening PEF , percent of overnight decrease in PEF , number of awakenings , percent of nights with an awakening , number of puffs of rescue medication , asthma symptoms during the day and night , and mean tremor score ) also showed no significant difference between bambuterol and salmeterol . Both treatments , at the doses given , were well tolerated . Once-daily oral bambuterol is a convenient , effective , and less expensive alternative to twice-daily inhaled salmeterol for treating nocturnal asthma Background : In Russia , current therapy for the long-term management of asthma is mainly nonsteroidal . This situation provides the opportunity to evaluate new asthma treatments in a patient cohort with little previous exposure to inhaled corticosteroids . Objectives : To compare the effect of formoterol ( Oxis ® ) Turbuhaler ® plus budesonide ( Pulmicort ® ) Turbuhaler with budesonide Turbuhaler alone , on the health-related quality of life ( HRQL ) of patients with mild to moderate asthma . Methods : A double-blind , parallel-group , r and omized , 12-week study compared formoterol Turbuhaler plus budesonide Turbuhaler and budesonide Turbuhaler alone with an open control group of the investigator ’s choice of noncorticosteroid therapy . Patients completed the Short Form 36 ( SF-36 ) and the Asthma Quality of Life Question naire ( AQLQ ) . Results : The improvement in HRQL scores for patients treated with noncorticosteroids was significantly less ( p < 0.05 ) than those treated with formoterol plus budesonide and budesonide alone in all domains of the SF-36 and AQLQ with one marginal exception ( budesonide versus investigator ’s choice , SF-36 , Mental Component Scale , p = 0.053 ) . Improvements in HRQL scores  of formoterol plus budesonide , compared with budesonide alone , although generally higher , were not significantly different . Formoterol plus budesonide was more effective in improving lung function and reducing both symptoms and the need for relief terbutaline inhalation . Conclusion : Formoterol Turbuhaler plus budesonide Turbuhaler and budesonide Turbuhaler alone significantly improved the HRQL of patients with mild to moderate asthma compared with noncorticosteroid treatment The pulmonary distribution and clearance of 99m-Tc-labelled beclomethasone dipropionate (Bec)--dilauroylphosphatidylcholine ( DLPC ) were compared in nine asthmatic patients on inhaled steroids after a 1-week medical treatment period of long-acting beta2-agonist formoterol .  The patients were given formoterol 12 microg ( OxisTurbuhaler ) twice daily in addition to their own regular inhaled corticosteroid therapy . Gamma lung scintigraphy and lung function tests were performed before and after formoterol treatment . The bronchodilating effect ofthe combined therapy was significant : 1-week usage of inhaled formoterol enhanced peripheral lung deposition of beclomethasone liposome and thus diminished central /peripheral deposition ratio ( C/P ratio ) . All measured lung function values except FEV1/FVC% improved after the medication period , although statistically significant levels were not reached . A systemic positive connection was seen between enhanced lung functions and greater lung deposition measured as AUC(0 - 24h)/24 Beclomethasone liposome formulation maintained its long-lasting effect in connection with formoterol treatment . At the 4-h measurement , 76 % of the liposome-entrapped radioactivity still remained in the lungs before and 75 % after the medication period BACKGROUND The effects of budesonide , nedocromil sodium and salmeterol on  bronchial hyperresponsiveness  were determined over a period of 3 weeks . METHODS Forty-three asymptomatic children ( 22 male , 21 female , aged 7 - 17 years ) with mild-to-moderate asthma were evaluated . The study was placebo-controlled and double-blind . At the beginning the forced expiratory volume in 1 second ( FEV1 ) was measured and a methacholine challenge was performed to determine PC20 ( provocative concentration of inhaled methacholine required to reduce FEV1 by 20 % ) . The patients in group I ( n = 12 ) , group II ( n = 10 ) , group III ( n = 11 ) , and group IV ( n = 10 ) inhaled 200 micrograms of budesonide , 2 mg of nedocromil sodium , 25 micrograms of salmeterol and a placebo , respectively , twice a day over the period of 3 weeks . Then the methacholine PC20 values of all patients were measured again and the results were compared statistically with their previous values . RESULTS The statistical data revealed that the methacholine doses in PC20 before and after treatment were different in group I ( P < 0.01 ) . However , these differences were not statistically significant in the other groups ( P > 0.05 ) . CONCLUSIONS The short term usage of budesonide decreases bronchial hyperresponsiveness , but nedocromil sodium and salmeterol in the given dises do not affect bronchial hyperresponsiveness This r and omized , double-blind , parallel , multi-center study was design ed to determine whether the addition of salmeterol to existing inhaled corticosteroid therapy provides greater therapeutic benefit than doubling the dose of inhaled corticosteroids in symptomatic patients with asthma . A total of 514 adults were r and omized to either beclomethasone 168 micrograms plus salmeterol 42 micrograms twice daily or beclomethasone 336 micrograms twice daily for 24 weeks . Both treatments result ed in significantly improved symptom control and increased pulmonary function . However , beclomethasone plus salmeterol provided greater improvements than doubling the dose of beclomethasone ( p < or = 0.05 ) in FEV1 and in daily-recorded measurements of morning ( 38 L/minute versus 20 L/minute after treatment with higher dose beclomethasone ) and evening peak expiratory flow , asthma symptom scores , symptom-free days , supplemental albuterol use , and days and nights not requiring albuterol . There were no significant differences between treatment groups in the number of patients with abnormal response to corticotropin stimulation at Treatment Week 24 . No treatment differences in asthma exacerbation and adverse event frequency rates were seen . Beclomethasone 168 micrograms plus salmeterol 42 micrograms administered twice daily was superior to beclomethasone 336 micrograms taken twice daily in patients symptomatic on beclomethasone 168 micrograms , with no added safety risks A study was done to compare the efficacy and safety of the coprescription of salmeterol 50 microgram twice daily or 100 microgram twice daily with beclomethasone dipropionate ( BDP ) 500 micrograms twice daily ( SALM 50 and SALM 100 ) with BDP 1,000 microgram twice daily ( BDP 1,000 ) in patients with asthma not controlled by BDP 500 microgram twice daily ( or the equivalent ) . Following a run-in period , 738 patients at 72 centers were r and omized to treatment for 24 wk in a double-blind , parallel-group study during which they maintained a daily record of peak expiratory flow rates ( PEFRs ) and symptom scores . At about 40 of the centers , bronchial hyperresponsiveness ( BHR ) to histamine was measured during and at 3 and 14 d after stopping treatment . Both groups taking salmeterol showed an improvement of more than 45 L/min in their morning PEFR and 30 L/min in their evening PEFR , compared with respective improvements of 16 L/min and 6 L/min in the group taking BDP 1,000 . Both the SALM 50 and SALM 100 groups had a significantly increased percentage of symptom-free and rescue-free days and nights compared with the BDP 1,000 group , and there was no difference between the two salmeterol groups . None of the treatments altered BHR . Exacerbation rates did not differ among the three groups . We conclude that in this selected group of symptomatic patients taking BDP 500 micrograms twice daily , the addition of salmeterol provides better improvement in lung function and symptom control , without altering BHR or increasing exacerbation rates , than does doubling the dose of BDP Formoterol has a similar onset of effect to salbutamol but a prolonged duration of action . However , the relative efficacy of the two drugs in acute severe asthma is not known . This double-blind , double-dummy study compared the safety and efficacy of the maximum recommended daily dose of formoterol and a predicted equivalent dose of salbutamol in 88 patients presenting to the emergency department with acute severe asthma . Patients were r and omized  to formoterol 54 microg via Turbuhaler or salbutamol 2400 microg via pressurized metered dose inhaler ( pMDI ) plus spacer in three equal doses over 1 h. Following the full dose , mean FEV1 at 75 min increased by 37 % for formoterol and 28 % for salbutamol ( P = 0.18 ) . The maximum increase in FEV1 over 4 h was significantly greater with formoterol compared with salbutamol ( 51 % vs. 36 % , respectively P < 0.05 ) and formoterol was as effective as salbutamol at improving symptoms and wellbeing . Both treatments were well tolerated . Formoterol caused a greater decrease in serum potassium ( difference -0.2 mmol/l ) . In severe acute asthma , bronchodilator therapy with high-dose ( 54 microg ) formoterol Turbuhaler provided equally rapid improvements in lung function of greater magnitude over 4 h than high-dose ( 2400 microg ) salbutamol pMDI plus spacer Background Anti‐allergic mattress encasing may provide clinical benefit in asthmatic patients . However , the effect of mattress encasings on allergen‐specific parameters , such as bronchial reactions to house dust mite ( HDM ) challenge , is not clear This study evaluated the economic and health-related consequences of the as-needed use of a long-acting beta2-agonist with fast onset ( formoterol , Oxis Turbuhaler 4.5 microg ) versus a short-acting beta2-agonist ( terbutaline , Bricanyl Turbuhaler 0.5 mg ) in patients with moderate to severe asthma . A multi-national ( Sweden , Norway , The Netherl and s and Greece ) , multi-centre ( 35 centres ) , r and omized , double-blind clinical trial was conducted using 362 patients on inhaled steroids during a 12-week period . The effectiveness results were pooled and the total costs included estimates for beta2-agonists , inhaled steroids , oral steroids , physician visits and sick-leave . The 182 patients in the formoterol group had 14,404 days of exposure and 29 severe exacerbations , and the 180 patients in the terbutaline group had 13,655 days of exposure and 48 severe exacerbations . The terbutaline group had 62 % more severe exacerbations than the formoterol group ( P=0.039 ) , based on exposure time . Per patient , the calculated total costs were SEK 3386 for the formoterol group and SEK 3709 for the terbutaline group over the 12-week period . The conclusion is that the use of Oxis Turbuhaler instead of Bricanyl Turbuhaler for as-needed treatment is a more effective treatment generating cost savings from a societal perspective BACKGROUND There is a paucity of data comparing the long-term safety and efficacy of long-acting inhaled beta2-agonists versus low-dose inhaled corticosteroids in the treatment of asthma . OBJECTIVE To compare the safety and efficacy of salmeterol xinafoate , beclomethasone dipropionate ( BDP ) , and placebo over a 6-month treatment period in patients with persistent asthma . METHODS Salmeterol ( 42 microg twice daily ) , BDP ( 84 microg four times daily ) , or placebo was administered via metered-dose inhaler to 386 adolescent and adult inhaled corticosteroid-naive patients in a r and omized , double-blind , double-dummy , parallel-group study . Eligible patients demonstrated a forced expiratory volume in 1 second ( FEV1 ) from 65 % to 90 % of predicted values .  Pulmonary function , symptom control , frequency of asthma exacerbations , bronchial hyperresponsiveness ( BHR ) to methacholine challenge , and adverse events were assessed . RESULTS There were few statistically significant differences between the two active treatments over 6 months of therapy . Asthma symptoms and lung function were significantly improved with both salmeterol and BDP compared with placebo ( changes from baseline in FEV1 of 0.28 L ( SE = 0.04 ) and 0.23 L ( SE = 0.04 ) , respectively , compared with 0.08 L ( SE = 0.04 ) ; P < or = .014 ) . There were no significant differences among the treatment groups with respect to the distribution of asthma exacerbations over time . Both salmeterol and BDP significantly reduced BHR compared with placebo ( P < or = .033 ; changes from baseline of 1.29 ( SE = 0.26 ) and 1.42 ( SE = 0.24 ) doubling doses at 6 months , respectively , compared with 0.24 ( SE = 0.29 ) doubling dose for placebo ) . No rebound effect in BHR was seen upon cessation of any of the three treatment regimens . There were no clinical ly important differences in the safety profiles among the three treatments . CONCLUSIONS Both salmeterol and BDP are effective and well-tolerated when administered for 6 months to inhaled corticosteroid-naive patients with persistent asthma BACKGROUND The long-term efficacy and safety of formoterol dry powder capsules for inhalation in pediatric asthma have not previously been evaluated . OBJECTIVE We examined the effectiveness of inhaled formoterol over a period of 12 months in asthmatic children who were still symptomatic despite anti-inflammatory treatment . METHODS After a run-in period , 518 patients ( 5 to 12 years old ) were r and omized in a double-blind manner to receive 12 or 24 microg formoterol dry powder ( Foradil , Novartis Pharma AG , Basel , Switzerl and ) or placebo twice daily for 12 months . The drug was administered by inhaler ( Aerolizer , Novartis Pharma AG ) and was given in addition to their anti-inflammatory treatment . The primary variable was the area under the curve for forced expiratory volume in 1 second measured over 12 hours after the morning dose of study medication . RESULTS The area under the curve for forced expiratory volume in 1 second after the first dose of treatment and after 3 and 12 months of treatment was significantly greater for patients receiving formoterol 12 microg and 24 microg than for patients receiving placebo ( all P < or = 0.0062 ) . Compared with placebo , both doses of formoterol significantly improved morning and evening premedication peak expiratory flow rate ( all P < 0.001 ) . In the group treated with formoterol 24 microg , median symptom score and median dose of rescue medication at night were lower than during the run-in period , whereas the opposite occurred in the placebo group . The incidence of hospitalizations for asthma was higher in the formoterol groups than in the placebo group . CONCLUSION Our results indicate that , in asthmatic children who are still symptomatic despite anti-inflammatory therapy , the addition of formoterol consistently improves airflow obstruction and nocturnal symptoms and reduces the use of rescue medication . However , this treatment requires close disease monitoring to detect early signs of acute exacerbation OBJECTIVE To compare the efficacy and safety of a new combination Diskus inhaler containing both salmeterol 50 mg and fluticasone propionate 250 mg ( Seretide ) with the two drugs delivered via separate Diskus inhalers . DESIGN A multicentre , double-blind , double-dummy study . Three hundred and seventy-one symptomatic asthma patients ( age range 13 to 75 years , mean 42 years ) receiving inhaled corticosteroids were r and omly assigned to two treatment groups : 28 weeks ' treatment with either salmeterol/fluticasone propionate ( 50/250 microg bid ) via a single Diskus inhaler ( combination ) and placebo bid via another Diskus inhaler , or salmeterol 50 microg bid via one Diskus inhaler and fluticasone propionate 250 microg bid via another ( concurrent ) . Morning peak expiratory flow rate ( PEFR ) and symptoms were measured for the first 12 weeks and safety data were collected throughout the study . RESULTS Over weeks 1 to 12 , adjusted mean improvements in morning PEFR were 43 and 36 L/min for combination and concurrent therapies , respectively . The difference between the two treatment arms was 6 L/min ( 90 % CI -13 to 0 L/min ; P=0.114 ) , which was within the predefined criteria for clinical equivalence . Adjusted mean improvements in forced expiratory volume in 1 s from baseline for week 28 were also similar between the two therapies . Thirty-five per cent of patients receiving combination inhaler and 31 % of those receiving concurrent therapy had a mean daytime symptom score of zero over weeks 1 to 12 compared with 1 % and 2 % , respectively , at baseline . There was no difference in the incidence of adverse events between the two treatment arms . Mean serum cortisol levels were similar , and no differences in frequency of abnormal results were noted between the two groups . CONCLUSIONS This study shows that the combination of salmeterol and fluticasone propionate in a single inhaler is as efficacious in achieving asthma control and as well tolerated over a 28-week period as the two drugs administered individually This study aim ed to investigate the effect of treating patients with moderate asthma with formoterol on quality of life ( QoL ) and to compare several question naires in their ability to detect changes in QoL. In an eight month multicentre , r and omized , placebo-controlled trial , patients with asthma using daily inhaled corticosteroids and beta2-agonists ( > or = 5 inhalations x week(-1 ) ) were r and omized to 6 months treatment with formoterol 24 microg b.i.d . ( by Turbuhaler ) or a matching placebo . Patients recorded symptoms ( maximal score 21 ) and peak expiratory flow ( PEF ) twice daily . QoL was measured with two asthma-specific question naires , the Asthma Quality of Life Question naire ( AQLQ ) and the  Living with Asthma Question naire ( LWAQ ) , and with two generic QoL forms , i.e. the Short Form 36 ( SF36 ) and the Psychological and General Well-Being scale ( PGWB ) at r and omization and after 6 months of treatment . Out of 110 patients studied , 56 received  formoterol and 54 placebo .  Mean baseline forced expiratory volume in one second was 65 % predicted . Mean morning PEF was 369 L x min(-1 ) . Mean total symptom score was 3.6 . Morning PEF increased ( 26.8 L x min(-1 ) , p=0.0001 ) and symptoms decreased ( -1.23 , p=0.012 ) in the formoterol group in contrast to placebo . QoL improvements were measured in the LWAQ total score ( baseline 0.61 , change -0.05 , p=0.048 ) and the physical construct of the LWAQ ( baseline 0.71 , change 0.07 , p=0.044 ) . The AQLQ and the generic QoL instruments showed no significant changes . In conclusion , the improvement in quality of life reported after 6 months was very small and only reflected by the Living with Asthma Question naire OBJECTIVE To compare the efficacy and safety of inhaled salmeterol xinafoate , a long-acting beta 2-adrenoceptor agonist , with that of albuterol , a short-acting inhaled beta 2-agonist , in the treatment of asthma . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Eleven outpatient clinical centers . SUBJECTS A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy . INTERVENTION Patients were treated with salmeterol xinafoate ( 42 micrograms inhaled twice daily ) , albuterol ( 180 micrograms inhaled four times daily ) , or placebo ( four times a day ) for 12 weeks ; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms . MAIN OUTCOME MEASURES Serial 12-hour forced expiratory flow in 1 second ( FEV1 ) , peak expiratory flow ( PEF ) , asthma symptoms , nocturnal awakenings due to asthma , episodes of asthma exacerbations , and electrocardiography . RESULTS The mean area under the curve for FEV1 throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart ( P < .001 ) , with the difference ranging from 3.1 to 4.3 L.h . Salmeterol produced an average increase in morning and evening PEF of 26 and 29 L/min , respectively , over pretreatment values compared with decreases of -13 and -3 L/min , respectively , in the albuterol group and -2 L/min both in the morning and evening in the placebo group ( P < .001 ) . Patients in the salmeterol group had significantly fewer days and nights with symptoms than did either the albuterol or placebo group ( P < .001 ) . Responses to salmeterol were similar at day 1 and at week 12 . Adverse events in all treatment groups were equally infrequent , and no clinical ly significant change in cardiac rhythm was observed with salmeterol treatment . CONCLUSION Salmeterol inhaled twice daily is more effective than albuterol inhaled four times a day ( or as needed ) in patients with asthma requiring maintenance therapy . No deterioration of asthma control was observed with the use of salmeterol over a 3-month period BACKGROUND A budesonide/formoterol single inhaler has been developed for convenient treatment of patients whose asthma is inadequately controlled by inhaled glucocorticosteroids alone . OBJECTIVES To compare long-term safety and efficacy of budesonide/formoterol single inhaler with budesonide plus formoterol via separate inhalers in adults with asthma . METHODS In this open , r and omized , parallel-group 6-month extension conducted in a subset of centres from a previous 6-month study , patients ( n=321 ) received two inhalations bid of budesonide/formoterol ( Symbicort Turbuhaler ) 160/4.5 microg delivered dose or corresponding doses of budesonide ( Pulmicort Turbuhaler ) plus formoterol ( Oxis Turbuhaler ) via separate inhalers . RESULTS Significantly fewer patients receiving budesonide/formoterol single inhaler withdrew compared with budesonide plus formoterol ( 9 vs. 19 % , P=0.008 ) . Incidence and severity of AEs were low and similar in both groups . No clinical ly important differences between groups , or changes , were identified in laboratory measurements , vital signs or ECG . Treatments produced similar improvements in lung function , ACQ scores and Mini AQLQ domains that were maintained throughout 12 months . CONCLUSIONS Budesonide/formoterol in a single inhaler is as safe and effective in the long-term treatment of asthma as budesonide plus formoterol via separate inhalers . The lower number of withdrawals with budesonide/formoterol may reflect better adherence to treatment compared with budesonide plus formoterol Twenty-four children aged 12 - 17 years entered a r and omized , double-blind placebo-controlled study investigating the use of salmeterol in chronic severe asthma . In addition to their usual medication , the children were given either placebo or 100 micrograms salmeterol b.d . by dry powder inhalation . Treatment was continued throughout one term at a residential school for asthma . Symptom scores , peak expiratory flow rates , spirometry and quality -of-life scores were compared between the two treatment groups . One child withdrew during the run-in period . Twelve pupils received placebo and 11 pupils received salmeterol . There were consistent improvements in favour of salmeterol , reaching statistical significance for morning and evening peak flow rates and spirometry when measured on four occasions during the study period . There were no medication-related adverse events recorded and no pulse rate changes . Salmeterol ( 100 micrograms b.d . ) is well tolerated and efficacious in older children with chronic severe asthma SUMMARY Background : Current asthma guidelines recommend that patients are educated to adjust their medication according to their asthma severity using physician-guided self-management plans . However , many patients take a fixed dose of their controller medication and adjust their reliever medication according to asthma symptoms . Objectives : This study examined whether asthma control improved if patients adjusted the maintenance dose of budesonide/formoterol ( Symbicort Turbuhaler * 160/4.5 |ig ) according to asthma severity compared with traditional fixed dosing ( FD ) regimens . * Symbicort and Turbuhaler are registered trademarks owned by the AstraZeneca group , t Seretide and Diskus are trademarks of GlaxoSmithKline . Methods : Symptomatic patients with asthma ( n = 658 , mean symptom score 1.5 , mean inhaled corticosteroids 735|ig/day , mean forced expiratory volume in 1 second [ FEV1 ] 84 % predicted ) were r and omised after 2 weeks ' run-in to either : budesonide/formoterol adjustable maintenance dosing ( AMD ) , budesonide/formoterol FD or salmeterol/fluticasone ( Seretide Diskust 50/250 |ig ) FD . In a 4-week double-blind period , both budesonide/formoterol AMD and FD groups received two inhalations twice daily ( bid ) and salmeterol/fluticasone FD patients received one inhalation bid . In the following 6-month open extension , both FD groups continued with the same treatment . Patients in the AMD group with well-controlled asthma stepped down to one inhalation bid ; others continued with two inhalations bid . All AMD patients could increase to four inhalations bid for 7 - 14 days if symptoms worsened . All patients used terbutaline or salbutamol for symptom relief throughout . The primary variable was the odds of achieving a well-controlled asthma week ( WCAW ) . Results : The odds ratio for achieving a WCAW did not differ between the FD regimens ; however , during the open period , budesonide/formoterol AMD increased the odds of achieving a WCAW vs. budesonide/formoterol FD ( odds ratio 1.335 ; 95 % CI : 1.001,1.783 ; p = 0.049 ) despite a 15 % reduction in average study drug use . Budesonide/formoterol AMD patients had a lower exacerbation rate over the study : 40 % lower vs. salmeterol/fluticasone FD ( p = 0.018 ) ; 32 % lower vs. budesonide/formoterol FD ( NS ) . During the double-blind period , there were no clinical ly relevant differences between the budesonide/formoterol FD and salmeterol/fluticasone FD groups . Budesonide/formoterol AMD patients used less reliever medication in the open extension : 0.58 vs. 0.92 occasions/day for budesonide/formoterol FD ( p = 0.001 ) and 0.80 occasions/day for salmeterol/fluticasone FD ( p = 0.011 ) . Conclusions : Adjustable maintenance dosing with budesonide/formoterol provides more effective asthma control by reducing exacerbations and reliever medication usage compared with fixed-dose salmeterol/fluticasone We hypothesized that regular use of long-acting beta-agonists could delay recognition of ( " mask " ) increasing airway inflammation . We studied steroid-sparing and " masking " effects of salmeterol versus placebo in 13 asthmatic individuals requiring > = 1,500 microgram inhaled corticosteroid daily .  Corticosteroid doses were reduced weekly until criteria were met for an exacerbation or the corticosteroid was fully withdrawn . Subjects were restabilized on their original dose of inhaled corticosteroid for 4 wk before crossover to the alternative treatment . Subjects maintained symptom and peak expiratory flow ( PEF ) diaries , and underwent weekly spirometric , methacholine challenge , sputum eosinophil , and serum eosinophil cationic protein ( ECP ) measurements . Mean corticosteroid dose was reduced by 87 % during salmeterol treatment , versus 69 % with placebo ( p = 0.04 ) . Sputum eosinophils increased before exacerbation despite stable symptoms , FEV1 , and PEF . In the week before clinical exacerbation , sputum eosinophil counts were higher in the salmeterol-treatment arm ( 19.9 + /- 29.8 % [ mean + /- SD ] , versus placebo 9.3 + /- 17.6 % ; p = 0.006 ) . Five subjects showed > 10 % sputum eosinophilia before exacerbation during salmeterol treatment , as compared with two receiving placebo . In this model , salmeterol controlled symptoms and lung function until inflammation became significantly more advanced . We conclude that the bronchodilating and symptom-relieving effects of salmeterol can mask increasing inflammation and delay awareness of worsening asthma STUDY OBJECTIVES To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice setting s. DESIGN A r and omized , double-blind , 6-month , parallel-group study involving 253 centers . SETTING Primarily nonspecialist practice s ( n = 232 ) . PATIENTS A total of 911 subjects ( 417 men ; 494 women ) who met American Thoracic Society asthma criteria were enrolled and r and omized to treatment with either twice-daily salmeterol aerosol ( 50 microg ; n = 455 ) or matching placebo twice daily ( n = 456 ) . Both groups were allowed to take salbutamol as needed . All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study . MEASUREMENTS AND RESULTS The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization , emergency department visit , or use of prednisone during the treatment period . A total of 712 subjects competed the study . There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups ( 20.8 % vs 20.9 % , respectively ; p = 0.935 ; power > 88 % ) . Peak expiratory flow was significantly higher in the salmeterol group ( 398 L/min vs 386 L/min for placebo ; p < 0.01 ) . Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo ( p < 0.001 ) . The proportion of subjects sleeping through the night was significantly higher in the salmeterol group ( 74 % ) as compared to placebo ( 68 % ; p = 0.028 ) . CONCLUSIONS Salmeterol treatment is effective in subjects typically cared for in the primary -care setting and does not increase the frequency of severe exacerbations BACKGROUND The current stepwise approach to pharmacotherapy in the treatment of asthma includes the initiation of an inhaled corticosteroid with the addition of a long-acting inhaled bronchodilator if low dose inhaled corticosteroid fails to control asthma symptoms . OBJECTIVE To determine whether initiation of salmeterol and fluticasone propionate treatment together improves asthma control greater than initiation of monotherapy with the individual agents alone with no additional safety risk in patients with asthma who had not previously been treated with inhaled corticosteroids . METHODS A total of 136 male and female patients at least 12 years of age with asthma [ forced expiratory volume in 1 second ( FEV ) between 50 % and 80 % of predicted ] were r and omized to twice daily salmeterol 42 microg , fluticasone propionate 88 microg , fluticasone propionate 220 microg , salmeterol 42 microg plus fluticasone propionate 88 microg , salmeterol 42 microg plus fluticasone propionate 220 microg , or placebo for 4 weeks . RESULTS Patients treated with salmeterol combined with fluticasone propionate had improvements over baseline in FEV at endpoint that were at least twice as great ( 0.6 to 0.7 L ) as improvements in patients treated with salmeterol ( 0.3 L ) or fluticasone propionate alone ( 0.3 L ) ( P < .05 ) . Patient-rated data ( peak expiratory flow , asthma symptom scores , percent of days with no asthma symptoms ) confirmed greater ( P < .05 ) mean change from baseline improvements after combined treatment compared with fluticasone propionate alone . No clinical ly significant differences were noted between treatment groups in any safety measurement . CONCLUSION Initiation of maintenance therapy with salmeterol and fluticasone propionate in patients with asthma treated with short-acting beta2-agonists alone provides greater improvements in pulmonary function and symptom control than initiation of maintenance therapy with fluticasone propionate alone The present study was design ed to observe the effects of 8 wk of treatment with formoterol ( Foradil ) 24 microgram , budesonide 400 microgram , and matched placebo inhaled twice a day on inflammatory indices in the bronchial mucosa of 64 patients with mild atopic asthma . Biopsies were obtained at the start and 1 wk before stopping a 9-wk period of treatment , and inflammatory cell numbers were assessed in the submucosa and epithelium by immunohistochemistry . Regular formoterol significantly reduced the number of submucosal mast cells , with a similar trend for eosinophils but not activated T cells . A subgroup analysis conducted in biopsies with > = 10 eosinophils per mm2 revealed a significant reduction in eosinophil numbers when compared with both pretreatment baseline ( p < 0.01 ) and changes after placebo ( p < 0.01 ) . Parallel , but less pronounced , effects were observed on mast cell but not on CD25(+ ) T cell numbers . There was no effect of any of the three treatments on BAL levels of mast cell or eosinophil mediators . We conclude that regular treatment with inhaled formoterol reduces rather than increases inflammatory cells in the mucosa of asthmatic patients . It is possible that these cellular effects of formoterol may contribute to the therapeutic efficacy of this drug when used regularly in the Premenstrual exacerbation ( PME ) of asthma occurs during the 5 - 10 days leading up to the menses and can be demonstrated in about 40 % of asthmatic females .  Peak expiratory flow rate ( PEFR ) and beta2-agonist consumption were recorded during three menstrual cycles in 67 females with mild-severe asthma . All were treated with inhaled glucocorticosteroids ( IGC ) and beta2-agonists , as required . Following , the patients with a premenstrual reduction in PEFR > 20 % , received either salmeterol , 50 microg x 2 day(-1 ) or placebo , in the 10 days leading up to the menses , in a r and omized , double-blind , cross-over design . Thirteen patients ( 19.4 % ) showed PME ( mean + /- SEM decrease in PEFR 27 + /- 2.2 % ) in association with a significant increase in the mean daily beta2-agonist consumption . Following administration of salmeterol , there was a complete ablation of the PME in seven patients , a partial ablation in two patients and no effect in the remaining four patients . Only one patient showed a partial ablation of the PME following placebo . There was also a significant decrease in the beta2-agonists consumption in the responders . About 20 % of the women with asthma , under chronic IGC treatment , had PME of asthma . In 54 % of them , it could be prevented by the use of long-acting bronchodilators ( LABD ) during the 10 days leading up to the menses , and partially prevented in another 15 % The objective of this study was to compare the inflammatory marker eosinophil cationic protein ( ECP ) with peak expiratory flow ( PEF ) in determining the therapeutic needs of inhaled corticosteroids in asthma patients assessed as asthma symptoms . A r and omized , single-blind study over 6 months was performed at six specialist centres in Europe . In total , 164 adult patients with moderate to severe symptomatic asthma and regular use of inhaled corticosteroids were included . After a run-in period of 2 weeks patients were r and omly allocated to the ECP or the PEF monitoring group . The dose of inhaled cort costeroids was adjusted every fourth week based on the current serum ECP value or pre-bronchodilator morning PEF values as surrogate markers of therapeutic needs . At the end of the study there were no statistically significant differences in the mean daily symptom score or the percentage of symptom-free days between the two groups . The mean daily dose of inhaled corticosteroids was similar in the two groups at the start of the study but the algorithms used to adjust the dose of inhaled corticosteroids result ed in an increased use of inhaled corticosteroids in both groups . The mean daily dose of inhaled corticosteroids over the whole study period was significantly lower in the ECP group compared withthe PEF group ( 1246 vs. 1667 microg , P = 0.026 ) . In the ECP group , forced expiratory volume in I sec (FEV)% predicted was lower at the end ofthe study compared with the begining ( 92 % vs. 87 % , P = 0 .0009 ) , although there was no significant difference between the two groups . None of the used algorithms for ECP and PEF led to improvement in symptom scores , in spite of increased doses of inhaled corticosteroids . In this respect , both methods were equivalent and insufficient . Recommendations suggesting lung function tests in current guidelines may be difficult to translate into clinical practice , however , a combination of inflammatory markers , lung function and symptoms may still improve asthma control BACKGROUND Asthma is a chronic disease characterized by inflammation and bronchoconstriction . Medications that are able to effectively treat both components are advantageous . OBJECTIVE To compare the efficacy of an inhaled corticosteroid and a long-acting beta2-agonist combination product with a leukotriene antagonist for initial maintenance therapy in patients who were symptomatic while receiving short-acting beta2-agonists alone . METHODS A 12-week , r and omized , double-blind , double-dummy , multicenter study was conducted in 432 patients 15 years of age and older with persistent asthma who were symptomatic on short-acting beta2-agonists alone . Fluticasone propionate 100 microg and salmeterol 50 microg combination product ( FSC ) twice daily or montelukast 10 mg once daily was administered . RESULTS At endpoint , compared with montelukast , FSC significantly increased morning predose forced expiratory volume in 1 second ( 0.61 + /- 0.03 L vs 0.32 + /- 0.03 L ) , morning peak expiratory flow rate ( peak expiratory flow rate ; 81.4 + /- 5.9 L/minute vs 41.9 + /- 4.8 L/minute ) , evening peak expiratory flow rate ( 64.6 + /- 5.3 L/minute vs 38.8 + /- 4.7 L/minute ) , the percentage of symptom-free days ( 40.3 + /- 2.9 % vs 27.0 + /- 2.7 % ) , the percentage of rescue-free days ( 53.4 + /- 2.8 % vs 26.7 + /- 2.5 % ) , and the percentage of nights with no awakenings ( 29.8 + /- 2.5 % vs 19.6 + /- 2.1 % ) ( P < or = 0.011 , all comparisons ) . At endpoint , FSC significantly reduced asthma symptom scores ( -1.0 + /- 0.1 vs -0.7 + /- 0.1 ) and rescue albuterol use ( -3.6 + /- 0.2 puffs/day vs -2.2 + /- 0.2 puffs/day ) compared with montelukast ( P < 0.001 ) . At endpoint , patients treated with FSC also had a significantly greater improvement in quality of life scores and were more satisfied with their treatment compared with montelukast-treated patients ( P < or = 0.001 ) . Both treatments were well tolerated . CONCLUSIONS Initial maintenance therapy with FSC provides greater improvement in asthma control and patient satisfaction than montelukast Inhalation of dust from swine confinement buildings induces airway inflammation with an increase in both inflammatory cell numbers and secretion of proinflammatory cytokines in the lungs . It is not known whether anti‐asthma drugs , which influence airway inflammation in asthma , also influence the airway reaction to inhaled organic dust . In the present study we examined the effects of a ß2‐agonist ( salmeterol ) and an inhaled steroid ( fluticasone ) on the swine dust‐induced cell and cytokine content of the lower airways , and cytokine release in cultured alveolar macrophages . Healthy volunteers were pretreated with inhaled salmeterol ( n = 8) , fluticasone propionate ( n = 8) or placebo ( n = 8) for about 2 weeks and exposed to dust in a pig house . Bronchoalveolar lavage was performed both before medication and after dust exposure . Cell differential counts and cytokine analyses in bronchoalveolar lavage fluid ( BALF ) were examined . Alveolar macrophages were cultured and cytokine release was studied , both in unstimulated cells and after lipopolysaccharide ( LPS ) stimulation . Unstimulated alveolar macrophages from swine dust‐exposed individuals released less IL‐6 , IL‐8 and tumour necrosis factor‐alpha ( TNF‐α ) after , than before , exposure ( P < 0·01 ) . Medication did not influence basal cytokine production . Fluticasone  inhibited LPS‐induced IL‐6 and IL‐8 release ( P < 0·05 ) . There was no significant difference between the groups . There was a large and significant increase ( P < 0·05 ) in alveolar macrophage , granulocyte , lymphocyte numbers , and IL‐6 and TNF‐α content in BALF in all three groups following dust exposure , with no significant difference between the groups . These findings suggest that drugs which are known to influence and control airway inflammation in asthma do not have major effects on airway inflammation induced by the inhalation of organic dust Abstract Objective : The efficacy and tolerability of a new combination inhaler containing both salmeterol 50μg and fluticasone 100μg in a single device was compared with the delivery of the two drugs via two separate inhalers in a multicentre , double-blind , double-dummy study . Patients : 244 symptomatic asthma patients ( age range 12 to 78 years ) were r and omised to a 12-week treatment period with either salmeterol/fluticasone ( 50/100μg twice daily ) via a single inhaler ( combination ) and placebo twice daily via another , or salmeterol 50μg twice daily via one inhaler and fluticasone 100μg twice daily via another ( concurrent ) . Results : Morning peak expiratory flow rate ( PEFR ) , symptoms and tolerability were collected throughout the treatment period . Adjusted mean improvements in morning PEFR were 42 and 33 L/min for combination and concurrent therapies , respectively , over the 12-week treatment period . Adjusted mean improvements in forced expiratory volume in 1 second ( FEV1 ) from baseline at week 12 were 0.20 and 0.17L for combination and concurrent therapies , respectively . 60 % of patients receiving combination inhaler and 64 % of those receiving concurrent therapy had a mean daytime symptom score of zero over the treatment period compared with 17 and 15 % , respectively , at baseline . Both treatments were well tolerated . Geometric mean morning serum cortisol levels were similar and no differences in the frequency of abnormal results were noted between the two groups . Conclusion : This was the first study reporting the control of asthma by administration of salmeterol and fluticasone in combination via a single inhaler . The new combination inhaler was as effective and well tolerated as the two drugs administered individually and has potential advantages in terms of convenience BACKGROUND The clinical benefit of combining long-acting beta(2)-agonists with inhaled corticosteroids rather than doubling the dose of corticosteroid has been well-documented . However , there are concerns that this might result in a masking of underlying airway inflammation . OBJECTIVE The aim of this study was to test the hypothesis that the addition of the long-acting beta(2)-agonist salmeterol ( SALM ) to a low dose of the inhaled corticosteroid fluticasone propionate ( FP ) has a steroid-sparing effect and does not result in a worsening of bronchial inflammation compared to doubling the dose of inhaled corticosteroid . METHODS Fifty-six asthmatic subjects , previously not well-controlled on inhaled corticosteroids , were r and omized to receive 3 months of treatment with inhaled FP 500 microg twice a day ( FP 1000 ) or FP 200 microg twice a day plus SALM 50 microg twice a day ( FP 400 + SALM ) . Fluticasone propionate 200 microg twice a day served as the control ( FP400 ) . Bronchial mucosal biopsy specimens , bronchial washings ( BW ) , and bronchoalveolar lavage were obtained before and after treatment . The primary end points for the study were submucosal mast cell and eosinophil counts . RESULTS There was a significant improvement in FEV(1 ) in the FP400 + SALM group compared to both the FP400 and FP1000 groups . This was accompanied by a significant improvement in peak expiratory flow in the FP400 + SALM group in both the morning and evening compared to the FP1000 group . There were no significant between treatment differences in the change in the number of submucosal mast cells or eosinophils . However , in the FP400 + SALM group there was a significant decrease in submucosal mast cells after 12 weeks of treatment . The addition of SALM to FP was not associated with any increases in airway inflammation in the biopsy specimens , bronchoalveolar lavage , or bronchial washings . CONCLUSION These findings confirm that addition of SALM to FP has clinical benefits but does not mask or exacerbate airway inflammation and suggest that long-acting beta(2)-adrenoceptor agonists might influence mast cell numbers OBJECTIVE To compare the relapse rate after a single intramuscular injection of a long acting corticosteroid , betamethasone , with oral prednisone in patients discharged from the emergency department ( ED ) for acute exacerbations of asthma . PATIENTS AND METHODS Patients with acute exacerbations of asthma who were suitable for discharge from the ED were enrolled in a double-blind , r and omized , placebo controlled pilot study . At discharge , patients were r and omly assigned to receive either intramuscular betamethasone 12 mg and placebo capsules , or a placebo intramuscular injection and prednisone 50 mg daily for seven days . At days 7 and 21 , patients were contacted by telephone to determine relapse . Relapse was defined as an unscheduled visit to a physician for treatment of continuing or worsening symptoms of asthma . RESULTS One hundred and seventy-one patients were enrolled , of whom 87 were r and omly assigned to the betamethasone group and 84 to the prednisone group . Baseline characteristics were matched evenly between the groups , with the exception of asthma duration ( 15.5 versus 21.2 years , respectively ) and use of inhaled corticosteroids ( 46 % versus 64.3 % respectively ) ( P<0.05 ) . Using intention-to-treat analysis , the relapse rates for betamethasone and prednisone at day 7 were 14.9 % ( 13 of 87 patients ) and 25 % ( 21 of 84 patients ) , respectively ( P=0.1 ) , and at day 21 , the rates were 36.8 % ( 32 of 87 patients ) and 31 % ( 26 of 84 patients ) , respectively ( P=0.4 ) . There were no differences in symptom score , peak flows and adverse effects between the two groups at days 7 and 21 . CONCLUSIONS A single dose of intramuscular betamethasone 12 mg was safe and as efficacious as prednisone in preventing the relapse of acute asthma . There was a trend toward a reduced relapse rate at seven days . In select ED patients discharged for acute asthma , intramuscular betamethasone may be an effective alternative to prednisone AIMS Whether chronic dosing with montelukast confers benefit in patients with moderate to severe asthma remains to be fully established . A proof of concept study was performed evaluating putative benefits with montelukast in moderate persistent asthmatics who were taken off inhaled corticosteroids ( ICS ) and switched to  salmeterol . The latter was done to dissociate the effects of montelukast from ICS . METHODS Twenty moderate to severe persistent asthmatics completed a r and omized double-blind crossover study . Subjects received montelukast 10 mg daily or placebo for 2 weeks each . This was preceded by a 2-week run-in when ICS were discontinued and salmeterol started , and used on a regular basis throughout the study . Measurements were made after run-in and after both r and omized treatments . RESULTS There were no significant sequence effects for responses as to whether placebo or montelukast were given first or second . Methacholine PD20 values after run-in , first and second placebo were 63 micro g , 60 micro g and 64 micro g , respectively ( corresponding to 2 , 4 and 6 weeks of ICS washout , respectively ) . Lung function deteriorated pre vs post run-in , which was significant ( P < 0.05 ) for FEF25 - 75 % predicted . Montelukast conferred significant ( P < 0.05 ) improvements as change from post run-in compared with placebo in methacholine PD20 , FEV1 % predicted , FEF25 - 75 % predicted , diurnal peak expiratory flow , symptoms and salbutamol use . For the primary outcome of methacholine PD20 , this amounted to a 1.6-fold difference ( 95 % CI 1.1 , 2.5 ) . CONCLUSIONS In moderate persistent asthmatics switched from taking ICS to salmeterol alone , adding montelukast conferred significant benefits on all parameters of asthma control . Further studies are indicated to evaluate whether montelukast exhibits additive effects to ICS/long-acting beta2-adrenoceptor agonist combination inhalers upon clinical ly important outcomes The aim of this study was to compare the safety and efficacy of budesonide/formoterol 160/4.5 microg , two inhalations twice daily , with that of the mono-products administered at the same daily doses via separate inhalers . A total of 586 patients ( mean age 45 years ) was included in this six-month , open , r and omised , multicentre study . Patients received either budesonide/formoterol ( n=390 ) or budesonide plus formoterol ( n=190 ) . Safety was assessed by adverse events , vital signs and laboratory values . Efficacy was evaluated using spirometry tests , the Mini Asthma Quality of Life Question naire and the Asthma Control Question naire . Both treatments were well tolerated , with no differences in safety parameters between the groups . Mean FEV1 increased by 5 - 6 % over baseline in both groups . There was no significant difference in the change from baseline between the groups using the disease-specific question naires . Asthma exacerbations occurred with low frequency in both groups . Withdrawal rates were also comparable between the groups ( p=0.085 ) . Budesonide/formoterol in a single inhaler was as effective and as well tolerated as budesonide plus formoterol via separate inhalers BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density INTRODUCTION Twice-daily inhaled salmeterol produces rapid reduction in its acute bronchoprotective effect against methacholine in patients with mild asthma . This investigation examined this effect in patients with moderate asthma who were using inhaled corticosteroids . SUBJECTS AND METHODS Eight asthmatic volunteers who required inhaled corticosteroids for control of their symptoms and who were able to withhold treatment with beta 2-agonists for 4 weeks before and during the study participated in a double-blind , crossover , placebo-controlled study with two r and om-order treatment periods : inhaled salmeterol , 50 microg twice a day for seven doses , and placebo in similar fashion , with a 7-day or greater washout between these periods . Methacholine inhalation tests were done 1 h after doses 1 , 3 , 5 , and 7 , and then 24 h after the last dose of the study inhaler , 10 min post-200 microg salbutamol . RESULTS Baseline FEV1 measurements before doses 3 , 5 , and 7 of salmeterol , ie , 12 h after salmeterol , were significantly higher than all other baseline values . Twenty-four hours after the last dose of salmeterol , the FEV1 was no different from that during the placebo period . The geometric mean methacholine concentration causing a 20 % fall in FEV1 ( PC20 ) following the third dose of salmeterol ( 6.8 mg/mL ) was significantly lower than after the first dose of salmeterol ( 12.0 mg/mL ; p=0.031 ) , and this reduction of bronchoprotection persisted following doses 5 and 7 . The methacholine PC20 10 min postsalbutamol measured after the salmeterol period was significantly lower than after placebo ( 5.6 vs 13.3 mg/mL ; p<0.001 ) . CONCLUSIONS Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and persisted after the seventh dose . Tolerance to the acute bronchoprotective effect of salbutamol was also significant after regular use of salmeterol for seven doses . These effects , in subjects using inhaled corticosteroids regularly , were similar to the those previously seen in patients with mild asthma using as-required beta 2-agonists only , indicating that tolerance is not prevented by use of inhaled corticosteroids OBJECTIVE To evaluate the effect of salmeterol on asthma-specific quality of life in patients experiencing significant nocturnal symptoms . DESIGN R and omized , double-blind , placebo-controlled , multicenter clinical trial . SETTING Allergy/respiratory care clinics . PATIENTS Nonsmokers > or = 12 years of age with nocturnal asthma symptoms on at least 6 of 14 days during screening and > or = 15 % decrease in peak expiratory flow ( PEF ) from baseline on nocturnal awakening at least once during screening . INTERVENTIONS Salmeterol , 42 microg , or placebo twice daily . Patients were allowed to continue theophylline , inhaled corticosteroids , and " as-needed " albuterol . MEASUREMENTS AND RESULTS Outcome measures included Asthma Quality of Life Question naire ( AQLQ ) global and individual domain scores , FEV1 , PEF , nighttime awakenings , asthma symptoms , and supplemental albuterol use . Mean change from baseline for the global and domain AQLQ scores was significantly greater ( p < or = 0.005 ) with salmeterol compared with placebo . At week 12 , salmeterol significantly ( p < 0.001 compared with placebo ) increased mean change from baseline in FEV1 , morning and evening PEF , percentage of symptom-free days , percentage of nights with no awakenings due to asthma , and the percentage of days and nights with no supplemental albuterol use . Significant improvements in PEF were observed after treatment with salmeterol regardless of concomitant treatment with theophylline ( p < 0.05 ) . CONCLUSIONS These results provide evidence that vali date s the role of salmeterol in improving quality of life in patients with moderate persistent asthma who exhibited nocturnal asthma symptoms and supports the efficacy of salmeterol compared with that of placebo ( ie , " as-needed " albuterol ) This r and omised , double-blind , double-dummy , cross-over study was conducted at 29 general practitioners ' offices . Ninety-two patients with stable asthma were r and omised to treatment with either Salmeterol 50 micrograms ( b.i.d . ) or Salbutamol 400 micrograms ( q.i.d . ) . After four weeks treatment the patients continued another four weeks with the alternative treatment . During the study period the patients were allowed to use Salbutamol on a prn . basis . Inhaled steroids , if any , were continued . On diary cards patients recorded peak expiratory flow rate ( PEFR ) morning and evening before medication , asthma symptomscore , and use of additional doses of prn . beta 2-agonist . After the end of the last treatment period patients were asked which period they had preferred . Judged from all effect parameters , Salmeterol gave a better asthma control than Salbutamol . All improvements -except evening peak-flow and daily use of prn . salbutamol -were statistically significant . Most patients preferred Salmeterol treatment . Finally , the effect of Salmeterol was independent of any concurrent inhaled steroid treatment
BACKGROUND Consensus statements recommend the addition of long-acting inhaled beta2-agonists only in asthmatic patients who are inadequately controlled on inhaled corticosteroids .
OBJECTIVES To compare the efficacy of initiating anti-inflammatory therapy using the combination of inhaled corticosteroids and long-acting beta2-agonists ( ICS+LABA ) as compared to inhaled corticosteroids alone ( ICS alone ) in steroid-naive children and adults with persistent asthma .