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Intracoronary Injections of Salbutamol Demonstrate the Presence of Functional ft-Adrenoceptors in the Human Heart Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma Formoterol Delivered via the Dry Powder Aerolizer® Inhaler Versus Albuterol MDI and Placebo in Mild-to-Moderate Asthma: A Randomized, Double-Blind, Double-Dummy Trial Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma. Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study. The correlation between asthma control and health status: the GOAL study Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five-month multicentre Canadian study. Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma. Serum potassium levels, CPK-MB and ECG in children suffering asthma treated with beclomethasone or beclomethasone-salmeterol. Systemic effects of salbutamol and salmeterol in patients with asthma. Inhaled steroid/long-acting β2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients A comparison of the speeds of action of salmeterol and salbutamol in reversing methacholine-induced bronchoconstriction. An economic evaluation of combination treatment with budesonide and formoterol in patients with mild-to-moderate persistent asthma. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma Tolerance to beta-agonists during acute bronchoconstriction. Efficacy of budesonide/formoterol pressurized metered-dose inhaler versus budesonide pressurized metered-dose inhaler alone in Hispanic adults and adolescents with asthma: a randomized, controlled trial. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. Adjustable and fixed dosing with budesonide/ formoterol via a single inhaler in asthma patients: the ASSURE study. Once-daily dosing with budesonide/formoterol compared with twice-daily budesonide/formoterol and once-daily budesonide in adults with mild to moderate asthma. Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Salmeterol/Fluticasone Propionate in a Single Inhaler is Superior to Budesonide Alone in Control of Chinese Asthmatic Adults Once- vs Twice-Daily Budesonide/Formoterol in 6- to 15-Year-Old Patients With Stable Asthma Combination therapy with a long-acting beta-agonist and a leukotriene antagonist in moderate asthma. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Efficacy and safety of high-dose budesonide/formoterol (Symbicort) compared with budesonide administered either concomitantly with formoterol or alone in patients with persistent symptomatic asthma. An individualized, adjustable maintenance regimen of budesonide/formoterol provides effective asthma symptom control at a lower overall dose than fixed dosing. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. 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Salmeterol/fluticasone propionate (50/100 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in children with asthma. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Long-term safety and asthma control with budesonide/formoterol versus budesonide pressurized metered-dose inhaler in asthma patients. Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing. The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone in children. Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Initiation of Maintenance Therapy with Salmeterol/Fluticasone Propionate Combination Therapy in Moderate Asthma: A Comparison with Fluticasone Propionate The effect of budesonide and formoterol in one pressurized metered-dose inhaler on patient-reported outcomes in adults with mild-to-moderate persistent asthma Initial treatment of symptomatic mild to moderate bronchial asthma with the salmeterol/fluticasone propionate (50/250 microg) combination product (SAS 40023). Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma. A randomized, double-blind trial of the effect of anti-asthma treatment on lung function in children with asthma. Efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler: randomized controlled trial comparing once- and twice-daily dosing in patients with asthma. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. The salmeterol/fluticasone combination is more effective than fluticasone plus oral montelukast in asthma. Formoterol (Foradil) and medium-high doses of inhaled corticosteroids are more effective than high doses of corticosteroids in moderate-to-severe asthma. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Low-dose fluticasone propionate with and without salmeterol in steroid-naïve patients with mild, uncontrolled asthma. Down-titration from high-dose combination therapy in asthma: Removal of long-acting beta(2)-agonist. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Comparison of fluticasone propionate-salmeterol combination therapy and montelukast in patients who are symptomatic on short-acting beta(2)-agonists alone. [Fixed-dose fluticasone-salmeterol combination: at least effective and better tolerated than open-dose combinations]. Efficacy and Safety of Fluticasone Propionate/Salmeterol HFA 134A MDI in Patients with Mild‐to‐Moderate Persistent Asthma Initiation of maintenance treatment of persistent asthma: salmeterol/fluticasone propionate combination treatment is more effective than inhaled steroid alone. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Salmeterol compared with current therapies in chronic asthma. 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 Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma:an efficacy and cost-effectiveness study Regular inhaled salbutamol and airway responsiveness to allergen Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study. Formoterol added to low-dose budesonide has no additional antiinflammatory effect in asthmatic patients. Asthma therapy modulates priming-associated blood eosinophil responsiveness in allergic asthmatics. The extrapulmonary effects of increasing doses of formoterol in patients with asthma Control of mild to moderate asthma over 1-year with the combination of salmeterol and fluticasone propionate. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Combination Therapy with Single Inhaler Budesonide/Formoterol Compared with High Dose of Fluticasone Propionate Alone in Patients with Moderate Persistent Asthma Hypokalemia from beta2-receptor stimulation by circulating epinephrine. [Efficacy and acceptability of the fixed fluticasone + salmeterol combination in the treatment of acute asthma attacks. Results of a one-year comparative study]. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Addition of Formoterol or Montelukast to Low-Dose Budesonide: An Efficacy Comparison in Short- and Long-Term Asthma Control Fluticasone propionate and salmeterol administered via Diskus compared with salmeterol or fluticasone propionate alone in patients suboptimally controlled with short-acting beta2-agonists. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. 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. Long-term effects of formoterol and salbutamol on bronchial hyperreactivity and beta-adrenoceptor density on lymphocytes in children with bronchial asthma. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma. Budesonide/Formoterol Pressurized Metered-Dose Inhaler versus Budesonide: A Randomized Controlled Trial in Black Patients with Asthma Asthma control can be maintained when fluticasone propionate/salmeterol in a single inhaler is stepped down. Efficacy and safety of fluticasone propionate/salmeterol 250/50 mcg Diskus administered once daily. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose Efficacy and safety of a new pressurised metered-dose inhaler formulation of budesonide/formoterol in children with asthma: a superiority and therapeutic equivalence study. Adjustable maintenance dosing with budesonide/formoterol or budesonide: double-blind study. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma. Efficacy and safety of salmeterol/fluticasone propionate delivered via a hydrofluoroalkane metered dose inhaler in Chinese patients with moderate asthma poorly controlled with inhaled corticosteroids. Formoterol and beclomethasone versus higher dose beclomethasone as maintenance therapy in adult asthma. Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma? Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. 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. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. 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. Randomized comparison of strategies for reducing treatment in mild persistent asthma. Step-up therapy for children with uncontrolled asthma receiving 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 Budesonide/formoterol in a single inhaler (Symbicort) reduces healthcare costs compared with separate inhalers in the treatment of asthma over 12 months. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. The Canadian FO/OD1 Study Group. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Cost Effectiveness of Fluticasone Propionate Plus Salmeterol Versus Fluticasone Propionate Plus Montelukast in the Treatment of Persistent Asthma Salmeterol and fluticasone propionate (50/250 microg) administered via combination Diskus inhaler: as effective as when given via separate Diskus inhalers. Short-Term Safety and Tolerability of Double-Dose Salmeterol/Fluticasone Propionate in Adult Asthmatic Patients One-year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler) for the treatment of asthma. Control of airway inflammation maintained at a lower steroid dose with 100/50 microg of fluticasone propionate/salmeterol. Impact of Inhaled Salmeterol/Fluticasone Propionate Combination Product versus Budesonide on the Health-Related Quality of Life of Patients with 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. [Evaluation of the clinical efficacy and the safety of salmeterol/fluticasone propionate accuhaler compared to budesonide turbuhalar in the control of adult asthma]. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study. Salmeterol/Fluticasone Combination Inhaler Effect of inhaled fluticasone with and without salmeterol on airway inflammation in asthma. Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma. The safety and efficacy of formoterol (Oxis) turbuhaler plus budesonide (Pulmicort) turbuhaler in mild to moderate asthma: a comparison with budesonide Turbuhaler alone and current non-corticosteroid therapy in Russia. Adding salmeterol to an inhaled corticosteroid reduces allergen-induced serum IL-5 and peripheral blood eosinophils. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. Regular inhaled beta-agonist treatment in bronchial asthma
BACKGROUND Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting β(2)-adrenergic agonist medications in African American asthmatic patients is limited . OBJECTIVE We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus budesonide over 1 year in African American patients . METHODS This 52-week , r and omized , double-blind , parallel-group , multicenter , phase 3B safety study ( NCT00419952 ) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids . After 2 weeks using a 320 μg twice-daily budesonide pMDI , patients were r and omized 1:1 to 320/9 μg twice-daily budesonide/formoterol pMDI or 320 μg twice-daily budesonide pMDI . RESULTS Both treatments were well tolerated . Asthma exacerbation incidence and rate ( per patient-treatment year ) were lower with budesonide/formoterol versus budesonide ( incidence , 7.7 % vs 14.0 % [ P= .006 ] ; rate ratio , 0.615 [ P= .002 ] ) . Time to first asthma exacerbation was longer ( P= .018 ) with budesonide/formoterol versus budesonide . The most common adverse events , regardless of study drug relationship , were headache ( 9.5 % and 7.7 % ) , nasopharyngitis ( 6.9 % and 8.0 % ) , sinusitis ( 4.0 % and 6.3 % ) , and viral upper respiratory tract infection ( 5.8 % and 4.4 % ) for budesonide/formoterol and budesonide , respectively . Serious adverse events occurred in 12 and 15 patients , respectively ; none were considered drug related . No substantial or unexpected patterns of abnormalities were observed in laboratory , electrocardiographic , or Holter monitoring assessment s. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups , respectively . Pulmonary function and asthma control measures generally favored budesonide/formoterol . CONCLUSIONS In this population budesonide/formoterol pMDI was well tolerated over 12 months , with a safety profile similar to that of budesonide ; the asthma exacerbation rate was reduced by 38.5 % versus budesonide A r and omised , double-blind trial was undertaken to investigate the efficacy and tolerability of formoterol Turbuhaler in children with mild to moderate asthma . After a two-week run-in , 248 children aged 6 - 17 years were r and omised to receive formoterol 4.5 and 9 pmicro b.i.d . or placebo for 12 weeks . Morning PEF ( primary variable ) , was significantly improved versus placebo only in the formoterol 9 pmicro b.i.d . group ( 13 l/min , 95 % CCI 1.9 , 24.2 % ; p = 0 .02 ) . Both formoterol 4.5 and 9 pmicro significantly increased the pre-bronchodilator FEV1 by 5.2 - 6.7 % ( p < 0 .05 ) and reduced use of daytime relief medication versus placebo ( p < 0 .05 ) . Formoterol 9 pmicro significantly reduced night-time reliever use and awakenings due to asthma versus placebo ( p < 0.05 ) . Both doses of formoterol were as well tolerated as placebo . In conclusion , formoterol 4.5 and 9 micro b.i.d . is effective and well tolerated as maintenance therapy in children with mild to moderate asthma BACKGROUND For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid ( ICS ) therapy , the preferred treatment is to add an inhaled long-acting beta2-agonist vs increasing the ICS dose . OBJECTIVE To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma . METHODS A r and omized , multicenter , double-blind , active-controlled , parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy . Patients received fluticasone propionate-salmeterol ( 100/50 microg ) or fluticasone propionate ( 100 microg ) alone twice daily for 12 weeks . RESULTS The safety profile of fluticasone propionate-salmeterol was similar to that of fluticasone propionate alone . The overall incidence of adverse events was 59 % for fluticasone propionate-salmeterol and 57 % for fluticasone propionate . Both treatments were well tolerated . Two patients receiving fluticasone propionate-salmeterol and 5 receiving fluticasone propionate withdrew from the study because of worsening asthma . Changes in heart rate , blood pressure , and laboratory variables were infrequent and were similar between treatments . No patients had clinical ly significant abnormal electrocardiographic findings during treatment . Geometric mean 24-hour urinary cortisol excretion at baseline and after 12 weeks of treatment was comparable within and between groups ; no patient in either group had abnormally low 24-hour urinary cortisol excretion after 12 weeks of treatment . The incidence of withdrawals due to asthma exacerbations was 2 % in the fluticasone propionate-salmeterol group and 5 % in the fluticasone propionate group . CONCLUSIONS In pediatric patients with persistent asthma , fluticasone propionate-salmeterol twice daily was well tolerated , with a safety profile similar to that of fluticasone propionate used alone 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 In vitro the long acting β2 agonist salmeterol can , in contrast to formoterol , behave as a partial agonist and become a partial antagonist to other β2 agonists . To study this in vivo , the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists . METHODS A r and omised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second ( FEV1 ) of 88.4 % predicted and median concentration of methacholine provoking a fall in FEV1 of 20 % or more ( PC20 ) of 0.62 mg/ml at entry . One hour after the last dose of 2 weeks of treatment with formoterol ( 24 μg twice daily by Turbuhaler ) , salmeterol ( 100 μg twice daily by Diskhaler ) , or placebo a methacholine provocation test was performed and continued until there was at least a 30 % decrease in FEV1 . Salbutamol ( 50 μg ) was administered immediately thereafter , followed by ipratropium bromide ( 40 μg ) after a further 30 minutes . Lung function was monitored for 1 hour after provocation . RESULTS There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment . The dose of methacholine needed to provoke a fall in FEV1 of ⩾30 % was higher after pretreatment with formoterol ( 2.48 mg ) than with salmeterol ( 1.58 mg ) or placebo ( 0.74 mg ) . The difference between formoterol and salmeterol was statistically significant : 0.7 doubling dose steps ( 95 % CI 0.1 to 1.2 , p=0.016 ) . The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs ( p<0.0003 for both ) . Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8 % , 7.3 % , and 5.5 % for placebo , formoterol and salmeterol , respectively ( equivalent to increases of 26 % , 14 % , and 12 % , respectively , from the lowest FEV1after methacholine ) . At 30 minutes significant differences remained , but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups . CONCLUSION Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent , indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo . Irrespective of this , prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally , indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol . Patients on regular treatment with long acting β2 agonists  should be made aware that an additional single dose of a short acting β2 agonist may become less effective 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 BACKGROUND The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity . The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects . METHODS A double blind , r and omised , crossover study was carried out in 16 healthy subjects who inhaled formoterol 24 , 48 and 96 μg ( via Turbuhaler ® ) , salmeterol 100 , 200 and 400 μg ( via Diskhaler ® ) , or placebo on separate days . Heart rate , systolic and diastolic blood pressure , and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose . Mean maximum ( or minimum ) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs . Lunch was taken after the four hour readings and , since this caused additional changes to the main outcome measures , data from the first four hours are also presented in a post hoc analysis . RESULTS Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration ; formoterol also caused an early increase in systolic blood pressure . The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol , apart from the glycaemic response . The effects of salmeterol were slightly more prolonged than those of formoterol , although some dose related effects were apparent at eight hours with both drugs . The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values . Relative dose potencies ( 95 % CI ) for maximum heart rate and plasma potassium concentrations were 4.1 ( 3.0 to 5.6 ) and 5.8 ( 4.1 to 8.6 ) over four hours and 2.4 ( 1.2 to 3.8 ) and 3.0 ( 1.2 to 5.7 ) over eight hours . CONCLUSIONS Formoterol and salmeterol cause dose related changes in heart rate , diastolic blood pressure , and plasma glucose and potassium concentrations . Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity . Both drugs have a relatively modest therapeutic window . The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses . Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained BACKGROUND Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear . Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects . A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow ( FBF ) as a measure of peripheral vasodilatation . METHODS Eight men with mild asthma underwent the following treatments : normoxia + placebo ( NP ) , normoxia + salbutamol ( NS ) , hypoxia + placebo ( HP ) , and hypoxia + salbutamol ( HS ) . The period of mask breathing started at t=0 minutes , lasted for 60 minutes , and at 30 minutes 800 μg salbutamol was inhaled . The experiment was completed 30 minutes after the inhalation ( t=60 minutes ) . For the hypoxia treatment the Spo 2 level was 82 % . Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value . RESULTS There were no significant differences in blood pressure and potassium levels between the treatments . After 60 minutes the increase in FBF was 13 % ( 95 % CI –12 to 39 ) more for HP treatment than for NP , 21 % ( 95 % CI –5 to 46 ) more for NS than for NP , and 32 % ( 95 % CI 7 to 58 ) more for HS than for HP ( p=0.016 ) . The inhalation of salbutamol during hypoxia result ed in a significant increase in FBF of 45 % ( 95 % CI 20 to 71 ) compared with NP ( p=0.001 ) . CONCLUSION Patients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death AIMS Inhalers combining long acting beta2-adrenoceptor agonists ( LABA ) and corticosteroids ( ICS ) are indicated at Step 3 of current asthma guidelines . We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function , bronchoprotection , acute salbutamol recovery following methacholine bronchial challenge , and surrogate inflammatory markers in patients with moderate persistent asthma . METHODS Twenty-nine patients with mean FEV1 ( + /- SEM ) of 78 + /- 3 % predicted completed a r and omized , double-blind , double-dummy , cross-over study . Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg ( BUD + FM ) combination twice daily followed by 1 week of BUD 400 microg alone twice daily , or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg ( FP + SM ) combination twice daily followed by 1 week of FP 250 microg alone twice daily . Measurements were made at baseline and following each r and omized treatment . RESULTS FEV1 increase from pretreatment baseline as mean ( + /- SEM ) % predicted was significantly higher ( P < 0.05 ) for BUD + FM ( 8 + /- 1 % ) vs BUD ( 2 + /- 1 % ) , and for FP + SM ( 8 + /- 1 % ) vs FP ( 2 + /- 1 % ) . The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups ; BUD + FM ( 22 + /- 1 % ) , BUD ( 24 + /- 1 % ) , FP + SM ( 23 + /- 1 % ) and FP ( 23 + /- 1 % ) . Salbutamol recovery over 30 min following methacholine challenge as area under curve ( AUC % .min ) was significantly blunted ( P < 0.05 ) with BUD + FM ( 486.7 + /- 35.5 ) vs BUD ( 281.1 + /- 52.8 ) , and with FP + SM ( 553.1 + /- 34.1 ) vs FP ( 368.3 + /- 46.7 ) . There were no significant differences between respective combination inhalers or between respective ICS alone . Decreases in exhaled nitric oxide ( NO ) and serum eosinophilic cationic protein ( ECP ) from baseline were not significantly different between treatments . CONCLUSIONS Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone , but delay acute salbutamol recovery after bronchoconstriction To demonstrate the presence of functional cardiac β2-adrenoceptors in man , we studied the responses to intracoronary injections of salbutamol in three groups of six patients . We injected salbutamol , a selective β2-adrenoceptor agonist , into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly . Salbutamol injections caused a sinus tachycardia . The same doses of salbutamol injected into the aortic root caused no change in heart rate , ruling out a systemic effect . The mean dose required to cause an increase in heart rate of 30 beats/min ( IHR30 ) was 2.6 μg in the first group of six patients . In 12 other patients salbutamol was given after β-blockade to confirm the β2-selectivity of the responses . Doses of practolol ( β1,-selective blockade ) and of propranolol ( β1- and β2-blockade ) that had equal β1-blocking activity were used . In six patients who were given practolol  , the mean IHR30 dose was 2.1 μg . In six patients who were given propranolol , the mean IHR30 dose was significantly greater at 64 μg ( p < 0.001 , practolol vs. propranolol ) . This study demonstrates that direct cardiac β2-adrenoceptor stimulation in man has a positive chronotropic effect Background : Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids . However , little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process , control of which is considered important for the long term outcome of asthma . Methods : After a 4 week fluticasone run-in period , 54 patients with allergic asthma were r and omised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind , parallel group design ( total daily dose of fluticasone 500 μg in both treatment groups ) . Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations . Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker . The effects on allergen induced changes were determined before and at the end of the treatment period . Results : Adding salmeterol to fluticasone result ed in improved peak expiratory flow , symptom scores , rescue medication usage , and bronchial hyperresponsiveness ( p<0.05 for all ) . There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment ( p>0.05 ) . However , adding salmeterol significantly reduced sputum ratios of α2-macroglobulin and albumin during the treatment period ( p = 0.001 ) . Conclusions : The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane . This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids The objectives of this study were to compare the efficacy and tolerability of twice-daily formoterol dry powder 12 µg and 24 µg ( Foradil ) delivered via Aerolizer inhaler with four times daily albuterol ( salbutamol ) 180 µg delivered via metered dose inhaler ( MDI ) and placebo .  A total of 554 adolescents and adults ( ages 12–75 years ) with mild-to-moderate asthma were r and omized to this 12-week , multicenter , double-blind , double-dummy , placebo-controlled , parallel-group study . Twelve-hour spirometry measurements were taken at weeks 0 , 4 , 8 , and 12 . A total of 484 patients completed the study ( 122 , 116 , 127 , and 119 given formoterol 12 µg , formoterol 24 µg , albuterol , and placebo , respectively ) . For the primary efficacy variable , the forced expiratory volume in 1 second ( FEV1 ) , both formoterol 12 µg and 24 µg were statistically superior to placebo at all time points on all test days ( p ≤ 0.017 ) and to albuterol at most time points on all test days ( p ≤ 0.001 ) . The onset of improvement in FEV1 was rapid , with 15 % increase within 5 min in 57 % , 71 % , and 65 % of formoterol 12 µg , formoterol 24 µg , and albuterol patients , respectively . Formoterol was also superior to placebo and albuterol in terms of secondary efficacy variables : FEV1 area under the curve , percentage of predicted FEV1 , forced vital capacity and forced expiratory flow , asthma symptom scores , and peak expiratory flows . In conclusion , both formoterol doses were superior to placebo in all lung function measurements . Overall , compared with  albuterol , both formoterol doses produced superior bronchodilation  . Formoterol and albuterol  were safe and well-tolerated 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 BACKGROUND For patients whose asthma is uncontrolled with low-dose inhaled corticosteroids , addition of alternative therapy instead of increasing the steroid dose is recommended by current treatment guidelines . OBJECTIVE To compare montelukast , a once-daily leukotriene receptor antagonist , and salmeterol , a twice-daily , long-acting beta-agonist , concomitantly administered with inhaled fluticasone , according to the percentage of patients without an asthma attack for 1 year . METHODS A r and omized , double-blind , double-dummy , multicenter study was conducted . Adult patients with moderate-to-severe persistent asthma ( ages 14 - 73 years ) receiving inhaled fluticasone ( 220 microg/d ) who remained symptomatic during a 4-week run-in period were r and omized to the addition of salmeterol ( 84 microg/d ) or montelukast ( 10 mg/d ) for 48 weeks . RESULTS Of the 1,473 r and omized patients , 743 were r and omized to montelukast and 730 to salmeterol ; 1,059 patients completed the study . Eighty percent of patients in the montelukast group and 83.3 % of patients in the salmeterol group remained attack free during the 48 weeks of treatment ( relative risk , 1.20 ; 95 % confidence interval , 0.96 - 1.49 ) . Montelukast significantly reduced blood eosinophil counts compared with salmeterol , whereas salmeterol significantly increased prealbuterol forced expiratory volume in 1 second , asthma-specific quality of life , morning peak expiratory flow rate , and decreased nocturnal awakenings compared with montelukast . Differences between treatments were small , and both treatments were generally well tolerated . CONCLUSIONS Addition of montelukast or salmeterol to an inhaled corticosteroid similarly protected most patients from experiencing an asthma attack during a 1-year period , but , based on noninferiority limits , the study was inconclusive with regard to a difference between treatment groups The present study examined the association between guideline -derived asthma control and health-related quality of life , assessed using the Asthma Quality of Life Question naire ( AQLQ ) , in patients with uncontrolled asthma whose treatment was directed towards achieving the highest possible level of control . The present r and omised , double-blind , parallel-group study compared the efficacy of fluticasone propionate ( FP ) and salmeterol/fluticasone propionate combination ( SFC ) in achieving two composite , guideline -derived measures of control : total control ( TC ) and well-controlled ( WC ) asthma . Not achieving these levels was classed as not well-controlled ( NWC ) . Doses were augmented until patients achieved TC or reached the maximum dose . This dose was maintained for the remainder of the study . AQLQ was assessed at baseline and at each clinic visit . AQLQ scores improved throughout the study , reaching near-maximal levels in patients achieving TC and WC , and 52-week mean scores in the three control groups were statistically significantly different . Clinical ly meaningful improvements ( mean change from baseline ) were : TC group ( SFC 1.9 , FP 1.8 ) , WC ( SFC 1.5 , FP 1.5 ) and NWC ( SFC 1.0 , FP 0.9 ) . In conclusion , the treatment aim ed at controlling asthma improves the health-related quality of life to levels approaching normal . The difference in Asthma Quality of Life Question naire scores between total control and well-controlled confirms that patients distinguish even between these high levels of control BACKGROUND Adjustable maintenance dosing with budesonide/formoterol in a single inhaler ( Symbicort , AstraZeneca , Lund , Sweden ) may provide a convenient means of maintaining asthma control with the minimum effective medication level . OBJECTIVES To compare adjustable and fixed maintenance dosing regimens of budesonide/formoterol in asthma . METHODS This was an open-label , r and omized , parallel-group , multicentre , Canadian study of asthma patients ( aged 12 years or older , postbronchodilator forced expiratory volume in 1 s 70 % or greater of predicted normal ) . Following a one-month run-in on budesonide/formoterol ( 100/6 µg or 200/6 µg metered doses , two inhalations twice daily ) , 995 patients were r and omly assigned either to continue on this fixed dosing regimen or to receive budesonide/formoterol adjustable dosing ( step down to one inhalation twice daily if symptoms were controlled or temporarily step up to four inhalations twice daily for seven or 14 days if asthma worsened ) . The primary efficacy variable was the occurrence of exacerbations ( requiring oral or inhaled corticosteroids , emergency department treatment , serious adverse events or added maintenance therapy because of asthma ) . RESULTS With adjustable dosing , significantly fewer patients experienced exacerbations compared with fixed dosing ( 4.0 % versus 8.9 % , P=0.002 ; number needed to treat=21 [ 95 % CI 13 to 59 ] ) . Patients required 36 % fewer overall doses of budesonide/formoterol  ( 2.5 versus 3.9 inhalations/day , P<0.001 ) , and total costs per patient were lower ( difference over five months -141 Canadian dollars [ 95 % CI -162 Canadian dollars to -116 Canadian dollars ] ) . Asthma symptom severity ( modified National Heart , Lung , and Blood Institute stage ) was maintained or improved in 97 % or greater of patients in both groups ( pre-run-in to end of treatment ) . Both treatments were well tolerated . CONCLUSIONS Budesonide/formoterol adjustable maintenance dosing provided more effective asthma control than fixed dosing , with a lower overall drug dose and reduced total cost BACKGROUND The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma . Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler ( pMDI ) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma , but it has not been assessed in patients with mild to moderate persistent asthma . OBJECTIVE The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI ( budesonide/formoterol pMDI ) , budesonide pMDI , formoterol dry powder inhaler ( DPI ) , and placebo . METHODS This 12-week , multicenter , double-blind , r and omized , placebo-controlled , double-dummy study was conducted at 56 centers across the United States . Patients aged > or = 12 years with mild to moderate persistent asthma treated with inhaled corticosteroids ( ICSs ) for > or = 4 weeks before screening and who had a forced expiratory volume in 1 second ( FEV(1 ) ) of > or = 60 % to < or = 90 % of predicted normal at screening were eligible . After 2 weeks ( current asthma therapy discontinued ) , patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations ( 160/9 microg ) , budesonide pMDI 80 microg x 2 inhalations ( 160 microg ) , formoterol DPI 4.5 microg x 2 inhalations ( 9 microg ) , or placebo . The co primary efficacy variables were changes from baseline in morning predose FEV(1 ) and 12-hour mean FEV(1 ) ( from serial spirometry ) after administration of the morning dose of study medication . Tolerability was assessed based on adverse events ( AEs ) ; routine laboratory assessment s ; electrocardiography ; 24-hour Holter monitor assessment s ; and physical examinations , including vital signs ( eg , systolic and diastolic blood pressure and heart rate ) . AEs were recorded manually by the patient in paper notebooks and review ed at each clinic visit by the investigator and during a final follow-up phone call . RESULTS A total of 480 patients were r and omized ( 299 females , 181 males ; mean age , 36 years ; mean FEV(1 ) , 2.4 L ; budesonide/formoterol pMDI , 123 patients ; budesonide pMDI , 121 ; formoterol DPI , 114 ; placebo , 122 ) . At end of treatment , the mean increases from baseline in predose FEV(1 ) were greater with budesonide/formoterol pMDI versus budesonide pMDI , formoterol DPI , and placebo ( 0.37 vs 0.23 , 0.17 , and 0.03 L , respectively ; all , P<0.005 ) . 0.005 ) . After administration of the first dose and at weeks 2 and 12 , mean increases in 12-hour mean FEV(1 ) were significantly greater with budesonide/formoterol pMDI ( 0.41 , 0.47 , and 0.50 L , respectively ) versus budesonide pMDI ( 0.17 , 0.30 , and 0.32 L ) and placebo ( 0.15 , 0.12 , and 0.12 L ) ( all , P < 0.001 ) . Fewer patients receiving budesonide/formoterol pMDI met criteria for ( 18.7 % ; P < 0.001 ) or withdrew because of ( 7.3 % ; P < or = 0.010 ) worsening asthma versus formoterol DPI ( 42.1 % and 18.4 % , respectively ) and placebo ( 56.6 % and 32.8 % ) ; results were similar between budesonide pMDI ( 21.5 % and 6.6 % , respectively ) and budesonide/formoterol pMDI . Three patients experienced serious AEs ; none was considered related to study medication . The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups . CONCLUSIONS In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs , twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents . All study drugs were generally well tolerated 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 BACKGROUND --Knowing the extent of the systemic effects of a new beta 2 agonist relative to an established drug is important for the prediction and interpretation of side effects . A recent study in which the effect of cumulative doses of salbutamol was compared with single doses of salmetreol suggested that , weight for weight , salmeterol may be up to 10 times more potent than salbutamol . This current study was design ed to investigate further the dose equivalence of salmeterol and salbutamol . METHODS --Twelve patients with mild asthma inhaled cumulative doses of placebo , salmeterol 25 , 50 , 100 , and 200 micrograms , and salbutamol 100 , 500 , 1000 , and 1000 micrograms on separate days at hourly intervals in a r and omised double blind crossover study . Changes in forced expiratory volume in one second ( FEV1 ) , heart rate , plasma potassium concentration , systolic and diastolic blood pressure were measured . Dose equivalence was determined as the dose ratio of salmeterol to salbutamol for the 50 % maximum response to salbutamol . RESULTS --No important changes occurred in any measurements following placebo . Salmeterol and salbutamol caused a near maximum increase in FEV1 following the first dose so the dose equivalence for the airway effects could not be estimated . Heart rate increased and plasma potassium concentration and diastolic blood pressure decreased in a dose dependent manner following salmeterol and salbutamol , with median dose equivalences for salmeterol compared with salbutamol of 17.7 , 7.8 , and 7.6 , respectively . CONCLUSIONS --These results confirm that the systemic activity of salmeterol compared with salbutamol is higher than would be expected from in vitro data , particularly for heart rate . Whether this is because of the relatively high dose of salmeterol used or pharmacokinetic differences between the two drugs is uncertain Background The combination of inhaled corticosteroids ( ICS ) and long-acting β2-agonists ( LABA ) is recommended by treatment guidelines for the treatment of persistent asthma . Two such combination products , salmeterol/fluticasone propionate ( SFC , Seretide ™ GSK , UK ) and formoterol/budesonide ( FBC , Symbicort ™ , AstraZeneca , UK ) are commercially available . Objectives The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose . Methods Two r and omised , double blind , placebo-controlled , crossover studies were performed . Study A was conducted in 33 asthmatic adults receiving 400–1200 mcg of budesonide or equivalent .  Serial forced expiratory volume in one second ( FEV1 ) was measured over 24 hours to determine the duration of effect of both SFC ( 50/100 mcg ) and FBC ( 4.5/160 mcg ) . Study B was conducted in 75 asthmatic adults receiving 800–1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide ™ followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner . Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment . Results In study A , a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L ( 95 % CI 0.19 , 0.35 L ) for SFC and 0.25 L ( 95 % CI 0.21 , 0.37 L ) for FBC , which was significantly greater than placebo for both treatments ( -0.05 L ; p < 0.001 ) . In study B , the slope of decline in FEV1 from 2–24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC . The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively Conclusion Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 We compared the speed of action of the long acting beta-agonist salmeterol with that of salbutamol in order to assess whether reported in vitro differences are likely to have clinical significance . We used methacholine tests to produce a st and ardized level of bronchoconstriction and then observed the rate of recovery of FEV1 towards baseline after the administration by metered dose inhaler of salmeterol 50 micrograms or salbutamol 200 micrograms -- doses which are considered to have similar bronchodilator potency . Twenty asthmatic subjects participated , and a double-blind , r and omized , cross-over study design was followed . Salmeterol showed a significantly slower speed of action with median recovery to 90 % and 95 % of the baseline FEV1 ( pre-methacholine ) occurring after 9.6 and 19.4 min , respectively , compared with 4.8 and 8.3 min , respectively , for salbutamol ( P less than 0.01 ) . These observations are consistent with in vitro findings and suggest that salmeterol is likely to be less satisfactory than salbutamol as a ' rescue medication ' for the treatment of acute episodes of bronchoconstriction Patients with mild asthma may benefit from increasing their inhaled corticosteroid dose , adding a long-acting beta2-agonist , or both . This study assessed the cost-effectiveness of these options . Patients aged > or = 12 years with mild-to-moderate persistent asthma ( n = 1272 ) were r and omised to twice-daily , double-blind treatment with budesonide 100 microg , budesonide 100 microg plus formoterol 4.5 microg , budesonide 200 microg , or budesonide 200 microg plus formoterol 4.5 microg for 12 months . Clinical variables included lung function , number of symptom-free days and number of severe exacerbations . Data on medication use , hospitalisation , visits to health professionals and time off work due to asthma were combined with Swedish unit cost data ( 1999 ) to estimate the mean annual cost per patient . Budesonide 200 microg plus formoterol 4.5 microg had the greatest efficacy and effectiveness .  Budesonide 200 microg plus formoterol 4.5 microg was both more effective and less costly than budesonide 100 microg plus formoterol 4.5 microg , so a cost-effectiveness ratio was not calculated for this comparison . The cost-effectiveness ratio for budesonide 200 microg plus formoterol 4.5 microg compared with budesonide 200 microg alone was SEK 21 per symptom-free days gained . The combination of budesonide and formoterol in mild-to-moderate persistent asthma improved effectiveness at modest additional cost The airway response and cardiovascular and hypokalaemic effects of fenoterol , salbutamol , and terbutaline given in multiples of st and ard doses from metered-dose inhalers were studied in ten patients with mild asthma . In a double-blind , crossover , placebo-controlled study the subjects received 2 , 6 , and 18 puffs of each drug with intervals of 90 min , and forced expiratory volume in 1 s , heart rate , QTc interval , plasma potassium concentration , tremor , and bronchial reactivity to histamine were measured . All three drugs produced similar bronchodilatation . However , the rises in heart rate , QTc interval , and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline . The maximum mean ( SD ) increases in heart rate for fenoterol , salbutamol , and terbutaline were 29 ( 24 ) bpm , 8 ( 9 ) bpm , and 8 ( 14 ) bpm , respectively ; falls in plasma potassium were 0.76 ( 0.62 ) mmol/l , 0.46 ( 0.32 ) mmol/l , and 0.52 ( 0.39 ) mmol/l , respectively . Fenoterol afforded no additional protection against histamine compared with salbutamol . These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline . The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists ; fenoterol may in addition be less selective for beta 2 receptors Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects . However , most studies have been conducted in stable asthma . This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction . Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline ( 1 mg q.i.d . ) , budesonide ( 400 microg , b.i.d . ) , both drugs or placebo in a r and omized , double-blind , cross-over study . After each treatment methacholine was administered to induce a 20 % fall in the forced expiratory volume in one second ( FEV1 ) . The response to inhaled salbutamol 100 , 100 , 200 microg at 5 min intervals ) was then measured . Dose-response curves were compared using an analysis of covariance . Pre-methacholine FEV1 , the highest pre-methacholine FEV1 , the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20 % fall in FEV1 ( PD20 ) were used as covariates . There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment : the mean ( 95 % confidence intervals ( CI ) ) area under the dose-response curve was reduced by 36 % ( 24 , 47 ) compared to placebo ( p<0.0001 ) . The reduction in bronchodilator response was not affected by concomitant treatment with budesonide . Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction . Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations BACKGROUND Few clinical trials in asthma have focused on Hispanic population s. OBJECTIVE To compare the efficacy and safety of budesonide/formoterol ( BUD/FM ) with BUD in an ethnically diverse group of Hispanic participants with asthma previously treated with inhaled corticosteroids ( ICS ) . METHODS This 12-week , r and omized , double-blind , active-controlled study ( NCT00419757 ) was design ed to enroll Hispanic participants ( self-reported ) ( ≥12 years of age ) with moderate to severe asthma requiring medium- to high-dose ICS . After a 2-week run-in period ( low-dose BUD pressurized metered-dose inhaler [ pMDI ] 80 μg × 2 inhalations [ 160 μg ] twice daily ) , participants with a symptom score greater than 0 ( scale : 0 - 3 ) on 3 or more of 7 run-in days and forced expiratory volume in 1 second ( FEV(1 ) ) 45%-85 % predicted were r and omized to BUD/FM pMDI 160/4.5 μg × 2 inhalations ( 320/9 μg ) twice daily or BUD pMDI 160 μg × 2 inhalations ( 320 μg ) twice daily . RESULTS R and omized participants ( n = 127 BUD/FM ; n = 123 BUD ) were predominately Mexican ( 51 % ) or Puerto Rican ( 21 % ) . During low-dose ICS run-in , the mean symptom score was 1.0 ; however , mean predose FEV(1 ) improved ( 2.10 - 2.21 L ) . During r and omized treatment , small , but not statistically significant , improvements favored BUD/FM vs BUD ( am peak expiratory flow [ PEF ; primary efficacy variable ] 25.4 vs 19.9 L/min ; pm PEF 20.6 vs 15.8 L/min ; predose FEV(1 ) 0.16 vs 0.11 L ; rescue medication use -0.7 vs -0.6 inhalations/d ) . Most adverse events were mild or moderate in intensity . CONCLUSIONS Improvement in clinical ly relevant control end points occurred in both BUD/FM and BUD groups ; both treatments were well tolerated in this Hispanic asthma population but were not significantly differentiated 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 Patient-guided management of asthma using adjustable dosing of budesonide/formoterol in a single inhaler ( Symbicort ) was compared with fixed dosing in an open-label , multicentre , r and omised study . Patients , uncontrolled on an inhaled corticosteroid ( ICS ) or controlled on an ICS and a long-acting beta2-agonist , entered a 4-week run-in period and received budesonide/formoterol ( 80/4.5 or 160/4.5 microg ) , 2 inhalations b.i.d . Following r and omisation , the fixed-dosing group ( n = 764 ) continued this regimen for a further 12 weeks . The adjustable-dosing group ( n = 775 ) could step down to 1 inhalation b.i.d . if symptoms were controlled , and , at early signs of worsening symptoms , promptly step up to 4 inhalations b.i.d . for < or = 2 weeks . During run-in , National Heart , Lung and Blood Institute symptom-severity grading was maintained in 60 % and improved in 31 % of patients , clinic peak flow increased from 400 to 4191/min ( P<0.001 ) , and health-related quality of life ( overall MiniAQLQ ) improved from 4.6 to 5.4 ( P<0.001 ) . Patients effectively used the adjustable-dosing regimen ; 79 % reduced budesonide/formoterol dosage and , compared with fixed dosing , the number of inhalations were significantly lowered ( 3.2 vs. 3.8 inhalations/day , P<0.05 ) . Both regimens were well tolerated . In both groups , symptom control was maintained or improved in 85 - 86 % of patients , and 94 % experienced no treatment failures . Consistent with current guidelines , adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma control at reduced medication doses Adherence to maintenance therapy is often poor in patients with asthma . Simplifying dosing regimens has the potential to improve both adherence and asthma-related morbidity . In this 12-week , r and omized , double-blind , double-dummy , parallel-group study , 617 patients with mild to moderate persistent asthma ( mean forced expiratory volume in 1s [ FEV1 ] 78.5 % predicted ) who were not optimally controlled on inhaled corticosteroids ( 200 - 500 microg/day ) were r and omized to once-daily budesonide/formoterol ( 80/4.5 microg , 2 inhalations in the evening ) , twice-daily budesonide/formoterol ( 80/4.5 microg , 1 inhalation ) , or a corresponding dose of budesonide once-daily ( 200 microg , 1 inhalation in the evening ) . All patients received budesonide ( 100 microg twice daily ) during a 2-week run-in . Changes in mean morning peak expiratory flow ( PEF ) were similar for od budesonide/formoterol ( 23.4 l/min ) and twice-daily budesonide/formoterol ( 24.1 l/min ) , and both were greater than with budesonide ( 5.5 l/min ; both P<0.001 ) . Evening PEF , symptom-free days , reliever-free days , and asthma control days were improved with budesonide/formoterol therapy vs. budesonide ( P<0.05 vs. budesonide for all variables ) . All treatments were well tolerated . Budesonide/formoterol administered once daily in the evening is a convenient treatment regimen that is as effective in improving asthma control as twice-daily dosing in patients with mild to moderate persistent asthma Background To compare the efficacy and safety of budesonide/formoterol ( Symbicort ® ) with formoterol ( Oxis ® ) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β2-agonist therapy . Methods In a 3 hour , r and omized , double-blind study , a total of 115 patients with acute asthma ( mean FEV1 40 % of predicted normal ) and a refractory response to salbutamol ( mean reversibility 2 % of predicted normal after inhalation of 400 μg ) , were r and omized to receive either budesonide/formoterol ( 320/9 μg , 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [ total dose 1280/36 μg ] ) or formoterol ( 9 μg , 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [ total dose 36 μg ] ) . The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes . Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes . Treatment success , treatment failure and patient assessment of the effectiveness of the study medication were also measured . Results FEV1 increased after administration of the study medication in both treatment groups . No statistically significant difference between the treatment groups was apparent for the primary outcome variable , or for any of the other efficacy endpoints . There were no statistically significant between-group differences for treatment success , treatment failure or patient assessment of medication effectiveness . Both treatments were well tolerated . Conclusion Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β2-agonist The aim of the study was to compare the safety and effectiveness of as-needed formoterol with salbutamol in a large international real-life asthma study . Children and adults ( n=18,124 ) were r and omised to 6 months as-needed treatment with open-label formoterol 4.5 µg Turbuhaler ® or salbutamol 200 µg pressurised metered dose inhaler or equivalent . Primary safety variables were asthma-related and nonasthma-related serious adverse events (SAE)s and adverse events (AE)s result ing in discontinuation (DAE)s . The primary efficacy variable was time to first asthma exacerbation . The incidences of AEs , SAEs and DAEs arising from SAEs were not significantly different between treatments . DAEs for nonserious AEs were higher  with formoterol . Asthma-related AEs decreased with formoterol ( 1,098 ( 12.3 % ) versus 1,206 ( 13.5 % ) ) , asthma-related SAEs were similar ( 108 ( 1.2 % ) versus 121 ( 1.4 % ) ) but more asthma-related DAEs occurred in the formoterol group ( 89 ( 1.0 % ) versus 48 ( 0.5 % ) ) . Time to first exacerbation was prolonged ( hazard ratio 0.86 ) and less as-needed and maintenance medication was used with formoterol . Reductions of exacerbations with as-needed  formoterol versus salbutamol increased with increasing age and asthma medication level . This real-life study demonstrates that formoterol as-needed has a similar safety profile  to salbutamol , and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations 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 Abstract Objective and design : There is comparatively little information on asthma management in China . A multicentre , r and omised , open-label , parallel-group , 6-week treatment study was conducted to evaluate the efficacy and safety of salmeterol/fluticasone propionate combination treatment in Chinese adult asthmatic patients . Setting and patients : 398 patients with a documented history of moderate-to-severe asthma were r and omised to treatment . Interventions : Salmeterol 50μg/fluticasone propionate 100μg twice daily for 6 weeks via Accuhaler ® ( Diskus ™ ) inhaler and budesonide 400μg twice daily for 6 weeks via Turbuhaler ® inhaler . Main outcome measures and results : Morning peak expiratory flow ( PEF ) was investigated as the primary efficacy endpoint ; evening PEF , use of salbutamol ( albuterol ) as rescue medication , and day- and night-time asthma symptom scores were secondary efficacy endpoints . Safety was assessed according to adverse events recorded . Over the 6-week treatment period , salmeterol/fluticasone propionate led to a significantly greater increase in morning ( p < 0.0001 ) and evening ( p = 0.0066 ) PEF compared with budesonide . Moreover , the significant benefit of salmeterol/fluticasone propionate was evident from the first week . Similarly , salmeterol/fluticasone propionate led to significantly greater improvements in the use of rescue medication and day- and night-time asthma symptom scores , compared with budesonide . Both treatments were well tolerated , with a similar incidence ( 23 % ) of adverse events in both treatment groups and no serious adverse events . Conclusions : Salmeterol/fluticasone propionate 50μg /100μg twice daily was significantly more effective than budesonide 400μg twice daily in improving lung function and reducing symptoms and use of rescue medication in Chinese asthmatic patients who were poorly controlled on low-dose inhaled corticosteroids . This confirms the findings of superior efficacy of this combination product over budesonide in other population OBJECTIVE : To assess efficacy/tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus budesonide pMDI ( primary ) and twice-daily budesonide/formoterol ( secondary ) in children/adolescents with asthma stabilized with twice-daily budesonide/formoterol . METHODS : This 12-week multicenter , double-blind r and omized controlled study ( www . clinical trials.gov identifier NCT00646321 ) included 521 patients aged 6 to 15 years with mild/moderate persistent asthma . Patients stabilized during a 4- to 5-week run-in with twice-daily budesonide/formoterol pMDI 40/4.5 μg × 2 inhalations ( 160/18 μg daily ) received twice-daily budesonide/formoterol pMDI 40/4.5 μg × 2 inhalations ( 160/18 μg daily ) , once-daily budesonide/formoterol pMDI 80/4.5 μg × 2 inhalations ( 160/9 μg daily ; evening ) , or once-daily budesonide pMDI 80 μg × 2 inhalations ( 160 μg daily ; evening ) . RESULTS : Once- or twice-daily budesonide/formoterol was more effective than budesonide for evening peak expiratory flow ( primary variable ) at the end of the 24-hour once-daily dosing interval ( P ≤ .027 ) . Twice-daily budesonide/formoterol  demonstrated better efficacy versus once-daily treatments for evening predose forced expiratory volume in 1 second ( P ≤ .011 ) , versus budesonide for daytime/nighttime rescue medication ( P ≤ .023 ) , and versus once-daily budesonide/formoterol  for daytime rescue medication ( last 12 hours of once-daily dosing ) ( P = .032 ) . There were no significant between-group differences for daytime/nighttime asthma symptoms , nighttime awakenings attributed to asthma , or health-related quality of life . Fewer patients experienced asthma worsening ( predefined criteria ) with twice-daily budesonide/formoterol ( 8.2 % ) versus once-daily budesonide ( 15.5 % ) ( P = .036 ) or once-daily budesonide/formoterol ( 19.6 % ) ( P = .002 ) . All treatments were well tolerated . CONCLUSIONS : Once-daily budesonide/formoterol demonstrated significantly better efficacy than once-daily budesonide for most pulmonary-function variables . Twice-daily budesonide/formoterol ( 160/18 μg daily ) maintenance therapy was generally more effective than stepping down to once-daily dosing ( 160/9 μg daily ) . Treatments were well tolerated , and there was no evident safety benefit for once- versus twice-daily dosing RATIONALE Long-acting beta-agonists ( LABAs ) and inhaled corticosteroids administered together appear to be complementary in terms of effects on  asthma control .  The elements of asthma control achieved by LABAs ( improved lung function ) and leukotriene receptor antagonists ( LTRAs ; protection against exacerbations ) may be complementary as well . OBJECTIVE We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma . METHODS AND MEASUREMENTS In a r and omized , placebo-controlled , crossover study of 192 subjects with moderate asthma , we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma . The primary efficacy outcome was time to treatment failure . MAIN RESULTS Three months after the r and omization of the last subject , the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial . The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures ( p = 0.0008 ) , lung function ( 26 L/min difference in a.m. peak expiratory flow rate , p = 0.011 ) , asthma control score ( 0.22 difference in Asthma Control Question naire score , p = 0.038 ) , and markers of inflammation and airway reactivity . CONCLUSIONS Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA STUDY OBJECTIVE To compare a novel asthma management strategy --budesonide/formoterol in a single inhaler for both maintenance therapy and symptom relief -- with a higher dose of budesonide plus as-needed terbutaline . METHODS This was a 6-month , r and omized , double-blind , parallel-group study in patients with mild-to-moderate asthma ( n = 697 ; mean age , 38 years [ range , 11 to 79 years ] ; mean baseline FEV1 , 75 % of predicted ; mean inhaled corticosteroid [ ICS ] dosage , 348 microg/d ) . Following a 2-week run-in period , all patients received two blinded , dry powder inhalers , one containing maintenance medication and one containing medication to be used as needed for the relief of symptoms . Patients were r and omized to receive either budesonide/formoterol ( 80 microg/4.5 microg , two inhalations qd ) for maintenance plus additional inhalations as needed for symptom relief , or budesonide ( 160 microg , two inhalations qd ) for maintenance medication plus terbutaline ( 0.4 mg ) as needed . The primary efficacy variable was morning peak expiratory flow ( PEF ) . RESULTS Patients receiving budesonide/formoterol showed greater improvements in morning PEF than patients receiving budesonide ( increases of 34.5 L/min vs 9.5 L/min , respectively ; p < 0.001 ) . The risk of having a severe exacerbation ( hospitalization/emergency department [ ED ] treatment , oral steroids for asthma , or a > or = 30 % decrease from baseline in morning PEF on 2 consecutive days ) was 54 % lower with budesonide/formoterol vs budesonide ( p = 0.0011 ) . Budesonide/formoterol patients experienced 90 % fewer hospitalizations/ED treatments due to asthma than budesonide patients ( 1 vs 10 , respectively ; p = 0.026 ) . The increased efficacy with budesonide/formoterol was achieved with less ICS than was used in the budesonide group ( mean dose , 240 microg/d vs 320 microg/d , respectively ) and with 77 % fewer oral steroid treatment days vs budesonide ( 114 days vs 498 days , respectively ) . Both treatments were well tolerated . CONCLUSIONS Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline OBJECTIVE AND BACKGROUND Budesonide/formoterol 160/4.5 microg , two inhalations bd , is an effective and well-tolerated maintenance therapy for patients not controlled on inhaled corticosteroids alone . The authors assessed the efficacy and safety of a higher dose of budesonide/formoterol in patients with persistent symptomatic asthma . METHODS This was a 24-week , double-blind , double-dummy r and omized study . Budesonide/formoterol 320/9 microg , two inhalations bd ( 1280/36 microg/day ) , was compared with corresponding doses of budesonide during weeks 1 - 12 and budesonide plus formoterol via separate inhalers during weeks 1 - 24 . Efficacy was assessed during weeks 1 - 12 ; the primary variable was morning PEF . Safety was assessed over weeks 1 - 24 . RESULTS Patients ( n=456 ; aged 12 - 79 years ) had a mean reversibility in FEV1 of 28 % and mean pre- study inhaled corticosteroid dose of 1038 microg/day .  Mean morning PEF increased by 37 L/min and 36 L/min with budesonide/formoterol and budesonide plus formoterol , respectively , versus an increase of 5 L/min with budesonide ( P<0.001 for both vs. budesonide ) . Budesonide/formoterol increased time to first mild exacerbation ( P<0.005 ) versus budesonide . Budesonide/formoterol and budesonide plus formoterol had similar efficacy . All treatments were well tolerated and the incidence of class-related adverse events was similarly low in all groups . Changes in serum potassium and plasma cortisol were comparable across treatments . CONCLUSIONS High-dose budesonide/formoterol ( 320/9 microg , two inhalations bd ) is effective and well tolerated in patients with persistent symptomatic asthma . The findings also support the safety of regular high-dose formoterol ( 36 microg/day ) PRINCIPLES Current asthma management employing inhaled corticosteroids ( ICS ) and longacting b2-agonists ( LABA ) aims to rapidly achieve and then maintain overall asthma control including symptoms with minimal medication . This study compared self-guided adjustable maintenance dosing with budesonide/formoterol in a single inhaler with fixed dosing . METHODS In an open-label , parallel-group , multicentre study , 127 asthmatic patients , well controlled on ICS and LABA , were treated with budesonide/formoterol ( Symbicort ) Turbuhaler ) 200/6 mg ( equivalent to 160/4.5 mg delivered dose ) 2 inhalations bid for 4 weeks , and were then r and omised to budesonide/formoterol adjustable dosing ( n = 69 ) ( guided self-adjustment of dose : 1 inhalation bid or 2 inhalations at night with interim step ups to 2 inhalations bid and if not sufficient up to 4 inhalations bid for 14 days ) or fixed dosing ( 2 inhalations bid ) ( n = 58 ) for 12 weeks . RESULTS Patients used adjustable dosing effectively ; > 50 % used a decreased maintenance dose on > 50 % of the days . Seventy-two percent ( 50/69 ) from the adjustable-dosing group reduced their maintenance dose within the first 2 treatment weeks . Thirteen adjustable-dose patients ( 18.8 % ) never reduced their dose and 4 ( 5.8 % ) stepped up their dose . Symptom severity ( NHLBI severity grade ) decreased in both groups ; however , the decrease was only statistically significant ( p = 0.004 ) in the adjustable-dosing group . Treatment failures occurred in 17 % and 24 % of patients ( adjustable and fixed dosing , respectively p = 0.35 ) . Nocturnal awakenings ( 0.057 vs. 0.067/night , p = 0.006 ) and rescue medication use ( 0.15 vs. 0.23 inhalations/day , p < 0.0001 ) were significantly less frequent with adjustable dosing , and the average daily medication dose was significantly reduced ( 3.0 vs. 3.9 , p < 0.0001 ) compared with fixed dosing . Lung function measurements ( FEV1 and PEF ) were not significantly different between groups during the study . There were no asthma-related hospital admissions . CONCLUSION Asthma patients on adjustable maintenance dosing with budesonide/ formoterol maintained control of symptoms using significantly less medication overall than fixed dosing . Thus , adjustable maintenance dosing achieved guideline goals of effective asthma control at an appropriately low maintenance dose . However , larger studies on adjustable maintenance dosing are needed 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 The present study was design ed to compare the fixed combination of beclomethasone and formoterol in a hydrofluoroalkane Modulite ® ( Chiesi Farmaceutici , Parma , Italy ) pressurised metered-dose inhaler ( pMDI ) , with a combination of budesonide and formoterol administered via a Turbuhaler ® ( AstraZeneca , Lund , Sweden ) dry powder inhaler ( DPI ) . This was a phase III , multinational , multicentre , double-blind , double-dummy , r and omised , two-arm parallel groups , controlled study design . After a 2-week run-in period , 219 patients with moderate-to-severe asthma were r and omised to a 12-week treatment with beclomethasone 200 μg plus formoterol 12 μg b.i.d . delivered via a pMDI or budesonide 400 μg plus formoterol 12 μg b.i.d . delivered via a DPI . The analysis of noninferiority on primary outcome , morning peak expiratory flow in the last 2 weeks of treatment , showed no difference between groups . A statistically significant improvement from baseline in lung function , symptoms and rescue medication use was observed in both groups at all time-points . No differences were observed between treatments in either rate of asthma exacerbations or frequency of adverse events . The new fixed combination of beclomethasone and formoterol in hydrofluoroalkane Modulite ® pressurised metered-dose inhaler is equivalent to the marketed combination of budesonide and formoterol in terms of efficacy and tolerability profile 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 Budesonide/formoterol as single inhaler was developed for treating asthma patients who are not adequately controlled on glucocorticoides alone . The aim of this study was to evaluate efficacy , safety and patient/physician satisfaction of budesonide/formoterol therapy .  Total of 268 asthma patients ( 120 men , mean age 38.8 + /- 37.2 years , and 148 women , mean age 42.2 + /- 32 years ) were included in the study . All patients received budesonide/formoterol bid ( 640 mcg of budesonide and 18 mcg of formoterol daily ) during run-in period for three weeks . Patients were followed during 14 weeks at 5 visits . At each visit lung function ( FEV1 and PEF ) was measured , presence of side affects was recorded and question naire was given to patients and physicians to estimate the level of satisfaction with budesonide/formoterol therapy ( 1 very unsatisfied to 5 very satisfied ) . Significant improvement was noticed in FEV1 , from 76.25 % of predicted value to 86.94 % ( p < 0.01 ) ; and in PEF from 380.84 L/min to 442.29 L/min ( p < 0.01 ) in all patients . At the end of the study patients ' satisfaction with budesonide/formeterol therapy was significantly improved comparing with satisfaction with previously taken therapy , in average grade , from 2.94 to 4.56 ( p < 0.01 ) , and similar results were noticed with physicians ' satisfaction , from 2.60 to 4.41 ( p < 0.01 ) . Budesonide/formoterol in single inhaler , significantly improved lung function in patients with asthma BACKGROUND Previous studies on inhaled steroid and long-acting beta2-agonist combination products may not be representative for the asthma and chronic obstructive pulmonary disease ( COPD ) patients in family practice . OBJECTIVES To compare in a group of doctor-diagnosed patients with asthma or COPD , the effects of a lower dose of fluticasone in a combination product with salmeterol with conventional treatment ( i.e. a higher dose of fluticasone ) , both supplemented with as-needed use of a short-acting bronchodilator . METHODS The study was a 12-week multicentre , r and omized controlled , double-blind trial . In all , 41 family practice s recruited 137 patients diagnosed with asthma and 40 patients diagnosed with COPD . Primary outcome was the forced expiratory volume in 1 second ( FEV1 ) as percentage of predicted . Morning peak expiratory flow ( PEF ) , symptom-free days , health status [ Asthma Quality of Life Question naire ( AQLQ ) and St. George 's Respiratory Question naire ( SGRQ ) ] , exacerbations , use of short-acting bronchodilators and adverse events were secondary outcomes . RESULTS FEV1 % predicted increased 2.6 % ( SD 8.3 ) in fluticasone/salmeterol- and 0.01 % ( SD 6.6 ) in fluticasone-treated patients ( overall : P=0.036 , asthma : P=0.025 and COPD : P=0.700 ) . PEF increased in favour of fluticasone/salmeterol in asthma patients only ( P=0.016 ) . Fluticasone/salmeterol-treated asthma patients had 1.1 more symptom-free days per week ( P=0.044 ) ; no such effect was observed for COPD ( P=0.769 ) . There were no differences in total AQLQ and SGRQ scores , exacerbations , use of reliever puffs or adverse effects . CONCLUSIONS In family practice patients diagnosed with asthma , several treatment goals were better achieved with a lower dose of fluticasone and salmeterol in a combination product than with a higher dose of fluticasone . We found no differences between the two approaches for patients with COPD Patients with mild intermittent asthma sometimes show signs of inflammation , and guidelines suggesting bronchodilator therapy alone as needed may be question ed . The current study compared as-needed use of a rapid-acting β2-agonist with as-needed use of a β2-agonist and corticosteroid combination as the only medication in asthma patients with intermittent symptoms . A total of 92 nonsmoking asthma patients ( of 187 screened ) using only an inhaled β2-agonist as needed ( 28 males , 64 females ; mean age 37 yrs ; mean forced expiratory volume in one second ( FEV1 ) 101 % predicted , mean reversibility 6.5 % pred and fractional exhaled nitric oxide ( FeNO ) ≥20 parts per billion ( ppb ) ) were r and omised to treatment with formoterol ( Oxis ® Turbuhaler ® ) 4.5 μg as needed ( n = 47 ) or budesonide/formoterol ( Symbicort ® Turbuhaler ® ) 160/4.5 μg as needed ( n = 45 ) in a double-blind , parallel-group 24-week study . The primary variable of efficacy was change in FeNO . Baseline FeNO was 60 ppb and 59 ppb in the budesonide/formoterol and formoterol groups , respectively . Mean reductions in FeNO in the budesonide/formoterol and formoterol groups were 18.2 ppb and 2.8 ppb , respectively ( 95 % confidence interval ( CI ) 7.5–23.5 ppb ) . The reduction in the budesonide/formoterol group occurred during the first 4 weeks of treatment and remained at this low level . Mean FEV1 increased by 1.8 % pred normal value in the budesonide/formoterol group and decreased by 0.9 % pred normal value in the formoterol group ( 95 % CI -4.7– -0.7 ) . In the budesonide/formoterol group , use of ≥4 inhalations·day-1 of study medication was seen on 21 treatment days compared with 74 in the formoterol group . In conclusion , as-needed use of an inhaled corticosteroid together with a rapid-acting bronchodilator may be more beneficial than a β2-agonist alone in patients with intermittent asthma and signs of airway inflammation . The long-term benefits are unknown 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 Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction . This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist , formoterol . The modifying effect of intravenous corticosteroid was also studied . Ten asthmatic subjects ( using inhaled steroids ) participated in a r and omised , double-blind , placebo-controlled , cross-over study . Formoterol 12 microg b.i.d . or matching placebo was given for 10 - 14 days with > 2 weeks washout . Following each treatment , patients underwent a methacholine challenge to induce a fall in forced expired volume in one second ( FEV1 ) of at least 20 % , then salbutamol 100 microg , 100 microg , and 200 microg was inhaled via a spacer at 5 min intervals , with a further 400 microg at 45 min . After a third single-blind formoterol treatment period , hydrocortisone 200 mg was given intravenously prior to salbutamol . Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry . Regular formoterol result ed in a significantly lower FEV1 after salbutamol at each time point compared to placebo ( p<0.01 ) . The area under the curves ( AUCs ) for 15 ( AUC0 - 15 ) and 45 ( AUC0 - 45 ) min were 28.8 % and 29.5 % lower following formoterol treatment ( p<0.001 ) . Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration . It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol . This bronchodilator tolerance is evident in circumstances of acute bronchconstriction 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 Abstract Background and objective : Asthma is a chronic-episodic disease characterised by acute , symptomatic episodes of varying severity . We developed a Markov model that can be used to estimate the cost effectiveness of alternative asthma treatments . Because of the costs they incur , asthma exacerbations ( ‘ attacks ’ ) requiring intervention by a healthcare professional were a central consideration in the development of the model . Methods : Treatment success was assessed as asthma control , a composite measure based on goals defined in world-wide asthma management guidelines and in terms of quality -adjusted life-years ( QALYs ) . The data from which the transition probabilities were derived came from patients with asthma who received either salmeterol/fluticasone propionate combination ( SFC ) 50/100μg or fluticasone propionate ( FP ) 100μg , administered twice daily via an inhaler , in a 12-week , r and omised , double-blind , clinical trial . Costs were estimated from re source profiles defined for each of the model states . A key aspect of the model was the use of probabilistic sensitivity analysis techniques to examine the uncertainty in the cost-effectiveness results . Distributions were fitted to transition probabilities and to cost input parameters and values were sample d at r and om from these distributions using a second order Monte Carlo simulation technique . This produced a distribution for incremental cost effectiveness that was employed to construct 95 % uncertainty intervals and to construct cost effectiveness acceptability curves . Results : In this analysis , the model was run over a 12-week period using transition probabilities derived from the trial data . The results showed that treatment with SFC result ed in a higher proportion of successfully controlled weeks per patient than treatment with FP(66 vs 47 % ) , and higher mean weekly direct asthma management costs ( £ 15.77 vs £ 11.83 ; 2000 values ) . The average incremental cost per successfully controlled week with SFC was £ 20.83.Probabilistic sensitivity analysis showed that the 95 % uncertainty intervals for the incremental cost-effectiveness ratio was −£64.94 to £ 112.66 . In approximately 25 % of cases , SFC was dominant ( more effective and less costly ) , but in the remaining cases , it was both more effective and more costly . It was shown that if decision makers are willing to pay approximately £ 45 for an additional successfully controlled week , SFC will be the more cost-effective strategy in this patient population for 80 % of the time . Conclusions : This is one of the first decision-analytic models of asthma to incorporate probabilistic sensitivity analysis techniques to explore uncertainty . The model ’s flexible yet st and ardised framework permits the cost effectiveness of alternative asthma management strategies in different healthcare setting s to be established To compare the dose-related bronchodilator efficacy and tolerability of formoterol ( Oxis ) Turbuhaler with salmeterol Diskhaler and placebo in children with asthma . A single-dose , r and omized , double-blind , incomplete crossover study of 68 children ( 7 - 17 years ) , with moderate-to-severe asthma , 82 % receiving inhaled corticosteroids .  Patients received four of six treatments [ 4.5 , 9 , 18 , or 36 microg formoterol ( 6 , 12 , 24 or 48 microg metered doses ) , 50 microg salmeterol ( metered dose ) or placebo ] at 12-h visits , separated by > or =3 days . Forced expiratory volume in 1 s ( FEV1 ) , pulse , blood pressure , electrocardiogram , adverse events and urine formoterol  were assessed . The therapeutic ratio of formoterol vs. salmeterol was estimated from the efficacy and systemic effects results . All active treatments significantly improved FEV1 compared with placebo . Formoterol 9 - 36 microg provided dose-related increases over salmeterol in lung function : average 12-h FEV1 ( increases of 4.9 - 8.7 % , p < 0.001 ) and FEV1 at 12 h post-dose ( 7.0 - 12.2 % , p < 0.001 ) . The onset of effect of formoterol was also significantly faster than salmeterol for doses > or = 9 microg . Salmeterol 50 microg was estimated to be equieffective to 3.3 microg formoterol for 12-h average FEV1 and the estimated equieffective dose for a variety of systemic effects was 7.8 - 13.5 microg formoterol . All treatments were well tolerated .  Formoterol ( Oxis ) Turbuhaler 4.5 - 36 microg provided dose-related improvements in bronchodilator efficacy in children with asthma . Formoterol > or = 9 microg provided superior bronchodilator efficacy over 12 h compared with salmeterol Diskhaler 50 microg with no increase in systemic effects This r and omised , double-blind , double-dummy , crossover , placebo-controlled study assessed the acute tolerability of budesonide/formoterol in a single inhaler ( Symbicort Turbuhaler , AstraZeneca ) administered as a high dose . Fourteen patients with asthma receiving budesonide/formoterol maintenance treatment ( two inhalations of 160/4.5 microg twice daily ) inhaled 10 additional doses of budesonide/formoterol 1600/45 microg ( total daily dose including morning dose of maintenance treatment 1920/54 microg ) or formoterol 45 microg ( Oxis Turbuhaler , AstraZeneca ; total daily dose including morning dose of maintenance treatment 54 microg formoterol ) or placebo in addition to the morning dose of maintenance treatment on 3 separate study days . Serum potassium , pulse rate , blood pressure and ECG were assessed at regular intervals over a 12-h period following dosing . Blood glucose and plasma lactate were assessed over 3 h following dosing . Changes in serum potassium , pulse rate , blood pressure , QTc , blood glucose and plasma lactate occurring with budesonide/formoterol , though statistically significantly different from placebo ( P<0.05 ) , were considered clinical ly unimportant . No clinical ly relevant differences were identified between active treatments . In conclusion , budesonide/formoterol in a single inhaler is well tolerated at high doses such as might be used by patients using budesonide/formoterol  for relief of symptoms of asthma SUMMARY Background : Budesonide/formoterol in a single inhaler is an effective therapy for asthma . We investigated whether adjustable maintenance dosing with budesonide/formoterol could maintain health-related quality of life ( HRQL ) and asthma control . Patients / methods : Asthma patients ( n = 4025 ) received budesonide/formoterol ( Symbicort * 160/4.5 µg ) 2 inhalations twice daily ( bid ) for 4 weeks during run-in of this open , multicentre study . Patients were r and omised to adjustable dosing ( budesonide/formoterol 1 inhalation bid ; stepping up to 2 or 4 inhalations bid for 1 week if asthma worsened ) or fixed dosing ( budesonide/formoterol 2 inhalations bid ) , for 12 weeks . Change in HRQL ( st and ardised Asthma Quality of Life Question naire , AQLQ[S ] , score ) during r and omised treatment was the primary efficacy variable . Secondary variables included asthma control ( peak expiratory flow [ PEF ] , symptom-severity score , nocturnal awakenings , reliever-medication use ) and study -medication intake . Results : Clinical ly significant ( ≥ 0.5 ) improvements in AQLQ(S ) score ( mean 0.73 ) , morning and evening PEF ( mean 42.5 and 24.8 L/min , respectively ) , and symptom-severity score ( mean 0.36 ) were achieved during run-in . The improvements were maintained in both groups although , overall , adjustable-dosing patients took fewer daily inhalations of budesonide/formoterol than fixed-dosing patients ( mean 2.63 versus 3.82 , p < 0.001 ) . Conclusion : Adjustable maintenance dosing with budesonide/formoterol  maintains HRQL and asthma control as effectively as fixed dosing and is associated with a reduced drug load overall BACKGROUND Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma . However , approximately one-third of patients show little or no initial response to this partial beta(2)-agonist . METHODS We conducted a r and omized , double-blind , proof-of-concept study to investigate whether a full beta(2)-agonist , isoproterenol , offers a therapeutic advantage in adults presenting with acute severe asthma ( FEV(1)<50 % ) who fail to respond to an initial treatment of the partial beta(2)-agonist , albuterol . Study subjects were r and omized to receive a 2-h continuous nebulization of either albuterol ( 7.5mg/h ) ( n=10 , mean FEV(1)=37 % predicted ) or isoproterenol ( 7.5mg/h ) ( n=9 , mean FEV(1)=33 % predicted ) . Respiratory symptoms , vital signs and pulmonary function measures were collected . RESULTS Subjects from both treatment groups had similar baseline characteristics . The percent improvements from baseline FEV(1 ) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol ( 44 vs. 17 % and 63 vs. 24 % , respectively , P<0.05 ) . The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol ( P<0.01 ) . Both treatments were well tolerated , though the mean increase in pulse rate at 60 and 120min ( 21 vs. 1 and 23 vs. 6beats/min , respectively , P<0.05 ) and the mean change in serum potassium at 120min ( -0.52 vs. -0.07meq/L , P<0.05 ) from baseline were significantly greater in the isoproterenol group . CONCLUSIONS Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol , the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms BACKGROUND Current UK and international guidelines on asthma management recommend that , in pediatric patients still symptomatic on treatment with high-dose inhaled corticosteroids , consideration should be given to the introduction of regular twice daily long-acting beta 2-agonists . OBJECTIVE The purpose of this study was to assess the efficacy and safety of inhaled salmeterol xinafoate 50 micrograms bid via the Diskhaler when added to the existing treatment of children with moderate to severe asthma . METHODS A 12-week multicenter , double-blind , placebo-controlled , parallel group study was conducted at 78 hospital centers throughout the United Kingdom , involving 210 asthmatic children aged between 4 and 16 years of age .  Morning peak expiratory flow ( PEF ) , evening PEF , night-time and daytime symptoms and relief medication usage were recorded daily by the patient or parent over a 12-week treatment period . RESULTS Compared with placebo , the addition of salmeterol xinafoate to existing high dose inhaled corticosteroid treatment significantly improved mean morning PEF expressed as percent predicted ( PEF-PP ) during the first 4 weeks of treatment ( median increase 6.5 percentage points P < .001 ) . This effect persisted throughout the 12-week treatment period ( P < .05 ) . Both groups demonstrated an overall improvement in mean morning PEF-PP , 7.5 percentage points for salmeterol xinafoate and 4 percentage points for placebo .  The mean evening PEF-PP followed a similar although less pronounced trend which was significant only during the first 4 weeks of treatment ( P = .014 ) . Daytime relief medication and recorded symptoms were reduced significantly in both groups . There was a greater improvement in the number of symptom-free days during the first 4 weeks ( P < .01 ) and the last 4 weeks ( P < .05 ) of treatment for salmeterol xinafoate . The overall incidence and nature of minor adverse events was similar in both groups . CONCLUSIONS This study demonstrates that the addition of salmeterol xinafoate to inhaled corticosteroid therapy in symptomatic asthmatic children significantly improves morning PEF-PP , and reduces their symptoms and use of relief medication BACKGROUND Recent studies suggest that there might be an association between albuterol use and worsening asthma in patients homozygous for arginine ( Arg/Arg ) at codon 16 of the beta-receptor . However , it is not known whether similar responses occur in Arg/Arg patients receiving long-acting beta2-agonists . OBJECTIVE We sought to evaluate the effects of variation in the beta2-adrenergic receptor gene ( ADRB2 ) on clinical response to salmeterol administered with fluticasone propionate . METHODS Subjects ( n = 183 ) currently receiving short-acting beta2-agonists were r and omized to twice-daily therapy with salmeterol , 50 microg , administered with fluticasone propionate , 100 microg , in a single inhaler or daily therapy with montelukast for 12 weeks , followed by a 2- to 4-day run-out period . RESULTS There was sustained and significant improvement ( P < .001 ) over baseline in all measures of asthma control in subjects receiving salmeterol , regardless of Arg16Gly genotype . Morning peak expiratory flow in subjects with the Arg/Arg genotype showed 89.0 + /- 16.1 L/min improvement over baseline compared with 93.7 + /- 12.7 L/min for Gly/Gly subjects and 92.5 + /- 11.9 L/min for Arg/Gly subjects . Pairwise changes were similar for Arg/Arg compared with Gly/Gly or Arg/Gly genotypes ( estimated differences , 4.7 L/min and 3.5 L/min , respectively ) . Responses did not appear to be modified by haplotype pairs . During the run-out period , all subjects had predictable and similar decreases in measures of asthma control , with no differences between genotypes . CONCLUSION Response to salmeterol does not vary between ADRB2 genotypes after chronic dosing with an inhaled corticosteroid . CLINICAL IMPLICATION S Analyses from this study indicate that genetic polymorphisms leading to Arg16Gly sequence changes within the beta2-adrenergic receptor do not affect patients ' responses to recommended asthma therapy with salmeterol and fluticasone propionate 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 Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists . However , fluctuating asthma control still occurs . We hypothesized that in patients receiving low maintenance dose budesonide/formoterol ( bud/form ) , replacing short-acting beta2-agonist ( SABA ) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy , thereby reducing exacerbations . In this double-blind , r and omized , parallel-group study , 2,760 patients with asthma aged 4 - 80 years ( FEV1 60 - 100 % predicted ) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day ( bud/form + SABA ) or bud 320 microg twice a day ( bud + SABA ) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed ( bud/form maintenance + relief ) . Children used a once-nocte maintenance dose . Bud/form maintenance + relief prolonged time to first severe exacerbation ( p < 0.001 ; primary endpoint ) , result ing in a 45 - 47 % lower exacerbation risk versus bud/form + SABA ( hazard ratio , 0.55 ; 95 % confidence interval , 0.44 , 0.67 ) or bud + SABA ( hazard ratio , 0.53 ; 95 % confidence interval 0.43 , 0.65 ) . Bud/form maintenance + relief also prolonged the time to the first , second , and third exacerbation requiring medical intervention ( p < 0.001 ) , reduced severe exacerbation rate , and improved symptoms , awakenings , and lung function compared with both fixed dosing regimens 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 We evaluated the profile of the bronchodilatory effect of three inhaled beta2-agonists , 24 microg formoterol , 50 microg salmeterol and 200 microg salbutamol , in patients with stable , moderately severe asthma . Thirty asthmatics ( mean+/-SD age 54+/-8 yrs ; forced expiratory volume in one second ( FEV1 ) 58+/-12 % predicted ; reversibility of FEV1 21+/-8 % from baseline ) participated in a single-centre , double-blind , r and omized , single-dose , cross-over study . FEV1 was obtained in baseline condition and 10 , 20 , 30 , 60 min , and every hour up to 12 h after inhalation of the trial drug . Specific airway conductance ( sGaw ) was measured at baseline condition and 1 , 3 , 5 , 7 , 10 , 20 , 30 , 60 min , and every hour up to 12 h after inhalation . Formoterol produced a mean increase in sGaw ( as % of baseline ) of 44 % after 1 min , maximal ( 135 % ) after 2 h , and 56 % after 12 h. The mean increase in FEV1 was maximal ( 27 % ) after 2h , and 10 % after 12 h. After salmeterol , mean increase in sGaw amounted to 16 % after 3 min , maximal ( 111 % ) after 2 - 4 h , and 58 % after 12 h. The mean increase in FEV1 was maximally 25 % after 3h , being 11 % after 12 h. After salbutamol , mean increase in sGaw was 44 % after 1 min and maximal ( 100 % ) after 30 min . The peak increase in FEV1 was 25 % . We conclude that formoterol ( 24 microg ) and salmeterol ( 50 microg ) had an equal bronchodilatory capacity , which was similar to that of 200 microg salbutamol and lasted for at least 12 h in patients with asthma . However , formoterol had a more rapid onset of action than salmeterol , equal to that of salbutamol Safety concerns have been raised regarding the regular use of long-acting beta(2)-adrenergic agonists ( LABAs ) alone or with inhaled corticosteroids ( ICSs ) . The purpose of this study was to examine the long-term safety of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) . This 52-week , double-blind study ( SD-039 - 0728 ; n=708 ) included patients > or=12 years of age with moderate to severe persistent asthma previously receiving ICSs .  After 2 weeks on budesonide pMDI 320 microg twice daily ( b.i.d . ) , patients were r and omized 3:1:1 overall to budesonide/formoterol pMDI 640/18 microg b.i.d . , budesonide/formoterol pMDI 320/9 microg b.i.d . , or budesonide pMDI 640 microg b.i.d . The incidence of adverse events ( AEs ) was similar across the groups . Drug-related AEs ( > or=2 % overall ) were oral c and idiasis , tremor , and pharyngolaryngeal pain . No clinical ly meaningful differences in laboratory , electrocardiogram , or Holter monitor variables were observed . The percentage of patients with > or=1 asthma exacerbation was significantly lower ( p=0.006 ) with budesonide/formoterol 640/18 ( 12.2 % ) and numerically lower with budesonide/formoterol 320/9 ( 14.4 % ) versus budesonide ( 21.8 % ) . The number of asthma exacerbations per patient-treatment year was lower with budesonide/formoterol 640/18 ( 0.174 ; p=0.004 ) and budesonide/formoterol 320/9 ( 0.185 ; p=0.049 ) versus budesonide ( 0.315 ) . Improvements in forced expiratory volume in 1 second and diary variables were significantly greater ( p<0.001 ) with both budesonide/formoterol doses versus budesonide . Budesonide/formoterol 640/18 and 320/9 microg b.i.d . showed an acceptable safety profile relative to budesonide , with no significant or unexpected patterns of abnormalities observed by adding a LABA to budesonide for up to 1 year in this patient population . Improvements in asthma control were shown with both doses of budesonide/formoterol versus budesonide Asthma guidelines suggest a stepwise approach to maintenance pharmacological treatment of persistent asthma until control is attained , and a 3 month review of the fixed maintenance dosing for step-up or step-down adjustment . This 12-week study compared the efficacy and safety of budesonide/formoterol in a single inhaler ( Symbicort Turbuhaler 160/4.5 or 80/4.5 microg ) given as adjustable maintenance or fixed maintenance dosing .  Patients ( n = 2358 ) were r and omised to budesonide/formoterol fixed maintenance dosing ( two inhalations bid ) or adjustable maintenance dosing ( two inhalation bid ; stepping up to four inhalations bid if asthma worsened for a maximum of 14 days ; stepping down to two inhalations once nocte or one inhalation bid if symptoms were controlled ) for 12 weeks , following a 4-week run-in period on budesonide/formoterol two inhalations bid . Primary efficacy variables were frequency of asthma exacerbations and changes in patients ' asthma symptom severity . Secondary variables were asthma control , safety and health economics . Both adjustable maintenance dosing and fixed maintenance dosing were associated with similar low frequency of exacerbations ( 5 % both groups ; ns ) and similarly improved lung function , with similarly fewer nocturnal awakenings and less asthma symptoms compared with the mean value of the run-in period . However , patients on adjustable maintenance dosing used 24 % fewer study drug compared with fixed maintenance dosing ( 2.95 versus 3.86 inhalations daily ; p < 0.0001 ) and incurred in a significant ( p < 0.0001 ) reduction in total costs ( direct+indirect ) compared with fixed maintenance dosing . In conclusion , adjustable maintenance dosing with budesonide/formoterol effectively controls asthma at a reduced drug load with lower costs than fixed maintenance dosing Few studies have evaluated inhaled corticosteroid (ICS)/long-acting beta(2)-adrenergic agonist combination therapy in asthmatic children . This study was design ed to evaluate the safety ( primary ) and clinical benefits ( secondary ) of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus budesonide dry powder inhaler ( DPI ) in children with persistent asthma . This was a 26-week , multicenter , r and omized , open-label U.S. study of 187 children 6 - 11 years of age previously receiving ICS .  After 1 week of usual ICS therapy , subjects received twice-daily budesonide/formoterol pMDI 160/4.5 micrograms x 2 inhalations ( 320/9 micrograms ; n = 124 ) or budesonide DPI 200 micrograms x 2 inhalations ( 400 micrograms [ 320 micrograms delivered ex-mouthpiece ] ; n = 63 ) . Budesonide/formoterol and budesonide were well tolerated with a similar incidence of adverse events ( AEs ) ( 84.6 % and 85.7 % , respectively ) , most of mild or moderate intensity . Treatment-related AE incidence was low ( 5.4 % ) and similar across groups ( budesonide/formoterol , 4.9 % ; budesonide , 6.3 % ) . No clinical ly important treatment differences were observed for 12-lead electrocardiograms , hematology , serum glucose and potassium , and 24-hour urinary cortisol . Compared with budesonide , budesonide/formoterol decreased health care use ( urgent care visits and interference with daily activities [ child ] or work [ caregiver ] ; p < or = 0.012 ) and improved health-related quality of life ( Pediatric Asthma Quality of Life Question naire [ st and ardized ] and Pediatric Asthma Caregiver Quality of Life Question naire overall scores ; p < or = 0.006 ) and pulmonary function ( predose forced expiratory volume in 1 second and forced expiratory flow during the middle half of exhalation ; p < or = 0.007 ) . In this 26-week study of asthmatic children ( 6 - 11 years ) , safety profiles were similar and clinical benefits were greater with budesonide/formoterol than with budesonide 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 The objective of this study was to investigate initial maintenance treatment with salmeterol/fluticasone propionate ( Seretide ) 50/250 μ g twice daily ( SFC ) compared with fluticasone propionate ( Flixotide ) 250 μ g twice daily ( FP ) ( both via Diskus inhaler , GlaxoSmithKline , Greenford , UK ) in patients with moderate persistent asthma currently only treated with inhaled short-acting β2-agonists . A total of 362 adults and adolescents ( 12 to 80 years of age ) were r and omized to this 12-week double-blind parallel-group study . The primary endpoint was mean morning peak expiratory flow ( PEF ) . Secondary efficacy endpoints included median percentages of symptom-free and rescue-free days and nights ; the percentage of patients who achieved the pre-defined criteria for well-controlled asthma over weeks 5 to 12 ; and the incidence of asthma exacerbations . Safety was assessed by the incidence of adverse events . Superiority of SFC over FP alone was demonstrated for the primary and each secondary endpoint . The difference in adjusted mean change from baseline in morning PEF between SFC and FP was 21 L/min ( 95%CI : 11 , 31 ; p < 0.001 ) . Significantly more patients achieved well-controlled asthma during treatment with SFC ( 46 % ) compared with FP ( 32 % ) ( odds ratio 1.84 ; 95%CI : 1.17 , 2.89 ; p = 0.008 ) . Both treatments were safe and well-tolerated . This study demonstrates that initial maintenance treatment with SFC 50/250 μg twice daily provides superior efficacy to FP 250 μ g twice daily alone in patients with moderate persistent asthma ABSTRACT Objective : To determine the effects of budesonide and formoterol administered via one pressurized metered-dose inhaler ( budesonide/formoterol pMDI ) on patient-reported outcomes ( PROs ) and to determine the contributions of budesonide and formoterol to those effects in adults with asthma . Research design and methods : A 12-week , r and omized , double-blind , double-dummy , placebo-controlled , multicenter study was conducted in 480 patients aged ≥ 12 years with mild-to-moderate persistent asthma . After a 2-week run-in period during which current asthma therapy was discontinued , patients were r and omized to receive two inhalations twice daily of budesonide/formoterol pMDI 80/4.5 μg ( 160/9 μg ) , budesonide pMDI 80 μg ( 160 μg ) , formoterol via dry powder inhaler ( DPI ) 4.5 μg ( 9 μg ) , or placebo . Main outcome measures : Analyses included a sub population of 405 patients aged ≥ 18 years . PROs included the st and ardized Asthma Quality of Life Question naire ( AQLQ(S ) ) , the Medical Outcomes Study ( MOS ) Sleep Scale , the Patient Satisfaction with Asthma Medication ( PSAM ) question naire , and asthma control variables ( recorded via electronic diaries ) , such as asthma symptoms , rescue medication use , and nighttime awakenings due to asthma . Patient and physician global assessment s were collected at the end of the study . Results : Patients aged ≥ 18 years receiving budesonide/formoterol pMDI reported significantly greater improvements from baseline in AQLQ overall and domain scores , MOS Sleep Scale domain scores , and asthma control variables than patients receiving placebo ( p ≤ 0.033 ) . Improvements from baseline in AQLQ(S ) overall and domain scores , daily asthma symptoms scores , percentage of symptom-free days , percentage of rescue medication-free days , and percentage of asthma control days were significantly greater in patients receiving budesonide/formoterol pMDI versus formoterol DPI ( p ≤ 0.042 ) . Patients receiving budesonide/formoterol pMDI reported significantly greater PSAM scores than did patients in all other treatment arms ( p ≤ 0.004 ) . Study limitations may include the fact that the formoterol-alone arm used a different device and formulation than the other active arms as well as the absence of a treatment arm with budesonide and formoterol administered concomitantly in separate inhalers . In addition , these results may not be generalized to all patients with asthma , as this analysis included only patients aged ≥ 18 years . Conclusions : Patients receiving treatment with budesonide/formoterol  pMDI experienced significantly greater improvements from baseline in asthma-related quality of life , quality of sleep , and asthma control and greater satisfaction with treatment than patients receiving placebo . The combination of budesonide and formoterol in one pMDI is beneficial in improving how a patient feels and functions as a result of treatment 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 ABSTRACT Objective : This long-term prospect i ve study was conducted in African Americans with persistent asthma to examine the safety and effectiveness of the combination of the inhaled corticosteroid , fluticasone propionate ( FP ) , and the long-acting beta-agonist , salmeterol , compared with FP alone . Research and design methods : This was a r and omized , double-blind , parallel group , multi-center trial in adolescent and adult subjects ≥12 years of age symptomatic on a low dose of an inhaled corticosteroid ( ICS ) .  The study consisted of a 2-week screening period on low dose ICS ; a 4-week open-label FP 250 mcg twice daily ( BID ) run-in ; a 52-week double-blind period ( FP/salmeterol [ FSC ] 100/50 mcg [ n = 239 ] or FP 100 mcg [ n = 236 ] BID ) , and a 4-week FP 250 mcg BID run-out period . Annualized exacerbation rate was the primary outcome for comparing the two treatments . Other measures of asthma control included peak expiratory flow , asthma symptoms , and albuterol use . Safety was assessed through adverse events . Results : Exacerbation rates were not significantly different in those treated with FSC 100/50 mcg ( 0.449 per year ) compared with FP 100 mcg ( 0.529 per year , p = 0.169 ) . When the per- protocol analysis was applied , the rates were 0.465 and 0.769 per year for FSC 100/50 mcg and FP 100 mcg , respectively . Treatment with FSC 100/50 mcg provided statistically greater improvements in lung function measures and nighttime awakenings ( p ≤ 0.050 ) and demonstrated numerically lower daily symptoms ( p = 0.216 ) and albuterol use ( p = 0.122 ) . Two subjects treated with FSC 100/50 mcg were hospitalized for an asthma exacerbation compared to three treated with FP 100 mcg . The overall incidence of adverse effects during double-blind treatment was similar between the FSC 100/50 mcg and FP 100 mcg treatment groups ( 61 % and 68 % , respectively ) . Frequent study visits were required of subjects during this long-term study , and it remains unknown whether this intervention may affect generalizability . Conclusion : In this large , prospect i ve study among African Americans with asthma , the addition of salmeterol to FP result ed in a similar low rate of exacerbations and improved other markers of asthma control . Both FSC 100/50 mcg and FP 100 mcg were well-tolerated , and the overall safety-profiles were similar over 1 year of treatment 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 Pulmonary function tests ( PFTs ) and especially spirometry measures are useful tools in evaluating early response to treatment of asthma in children mainly due to their worldwide availability . The aim of our study was to determine the effects of anti-asthma treatment in children , equally on FEV(1 ) , FEF25 - 75 % , R(int ) and SR(aw ) values . METHODS Children 6 - 18 years of age with moderate atopic asthma were r and omized to 4-week , placebo-controlled , double-blind trial . Patients were r and omly allocated to receive 200 microg budesonide ( B ) ( n=29 ) , 5 or 10 mg ( according to age ) montelukast ( M ) ( n=29 ) , 200 microg B + 5 or 10 mg M ( n=29 ) , 200 microg B + 9 microg formoterol ( F ) ( n=29 ) or placebo ( n=27 ) . FEV(1 , ) FEF25 - 75 % , R(int ) , SR(aw ) were measured before and after treatment . RESULTS R(int ) , SR(aw ) , FEV(1 ) improved significantly in all active treatment groups while FEF25 - 75 % improved significantly only in BM group and M group . Combination therapy , showed significantly greater effects on R(int ) than monotherapy : BM group compared to B group ( P=0.01 ) and M group ( P=0.03 ) and BF group compared to B group ( P=0.01 ) and M group ( P=0.04 ) . CONCLUSION This study shows that using single parameter for monitoring asthma can be misleading . Using combination of lung function techniques provides better assessment of treatment . Results of our study confirm this hypothesis . The best effect on large and small airways was achieved with combined anti-inflammatory therapy Asthma guidelines recommend titrating maintenance medications to the lowest effective dose . This study assessed the efficacy and tolerability of reducing the frequency of dosing in patients previously controlled with twice-daily budesonide/formoterol ( BUD/FM ) pressurized metered-dose inhaler ( pMDI )  to once-daily regimens of BUD/FM pMDI or BUD pMDI . This was a 12-week , r and omized , double-blind , double-dummy , placebo (PBO)/active-controlled , multicenter study ( N = 752 ) of patients aged > or = 16 years with mild to moderate asthma . After 4 - 5 weeks on single-blind BUD/FM pMDI 160/9 micrograms twice daily ( 320/18 micrograms daily ) , patients with stable asthma received BUD/FM pMDI 160/9 micrograms twice daily ( 320/18 micrograms daily ; morning and evening ) , BUD/FM pMDI 320/9 micrograms once daily ( evening ) , BUD/FM pMDI 160/9 micrograms once daily ( evening ) , BUD pMDI 320 micrograms once daily ( evening ) , or PBO . BUD/FM ( once or twice daily ) was more effective ( p < or = 0.003 ) than BUD and PBO on evening peak expiratory flow ( primary variable ) , morning pulmonary function assessment s , daily symptoms , and nighttime rescue medication use . Twice-daily BUD/FM was more effective ( p < or = 0.05 ) than both once-daily doses for evening pulmonary function assessment s and daytime rescue medication use . All treatments were well tolerated . Once- or twice-daily BUD/FM showed better efficacy than BUD once daily or PBO ; results generally were more favorable with twice-daily dosing compared with both once-daily dosing regimens , which had one-half the daily FM dose 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 The aim of this study was to compare the efficacy and safety of salmeterol/fluticasone propionate combination product ( SFC ) with fluticasone propionate ( FP ) plus oral montelukast ( M ) over 12 weeks in symptomatic asthma patients . The study was a multinational , r and omised , double-blind , double-dummy , parallel-group design in patients aged > or = 15 years . After a 4-week run-in during which all patients received FP 100 microg twice daily , patients were r and omised to inhaled SFC ( 50/100 microg ) twice daily or inhaled FP 100 microg twice daily and oral M 10 mg once daily . Patients kept daily records of their peak expiratory flow ( PEF ) symptom scores and use of rescue medication . Over the 12-week treatment period , the adjusted increase in mean morning PEF was significantly greater in the SFC group ( 36 l/min ) than the FP/M group ( 19 l/min ; P < 0.001 ) . The improvement in FEV1 was also significantly greater in the SFC group ( mean treatment difference 0.11 l ; P < 0.001 ) . SFC provided significantly better control of daytime and night-time symptoms and there were fewer exacerbations . Patients in the SFC group were also significantly more likely to have a rescue-free day . Both treatments were equally well tolerated . Combination therapy with FP plus salmeterol ( SFC ) produced significantly greater improvements in lung function and asthma control than the addition of montelukastto FP This double-blind , r and omised , multi-centre , parallel-group study compared the effect of adding Foradil ( formoterol fumarate ) to existing medium-high doses of inhaled corticosteroids ( ICS ) with that of doubling the dose of ICS in patients with sub-optimally controlled asthma . After a run-in period , 203 patients with moderate-to-severe asthma who remained symptomatic despite treatment with 500 microg beclomethasone twice daily , were r and omised to receive either 12 microg formoterol twice daily ( Foradil Aerolizer ) , Novartis ) in addition to beclomethasone 500 microg twice daily , or beclomethasone 1000 microg twice daily and placebo for 12 weeks . The primary efficacy variable was mean morning pre-medication peak expiratory flow ( PEF ) during the last seven days of treatment . The difference in PEF between treatments was 27.78 l/min in favour of the formoterol/beclomethasone combination ( 95 % CI 13.42 , 42.14 l/min , p=0.0002 , intention-to-treat population ) . Significant differences in the urinary cortisol/creatinine ratio between treatment groups at 12 weeks ( p=0.001 ) indicated suppression of the hypothalamic-pituitary-adrenal axis in the patients on beclomethasone 1000 microg twice daily . The addition of formoterol 12 microg twice daily to beclomethasone in patients with asthma who were poorly controlled with  beclomethasone  500 microg twice daily was more effective than doubling the ICS dose and result ed in less suppression of the hypothalamic-pituitary-adrenal axis 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 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 BACKGROUND The role of combination ICS/LABA as initial controller therapy in mild , persistent asthma is uncertain . Therefore , the objective of this study was to compare the efficacy of initial controller therapy with fluticasone propionate ( FP ) 100 microg twice daily to the efficacy of fluticasone propionate/salmeterol xinafoate ( FSC ) 100/50 microg twice daily in patients with persistent asthma symptoms while using as-needed SABA alone . METHODS This r and omized , double-blind , parallel-group study was conducted at 45 general practice and 15 specialist centers . A total of 526 adult patients were r and omized to receive FP or FSC for 24 weeks . The primary efficacy endpoint was change in morning peak expiratory flow ( PEF ) from baseline . Secondary efficacy endpoints included symptom- and rescue-free days ; asthma exacerbation rate ; asthma-related health-care utilization ; and the onset of effect . Safety was assessed by monitoring adverse events . RESULTS Mean morning PEF was significantly greater in the FSC versus the FP group ( P<0.001 ) ; this greater effect was evident as early as the first week of treatment ( P<0.001 ) . The percentages of symptom-free days and rescue-free days in the FSC group were 7.7 % ( P=0.009 ) and 8.4 % ( P=0.001 ) higher than the FP group , respectively . Trends toward lower exacerbation-related health care-utilization for FSC versus FP were not statistically significant and exacerbation rates were not significantly different . The incidence of adverse events was low with both treatments . CONCLUSIONS : Treatment with FSC was a more effective initial controller therapy than FP monotherapy in ICS-naïve patients who had uncontrolled asthma while using as-needed SABA alone BACKGROUND Asthma guidelines recommend reducing inhaled corticosteroids ( ICS ) to the minimum effective dose , but the timing of long-acting beta(2)-agonist ( LABA ) withdrawal is unclear . Recent FDA guidelines recommend LABA withdrawal once asthma is well-controlled . This 13-month double-blind study of patients taking high-dose combination therapy investigated the effect of discontinuation of LABA before ICS down-titration . METHODS Adults using salmeterol/fluticasone combination ( SFC ) 50/500 microg bd were r and omized to SFC 50/500 microg bd or  fluticasone propionate ( FP ) 500 microg bd , with subsequent ICS down-titration 8-weekly using a clinical algorithm . The primary outcome was mean daily FP dose , including ICS for exacerbations . RESULTS 82 subjects were r and omized . Asthma was well-controlled at baseline , with mean FEV(1 ) 84.8 % predicted and Asthma Control Question naire ( ACQ ) score 0.9 . There was no significant difference in mean daily FP dose ( SFC : 721 microg , FP:816 microg , p = 0.3 ) , but final dose was lower with SFC ( 534 microg cf . 724 microg , p = 0.005 ) . ICS dose was reduced by > or=80 % in 41 % SFC and 15 % FP patients . Ambulatory lung function was significantly higher with SFC , but there were no differences between groups in rescue beta(2)-agonist use , clinic spirometry , airway responsiveness , ACQ , sputum eosinophils or FeNO . Baseline airway responsiveness , and pre-reduction blood eosinophils , were significant predictors of mean daily FP dose and dose reduction failure respectively . CONCLUSIONS Many patients prescribed high-dose combination therapy may be over-treated . Substantial reductions in dose can be achieved with a clinical algorithm , reaching lower FP doses with SFC than FP without losing asthma control or increasing disease activity . TRIAL REGISTRATION This study was commenced before m and atory registration of clinical trials 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 SUMMARY Objectives : This study evaluated the efficacy and safety of a novel asthma management strategy – budesonide/formoterol for both maintenance and symptom relief ( Symbicort Single Inhaler Therapy * ) – compared with a higher maintenance dose of budesonide in patients with moderate to severe asthma . Methods : This was a 12-month , r and omised , double-blind , parallel-group study . Symptomatic patients with asthma ( n = 1890 ; mean age 43 years [ range 11 years–80 years ] , mean baseline forced expiratory volume in 1 s [ FEV1 ] 70 % of predicted , mean inhaled corticosteroid [ ICS ] dose 746 µg/day ) received either budesonide ( 160 µg , 2 inhalations twice daily ) plus terbutaline 0.4 mg as needed or a daily maintenance dose of budesonide/formoterol ( 160/4.5 µg , 2 inhalations once daily ) with additional inhalations of budesonide/formoterol 160/4.5 µg as needed . Time to first severe exacerbation ( hospitalisation/emergency room [ ER ] treatment or systemic steroids due to asthma worsening or a fall in morning peak expiratory flow [ PEF ] to ≤ 70 % of baseline on 2 consecutive days ) was the primary outcome variable . Results : A total of 1890 patients were r and omised , of whom 1563 ( 83 % ) had severe asthma .  The time to first severe exacerbation was prolonged by budesonide/formoterol single inhaler therapy ( p < 0.001 ) compared with a higher dose of budesonide . The risk of having a severe exacerbation was 39 % lower with budesonide/ formoterol single inhaler therapy compared with budesonide ( p < 0.001 ) . The number needed to treat to prevent one severe exacerbation per year  with budesonide/formoterol compared with budesonide was 5 . The budesonide/formoterol group had 45 % fewer severe exacerbations requiring medical intervention per patient compared with the budesonide group ( p < 0.001 ) . Budesonide/formoterol patients had fewer hospitalisations/ER treatments ( 15 vs 25 events , respectively [ descriptive statistics ] ) and fewer treatment days with systemic steroids ( 1776 days vs 3177 days , respectively [ descriptive statistics ] ) compared with budesonide patients . Budesonide/formoterol single inhaler therapy patients used less as-needed medication compared with budesonide patients ( 0.90 vs 1.42 inhalations/day ; p < 0.001 ) . The mean daily ICS dose was lower in the budesonide/formoterol group than in the budesonide group ( 466 µg/day vs 640 µg/day ) . Over the 12-month study period , the budesonide/formoterol group achieved asthma control sufficient to not require any additional as-needed medication on 60 % of days . Overall , budesonide/formoterol single inhaler therapy gave 31 more asthma control days ( a night and day with no asthma symptoms and no as-needed medication use ) per patient-year and 12 additional undisturbed nights per patient-year compared with a higher dose of budesonide . Both treatments were well tolerated . Conclusion : Budesonide/formoterol single inhaler therapy has the potential to provide a complete asthma management approach with one inhaler , demonstrating a high level of efficacy in patients with moderate to severe asthma This study compared the efficacy and safety of budesonide/formoterol ( Symbicort ) Turbuhaler ) ) with salbutamol pressurized metered-dose inhaler ( pMDI ) with spacer for relief of acute bronchoconstriction in patients with asthma . In this r and omized , double-blind , parallel-group study , patients ( n = 104 allocated to treatment ; n = 103 received treatment ; mean age 45 years ) seeking medical attention for acute asthma ( mean FEV(1 ) 43 % of predicted ) received two doses repeated at t = -5 and 0 min of either budesonide/formoterol ( 320/9 microg , two inhalations ) or salbutamol ( 100 microg x eight inhalations ) ; total doses 1280/36 microg and 1600 microg , respectively . All patients received prednisolone 60 mg at 90 min and FEV(1 ) was assessed over 3h . FEV(1 ) 90 min after dosing ( primary variable ) increased compared with pre-dose FEV(1 ) by an average of 30 % and 32 % for budesonide/formoterol and salbutamol , respectively ( P = 0.66 ) , with similar increases at all timepoints from 3 to 180 min for both groups . Mean pulse rate over 3h was significantly higher in the salbutamol group versus the budesonide/formoterol group ( 92 vs. 88 bpm ; P < 0.01 ) . No treatment differences were seen for other vital signs , including ECG . High-dose budesonide/formoterol was effective and well tolerated for the treatment of acute asthma , with rapid onset of efficacy and a safety profile over 3h similar to high-dose salbutamol 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 BACKGROUND Asthma guidelines recommend combining inhaled corticosteroids and long-acting inhaled B2-agonists when inhaled corticosteroids alone are insufficient to achieve good control of the disease . OBJECTIVES To determine in routine practice whether the fixed-dose fluticasone-salmeterol combination ( FP/s ) is as least as effective as inhaled corticosteroids combined with long-acting B2-agonists administered separately and to study patient perception . METHODOLOGY An open multicentric r and omized study was conducted in two matched population s stratified by the prior treatment . Patients insufficiently controlled by moderate-dose inhaled corticosteroids + /- long-acting B2-agonists or high-dose inhaled corticosteroids alone  were treated for 3 months using one inhalation of FP/S twice daily or inhaled corticosteroids and long-acting B2-agonists given separately ( TC ) . RESULTS Mean improvement in morning PEFR at 3 months was 39.2 + /- 4.1 l/min with FP/S and 30.7 + /- 4.0 l/min with TC . The difference ( FP/S-TC : 8.5 l/min , CI95 : -0.7 - 17.7 l/min ) did not reach significance . There was no difference between the two groups for criteria other than TC . Tolerance was good in both groups . CONCLUSION The fixed-dose fluticasone-salmeterol combination is as least as effective as open combinations of inhaled corticosteroids and long-acting B2-agonists and is appreciated by patients ( easier dosing , easier administration ) The objective of this study was to compare the efficacy and safety of fluticasone propionate ( FP ) ( 44 µg)/salmeterol ( 21 µg ) delivered as two inhalations twice daily via a single hydrofluoroalkane ( HFA 134a ) metered dose inhaler ( MDI ) ( FSC ) with that of placebo HFA 134a ( PLA ) , fluticasone propionate 44 µg chlorofluorocarbon ( CFC ) alone and salmeterol 21 µg CFC alone ( S ) in patients ( n = 360 ) with persistent asthma previously treated with β2‐agonists ( short‐ or long‐acting ) or inhaled corticosteroids ( ICS ) . After 12 weeks of treatment , patients treated with FSC had a significantly greater increase ( p ≤ 0.006 ) in mean FEV1 AUC(bl ) compared with PLA , FP , or S. At end point , mean change from baseline in morning predose FEV1 for FSC ( 0.58 L ) was significantly ( p ≤ 0.004 ) greater than PLA ( 0.14 L ) , FP ( 0.36 L ) , and S ( 0.25 L ) . Patients treated with FSC also had a significantly higher probability of remaining in the study without being withdrawn due to worsening asthma ( 2 % ) compared with those in the PLA ( 29 % ) and S ( 25 % ) groups ( p < 0.001 ) . Finally , treatment with FSC result ed in significantly ( p ≤ 0.007 ) greater improvements in morning and evening peak expiratory flow , need for rescue albuterol , and asthma symptom scores compared with FP , S , and PLA . The safety profile of FSC was also similar to FP or S alone . Initial maintenance treatment of the two main components of asthma , inflammation , and smooth muscle dysfunction ( e.g. , bronchoconstriction ) , with FSC results in greater overall improvements in asthma control compared with treatment of either individual component alone OBJECTIVE To determine whether initiation of maintenance treatment with the salmeterol (S)/fluticasone propionate ( FP ) combination ( Seretide/Viani/Advair ) is more effective than inhaled steroid alone in patients with asthma symptomatic on short-acting bronchodilator alone . DESIGN 150 asthma patients with symptoms and prn use of short-acting bronchodilator at least once a week were r and omised to 24 weeks ' treatment with either S/FP 50/100 microg bd ( n = 78 ) or FP 100 microg bd ( n = 72 ) . The primary endpoint was the percentage of symptom-free ' day + night 's . RESULTS The percentage of symptom-free ' day + night 's increased significantly more for S/FP ( 20 to 64 % ) compared to FP ( 24 to 51 % ) . The treatment difference was 15.3 % , P = 0.008 . In the sub-group of patients with mild asthma the treatment difference was also statistically significant in favour of S/FP ( P = 0.0245 , n = 74 ) . S/FP was also significantly superior to FP alone for : lung function , salbutamol use prn , day symptom score , symptom-free days , and episode-free ' day + night 's . Treatments were equally well tolerated . CONCLUSION Initial maintenance treatment with S/FP is significantly more effective than with inhaled steroid alone for patients symptomatic when treated with short-acting bronchodilator alone . This also apply to patients with mild persistent asthma BACKGROUND Fluticasone and formoterol are well established medications for the treatment of asthma . This study ( Clinical trials.gov identifier : NCT00734318 ) compares the efficacy and safety of a combination of these drugs in a single inhaler ( fluticasone/formoterol ) versus the individual components ( fluticasone + formoterol ) . METHODS Patients aged ≥ 18 years ( n=620 ) with a history of severe , persistent reversible asthma for ≥ 6 months prior to screening were included in this r and omized , double-blind study , which consisted of a screening phase of up to 5 days , a 2-week run-in phase and an 8-week treatment period . RESULTS Fluticasone/formoterol ( 500/20 μg , b.i.d . ) was at least as effective as fluticasone + formoterol ( 500 μg + 24 μg , b.i.d . ) with respect to the primary outcome measure : there were similar increases in mean pre-morning dose forced expiratory volume in the first second ( FEV(1 ) ) in these two groups . Fluticasone/formoterol ( 500/20 μg , b.i.d . ) also demonstrated similar efficacy to fluticasone + formoterol in terms of change in mean FEV(1 ) from baseline pre-morning dose to 2 h post-morning dose at week 8 , as well as for several secondary parameters  . Fluticasone/formoterol ( 500/20 μg , b.i.d . ) demonstrated superiority to fluticasone monotherapy ( 500 μg , b.i.d . ) and fluticasone/formoterol ( 100/10 μg , b.i.d . ) for several secondary efficacy parameters  . Fluticasone/formoterol had a similar safety and tolerability profile to fluticasone + formoterol . CONCLUSION This study demonstrated that the fluticasone/formoterol combination is at least as effective as its components administered concurrently from separate inhalers . Fluticasone/formoterol ( 500/20 μg , b.i.d . ) showed superior efficacy to its inhaled corticosteroid component alone and the efficacy of fluticasone/formoterol was dose-dependent for several clinical ly important parameters BACKGROUND Therapy with salmeterol , a long-acting , selective , inhaled beta 2-adrenergic agonist , is effective and safe for patients with persistent asthma ; however , few long-term studies comparing salmeterol with current combination treatment regimens have been reported . METHODS A multicenter , r and omized , placebo-controlled , double-blind study was conducted in 386 patients over 41 to 46 weeks in 27 medical centers ( two thirds of the investigators were primary care physicians ) . Patients were r and omized to receive either salmeterol or placebo , and further r and omized to weaning or nonweaning from current asthma therapies ( except inhaled corticosteroids ) . Treatment groups were : salmeterol/weaning ( S + W ) , placebo/weaning ( P + W ) , salmeterol/no weaning ( S + NW ) , and placebo/no weaning ( P + NW ) . Attempts at active weaning were carried out at the discretion of the investigator for 2 to 6 weeks . Pulmonary function , albuterol use , and asthma symptoms were measured . RESULTS The clinical benefits of salmeterol occurred despite weaning off existing nonsteroidal asthma medications . The mean morning peak expiratory flow rate was significantly increased in the S + W group ( 32.3 L/min ) compared with both the P + W ( 4.9 L/min ) and P + NW ( 6.8 L/min ) groups ( P < .001 ) . Compared with the P + W and P + NW groups , the S + W group experienced significant ( P < .05 ) improvements in overall mean asthma symptom scores , mean number of puffs of supplemental albuterol , the percentage of days with no supplemental albuterol use , and the mean number of awakenings caused by asthma ( except for the P + NW comparison , P = .090 ) . No significant differences were noted between treatment groups in any safety evaluation , including 12-lead electrocardiograms . CONCLUSIONS The addition of salmeterol in the treatment of persistent asthma result ed in sustained improvement in pulmonary function and symptoms . The long-term use of salmeterol is safe and improves the clinical course and stability of asthma following reductions in nonsteroidal asthma therapy 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 OBJECTIVE --To compare safety of salmeterol and salbutamol in treating asthma . DESIGN --Double blind , r and omised clinical trial in parallel groups over 16 weeks . SETTING --General practice s throughout the United Kingdom . SUBJECTS--25,180 patients with asthma considered to require regular treatment with bronchodilators who were recruited by their general practitioner ( n = 3516 ) . INTERVENTIONS --Salmeterol ( Serevent ) ( 50 micrograms twice daily ) or salbutamol ( 200 micrograms four times a day ) r and omised in the ratio of two patients taking salmeterol to one taking salbutamol . All other drugs including prophylaxis against asthma were continued throughout the study . MAIN OUTCOME MEASURES --All serious events and reasons for withdrawals ( medical and non-medical ) whether or not they were considered to be related to the drugs . RESULTS --Fewer medical withdrawals due to asthma occurred in patients taking salmeterol than in those taking salbutamol ( 2.91 % v 3.79 % ; chi 2 = 13.6 , p = 0.0002 ) . Mortality and admissions to hospital were as expected . There was a small but non-significant excess mortality in the group taking salmeterol and a significant excess of asthma events including deaths in patients with severe asthma on entry . Use of more than two canisters of bronchodilator a month was particularly associated with the occurrence of an adverse asthma event . CONCLUSIONS --Treatment over 16 weeks with either salmeterol or salbutamol was not associated with an incidence of deaths related to asthma in excess of that predicted . Overall control of asthma was better in patients allocated to salmeterol . Serious adverse events occurred in patients most at risk on entry and were probably due to the disease rather than treatment ABSTRACT Objective : To evaluate efficacy and costeffectiveness of budesonide/formoterol ( Symbicort * ) maintenance ( one dose once or twice daily ) plus additional doses as needed ( Symbicort Maintenance And Reliever Therapy , SMART ) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma .  * Symbicort is a registered trade name of the AstraZeneca group of companies Study design and methods : 6‐month , open , r and omised study of 465 patients either not well controlled on an inhaled corticosteroid ( ICS ) , or well controlled on a combination of ICS and a long-acting β2‐agonist ( LABA ) . Treatments : budesonide/formoterol 160/4.5 µg , one inhalation , once or twice daily maintenance plus additional doses as-needed ( 1 × SMART or 2 × SMART ) , or budesonide/formoterol 160/4.5 µg two inhalations twice daily plus formoterol 4.5 µg as needed ( 2 × 2 FIX + F ) . Children 6–11 years old used an 80/4.5 µg dose strength . Primary variables of efficacy were the changes in the Asthma Control Question naire ( ACQ5 ) and morning peak expiratory flow ( PEF ) . Results : Mean age of patients 40 years ( range 6–82 years ) ; 53 % female . No differences between the groups were found in ACQ5 scores or asthma exacerbation rates . Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups ( differences 13 L/min and 9 L/min , respectively ; p < 0.002 ) . The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups . No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group . Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group . Conclusion : Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40 % lower in the SMART groups while maintaining equal ACQ5 scores . Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost . The one dose once daily maintenance treatment ( 1 × SMART ) result ed in a low level of treatment failure ( exacerbations ) but led to more days with symptoms . Therefore , a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma Regular inhaled beta 2 agonist causes tolerance to the acute protective effect of beta 2 agonist against bronchoconstriction induced by chemical stimuli such as AMP , histamine , and methacholine . We examined a more clinical ly relevant stimulus , inhaled allergen , in a double-blind , cross-over , r and om-order trial in 13 mild atopic asthmatics , who had not used beta 2 agonist for at least 4 weeks . We compared regular inhaled salbutamol ( 200 micrograms four times daily for 2 weeks ) with placebo ( 2 weeks ) for effects on bronchodilator response , baseline methacholine , and allergen airway responsiveness , and on the acute protective effect of salbutamol against both stimuli . Baseline forced expiratory volume in 1 s ( FEV1 ) , bronchodilator response , and methacholine responsiveness were the same during both treatment periods . After regular salbutamol , the allergen PC20 ( provocation concentration producing a 20 % FEV1 decrease ) fell by 0.91 ( SD 0.66 ) ( p = 0.0009 ) doubling doses , and the protective effects of salbutamol  on methacholine and allergen were both significantly reduced ( p = 0.026 and 0.025 , respectively ) . Taking into account the reduced baseline allergen PC20 , the post-salbutamol allergen PC20 was almost 2 doubling doses ( 1.94 [ 1.43 ] , p < 0.01 ) lower during salbutamol treatment . Thus , 2 weeks of regular inhaled salbutamol increased airway responsiveness to allergen but not to methacholine , and caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both stimuli . These effects of inhaled beta 2 agonist provide further evidence to support detrimental effects of their regular use For most patients , asthma is not controlled as defined by guidelines ; whether this is achievable has not been prospect ively studied . A 1-year , r and omized , stratified , double-blind , parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous , composite , guideline -based measures of control : totally and well-controlled asthma . Treatment was stepped-up until total control was achieved ( or maximum 500 microg corticosteroid twice a day ) . Significantly more patients in each stratum ( previously corticosteroid-free , low- and moderate-dose corticosteroid users ) achieved control with salmeterol/fluticasone than fluticasone .  Total control was achieved across all strata : 520 ( 31 % ) versus 326 ( 19 % ) patients after dose escalation ( p < 0.001 ) and 690 ( 41 % ) versus 468 ( 28 % ) at 1 year for salmeterol/fluticasone and fluticasone , respectively . Asthma became well controlled in 1,071 ( 63 % ) versus 846 ( 50 % ) after dose escalation ( p < 0.001 ) and 1,204 ( 71 % ) versus 988 ( 59 % ) at 1 year . Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone . Across all strata , 68 % and 76 % of the patients receiving salmeterol/fluticasone and fluticasone , respectively , were on the highest dose at the end of treatment . Exacerbation rates ( 0.07 - 0.27 per patient per year ) and improvement in health status were significantly better with salmeterol/fluticasone . This study confirms that the goal of guideline -derived asthma control was achieved in a majority of the patients UNLABELLED In patients controlled with SFC250 Diskus bd , this double-blind , r and omised 6-month study compared continuing SFC250 to stepping down to either SFC100 bd or FP250 bd .  Six hundred and three patients previously using 1,000 microg BDP ( or equivalent ) daily + LABA and controlled according to investigator 's judgement were recruited . Patients received SFC250 bd during an 8-week open run-in period . Four hundred and seventy six patients ( mean age=43 years , mean FEV(1)=2.9+/-1.0 ) who fulfilled the r and omisation criterion ( ' Well-controlled ' asthma according to the GOAL weekly definition for the last 2 weeks of the run-in period ) entered a 24-week treatment period . The statistical hypothesis was based on a non-inferiority of SFC100 or FP250 compared to SFC250 . The main criterion was the change from baseline in morning PEF over weeks 1 - 12 in the per- protocol population . The non-inferiority limit was -15 L/min . At inclusion , the three treatment groups were well balanced . Mean morning PEF was 476 , 470 and 465 L/min in the SFC250 , SFC100 and FP250 groups , respectively . The adjusted mean change in morning PEF over weeks 1 - 12 was + 1.76+/-2.43 L/min for SFC250 , -3.07+/-2.32 L/min for SFC100 and -16.51+/-2.46 L/min for FP250 . SFC100 was at least as effective as SFC250 ( treatment difference -4.83 [ -12.39 ; 2.72 ] , p=0.151 ) whereas FP250 was not ( treatment difference -18.27 [ -26.05 ; -10.49 ] , p<0.001 ) . Similar results were observed over weeks 13 - 24 in morning PEF ( SFC100-SFC250=-4.54+/-3.84 , p=0.238 ; FP250-SFC250=-20.11+/-3.92 , p<0.0001 ) . Secondary endpoints showed a similar pattern . Over weeks 1 - 12 , SFC250 was significantly more effective than FP250 on evening PEF , daily symptoms and bronchodilator use . There was no difference between SFC100 and SFC250 . The mean annual rate of moderate exacerbations was 0.16 in both SFC 250 and SFC 100 groups , and 0.21 in FP 250 group ( ns , Poisson analysis ) . All treatments were well tolerated . CONCLUSION In patients achieving asthma control with SFC250 , stepping treatment down with SFC100 was at least as effective on lung function and symptoms as continuing SFC250 , whereas FP250 was not STUDY OBJECTIVE Adding inhaled long-acting beta2-agonists to a low dose of inhaled corticosteroids ( ICSs ) results in better asthma control than increasing the dose of ICSs . An important , but as yet unresolved , question is whether this is due to an additional reduction of airway inflammation . DESIGN Double-blind , parallel-group trial . PATIENTS Forty asthma patients ( FEV1 , 50 to 90 % predicted ; provocative concentration of a substance [ methacholine ] causing a 20 % fall in FEV1 of < 8 mg/mL ; no ICSs in the last 4 weeks ) . INTERVENTIONS R and omization to 8 weeks of treatment with 100 microg of budesonide bid plus placebo ( BUD200 ) or 100 microg of budesonide bid plus 12 microg of formoterol ( BUD200 + F ) . Then the dose of budesonide ( BUD ) was increased to 400 microg bid in both groups for another 8 weeks . Bronchial biopsy specimens were collected before , and after 8 and 16 weeks of treatment . Eosinophils ( major basic protein [ MBP ] ) and mast cells ( tryptase ) were analyzed by immunohistochemistry . RESULTS BUD200 reduced the MBP staining ( p = 0.008 ) and tryptase staining ( p = 0.048 ) in the epithelium compared to baseline levels . There were no significant differences between the BUD200 and BUD200 + F groups . In both groups , increasing the dosage of BUD to 800 microg had no significant additional antiinflammatory effect . CONCLUSIONS Our results demonstrate that BUD administered at a low dose has significant antiinflammatory effects in patients with mild asthma . No significant additional antiinflammatory effects could be demonstrated either by adding formoterol or by increasing the dose of BUD 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 Objective : To assess the cardiovascular and metabolic responses to increasing doses of formoterol administered from a dry powder inhaler . Methods : Twenty patients with mild to moderate asthma were given 12 , 24 , 48 and 96 μg of formoterol or a matched placebo on separate days . The doses were administered using a r and omised , cross-over , double-blind design . The effects on heart rate , blood pressure , electromechanical systole ( QS2I ) , the electrocardiographic QTc interval , plasma potassium ( K ) ; blood glucose and FEV1 were assessed prior to , and for 9 h following each dose . Results : There was no difference between the maximum effects of formoterol 12 μg and placebo ; the 24 μg dose significantly decreased plasma K ( −0.2 mmol · l−1 ) and increased blood glucose ( 1.8 mmol · l−1 ) compared to placebo . The two highest doses affected most of the variables with the 96 μg dose being significantly different from placebo for all indices , heart rate ( 9 beats · min−1 ) , systol BP ( 4 mmHg ) , diastolic BP ( −3 mmHg ) , QS2I ( −11 ms ) , QTc ( 17 ms ) , plasma K ( −0.5 mmol · l−1 ) and blood glucose ( 2.6 mmol · l−1 ) . All doses of  formoterol increased FEV1 . Conclusion : Although there were dose-dependent effects on the extrapulmonary measurements , only the effects at the highest dose may be of clinical significance OBJECTIVE The aim of this study was to assess asthma control using salmeterol plus fluticasone propionate ( FP ) in combination ( SFC ) versus salmeterol or FP as monotherapy in patients with mild to moderate asthma . METHODS In this r and omised , double-blind , parallel-group study , 322 symptomatic patients were recruited , of which 282 were r and omised to receive either salmeterol ( 50 microg ) , FP ( 250 microg ) , or SFC ( 50 microg/250 microg ) , via a single Diskus inhaler twice daily for 12 months . Outcome variables included the number of patients requiring an increase in study medication and the number experiencing 2 exacerbations during the 12-month treatment period . Airway hyper-responsiveness ( AHR ) and lung function tests were performed at clinic visits . Peak expiratory flow , rescue medication use , symptom scores and adverse events were recorded in diary cards . RESULTS Fewer patients required an increase in study medication with SFC ( 10.5 % ) than with either FP ( 34.8 % ) or salmeterol ( 61.1 % ) ( P<0.001 ) . Significantly fewer patients experienced 2 exacerbations with SFC ( 4.2 % ) , compared with FP ( 17.4 % ; P<0.01 ) or salmeterol ( 40 % ; P<0.001 ) . SFC improved AHR to a significantly greater extent than FP ( methacholine PC20=1.8 mg/ml vs. 1.1 mg/ml ; P<0.05 ) or salmeterol ( methacholine PC20=1.8 mg/ml vs. 0.7 mg/ml ; P<0.001 ) . CONCLUSIONS The protection against exacerbations may be attributed to better control of inflammation , AHR and lung function parameters achieved with salmeterol and FP in combination , compared with either treatment alone Studies performed on airway smooth muscle in vitro have indicated that salmeterol is a partial agonist on the beta2-receptor in comparison to formoterol . In the present study we evaluated whether these pharmacological differences between salmeterol and formoterol also are applicable to asthmatic patients . The protective effects by increasing cumulative doses of formoterol ( 12 , 60 , 120 micrograms ) and salmeterol ( 50 , 250 , 500 micrograms ) on methacholine-induced bronchoconstriction were evaluated in a double-blind , crossover , placebo-controlled design . Patients were regularly treated with salbutamol 200 micrograms twice daily during the study period , to avoid variability in beta2-adrenoceptor tolerance . S-potassium , heart rate corrected Q-T interval ( Q-Tc ) , and tremor score were followed as measures of systemic effects .  Formoterol dose-dependently protected against methacholine responsiveness ( 4.6 doubling doses after 120 micrograms ) . Salmeterol , however , showed a flatter dose-response curve , and a significantly weaker maximal protective effect ( 2.8 doubling doses after 250 micrograms ) . Formoterol caused a significantly higher tremor score and a larger drop in S-potassium than salmeterol at the highest doses . These data show that salmeterol is a partial agonist on the beta2-receptor in relation to formoterol in human airways in vivo . Further studies are required to document the clinical consequences of this finding , for example in severe asthmatic patients 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 To determine whether epinephrine-induced hypokalemia is due to beta2-adrenoceptor stimulation , and whether hypokalemia can occur at physiologic concentrations of the agonist , epinephrine was infused into six normal volunteers at a rate of 0.1 microgram per kilogram of body weight per minute . The circulating  epinephrine concentration was increased to 1.74 + /- 0.65 ng per milliliter , plasma potassium was reduced by 0.82 + /- 0.19 meq per liter , plasma insulin fell by 12 + /- 4 mU per liter , plasma renin activity was elevated , and tachycardia occurred . Isoproterenol infused at 0.02 micrograms per kilogram per minute caused similar tachycardia ( 25 beats per minute ) and elevation in plasma renin activity ( 6.0 to 6.5 ng per milliliter per hour ) , but no hypokalemia . The difference in responses to the two catecholamines was ascribed to the relative beta2-selectivity of epinephrine . This hypothesis was tested in six subjects given infusions of epinephrine ( 0.05 micrograms per kilogram per minute ) after administration of either 2.5 or 5 mg of ICI 118551 - -a selective beta2-receptor antagonist -- or placebo . After placebo , epinephrine infusion elevated the circulating epinephrine concentration and reduced plasma potassium ; hypokalemia was prevented by the beta2-antagonist . This drug only partially inhibited the rises in plasma renin and glucose and the shortening of systolic time intervals ; there was no tachycardia . Fifteen-fold to 30-fold increases in circulating epinephrine concentration appear to cause hypokalemia by a specific beta2-receptor effect distinct from other actions of epinephrine . This phenomenon may be of physiologic importance after severe myocardial infa rct ion , when similar increases in plasma epinephrine have occurred BACKGROUND The objective of an asthma treatment is to control asthma , particularly to prevent exacerbations . OBJECTIVE To study the efficacy , acceptability and safety of the fluticasone/salmeterol ( FP/S ) combination in preventing asthma exacerbations in comparison with the continuation of previous treatment ( TA ) . METHODS This was a multicentre , r and omised , parallel-group study to compare the fixed combination FP/S to TA ( treatment with a free combination of an inhaled corticosteroid and a long-acting beta2-agonist ) over one year in patients whose asthma was well controlled with their current treatment . RESULTS Five hundred and twenty patients were r and omized and their data analyzed on an intent-to-treat basis . Seventy-four percent of the patients in the FP/S group and 71 % in the TA group had no exacerbation . The 3.12 % difference in favor of the FP/S group ( 90 % CI : -3.32 % to 9.56 % ) demonstrated that FP/S was at least as effective TA in preventing asthma exacerbations . Treatment acceptability , evaluated by the patient on visual analog scales ( inclusion as part of the daily habits , constraint , simplicity ) was better with FP/S ( p<0.001 ) than with TA .  Clinical safety was good and comparable in the two groups . CONCLUSION The fixed fluticasone/salmeterol combination provided a protection as good as that obtained with free combinations over a one-year treatment period , with a significant improvement in treatment acceptability and a good clinical safety 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 Background : Asthma is a chronic inflammatory disease of the airways . Inhaled corticosteroids are very important in anti-inflammatory treatment , but to a great extent they can not control asthma alone . In addition to corticosteroids , long-acting β2 agonists and leukotriene antagonists are used for asthma control . Objective : In this study , the effect of the addition of formoterol and montelukast on asthma control in patients with moderately persistent asthma who were symptomatic while using a low dose of inhaled budesonide  was compared . Methods : At the beginning of the study , 40 symptomatic patients with moderately persistent asthma used  400 µg/day budesonide for a 4-week training period , and were then divided r and omly into two groups , each composed of 20 persons . For the first group ’s treatment regime , inhaled formoterol ( 9 µg ) twice a day was added , and for the second group ’s treatment regime , one-dose oral montelukast ( 10 µg ) was added . These patients were followed up for 8 weeks . The patients ’ peak expiratory flow ( PEF ) values measured in the morning and at night , changes in PEF , forced expiratory volume in 1 s , asthma symptom score and the symptom-relieving therapy used during the 12-week study period were recorded and evaluated in the clinic at the very beginning and at the end of each period . Results : Before the study , the morning PEF value of the group for whom formoterol was added to budesonide ( FB ) was 266.3 ± 59.3 liters/min , and in the group for whom montelukast was added to budesonide ( MB ) , it was 262.8 ± 53.8 liters/min ( p > 0.05 ) . After the 8-week treatment period , the morning PEF values were found to be 320.5 ± 54.4 liters/min in the FB group and 293.3 ± 52.4 liters/min in the MB group ; at the end of the study , it was seen that although there was an increase in morning PEF of 54.2 ± 15.2 liters/min in the FB group , there was an increase of only 30.5 ± 25.3 liters/min in the MB group ( p < 0.0001 ) . Before the study , night PEF values were 287 ± 56.6 liters/min in the FB group and 283 ± 48.5 liters/min in the MB group ( p > 0.05 ) . At the end of the treatment , the night PEF values were found to be 331.5 ± 56.1 liters/min in the FB group and 310 ± 53.1 liters/min in the MB group . At the end of the study , it was observed that although there was an increase in night PEF of 44.5 ± 23.3 liters/min in the FB group , there was an increase of only 27 ± 24.1 liters/min in the MB group ( p < 0.001 ) . Although asthma symptom scores and the use of symptom-relieving drugs showed similarities between the two groups at the beginning of the study , after treatment , the FB group had better results than the MB group with respect to these two parameters ( p < 0.0001 for both ) . It was also seen that the two treatments are tolerated equally well . Conclusion : FB treatment , which causes a considerable improvement in lung function , showed better asthma control than MB treatment in patients with moderately persistent asthma BACKGROUND Optimal therapy for many patients with persistent asthma requires control of both main components of this disease : inflammation and bronchoconstriction . OBJECTIVES To compare the efficacy and safety of initiating maintenance therapy with an inhaled , long-acting beta2-agonist and an inhaled corticosteroid administered from a single device with that of the individual agents alone . METHODS A 12-week , r and omized , double-blind study was conducted in patients 12 years and older with persistent asthma who were symptomatic while taking as-needed , short-acting beta2-agonists alone . Treatments were administered twice daily via the Diskus device : salmeterol , 50 microg ; fluticasone propionate , 100 microg ; or fluticasone propionate , 100 microg , with salmeterol , 50 microg . RESULTS Of 555 patients screened , 267 were r and omly assigned to treatment . At end point , fluticasone propionate and salmeterol significantly increased predose forced expiratory volume in 1 second ( FEV1 ) compared with salmeterol alone ( 0.51 + /- 0.05 L vs 0.38 + /- 0.04 L , P = .04 ) . Fluticasone propionate and salmeterol significantly increased area under the serial FEV1 curve at treatment week 12 relative to predose FEV1 ( baseline ) on treatment day 1 ( AUCb1 , 8.4 + /- 0.6 L/h ; P < or = .02 ) compared with salmeterol ( 6.2 + /- 0.5 L/h ) and fluticasone propionate ( 7.0 + /- 0.6 L/h ) . Fluticasone propionate and salmeterol were significantly ( P < or = .02 ) more effective than the individual agents used alone in improving morning and evening peak expiratory flow rate and asthma symptoms . In addition , fluticasone propionate and salmeterol effectively reduced rescue albuterol use ( P < or = .04 ) . All treatments were well tolerated . CONCLUSIONS In patients symptomatic while taking short-acting beta2-agonists alone , initial maintenance treatment of the 2 main components of asthma , inflammation and smooth muscle dysfunction , with fluticasone propionate and salmeterol , 100 and 50 microg , administered via the Diskus results in greater improvements in overall asthma control compared with treatment of either component alone 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 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 Long-term treatment with short-acting beta 2-sympathomimetic drugs has recently been suggested to be due to a rise in asthma mortality . This effect has been attributed to an increase in bronchial hyperreactivity , a desensitization of beta 2-adrenoceptors and /or a rebound effect after cessation of the therapy . Formoterol , a new long-acting beta 2-symathomimetic drug , has been reported to possess not only bronchodilatation but also antiinflammatory effects . The aim of the present study was to investigate whether long-term effects of salbutamol and /or formoterol could deteriorate asthma management . Therefore , in a trial lasting 90 days , we evaluated the effects of the two drugs on lung function , on the protection they provided against inhalative provocation with histamine , and on tachyphylaxis as monitored by the beta-adrenergic density on mononuclear leukocytes ( MNL ) .  Two groups of 11 children each with stable asthma were treated with daily doses of either 4 x 200 micrograms salbutamol or 2 x 24 micrograms formoterol in monotherapy . The lung function was measured six times during the trial period , on day 1 , and on day 90 , before and after inhaling the drug and at all investigations both with and without histamine provocation . In both groups , the bronchodilatory effect of either formoterol or salbutamol remained constant . The lung function values before and after drug inhalation ( specific airway resistance sRAW , forced expiration volume FEV1 , vital capacity VC ) did not alter significantly . After histamine provocation , the protection was more pronounced in the formoterol group . No changes in the beta-adrenoceptor density on MNL and no significant side effects were seen throughout the trial period . We therefore conclude that formoterol  protects significantly better against the bronchial challenge with histamine than does salbutamol . Both drugs did not deteriorate the lung function in asthmatic children . In addition , there was no evidence that long-term treatment leads to a desensitization of beta 2-sympathomimetic effects UNLABELLED We aim ed to compare the efficacy and safety of budesonide/formoterol ( Symbicort ) with budesonide alone ( Pulmicort ) or budesonide ( Pulmicort ) and formoterol ( Oxis ) administered via separate inhalers in children with asthma . In a 12 wk , double-blind study , a total of 630 children with asthma ( mean age 8 yr [ 4 - 11 yr ] ; mean forced expiratory volume in 1 s ( FEV(1 ) ) 92 % predicted ; mean inhaled corticosteroid dose 454 microg/day ) were r and omized to : budesonide/formoterol ( 80/4.5 microg , two inhalations twice daily ) ; a corresponding dose of budesonide alone ( 100 microg , two inhalations twice daily ) ; or a corresponding dose of budesonide ( 100 microg , two inhalations twice daily ) and formoterol ( 4.5 microg , two inhalations twice daily ) ( budesonide + formoterol in separate inhalers ) . The primary efficacy variable was the change from baseline to treatment ( average of the 12-wk treatment period ) in morning peak expiratory flow ( PEF ) . Other changes in lung function and asthma symptoms were assessed , as was safety .  Budesonide/formoterol significantly improved morning PEF , evening PEF and FEV(1 ) compared with budesonide ( all p < 0.001 ) ; there was no significant difference between budesonide/formoterol and budesonide + formoterol in separate inhalers for these variables . All other diary card variables improved from baseline in all treatment groups ; there were no significant between-group differences . Adverse-event profiles were similar in all groups ; there were no serious asthma-related adverse events in any treatment group . CONCLUSION budesonide/formoterol significantly improved  lung function in children ( aged 4 - 11 yr ) with asthma compared with budesonide alone . Budesonide/formoterol is a safe and effective treatment option for children with asthma Objective . Concerns exist that responses to long-acting β2-adrenergic agonists in black patients may differ from the general population . The efficacy and safety of budesonide/formoterol ( BUD/FM ) pressurized metered-dose inhaler ( pMDI ) versus budesonide dry powder inhaler ( BUD DPI ) were evaluated in adolescent and adult black asthma patients . Methods . This 12-week , r and omized , double-blind , multicenter , phase IV US study was conducted in 311 self-reported black patients aged ≥12 years with moderate to severe persistent asthma , previously receiving medium- to high-dose inhaled corticosteroid . After 2 weeks on BUD 90 μg × 2 inhalations twice daily ( bid ) , symptomatic patients were r and omized to BUD/FM 160/4.5 μg × 2 inhalations bid or BUD 180 μg × 2 inhalations bid . Results . Improvement in predose forced expiratory volume in 1 second from baseline to the treatment mean ( primary variable ) was greater with BUD/FM versus BUD ( 0.16 vs. 0.07 L ; p = .008 ) ; this effect was also observed at weeks 2 , 6 , and end of treatment ( p ≤ .032 ) . Greater improvements ( p < .001 ) in peak expiratory flow with BUD/FM versus BUD were seen at first measurement and maintained during 12 weeks ( morning : 25.34 vs. 7.53 L/minute , respectively ; evening : 21.61 vs. 7.67 L/minute , respectively ) ; greater improvements in daily asthma symptom score and rescue medication use were also observed ( p ≤ .039 ) . Both treatments were well tolerated , with similar safety profiles . Conclusions . In this population of black asthma patients , BUD/FM pMDI result ed in greater improvements in pulmonary function and asthma control versus BUD DPI , with similar safety profiles BACKGROUND Asthma control is the goal of treatment , but little data exist to support treatment strategies for stepping down treatment once control has been achieved . OBJECTIVE We assessed whether either the long-acting beta2-agonist or corticosteroid could be reduced without loss of asthma control once control had been attained with fluticasone propionate/salmeterol ( FSC ) . METHODS After 12 weeks of open-label treatment with FSC 250/50 microg twice daily , patients whose asthma was well controlled were r and omized to FSC 100/50 microg twice daily or fluticasone propionate ( FP ) 250 microg twice daily . for 12 weeks . The primary endpoint was mean morning peak expiratory flow over the r and omized study period . Secondary endpoints included symptom scores , rescue albuterol use , and asthma control . RESULTS During open-label treatment , improvements from baseline were seen , and 435 of 641 patients ( 68 % ) achieved well controlled status during each of the last 4 weeks of this period . A total of 246 patients received FSC 100/50 microg twice daily and 238 FP 250 microg twice daily . The adjusted mean change in morning peak expiratory flow from the end of open-label treatment was -0.3 L/min for FSC and -13.2 L/min for FP ( treatment difference , 12.9 L/min ; 95 % CI , 8.1 - 17.6 ; P<.001 ) . Secondary efficacy endpoints also showed FSC 100/50 microg twice daily to be more effective than FP 250 microg twice daily alone . The majority of patients remained well controlled , but the proportion was higher with FSC . CONCLUSION In patients achieving asthma control with FSC 250/50 microg twice daily , stepping treatment down to a lower dose of FSC 100/50 microg twice daily is more effective than switching to an inhaled corticosteroid alone BACKGROUND The twice daily administration of an inhaled corticosteroid ( ICS ) and long-acting beta(2)-agonist ( LABA ) has been shown to be effective in achieving asthma control . The once daily administration of an ICS/LABA may be a treatment option for some patients . OBJECTIVE To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler ( FSC ) administered once daily compared with FP once daily , FSC twice daily , or placebo . METHODS A 12-week , r and omized , double-blind multicenter study conducted in 844 patients > or = 12 years of age who were symptomatic while using a short-acting beta(2)-agonist alone . Blinded treatments included : FSC 250/50 mcg once daily in the evening ( FSC 250/50 QD ) , FP 250 mcg once daily in the evening ( FP 250 QD ) , FSC 100/50 mcg twice daily ( FSC 100/50 mcg BID ) , or placebo . All treatments were delivered via the Diskus device . RESULTS All treatments demonstrated greater improvements in efficacy measures compared with placebo . Overall , the greatest improvements were observed in the patients receiving FSC , either once or twice daily , compared with the FP 250 QD group . The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24h compared with twice daily dosing . All treatments were well tolerated . No suppression of HPA axis , as assessed by 24-h urinary cortisol excretion , was observed in any of the active treatment groups . CONCLUSION In patients symptomatic on a short-acting beta(2)-agonist alone , FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength ( FSC 250/50 mcg ) administered once daily . However , a once daily regimen was effective and may be a valuable treatment option for some patients . Registered at ( http://ctr.gsk.co.uk/welcome.asp ) ( SAS30022 ) 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 Background : Previous studies have indicated the benefits of adding long acting β2 agonists to inhaled corticosteroids in the maintenance treatment of moderate to severe asthma . The effects of adding eformoterol to corticosteroids on asthma control and exacerbations in patients with mild to moderate asthma were studied . Methods : After a run in period of 7–14 days on existing medication , 663 symptomatic patients were r and omised to receive budesonide Turbohaler 400 μg twice daily together with either eformoterol Turbohaler 9 μg ( delivered dose ) or placebo twice daily . After 4 weeks patients whose asthma was well controlled ( n=505 ) were re-r and omised to receive budesonide 400 μg daily and either eformoterol 9 μg or placebo twice daily for a further 6 months . Results : Patients receiving eformoterol  achieved asthma control 10 days sooner than those receiving budesonide alone , and improvements in lung function , symptoms , quality of life , and relief β2 agonist use were significantly greater with eformoterol . During the 6 month follow up the frequency of mild exacerbations was significantly lower in the eformoterol group than in those receiving budesonide alone ( 7.2 versus 10.5 per patient , 95 % confidence interval for ratio 0.49 to 0.96 , p=0.03 ) . The time to first day of poorly controlled asthma was 97 days in the eformoterol group compared with 42 days in the placebo group ( p=0.003 ) . Conclusions : Adding eformoterol to a low or moderate dose of budesonide in mild asthma result ed in faster and more effective control than treatment with budesonide alone . Eformoterol allowed the corticosteroid dose to be reduced while also decreasing the rate of mild exacerbations compared with budesonide alone . These data suggest a therapeutic advantage of adding eformoterol to inhaled corticosteroids in patients with mild to moderate asthma AIM This paediatric asthma study evaluated the efficacy and safety of a novel hydrofluoroalkane pressurised metered-dose inhaler ( pMDI ) formulation of budesonide/formoterol versus budesonide pMDI and budesonide/formoterol dry-powder inhaler ( DPI ) . METHODS The study was a 12-week , multinational , double-blind trial involving children ( aged 6 - 11 years ) with symptomatic asthma on inhaled corticosteroids ( 375 - 1000 microg/day ) , with a history of exercise-induced bronchoconstriction and peak expiratory flow ( PEF ) > or = 50 % of predicted . Patients were r and omised ( two inhalations twice daily ) to budesonide pMDI 100 microg , budesonide/formoterol DPI 80/4.5 microg or budesonide/formoterol pMDI 80/4.5 microg . The primary endpoint was change from baseline in morning PEF . RESULTS Overall , 622 patients were r and omised .  Increases in morning PEF with budesonide/formoterol pMDI and budesonide/formoterol DPI were therapeutically equivalent ( 29.5 versus 30.2l/min , respectively ; 95 % confidence interval : -6.0 to 4.6 ; P=0.78 , also confirmed by per- protocol analysis ) . Improvements in secondary efficacy endpoints with both budesonide/formoterol formulations were not significantly different . Significantly greater improvement was achieved with budesonide/formoterol pMDI versus budesonide pMDI for morning PEF ( + 9.6l/min ; P<0.001 ) and other lung function parameters . The safety profile of budesonide/formoterol pMDI was favourable and similar to that of budesonide/formoterol DPI and budesonide pMDI . CONCLUSION Budesonide/formoterol , administered via the therapeutically equivalent hydrofluoroalkane pMDI or DPI , is an effective and well-tolerated treatment for children with asthma Adjustable maintenance dosing with either budesonide/formoterol or budesonide was compared in asthma patients . This double-blind trial r and omized 133 patients ( mean forced expiratory volume in 1s 66 % predicted ) to receive 2 inhalations twice daily of budesonide/formoterol 160/4.5 microg ( 640/18 microg/day ) or budesonide 320 microg ( 1280 microg/day ) for 4 weeks . The study drug was adjusted in both groups according to symptoms to 2 - 4 inhalations daily during Weeks 5 - 8 and 1 - 4 inhalations daily during Weeks 9 - 20 . Asthma was well controlled in both groups , with minimal levels of treatment failure ( 5 budesonide/formoterol vs. 2 budesonide patients ; P = NS ) and minimal use of reliever therapy . Clinical ly important improvements in health-related quality of life ( HRQL ) occurred in the physical functioning and emotional role functioning domains ( both P<0.05 ) for the budesonide/formoterol group compared with budesonide .  Physician and patient treatment satisfaction favored budesonide/formoterol ( both P<0.05 ) . Budesonide/formoterol patients used fewer daily inhalations of study drug ( P=0.024 ) . The median average daily inhaled corticosteroid dose during the study was 448 microg with budesonide/formoterol and 1152 microg with budesonide . Adjustable maintenance dosing with budesonide/formoterol and budesonide result ed in high levels of asthma control . Adjustable budesonide/formoterol treatment achieved greater HRQL benefits and patient satisfaction , with lower overall drug use 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 A r and omised , open-label , multicentre study compared the efficacy and tolerability of salmeterol 25 microg/fluticasone propionate 125 microg ( two puffs , twice daily ) delivered via a hydrofluoroalkane metered-dose inhaler ( HFA-MDI ) and salmeterol 50microg/fluticasone propionate 250 microg ( one puff , twice daily ) delivered via a Diskus inhaler in Chinese patients with moderate asthma uncontrolled with inhaled corticosteroids ( ICSs ) .  Morning peak expiratory flow ( PEF ) was the primary efficacy endpoint . Secondary endpoints included evening PEF , forced expiratory volume in 1 s , day and night symptom scores , rescue medication and patient self-evaluation of efficacy . Safety was assessed according to adverse events recorded . Both treatments were equipotent and significantly improved morning PEF ( HFA-MDI 40 l/min ; Diskus 42 l/min ; p < 0.05 ) and all secondary endpoints ( p < 0.05 ) from baseline , over 1 - 4 weeks . Similarly , both treatments were well tolerated . Salmeterol/fluticasone propionate delivered via an HFA-MDI or Diskus inhaler provides a choice of efficacious delivery systems in Chinese patients whose asthma is poorly controlled on ICSs alone 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 RATIONALE Little is known about the use of biomarkers in guiding treatment decisions in routine asthma management . The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness ( BHR ) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR . METHODS After a 2-week run-in period , subjects ( > or = 12 years ) were r and omized to one of three treatment groups . Two groups followed a BHR treatment strategy ( based on clinical parameters [ lung function , asthma symptoms , and bronchodilator use ] and BHR ) and were treated with either fluticasone propionate/salmeterol ( FSC(BHR ) group ) or fluticasone propionate ( FP(BHR ) group ) ( n=156 each ) . The third group followed a clinical treatment algorithm ( based on clinical parameters alone ) and were treated with fluticasone propionate ( FP(REF ) group ; n=154 ) . All treatments were administered via Diskus . Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subject 's derived severity class , which was based on clinical measures of asthma control with or without BHR . RESULTS The mean total daily inhaled corticosteroids ( ICS ) dose during the double-blind treatment period was lower , although not statistically significant , in the FSC(BHR ) group compared with the FP(BHR ) group ( a difference of -42.9 mcg ; p=0.07 ) . Compared with the FP(REF ) group , the mean total daily ICS dose was higher in the FSC(BHR ) group ( a difference of 85.2 mcg ) and was significantly higher in the FP(BHR ) group ( a difference of 131.2 mcg , p=0.037 ) . CONCLUSION This study demonstrated that for most subjects , control of BHR was maintained when treatment was directed toward control of clinical parameters . In addition , there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol 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 Evidence of bronchodilator subsensitivity was sought in studies using the specific beta2 adrenergic agonist , albuterol . After a period of 1 or 2 weeks off all oral sympathomimetic agents , the mean response of the patients to the first dose of albuterol was consistently greater than the response after a period during which the drug had been administered regularly . Maximal decrease in response occurred after 2 weeks ' of treatment , and there was no further decrease after prolonged treatment with the same dose of albuterol for periods as long as 1 year 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 High doses of inhaled salbutamol produce substantial improvements in airway response in patients with asthma , and are associated with dose-dependent systemic beta-adrenoceptor responses . The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol .  Twelve asthmatic patients ( FEV1 , 81 + /- 4 % predicted ) , requiring only occasional inhaled beta-agonists as their sole therapy , were given a 14-day treatment with high dose inhaled salbutamol ( HDS ) , 4,000 micrograms daily , low dose inhaled salbutamol ( LDS ) , 800 micrograms daily , or placebo ( PI ) by metered-dose inhaler in a double-blind , r and omized crossover design . During the 14-day run-in and during washout periods , inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purpose s. At the end of each 14-day treatment , a dose-response curve ( DRC ) was performed , and airway ( FEV1 , FEF25 - 75 ) chronotropic ( HR ) , tremor , and metabolic ( K , Glu ) responses were measured at each step ( from 100 to 4,000 micrograms ) . Treatment had no significant effect on baseline values . There were dose-dependent increases in FEV1 and FEF25 - 75 ( p less than 0.001 ) , and pretreatment with HDS did not displace the DRC to the right . DRC for HR ( p less than 0.001 ) , K ( p less than 0.001 ) , and Glu ( p less than 0.005 ) were attenuated after treatment with HDS compared with PI . There were also differences between HDS and LDS for HR ( p less than 0.001 ) and Glu ( p less than 0.05 ) responses . Frequency and severity of subjective adverse effects were also reduced after HDS : tremor ( p less than 0.001 ) , palpitations ( p less than 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS 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 BACKGROUND Treatment guidelines recommend the use of inhaled corticosteroids in patients with asthma who have persistent symptoms and the " stepping down " of therapy to the minimum needed to maintain control of asthma . Whether patients with asthma that is well controlled with the use of inhaled corticosteroids twice daily can receive a step-down treatment with once-daily montelukast ( our primary hypothesis ) or once-daily fluticasone propionate plus salmeterol ( our secondary hypothesis ) has not yet been determined . METHODS We r and omly assigned 500 patients with asthma that was well controlled by inhaled fluticasone ( 100 microg twice daily ) to receive continued  fluticasone ( 100 microg twice daily ) ( 169 patients ) , montelukast ( 5 or 10 mg each night ) ( 166 patients ) , or fluticasone ( 100 microg ) plus salmeterol ( 50 microg ) each night ( 165 patients ) . Treatment was administered for 16 weeks in a double-blind manner . The primary outcome was the time to treatment failure . RESULTS Approximately 20 % of patients assigned to receive continued fluticasone or switched to treatment with fluticasone plus salmeterol had treatment failure , as compared with 30.3 % of subjects switched to montelukast . The hazard ratio for both comparisons was 1.6 ( 95 % confidence interval , 1.1 to 2.6 ; P=0.03 ) . The percentage of days on which patients were free of asthma symptoms ( 78.7 to 85.8 % ) was similar across the three groups . CONCLUSIONS Patients with asthma that is well controlled with the use of twice-daily inhaled fluticasone can be switched to once-daily fluticasone plus salmeterol without increased rates of treatment failure . A switch to montelukast results in an increased rate of treatment failure and decreased asthma control ; however , patients taking montelukast remained free of symptoms on 78.7 % of treatment days . ( Clinical Trials.gov number , NCT00156819 [ Clinical Trials.gov ] . ) BACKGROUND For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids ( ICS ) , evidence to guide step-up therapy is lacking . METHODS We r and omly assigned 182 children ( 6 to 17 years of age ) , who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily , to receive each of three blinded step-up therapies in r and om order for 16 weeks : 250 microg of fluticasone twice daily ( ICS step-up ) , 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily ( LABA step-up ) , or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily ( LTRA step-up ) . We used a triple-crossover design and a composite of three outcomes ( exacerbations , asthma-control days , and the forced expiratory volume in 1 second ) to determine whether the frequency of a differential response to the step-up regimens was more than 25 % . RESULTS A differential response occurred in 161 of 165 patients who were evaluated ( P<0.001 ) . The response to LABA step-up therapy was most likely to be the best response , as compared with responses to LTRA step-up ( relative probability , 1.6 ; 95 % confidence interval [ CI ] , 1.1 to 2.3 ; P=0.004 ) and ICS step-up ( relative probability , 1.7 ; 95 % CI , 1.2 to 2.4 ; P=0.002 ) . Higher scores on the Asthma Control Test before r and omization ( indicating better control at baseline ) predicted a better response to LABA step-up ( P=0.009 ) . White race predicted a better response to LABA step-up , whereas black patients were least likely to have a best response to LTRA step-up ( P=0.005 ) . CONCLUSIONS Nearly all the children had a differential response to each step-up therapy . LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up . However , many children had a best response to ICS or LTRA step-up therapy , highlighting the need to regularly monitor and appropriately adjust each child 's asthma therapy . ( Clinical Trials.gov number , NCT00395304 . 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 This open , multinational , r and omised , parallel-group , six-month extension conducted in the Swedish centres of a previous six-month study compared the costs of a total of 12 months of treatment with budesonide/formoterol in a single inhaler with budesonide plus formoterol separate inhalers in 320 adults with asthma . Patients received budesonide/formoterol ( Symbicort Turbuhaler ) 160/4.5 mg delivered doses , two inhalations b.i.d . , or corresponding doses of budesonide ( Pulmicort Turbuhaler ) plus formoterol ( Oxis Turbuhaler ) . Direct costs and indirect costs were estimated . Budesonide/formoterol treatment was associated with reduced healthcare service utilisation and statistically significant reductions in direct ( SEK1595 , p=0.0004 ) and total costs ( SEK1884 , p=0.043 ) per person per year compared with budesonide plus formoterol . Budesonide/formoterol reduced the average annual emergency room admission cost per person by SEK489.7 ( 31 % of direct cost reduction ) and physician costs by SEK235.4 (15%).The direct cost of study , relief and other medication was reduced by SEK893.8 ( 47 % of total reduction ) . There were no statistically significant differences in efficacy and safety parameters following treatment with budesonide/formoterol from single or separate inhalers , other than a significantly lower proportion of withdrawals with the single inhaler ( 9.2 % vs 19.4 % , p=0.008 ) . In summary , budesonide/formoterol treatment from a single inhaler reduced 12-month treatment costs compared with separate inhalers , while maintaining at least as good control of asthma STUDY OBJECTIVE To compare the safety of salmeterol xinafoate or placebo added to usual asthma care . DESIGN A 28-week , r and omized , double-blind , placebo-controlled , observational study . SETTING Study subjects were seen once in the study physician 's office for screening and were provided all blinded study medication for the entire study period . Follow-up by telephone was scheduled every 4 weeks . PARTICIPANTS Subjects ( > 12 years old ) with asthma as judged by the study physician were eligible . Individuals with a history of long-acting beta2-agonist use were excluded . INTERVENTIONS Salmeterol , 42 mug bid via metered-dose inhaler ( MDI ) , and placebo bid via MDI . MEASUREMENTS AND RESULTS Following an interim analysis in 26,355 subjects , the study was terminated due to findings in African Americans and difficulties in enrollment . The occurrence of the primary outcome , respiratory-related deaths , or life-threatening experiences was low and not significantly different for salmeterol vs placebo ( 50 vs 36 ; relative risk [ RR ] = 1.40 ; 95 % confidence interval [ CI ] , 0.91 to 2.14 ) . There was a small , significant increase in respiratory-related deaths ( 24 vs 11 ; RR , 2.16 ; 95 % CI , 1.06 to 4.41 ) and asthma-related deaths ( 13 vs 3 ; RR , 4.37 ; 95 % CI , 1.25 to 15.34 ) , and in combined asthma-related deaths or life-threatening experiences ( 37 vs 22 ; RR , 1.71 ; 95 % CI , 1.01 to 2.89 ) in subjects receiving salmeterol vs placebo . The imbalance occurred largely in the African-American sub population : respiratory-related deaths or life-threatening experiences ( 20 vs 5 ; RR , 4.10 ; 95 % CI , 1.54 to 10.90 ) and combined asthma-related deaths or life-threatening experiences ( 19 vs 4 ; RR , 4.92 ; 95 % CI , 1.68 to 14.45 ) in subjects receiving salmeterol vs placebo . CONCLUSIONS For the primary end point in the total population , there were no significant differences between treatments . There were small , but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol . Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects . Whether this risk is due to factors including but not limited to a physiologic treatment effect , genetic factors , or patient behaviors leading to poor outcomes remains unknown 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 BACKGROUND Recent studies have raised concern that regular inhalation of beta2 -agonists may cause a worsening of asthma control compared with on-dem and dosing regimens . OBJECTIVE The objective of this study was to compare the effect of twice daily formoterol ( Foradil ) , 4 times daily albuterol , and on-dem and albuterol on bronchial hyperresponsiveness ( BHR ) , lung function measurements , symptoms , and other indicators of disease control over 6 months in patients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids . We also looked for occurrence of rebound BHR on discontinuation of treatment . METHODS This was a multicenter , parallel-group , double-blind , clinical trial . Methacholine PC20 was the primary outcome variable . Other outcome variables included symptom scores , use of rescue medication , morning peak expiratory flow ( PEF ) , serial FEV1 measurements , and asthma exacerbations . RESULTS Of the 271 r and omized patients , 217 completed the study .  Formoterol was significantly superior to on-dem and albuterol with regard to methacholine PC20 , FEV1 , PEF , symptom scores , and use of rescue medication at each measured time point/interval . Regular albuterol was superior to on-dem and albuterol with regard to PC20 and FEV1 , but not PEF or various clinical scores . After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after r and omization , there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment . The formoterol group had the lowest number of exacerbation days , as defined by high intake of rescue bronchodilator and /or symptom scores , whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups . CONCLUSION In patients with asthma of moderate or greater severity receiving inhaled corticosteroids , formoterol taken twice daily result ed in superior bronchoprotection , bronchodilatation , and clinical control compared with on-dem and albuterol over 6 months . Four times daily albuterol was superior to on-dem and albuterol for only some of the end points . Progressive tolerance and a rebound increase in BHR on discontinuation of beta-agonists were not 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 Abstract Background : Asthma is a chronic disease , the two main components of which are inflammation and bronchoconstriction . Fluticasone propionate ( FP ) and salmeterol , a strategy that treats both main components of asthma , has been recently compared with FP plus montelukast in a r and omised clinical trial . The present study reports economic evaluation of these two strategies . Objective : To determine the relative cost effectiveness when persistent asthma is treated with FP/salmeterol 100/50μg twice daily administered via a single Diskus ® inhaler device versus treatment with FP 100μg twice daily via a Diskus ® inhaler plus oral montelukast 10 mg once daily . Study design : A cost-effectiveness analysis was performed by applying cost unit data to re source utilisation data collected prospect ively during a US r and omised , double-blind , 12-week trial of  FP/salmeterol ( n = 222 ) versus FP + montelukast ( n = 225 ) . Patients were ≥15 years of age and were symptomatic despite inhaled corticosteroid ( ICS ) therapy . Patients and methods : Efficacy measurements in this analysis included improvement in forced expiratory volume in 1 second ( FEV1 ) and symptom-free days . Direct costs included those related to study drugs , emergency room department visits , unscheduled physician visits , treatment of drug-related adverse events ( oral c and idiasis ) , and rescue medication ( salbutamol [ albuterol ] ) . The study assumed a US third-party payer ’s perspective with costs in 2001 US dollars . Results : Treatment with FP/salmeterol result ed in a significantly higher proportion ( p < 0.001 ) of patients who achieved a ≥12 % increase in FEV1 than treatment with FP + montelukast ( 54 % [ 95 % CI 47 % , 61 % ] vs 32 % [ 95 % CI 26 % , 38 % ] ) . Lower daily costs and greater efficacy of FP/salmeterol result ed in a cost-effectiveness ratio of $ US6.77 ( 95 % CI $ US5.99 , $ US7.66 ) per successfully treated patient in the FP/salmeterol group compared with $ US14.59 ( 95 % CI $ US12.12 , $ 17.77 ) for FP + montelukast . In addition , FP/salmeterol achieved similar efficacy in terms of symptom-free days compared with FP + montelukast ( 31 % [ 95 % CI 26 % , 35 % ] vs 27 % [ 95 % CI 23 % , 32 % ] ) , but at a significantly lower daily per-patient cost ( $ US3.64 [ 95 % CI $ US3.60 , $ US3.68 ] vs $ US4.64 [ 95 % CI $ US4.56 , $ US4.73 ] ) . Sensitivity analyses demonstrated the stability of the results over a range of assumptions . Conclusion : From a US third-party payer ’s perspective , these findings suggest that treating the two main components of asthma ( inflammation and bronchoconstriction ) with FP/salmeterol may not only be a more cost-effective strategy but may actually lead to cost savings compared with the addition of montelukast to low-dose FP in patients with persistent asthma . The results were found to be robust over a range of assumptions 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 Abstract Introduction : The incidence of asthma exacerbations in patients receiving salmeterol/fluticasone propionate ( Seretide ™ or Advair ® )  is low . However , when asthma control deteriorates , clinicians may instruct patients to double the dose of their inhaled corticosteroid medication for a short period . The purpose of this study was to demonstrate that doubling the dose of Seretide ™ for a period of 2 weeks in subjects with persistent asthma is safe and well tolerated . Methods : This r and omised , double-blind , parallel-group study was conducted in primary -care centres . Adults with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) of ≥70 % predicted were stratified to receive a single dose of Seretide ™ 50μ/100μ , 50μ/250μ or 50μ/500μ twice daily from a Diskus ™ inhaler for a 4-week run-in period , dependent on the dose of inhaled corticosteroid on entry . Subjects were then r and omised to receive either an extra inhalation of the same dose of Seretide ™ received during the run-in ( double dose ) or an inhalation of matching placebo ( single dose ) for 14 days in a 2 : 1 ratio . Subjects were asked to record any adverse events , morning and evening heart rate ( HR ) , peak flow and relief medication use in daily record cards . The primary endpoint was tremor as perceived by the subject . Clinic evaluations included HR , 12-lead ECG , and potassium and glucose levels . Results : 110 and 208 subjects received single- and double-dose Seretide ™ , respectively . Only one subject experienced tremor . This was classified as mild and occurred in a subject receiving double-dose Seretide ™ (50μ/l00μ ) . There was no difference between the treatment groups in the incidence of tremor ( difference < 1 % ; 95 % CI −6 , 8) . Other salmeterol-related adverse events ( palpitations , muscle cramps and headache ) and fluticasone propionate-related events ( oral c and idiasis and hoarseness ) occurred in a similar percentage of subjects in each treatment group . The treatment differences for morning and evening HR measurements showed small differences between the two groups ( < 2 beats/min ) . The adjusted mean treatment difference ( double dose — single dose ) in morning HR was 1.1 beats/min ( 95 % CI 0.2 , 2.0 ) and evening HR was 0.9 beats/min ( 95 % CI 0.1 , 1.7 ) . Seven percent of subjects receiving single-dose Seretide ™ and 8 % receiving double-dose Seretide ™ had a QTc change from baseline in the interval 30–59 msec . No increases above 59 msec were seen in either group . There were no clinical ly significant changes from baseline for potassium levels . Two percent of subjects in the single dose and ≪1 % in the double-dose group had a change from a non- clinical ly significant baseline blood glucose assessment to a clinical ly significant abnormality at the end of treatment . Conclusion : In circumstances in which a physician may be considering doubling the dose of Seretide ™ for a short period of time in adult asthmatics , this study demonstrates that doubling the dose for a period of 2 weeks is safe and well tolerated 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 BACKGROUND Inhaled corticosteroids ( ICSs ) have been shown to reverse epithelial damage and decrease lamina reticularis thickness in patients with asthma . OBJECTIVE This study investigated whether clinical asthma control and airway inflammation could be maintained after switching therapy from medium-dose fluticasone propionate ( FP ) to low-dose FP administered with the long-acting beta2-agonist ( LABA ) salmeterol . METHODS Eighty-eight subjects ( age , > or = 18 years ) who , during open-label screening , demonstrated improved asthma control after an increase from 100 microg of FP  twice daily to 250 microg of FP  twice daily were r and omized to receive 100/50 microg of FP/salmeterol through a Diskus inhaler ( GlaxoSmithKline , Research Triangle Park , NC ) twice daily or continue 250 microg of FP twice daily through a Diskus inhaler for 24 weeks . Clinical outcomes were monitored , and bronchial biopsy specimens and bronchoalveolar lavage fluid were obtained before and after 24 weeks of treatment . RESULTS There were no significant differences between treatments with respect to eosinophils in the bronchial mucosa and bronchoalveolar lavage fluid ; mucosal mast cells , neutrophils , or CD3 + , CD4 + , CD8 + , or CD25 + T lymphocytes ; or concentration of mediators ( GM-CSF , IL-8 , and eosinophil cationic protein ) . The 2 treatments were not different with respect to lamina reticularis thickness . Consistent with the airway inflammatory measures , clinical and physiologic measures of asthma control were also similar . CONCLUSION This study demonstrates that control of asthma and airway inflammation is maintained over the 24-week treatment period when patients requiring a medium-dose ICS are switched to a lower-dose ICS with a LABA . CLINICAL IMPLICATION S A lower-dose ICS with a LABA is effective in controlling inflammation and providing clinical asthma control , confirming current guideline recommendations Abstract Objective and design : Measurement of health-related quality of life ( HR-QOL ) may show benefits of asthma treatments not revealed by objective monitoring and can complement clinical and physiological assessment s of treatment outcome . HR-QOL was measured in four countries in a multicenter , double-blind , r and omized comparison of salmeterol/fluticasone propionate combination and budesonide in patients aged ≥12 years with moderate-to-severe asthma uncontrolled by inhaled corticosteroids . Methods : Patients received , twice daily , either salmeterol/fluticasone propionate 50/250μ , g ( Seretide ™ /Advair ™ 1 ) via Diskus ™ inhaler ( n = 55 ) or budesonide 800μg ( Pulmicort ™ ) via Turbuhaler ™ ( n = 58 ) . Patients completed the Asthma Quality of Life Question naire ( AQLQ ) at baseline and after 12 weeks treatment ( or early withdrawal ) . The analysis included 113 patients . Results : Mean improvement in AQLQ scores achieved clinical importance in all four domains in the salmeterol/fluticasone group ( AQLQ change ≥0.5 ) , but in only two domains in the budesonide group . Although the mean overall improvement in AQLQ scores observed in the salmeterol/fluticasone group was significantly greater than that observed in the budesonide group ( difference of 0.45 ; p = 0.002 ) , the difference was less than the minimal important difference ( 0.5 ) . Nevertheless , further analysis showed that the number-needed-to-treat was only 3.4 . This indicates that only 3.4 patients need to be treated with the salmeterol/fluticasone combination for one patient to experience a meaningful improvement in HR-QOL , relative to monotherapy with an increased dose of budesonide . Conclusion : Treatment of moderate-to-severe asthma with salmeterol/fluticasone propionate result ed in superior gains in HR-QOL relative to increasing the dose of inhaled corticosteroids 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 OBJECTIVE To evaluate the efficacy and the safety of low dose salmeterol/fluticasone ( SM/FP ) combination therapy as compared to morate dose of budesonide ( BUD ) in the management of adult asthma . METHODS A multicentre , r and omised , open-label , parallel-group , 6-week treatment study was conducted . 398 patients ( 18 - 70 years ) were given SM/FP ( 50/100 microg ) twice daily via Accuhaler or BUD 400 microg twice daily via Turbuhaler . RESULTS The morning and the evening peak expiratory flow ( PEF ) measurements both increased significantly ( P < 0.01 ) in the SM/FP group , and the increase was greater than that in the BUD group . The significant benefit of SM/FP was evident from the first week . SM/FP led to a more significant reduction in the use of rescue medication and in the day- and night-time asthma symptom scores , as compared to budesonide . Both treatments were well tolerated , and the adverse reactions showed no significant difference between the two groups . CONCLUSIONS Combination use of low doses of SM/FP is a better choice for the control of asthma . The addition of a low-dose long-acting beta(2 ) agonist is superior to the simple increase of the dosage of inhaled corticosteroids BACKGROUND There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting beta(2)-agonists . OBJECTIVES The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol , and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid . MATERIAL S AND METHODS Twelve patients ( mean [ SD ] age , 43 [ 15 ] years ; FEV(1 ) , 57 [ 17 ] % predicted ) with stable , moderate to severe persistent asthma who were all taking inhaled corticosteroids  were evaluated in a r and omized , placebo-controlled , double-blind , double-dummy , crossover study . Patients received treatments each for 2 weeks followed by a bolus ( IV/inhaled ) of corticosteroid or placebo : ( 1 ) placebo inhaler bid + bolus placebo ; ( 2 ) formoterol Turbuhaler 24 microg metered dosage bid ( delivered dosage 18 microg bid ) + placebo ; ( 3 ) formoterol 24 microg bid + bolus IV hydrocortisone , 200 mg ; or ( 4 ) formoterol 24 microg bid + bolus inhaled budesonide , 1,600 microg .  Bronchodilator response to repeated puffs of albuterol ( 200 to 1,600 microg ) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid . The study was powered at the 80 % level to detect a 20 % difference in area under curve between 20 and 80 min ( AUC ) for FEV(1 ) response to albuterol as change from baseline ( primary end point ) . RESULTS There was significant subsensitivity ( p = 0.01 ) of the mean albuterol FEV(1 ) response ( as AUC , L x s ) after formoterol alone ( 737 ) as compared to placebo ( 1,453 ) along with partial reversal by steroid administration : formoterol + hydrocortisone ( 1 , 050 ) , and formoterol + budesonide ( 942 ) . There was a similar pattern of subsensitivity ( p = 0.03 ) for the mean albuterol forced expiratory flow between 25 % and 75 % of vital capacity response ( as AUC , L ) : placebo ( 2,149 ) , formoterol alone ( 1,002 ) , formoterol + hydrocortisone ( 1,402 ) , and formoterol + budesonide ( 1,271 ) . CONCLUSION Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol , which was partially reversed by a bolus dose of systemic or inhaled corticosteroid OBJECTIVE This study compared the efficacy and tolerability of the combination of fluticasone propionate ( FP ) and salmeterol ( SAL ) delivered via a single hydrofluoroalkane ( HFA ) 134a metered-dose inhaler ( MDI ) with those of its 2 components alone delivered via a chlorofluorocarbon ( CFC ) MDI and placebo ( PLA ) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses ( equivalent to FP 440 - 660 microg/d ) of inhaled corticosteroids ( ICSs ) . METHODS This was a r and omized , double-blind , placebo-controlled , parallel-group study consisting of a 2-week , single-blind , placebo run-in period followed by a 12-week , double-blind treatment period . Participants had to be > or = 12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study . Patients had to have used ICS therapy for > or =3 months before the study and at a consistent dose for the previous month . Lack of asthma control was defined as a forced expiratory volume in 1 second ( FEV(1 ) ) that was 40 % to 85 % of the predicted value . Patients could not enter the double-blind treatment period if they had 3 days when they required > 12 puffs of rescue albuterol per day or > 3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the r and omization visit . Patients were r and omized to receive one of the following treatments delivered via MDI twice daily for 12 weeks : FSC 220/42 microg HFA ( 2 inhalations of FSC 110/21 microg ; 125 microg/21 microg ex-valve ) ; FP 220 microg CFC ( 2 inhalations of FP 110 microg ) ; SAL 42 microg CFC ( 2 inhalations of 21 microg ) ; or 2 inhalations of PLA HFA . The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV(1 ) curve relative to the prer and omization baseline ( FEV(1 ) AUC(bl ) ) . The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV(1 ) at end point and the probability of not being withdrawn from the study due to worsening asthma . Tolerability assessment s included electrocardiograms , routine clinical laboratory tests , vital signs , oropharyngeal examinations , and physical examinations . Adverse events were assessed at each clinic visit . RESULTS Thirty-two adolescent and 333 adult patients were r and omly assigned to receive double-blind treatment . The treatment groups were comparable at baseline with respect to demographic characteristics ( mean age , 38 - 41 years ; white race , 78%-88 % ) and pulmonary function ( mean percent predicted FEV(1 ) , 68%-69 % ; mean asthma symptom score , 1.6 [ scale 0 - 5 ] ; and mean daily albuterol use , 3.1 puffs ) . After 12 weeks of treatment , the mean FEV(1 ) AUC(bl ) was significantly greater in patients who received FSC compared with those who received FP , SAL , or PLA ( 7.0 , 3.6 , 5.3 , and 1.4 L-h , respectively ; all comparisons , P < or = 0.020 ) . At end point , the mean change from baseline in morning predose FEV(1 ) for FSC was significantly greater than that for FP , SAL , and PLA ( 0.41 , 0.19 , 0.15 , and -0.12 L ; all comparisons , P < or = 0.001 ) . During 12 weeks of treatment , 7 % of patients receiving FSC were withdrawn due to worsening asthma , compared with 24 % of patients receiving SAL and 54 % of patients receiving PLA ( P < 0.001 ) ; 11 % of patients receiving FP were withdrawn due to worsening asthma . Treatment with FSC result ed in significant improvements in morning and evening peak expiratory flow compared with FP , SAL , and PLA ( both , P < 0.001 ) ; need for rescue albuterol compared with FP and PLA ( P < or = 0.005 ) ; and asthma symptom scores compared with PLA ( P < 0.001 ) . The tolerability of FSC was similar to that of FP or SAL alone . The incidence of possibly drug-related adverse events was generally similar across treatment groups , and the most common ( occurring in > or= 2 % of patients ) were headache ( 1%-4 % ) , throat irritation ( 1%-2 % ) , c and idiasis of the mouth/throat ( 0%-2 % ) , unspecified oropharyngeal plaques ( 0%-2 % ) , and palpitations ( 0%-2 % ) . CONCLUSIONS In these adolescent and adult patients whose asthma was not controlled by medium doses of an ICS , FSC delivered via HFA 134a MDI ( 2 inhalations of 110/21-microg strength administered BID ) was more effective in improving lung function than FP or SAL monotherapy or PLA . All treatments were well tolerated 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 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 Current therapy in Russia for long-term management of asthma is mainly non-steroidal . This provided the opportunity to compare the efficacy and safety of formoterol ( Oxis ) Turbuhaler plus budesonide ( Pulmicort ) Turbuhaler with budesonide Turbuhaler alone in adults ( n=338 ) with mild to moderate asthma who had little previous exposure to inhaled corticosteroids . The 12-week study followed a r and omised , double-blind , parallel group design and included an open control group of patients who were treated with conventional non-corticosteroid therapy . Patients treated with formoterol plus budesonide benefited from a significantly greater improvement in their pulmonary function and asthma symptoms compared with budesonide alone ( 95 % Cl of difference in mean morning peak expiratory flow [ PEF ] 8.7 - 36.3 l/min , p=0.0015 ) .  Non-corticosteroid  treatment was significantly less effective than formoterol plus budesonide and budesonide alone ( 95 % CIs of differences in mean morning PEF were 36.4 - 63.6 l/min and 14.1 - 41.1 l/min , respectively , both p=0.0001 ) . Although the incidence and frequency of adverse events was not significantly different between the groups , formoterol plus budesonide and budesonide alone were better tolerated than non-corticosteroid treatment , and there were fewer incidences of asthma deterioration . Overall , formoterol Turbuhaler plus budesonide Turbuhaler was the safest and most effective treatment BACKGROUND Adding a long-acting beta(2)-agonist to inhaled corticosteroids results in better symptomatic asthma control than increasing the dose of inhaled corticosteroids . OBJECTIVE Investigating whether adding the long-acting beta(2)-agonist salmeterol to the inhaled corticosteroid fluticasone propionate has an effect on allergen-induced allergic inflammation in asthma . METHODS Bronchial allergen challenges were performed in 26 patients with allergic asthma , pretreating them with a single dose of either fluticasone/salmeterol ( 100/50 microg ) or fluticasone alone ( 100 microg ) , in a double-blind , r and omized , cross-over design . Sputum and serum markers of bronchial inflammation were measured after allergen challenge , as well as lung function parameters . Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein . RESULTS Asthmatic responses after allergen challenge were significantly reduced after pretreatment with fluticasone/salmeterol relative to fluticasone alone . Sputum inflammatory markers after allergen challenge were not significantly affected by fluticasone/salmeterol pretreatment . By contrast , serum IL-5 was significantly reduced ( geometric mean serum IL-5 [ SEM ] : 0.5 [ 0.3 ] vs 1.1 [ 0.3 ] pg/mL 1 hour and 0.6 [ 0.3 ] vs 1.1 [ 0.3 ] pg/mL 6 hours after challenge with fluticasone/salmeterol vs fluticasone alone pretreatment , respectively ; P values < .05 ) . Also , peripheral blood eosinophils were significantly reduced ( geometric mean number x 10(6)/L [ SEM ] : 172 [ 0.1 ] vs 237 [ 0.1 ] at 6 hours and 271 [ 0.1 ] vs 351 [ 0.1 ] at 24 hours with fluticasone/salmeterol vs fluticasone alone pretreatment , respectively ; P < .05 ) . CONCLUSION Adding salmeterol to fluticasone reduces allergen-induced serum IL-5 and peripheral blood eosinophils . This phenomenon may contribute to the improved clinical outcomes that result from adding a long-acting beta(2)-agonist to inhaled corticosteroids The peak response and the duration of bronchodilator effect were measured after four inhalations at 20 min intervals of 250 micrograms of aerosolized terbutaline in 13 patients with bronchial asthma . Patients were initially studied after strict avoidance of all adrenergic agents for 2 wk ; they were then studied at 2 wk intervals for 12 wk while receiving 500 micrograms of aerosolized terbutaline q.i.d . The initial testing ( TI ) and the testing at the end of 12 wk ( TII ) were double blind . Both peak response and duration of action decreased significantly between TI and TII . Cumulative dose-response curves showed that further improvement occurred after each inhalation during TI but that there was significant improvement only after the first inhalation during TII 89 subjects with stable asthma took part in a double-blind , placebo-controlled , r and omized , crossover study of the effects of regular versus on-dem and inhaled bronchodilator therapy . The subjects inhaled fenoterol or placebo by a dry powder delivery system for 24 weeks . Control of asthma was judged by daily morning and evening peak expiratory flow rates , symptom diaries , use of additional inhaled bronchodilator , and requirement for short courses of prednisone . Of 64 subjects who completed the trial , 57 showed a clear difference in degree of control of asthma between the fenoterol and placebo periods : in 17 ( 30 % [ 95 % confidence interval 18.4 - 43.4 % ] ) asthma was better controlled during regular inhaled bronchodilator treatment , whereas in 40 ( 70 % [ 56.6 - 81.6 % ] ) control was better during placebo treatment with bronchodilator for symptom relief only . Mean airway responsiveness to methacholine increased slightly during the fenoterol period . The adverse effect of regular bronchodilator inhalation occurred not only among subjects who used a bronchodilator as sole treatment ( 2 were better and 10 were worse during regular bronchodilator treatment ) but also among those who took inhaled corticosteroids ( 14 were better and 29 were worse ) . Thus , regular inhalation of a beta-sympathomimetic agent was associated with deterioration of asthma control in the majority of subjects . The trends to use of regular , higher doses or longer-acting inhaled beta-sympathomimetic treatment may be an important causal factor in the worldwide increase in morbidity from asthma
BACKGROUND Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality .
Much debate has surrounded possible causal links for this association and whether regular ( daily ) long-acting beta2-agonists are safe when used alone or in conjunction with inhaled corticosteroids .
This is an up date d Cochrane Review .
OBJECTIVES To assess the risk of fatal and non-fatal serious adverse events in people with chronic asthma given regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone .