Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial [The effect of triamcinolone acetonide, montelukast, nedocromil sodium, formoterol on levels levels of sICAM-1, sIL-2R in serum and clinical course of asthma in children]. Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma A randomized, double-blind trial of the effect of treatment with formoterol on clinical and inflammatory parameters of asthma in children. The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma. The effect of salmeterol on nocturnal symptoms, airway function, and inflammation in asthma. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations Effects of once-daily formoterol and budesonide given alone or in combination on surrogate inflammatory markers in asthmatic adults. Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study Effect of salmeterol on seasonal changes in airway responsiveness and exhaled nitric oxide in pollen-sensitive asthmatic subjects. Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma in vivo An antiinflammatory effect of salmeterol, a long-acting beta(2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. Salmeterol resolves airway obstruction but does not possess anti-eosinophil efficacy in newly diagnosed asthma: a randomized, double-blind, parallel group biopsy study comparing the effects of salmeterol, fluticasone propionate, and disodium cromoglycate. Effects of fluticasone plus salmeterol versus twice the dose of fluticasone in asthmatic patients Anti-inflammatory effects of salmeterol compared with beclomethasone in eosinophilic mild exacerbations of asthma: a randomized, placebo controlled trial. The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics. The salmeterol/fluticasone combination is more effective than fluticasone plus oral montelukast in asthma. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. A randomized, double‐blind trial of the effect of glucocorticoid, antileukotriene and bβ‐agonist treatment on IL‐10 serum levels in children with asthma Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma. Effect of fluticasone propionate-salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma. Formoterol added to low-dose budesonide has no additional antiinflammatory effect in asthmatic patients. Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma. Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide. Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Effects of fluticasone vs. fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in mild persistent asthma. [The effect of triamcinolone, montelukast and formoterol on serum levels of il-4, IgE and clinical parameters in children with asthma]. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Formoterol attenuates neutrophilic airway inflammation in asthma. Effect of inhaled fluticasone with and without salmeterol on airway inflammation in asthma. Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype. Comparison of salmeterol with placebo in mild asthma: effect on peripheral blood phagocyte function and cytokine levels.
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 One of the characteristics of asthma is the variability of inflammation . Thus , it is important to monitor inflammation serially in asthma , e.g. by the use of peripheral blood markers . To evaluate the effect of treatment on allergic inflammation , we measured serum levels of sIL-2R , sICAM-1  and clinical parameters before and after 4 weeks treatment with triamcinolon , montelukast , nedocromil and formoterol . It was 8 week , placebo-controlled and r and omized , double blind trial of 158 children with moderate atopic asthma . Patients were r and omly allocated to received 400 micrograms triamcinolon ( n = 28 ) , 5 or 10 mg ( according to age ) montelukast ( n = 27 ) , 16 mg nedocromil ( n = 30 ) , 24 micrograms formoterol ( n = 29 ) or placebo ( n = 44 ) . 140 children completed the study . After treatment with triamcinolon , montelukast and nedocromil sIL-2R and sICAM-1 serum level significantly decreased , and all clinical parameters improved ; treatment with triamcinolon had the strongest effect on most parameters ( except of FEV1 ) . Mean sIL-2R before and after treatment with triamcinolon were 724.1 pg/ml and 486.1 pg/ml respectively ( p < 0.001 ) ; with nedocromil were 760.2 pg/ml and 596.7 pg/ml respectively ( p < 0.001 ) ; with montelukast were 617.9 pg/ml and 491.2 pg/ml respectively ( p < 0.001 ) ; with formoterol were 705.4 pg/ml and 698.9 pg/ml respectively ( p = 0.8 ) . Mean sICAM-1 serum levels before and after treatment with triamcinolon were 262.4 ng/ml and 210.4 ng/ml respectively ( p < 0.001 ) ; with nedocromil were 292.9 ng/ml and 258.4 ng/ml respectively ( p < 0.001 ) ; with montelukast were 277.7 ng/ml and 242.9 ng/ml respectively ( p < 0.001 ) ; with formoterol were 262.6 ng/ml and 260.0 ng/ml ( p = 0.6 ) . We found significant correlation between : sIL-2R and hyperresponsiveness , sICAM-1 and hyper responsiveness , FEV1 and sICAM-1 , FEV1 and sIL-2R , sIL-2R and sICAM-1 after treatment . This study shows that triamcinolon , montelukast and nedocromil contribute to inhibition of allergic inflammation by decreasing sIL-2R and sICAM-1 serum levels . The serum level of sIL-2R and sICAM-1 seem to be a good clinical marker of monitoring the disease ; their levels decrease after treatment together with improvement in hyperresponsiveness and clinical parameters 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 BACKGROUND In addition to their bronchodilating effect , long-acting inhaled beta-agonists have recently been shown to have some anti-inflammatory properties . OBJECTIVE The purpose of this study was to evaluate the effect of formoterol on inflammatory mediators in children . METHODS In this double-blind , r and omized , placebo-controlled trial , 34 children , aged 6 to 18 years , with moderate atopic asthma , were r and omly allocated to receive formoterol or matching placebo for 4 weeks . The primary endpoint of this study was to determine changes in serum levels of inflammatory markers after treatment with formoterol ; secondary endpoints included clinical efficacy and bronchial hyperreactivity . The following parameters were measured : symptom score , forced expiratory volume in 1 second ( FEV1 ) , provocative concentration of histamine causing a 20 % fall in FEV1 ( PC20 ) for histamine and peripheral blood eosinophil count , serum levels of eosinophil cationic protein ( ECP ) , soluble receptor of interleukin-2 ( sIL-2R ) , level of interleukin-4 ( IL-4 ) , level of soluble intercellular adhesion molecule-1 ( ICAM-1 ) , and immunoglobulin E ( IgE ) level before and after treatment . RESULTS Compared with placebo , treatment with formoterol significantly improved lung function . The mean value of FEV1 changed from 74 % of predicted value before treatment to 80 % of predicted value after treatment ( P < 0.001 ) . The mean concentration of eosinophil blood count before and after treatment was 379 and 310 cells/mm3 ( P = 0.035 ) ; ECP was 93 and 83 mcg/L ; and serum IL-4 was 0.13 and 0.11 pg/mL ( P = 0.001 ) . There was no significant difference between formoterol and placebo recipients in PC20H , and serum concentration of sIL-2R , sICAM-1 , or IgE after treatment . The group that received formoterol showed improvement in pulmonary function as measured by FEV1 ( P < 0.001 ) , and PC20H ( P = 0.04 ) after 4 weeks of treatment . These patients also showed improvement of clinical symptoms ( P < 0.001 ) . Serum marker measurements in the formoterol group showed decreased concentrations of eosinophil blood count , ECP , and IL-4 , but there was no difference in before and after measurements of sIL-2R , sICAM-1 , and IgE. CONCLUSIONS These results indicate that formoterol has measurable anti-inflammatory properties and can diminish asthma symptoms and bronchial hyperreactivity Salmeterol xinafoate is an inhaled long-acting beta2-adrenoceptor agonist recently introduced for the treatment of asthma . Both in vitro and animal studies suggest that it may have anti-inflammatory activities of benefit in this disease . To assess this directly , the effects of 6 weeks ' treatment with salmeterol on indices of clinical activity , airway dysfunction and inflammation in subjects with stable atopic asthma were investigated . In a double blind study , asthmatic patients were r and omized to 6 weeks ' treatment with either salmeterol 50 microg twice daily ( n=14 ) or placebo ( n=12 ) . They underwent bronchoscopy with bronchoalveolar lavage ( BAL ) and bronchial biopsy immediately before starting treatment and again after 6 weeks . Treatment with salmeterol improved clinical indices of asthma activity , but there were no changes in BAL differential cell counts or mediator levels , and no change in T-cell numbers or activation status . In the biopsy specimens there were no changes in numbers of inflammatory cells , sub-basement membrane collagen deposition or mast cell degranulation . Regular treatment with salmeterol improves clinical indices of asthma but has no effect on the underlying inflammatory process . These findings strengthen guideline recommendations that long-acting beta2-agonists should not be prescribed as sole antiasthma medication STUDY OBJECTIVE To determine the efficacy of salmeterol alone in a group of patients with moderate asthma with nocturnal worsening of symptoms .  DESIGN Double-blind , r and omized , placebo-controlled crossover study . SETTING Tertiary care hospital specializing in respiratory diseases . PARTICIPANTS Ten patients with nocturnal asthma . INTERVENTIONS Subjects were r and omized to salmeterol , 100 micrograms twice daily , or placebo for 6 weeks with a 1-week washout between treatment periods . Symptoms , nocturnal awakenings , and beta 2-agonist use were recorded daily .  Spirometry  was performed at weeks 1 and 6 of each period at bedtime and at 4 AM , and methacholine challenge was performed at 4 AM followed by bronchoscopy with BAL . BAL fluid analysis included cell count and differential count , eosinophil cationic protein , Charcot-Leyden crystal protein , leukotriene B4 , and thromboxane B2 . RESULTS The percentage of nights with awakenings decreased significantly with salmeterol ( 69.8 + /- 8.7 % vs 30.6 + /- 10.8 % for placebo and salmeterol , respectively ; p = 0.02 ) . The percentage of 24-h days with supplemental inhaled beta 2-agonist use significantly decreased with salmeterol ( 85.9 + /- 9.4 % vs 70.4 + /- 10.1 % for placebo and salmeterol , respectively ; p = 0.04 ) . There were no significant differences in bronchial reactivity , 4 AM FEV1 , overnight percentage change in FEV1 , or indexes of airway inflammation . CONCLUSIONS Salmeterol alone improves the number of nocturnal awakenings and supplemental 24-h beta 2-agonist use in nocturnal asthma without significantly altering lung function and airway inflammation BACKGROUND Treatment decisions in asthma are based on assessment s of symptoms and simple measures of lung function , which do not relate closely to underlying eosinophilic airway inflammation . We aim ed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a st and ard management strategy . METHODS We recruited 74 patients with moderate to severe asthma from hospital clinics and r and omly allocated them to management either by st and ard British Thoracic Society asthma guidelines ( BTS management group ) or by normalisation of the induced sputum eosinophil count and reduction of symptoms ( sputum management group ) . We assessed patients nine times over 12 months . The results were used to manage those in the sputum management group , but were not disclosed in the BTS group . The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation , measured by induced sputum eosinophil count . Analyses were by intention to treat . FINDINGS The sputum eosinophil count was 63 % ( 95 % CI 24 - 100 ) lower over 12 months in the sputum management group than in the BTS management group ( p=0.002 ) . Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group ( 35 vs 109 ; p=0.01 ) and significantly fewer patients were admitted to hospital with asthma ( one vs six , p=0.047 ) . The average daily dose of inhaled or oral corticosteroids did not differ between the two groups . INTERPRETATION A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment One important goal of asthma treatment is to reduce exacerbations . The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal . A total of 117 adults with asthma were entered into a multicentre , r and omised , parallel group-effectiveness study for two treatment strategies over a 2-yr period . In one strategy ( the clinical strategy : CS ) treatment was based on symptoms and spirometry . In the other ( the sputum strategy : SS ) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils ≤2 % ; symptoms and spirometry were used to identify clinical control , exacerbations and other treatments . Patients were blind to sputum cell counts in both strategies and physicians were blind in the CS , thus removing bias . First , the minimum treatment to maintain control was identified in 107 patients ( Phase 1 ) and then this treatment was continued ( Phase 2 ) for the remaining of the 2 yrs . The primary outcomes were the relative risk reduction for the occurrence of the first exacerbation in Phase 2 and the length of time without exacerbation . The current authors also examined the type and severity of exacerbations and the cumulative dose of inhaled steroid needed . The duration and number of exacerbations in Phase 1 were similar in both groups . In Phase 2 there were a 126 exacerbations of which 79 occurred in the CS ( 62.7 % ) and 47 ( 37.3 % ) in the SS groups . The majority of the 126 exacerbations ( 101 ; 80.1 % ) were mild . The majority of the 102 exacerbations , where sputum examination was performed before any treatment ( n = 70 ) , were noneosinophilic . In the SS patients , the time to the first exacerbation was longer ( by 213 days ) especially in those considered to need treatment with a long acting β2-agonist ( by 490 days ) , the relative risk ratio was lower ( by 49 % ) , and the number of exacerbations needing prednisone was reduced ( 5 versus 15 ) . This benefit was seen mainly in patients needing treatment with inhaled steroid in a daily dose equivalent to fluticasone > 250 μg , and was due to fewer eosinophilic exacerbations . The cumulative dose of corticosteroid during the trial was similar in both groups . Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose . It had no influence on the frequency of noneosinophilic exacerbations , which were the most common exacerbations OBJECTIVES We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers . METHODS Fifteen patients with atopic persistent asthma were evaluated ( mean age , 32.4 years ; FEV(1 ) , 75.2 % predicted ) in a r and omized , double-blind , double-dummy , placebo-controlled crossover study with a 1-week placebo washout period , comparing the following once-daily nighttime treatments : ( 1 ) formoterol ( FM ) , 12 microg , for 2 weeks and FM , 24 microg , for 2 weeks ; or ( 2 ) budesonide ( BUD ) , 400 microg , for 2 weeks and BUD , 800 microg , for 2 weeks ; or ( 3 ) FM , 12 microg , plus BUD , 400 microg , for 2 weeks and FM , 24 microg , plus BUD , 800 microg , for 2 weeks . Adenosine monophosphate ( AMP ) bronchial challenge , exhaled nitric oxide ( NO ) , and serum eosinophilic cationic protein ( ECP ) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment . RESULTS The results of AMP challenge ( provocative concentration causing a 20 % fall in FEV(1 ) ) at 4 weeks showed significant ( p<0.05 ) improvements after patients had received all active treatments compared to placebo ( 20 mg/mL ) , with FM plus BUD , 261 mg/mL , being superior ( p<0.05 ) to FM alone , 82 mg/mL , but not to BUD , 201 mg/mL. NO and ECP showed significant ( p<0.05 ) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone . Combination therapy was associated with optimal patient preference ( rank order , FM plus BUD > FM > BUD ; p<0.0005 ) , highest domiciliary peak expiratory flow , and lowest rescue inhaler usage . All three treatments produced equivalent improvements in spirometry . CONCLUSIONS Patients preferred once-daily combination therapy , but this had no greater effect on inflammatory markers than therapy with BUD alone . FM alone had no anti-inflammatory activity but exhibited bronchoprotection . This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist Although the anti-inflammatory effects of inhaled corticosteroids in the treatment of asthma are established , the effects of long-acting β2-adrenergic receptor agonists on inflammation are the subject of debate . The aim of the present study was to determine the effect of salmeterol on the numbers of inflammatory cells in biopsy sample s of distinct immunophenotype and those expressing the genes for interleukin-4 and -5 , regulatory cytokines particularly relevant to asthma . Twenty patients ( aged 18–55 yrs ) with mild stable asthma were r and omised in a three-way crossover study to 6 weeks of treatment with : 1 ) salmeterol ( 50 µg b.d . ; SM50 ) ; 2 ) fluticasone propionate ( 250 µg b.d . ; FP250 ) , or 3 ) placebo . Compared with placebo , SM50 significantly reduced the numbers of neutrophils in bronchial biopsy sample s and the concentrations of myeloperoxidase and soluble E-selectin in serum , each of which reflect neutrophil involvement . Compared with FP250 , SM50 reduced neutrophil number and human neutrophil lipocalin level in bronchial lavage fluid and intercellular adhesion molecule-1 level in bronchoalveolar lavage fluid . Compared with placebo , FP250 significantly reduced the numbers of ( CD3 + ) T-lymphocytes , ( CD4 + ) T-helper cells , ( CD45RO+ ) activated T-helper cells and eosinophils in the biopsy sample s ; it also reduced the percentage of eosinophils and soluble intercellular adhesion molecule-1 in serum . The percentage of symptom-free days and nights and airways hyperresponsiveness improved significantly after SM50 compared to both placebo and FP250 . In conclusion , a novel antineutrophilic effect of the inhaled long-acting β2-adrenergic receptor agonist , salmeterol , in mild asthma is reported OBJECTIVE Using a model of natural allergen exposure , we examined the effect of regular treatment with salmeterol on allergen-induced  changes in airway responsiveness and exhaled nitric oxide ( ENO ) . DESIGN Double-blind , r and omized , parallel-group study . SETTING Specialist allergy unit in a university hospital . PATIENTS Asthmatic patients sensitized to pollen allergens were r and omly allocated to monotherapy with salmeterol ( n = 14 ) or placebo ( n = 13 ) . INTERVENTIONS Salmeterol , 25 micro g , and placebo inhalers , two puffs bid , for 6 weeks . MEASUREMENTS Spirometry , the level of a provocative concentration of a substance ( methacholine ) causing a 20 % fall in FEV(1 ) ( PC(20 ) ) , the PC(20 ) level for adenosine 5'-monophosphate ( AMP ) , and ENO were measured before the pollen season and were repeated at the height of the pollen season after 6 weeks of treatment with salmeterol or placebo . RESULTS The decrease in FEV(1 ) during the pollen season was significantly larger in the placebo group than in the salmeterol group , the mean difference in the change between the groups being 0.20 L ( 95 % confidence interval , 0.03 to 0.35 ; p = 0.047 ) . Changes in PC(20 ) for methacholine , PC(20 ) for AMP , and ENO levels were not significantly different between treatment groups . However , a mean ( + /- SEM ) decrease in the PC(20 ) for methacholine of -1.0 + /- 0.4 doubling concentrations was observed within the placebo group ( p = 0.03 ) , whereas no significant changes were observed within the salmeterol group . A significant decrease in PC(20 ) for AMP ( doubling concentrations ) was observed within the placebo group ( -2.1 + /- 0.6 ; p = 0.003 ) and the salmeterol group ( -1.5 + /- 0.4 ; p = 0.003 ) . ENO concentrations increased significantly among the placebo and the salmeterol groups during natural pollen exposure . CONCLUSION These observations indicate that natural allergen exposure and the regular use of salmeterol are not associated with a greater increase in ENO and airway responsiveness than allergen exposure alone In-vitro data suggest that long-acting β2-agonists may have a neutrophil-stabilising effect . A reduction in airway wall eosinophil number following introduction of salmeterol in persistent asthma has previously been described . There is currently interest in the “ neutrophil system ” in asthma , and thus the aim of the present study was to investigate the effect of salmeterol on interleukin (IL)-8 , neutrophils and myeloperoxidase ( MPO ) in persistent asthma . In the same 12-week double-blind parallel-group placebo-controlled study as described previously , the effects on bronchoalveolar lavage fluid ( BALF ) IL-8 , neutrophils and MPO of introducing salmeterol ( 50 µg b.i.d . ) or giving additional inhaled corticosteroid ( fluticasone 100 µg b.i.d . ) in 45 subjects with persistent asthma already on low/moderate doses of inhaled corticosteroids were further investigated . At baseline , BALF IL-8 but not neutrophil or MPO levels were significantly raised in the asthmatic subjects compared to normal controls . MPO levels correlated strongly with IL-8 levels , and weakly with BALF neutrophil numbers in the asthmatics . Fluticasone treatment result ed in significantly elevated neutrophil numbers , but not MPO or IL-8 levels . In contrast , introducing salmeterol significantly reduced IL-8 and MPO levels , but did not affect BALF neutrophil numbers . Interestingly , salmeterol and fluticasone showed significantly contrasting effects on MPO and neutrophils , and there was a divergent effect on IL-8 levels that almost reached significance . Excessive interleukin-8 levels may be relevant to asthma pathogenesis , even in the setting of moderate-dose inhaled corticosteroid therapy . Reduction in interleukin-8 production and possibly stabilisation of airway neutrophil numbers may explain the greater clinical benefit of adding a long-acting β2-agonist rather than merely increasing inhaled corticosteroid doses . Indeed , high-dose inhaled corticosteroid therapy alone may promote airway neutrophilia The addition of long-acting beta(2 ) agonists to inhaled corticosteroid ( ICS ) therapy in symptomatic patients with asthma improves clinical status more than increasing the dose of ICS . It has been suggested that these benefits could be at the cost of an increase in airway inflammation , but few histopathological studies have been performed in the relevant group . In a double-blind , parallel-group , placebo-controlled study , we r and omly assigned 50 symptomatic patients with asthma who were receiving ICS ( range , 100 -500 microgram/d ) to 12 wk of supplementary treatment with salmeterol ( 50 microgram twice daily ) or fluticasone ( 100 microgram twice daily ) or placebo . Bronchial biopsies and BAL were obtained from 45 patients before and after treatment and analyzed . After treatment with salmeterol there was no deterioration of airway inflammation as assessed by mast cells , lymphocytes , or macrophages in BAL or biopsies , but rather a significant fall in EG1-positive eosinophils in the lamina propria ( from a median 18.3 to 7.6 cells/mm , p = 0.01 ) , which was not seen after treatment with fluticasone . The only cellular effect of added fluticasone was a decrease in BAL lymphocyte activation . There was a concurrent improvement in clinical status , more marked with salmeterol than with increased ICS . Thus , adding salmeterol to ICS is not associated with increased " allergic " airway inflammation , but conversely with a complementary antieosinophil effect BACKGROUND Salmeterol ( SLM ) is a long-acting beta(2)-receptor agonist that produces bronchodilatation for 12 hours in asthmatic subjects . The effects of the regular use of long-acting beta(2)-agonists on airway inflammation are largely unknown . OBJECTIVES We examined the effects of 16 weeks of treatment with 50 microg SLM bid , 250 microg fluticasone propionate ( FP ) bid,5 mg disodium cromoglycate ( DSCG ) qid , or placebo on airway inflammation in bronchial mucosa . METHODS Airway inflammation was assessed in bronchial biopsy specimens before and after treatments and bronchial hyperresponsiveness ( BHR ) in 80 patients with newly diagnosed asthma . Inflammatory cells and tenascin in the basement membrane were studied with immunohistochemical methods . Peak expiratory flow rate ( PEF ) , symptoms , and need for rescue medication were recorded . RESULTS SLM , FP , and DSCG  reduced symptoms and need for rescue medication ( P < .04 ) . Both SLM and FP improved PEF and increased PD15FEV(1 ) to histamine by 2.8 and 5.2 doubling dose units , respectively . Both compounds reduced BHR more than placebo ( P < .05 ) . Both SLM and placebo had no effect on any inflammatory cell type . In both FP-treated and DSCG-treated patients , the number of EG2-positive eosinophils in the airway mucosa decreased ( P = .002 and P < .05 , respectively ) . CONCLUSIONS SLM showed no anti-eosinophil properties in this study , but it provided good symptom control . FP provided the best anti-eosinophil properties and symptom relief of the studied compounds Objective Current guidelines advocate adding a long acting β2-agonist ( LABA ) to an inhaled corticosteroid as an alternative to increasing the dose of the latter . Since it is unclear how this translates into effects on surrogate inflammatory markers , we evaluated the anti-inflammatory activity of fluticasone plus salmeterol in combination versus twice the dose of fluticasone alone . Methods Fifteen mild-to-moderate asthmatics ( mean FEV1 80 % predicted ) uncontrolled on inhaled corticosteroids ( mean dose 470 μg ) were r and omised in a single-blind crossover fashion to receive 2 weeks each of fluticasone 250 µg plus salmeterol 50 µg in combination ( FP+SM ) , 1 puff b.i.d . , and fluticasone 500 µg ( FP ) , 1 puff b.i.d . Prior to each r and omised treatment , there was a 2-week run-in and washout period during which patients used their usual inhaled corticosteroid therapy . Measurements were made before and after r and omised treatment periods . The primary outcome was airway hyper-responsiveness to adenosine monophosphate ( AMP PC20 ) , while secondary endpoints were exhaled tidal nitric oxide ( NO ) , forced expiratory volume in 1 second ( FEV1 ) and forced mid-expiratory flow ( FEF25–75 ) . Results For AMP PC20 , FP alone but not FP+SM conferred a significant ( P<0.05 ) improvement amounting to 3.27 ( 95 % CI 1.46–7.32 ) and 1.44 ( 95 % CI 0.64–3.23 ) geometric mean fold shifts , respectively , from baseline , while the difference between treatments was significantly ( P<0.05 ) greater with FP alone : a 2.26-fold ( 95 % CI 1.01–5.07 ) difference . Both FP alone and FP+SM conferred significant ( P<0.05 ) falls in NO from baseline : 2.33 ( 95 % CI 1.71–3.19 ) and 1.49 ( 95 % CI 1.09–2.03 ) geometric mean fold changes , respectively , while between treatments the reduction was significantly ( P<0.05 ) greater with FP alone : a 1.57-fold ( 95 % CI 1.15–2.14 ) difference . Neither treatment significantly improved FEV1 or FEF25–75 . Conclusion Double the dose of FP alone relative to FP+SM conferred superior effects on surrogate inflammatory markers but not on lung function . Long-term studies are required to evaluate whether these improvements on surrogate inflammatory markers translate into commensurate reductions in airway remodelling and exacerbations BACKGROUND Salmeterol is a potent long acting beta-agonist that is effective in relieving the symptoms and airflow limitation of asthma .  OBJECTIVE To determine whether the effect of salmeterol on clinical parameters in a mild eosinophilic exacerbation of asthma was similar to that of beclomethasone dipropionate ( BDP ) and , thus , is due to an anti-inflammatory property . PATIENTS AND METHODS Thirty-four asthmatics with a persistent increase in symptoms for at least two weeks and an increase of sputum eosinophils of 4 % or more were r and omized in a double-blind fashion to one of three groups that received daily treatment with 100 mg salmeterol , 1 mg BDP or placebo in divided doses using identical pressurized inhalers . Patients were treated with study medications for three weeks , followed by one week of open label BDP ( 500 mg bid ) . Patients were seen at weekly intervals , and sputum and blood were obtained on each visit . The primary outcome measure was a change in sputum eosinophils , and secondary outcomes were changes in blood eosinophils , eosinophilic cationic protein ( ECP ) and clinical parameters . Three patients ( one in each group ) could not produce any sputum after r and omization and were excluded from the analysis . RESULTS Twelve patients received salmeterol , 10 received BDP and nine received placebo . Salmeterol treatment had no effect on sputum eosinophils geometric mean , ( from 35.5 [ 24.9 ] to 26.9 % [ 25.8 ] ) , blood eosinophils ( from 7.6 [ 4.8 ] to 7.2 % [ 3.9 ] ) or ECP ( from 33.1 [ 18.1 ] to 27.8 [ 16.3 ] mg/L ) but improved morning peak expiratory flow ( PEF ) and diurnal variation of PEF , and decreased the use of rescue medication more than placebo ( P<0.05 for all comparisons ) . In contrast , BDP improved both inflammatory indexes ( sputum eosinophils from 22.5 [ 17.9 ] to 5.7 % [ 6.8 ] , blood eosinophils from 9.0 [ 5.5 ] to 2.1 % 1.0 , and serum ECP from 36.5 [ 22.0 ] to 16.1 [ 10.1 ] mg/L ) as well as clinical parameters . CONCLUSIONS These results show that salmeterol improves the symptoms and airway function of patients with asthma , but has no effect on eosinophilic airway infiltration . These findings support current asthma guidelines , which recommend the initial use of  inhaled steroid  to maximize clinical improvement .  While salmeterol also produces clinical improvement , it does not suppress sputum eosinophilia . The analysis of induced or spontaneous sputum for inflammatory indexes may be a valuable clinical test to guide the use of inhaled steroid and /or a long acting beta-agonist In a recent placebo-controlled study in mild atopic asthmatics , we observed a significant decrease in eosinophils in the bronchial submucosa , after 2 months oftreatment with inhaled formoterol and budesonide . Biopsy material from each treatment group ; formoterol ( 24 microg bid ) , budesonide ( 400 microg b. i. d. ) and placebo has been further assessed to investigatethe role of Th-2 cytokines by immunohistochemistry using Mabs to eosinophils as an index of inflammation , IL-4 and IL-5 . Treatment with formoterol significantly reduced the number of eosinophils ( EG2 + ) in the submucosa and epithelium , but this was not paralleled by changes in cytokine immunoreactivity In contrast , treatment with budesonide significantly reduced both the number of eosinophils ( EG2 + ) and immunoreactivity for IL-4 and IL-5 in the submucosa . Thus , while budesonide has effects on cytokines involved in eosinophil recruitmentthis explanation does not apply tothe eosinopaenia observed with the long-acting beta2 adrenoreceptor agonist formoterol 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 Adding inhaled long-acting beta(2)-agonists to a low dose of inhaled corticosteroids ( ICS ) , results in better clinical asthma control than increasing the dose of ICS . However , this approach may mask underlying airway inflammation . In a double-blind parallel-group study , we evaluated the effect of adding formoterol to a low dose of budesonide , compared with a higher dose of budesonide , on the composition of induced sputum . After a 4-wk run-in period of treatment with budesonide ( 800 microg , twice daily ) , 60 patients with moderate asthma were r and omly assigned to a 1-yr treatment with 400 microg of budesonide plus placebo , twice daily ( BUD800 ) , or 100 microg of budesonide plus 12 microg of formoterol , twice daily ( BUD200+F ) . All drugs were administered via Turbuhaler . Budesonide ( 800 microg , twice daily ) during run-in significantly reduced median sputum eosinophils from 4.5 to 0.68 % . No significant changes in the proportion of eosinophils , EG2(+ ) cells , other inflammatory cells , or ECP levels in sputum were observed over the ensuing 1-yr treatment with BUD200+F or BUD800 . Clinical asthma control was not significantly different between both groups . In conclusion , no significant differences in sputum markers of airway inflammation were observed during a 1-yr treatment with a low dose of inhaled budesonide plus formoterol compared with a higher dose of budesonide Background Levels of an immunoregulatory and anti‐inflammatory cytokine IL‐10 are reduced in asthmatic airways , potentially contributing to more intense inflammation . Triamcinolone has anti‐inflammatory properties and the anti‐inflammatory effects of montelukast and formoterol have been discussed The aim of this study was to investigate whether regular treatment with inhaled salmeterol modifies the dose-response curve to the inhaled short-acting beta2-agonist terbutaline or affects the concentration of nitric oxide ( NO ) in exhaled air of children with asthma . Twenty-two children aged 7 to 15 years ( mean = 11.6 years ) with mild asthma were treated with inhaled 50 microg salmeterol twice daily or placebo for 3 weeks in a r and omized double-blind cross-over study . These treatments were followed by treatment with inhaled 200 microg budesonide twice daily for 3 weeks . On the last day of each period , NO level was measured in exhaled air and a cumulative dose-response experiment with terbutaline ( cumulative dose : 1,475 microg ) was performed . Baseline lung functions after salmeterol treatment were significantly higher than baseline after placebo ( P + 0.05 ) . Salmeterol treatment flattened out the dose-response curve to terbutaline such that higher doses of terbutaline were required to produce the same degree of bronchodilation ( ED50 for FEV1 was increased by an estimated factor of 70 ( 95 % CI : 0.8 - 6307 ) and ED50 for FEF25 - 75 by a factor of 41 ( 95 % CI : 6.7 - 254 ) ; P < 0.05 ) . NO levels were unaffected by salmeterol treatment ( 12.7 ppb ; placebo = 10.7 ppb ) , but were significantly reduced during budesonide therapy ( 5.2 ppb ; P < 0.001 ) . The corresponding maximal NO levels were 19.5 ( placebo ) , 22.9 ( salmeterol ) , and 9.4 ppb ( budesonide ) . We conclude that 3 weeks treatment with salmeterol does not affect NO levels in exhaled air , but it significantly changes the dose-response curve to terbutaline BACKGROUND There has been concern that in allergic asthmatic patients there might be an interactive effect on inflammation between regular salmeterol use and exposure to allergens , result ing in increased airway responsiveness . OBJECTIVE To determine the effects of salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide ( ENO ) levels in allergic asthmatic patients concomitantly taking inhaled corticosteroids . METHODS Forty-two asthmatic patients sensitized to pollen allergens were r and omly allocated to treatment with fluticasone propionate-salmeterol ( n=21 ) or fluticasone propionate alone ( n=21 ) . Spirometry , the methacholine provocation concentration causing a 20 % decline in forced expiratory volume in 1 second ( PC20 ) , the adenosine 5'-monophosphate ( AMP ) PC20 , and ENO levels were measured before and at the height of the pollen season after 6 weeks of treatment . RESULTS Changes in the methacholine PC20 , the AMP PC20 , and ENO levels were not significantly different between treatment groups . No significant changes in the AMP PC20 were observed among the fluticasone propionate-salmeterol and fluticasone propionate groups during natural pollen exposure . However , a significant increase in the methacholine PC20 was observed in the fluticasone propionate-salmeterol group ( P = .03 ) and in the fluticasone propionate group ( P = .04 ) ; ENO concentrations decreased significantly in both groups during natural allergen exposure ( P = .009 and .005 ) . CONCLUSIONS In patients with pollen-induced asthma , treatment with either fluticasone propionate or fluticasone propionate-salmeterol is associated with significant reductions in methacholine responsiveness and ENO concentrations , even during natural pollen exposure . Furthermore , at least in patients with mild asthma , natural allergen exposure and the regular use of fluticasone propionate-salmeterol are not associated with a greater increase in ENO levels and airway responsiveness than natural allergen exposure and fluticasone propionate use alone 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 There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling , such as the increased subepithelial airway vascularity in patients with asthma . We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids ( ICS ) ( range 200 - 500 microg twice a day ) and 28 normal subjects without asthma as a control population . Subjects underwent bronchoscopy with airway biopsy  and subjects with asthma were then r and omized to receive supplementary inhaled salmeterol 50 microg twice a day , fluticasone propionate 100 microg twice a day , or placebo for 3 mo in addition to their baseline ICS . Biopsy of the airway was then repeated . The biopsies were analyzed for vascular structures in the subepithelial lamina propria . Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects . We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects ( 524 + /- 137 vessels/mm2 , n = 34 versus 425 + /- 130 vessels/mm2 , n = 28 ; p = 0.004 ) . There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline ( before , 535 + /- 153 vessels/mm2 versus after , 400 + /- 142 vessels/mm2 ; n = 12 ; p = 0.04 ) . There was no significant change within the fluticasone ( n = 11 ) or placebo ( n = 11 ) treatment groups , but also no significant differences between the groups . Notably , no treatment was associated with increased airway wall vascularity . The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study , which is complementary to the action of ICS on airway vascularity BACKGROUND Inhaled , long-acting beta2-agonists or antileukotrienes are alternatives as add-on therapy for asthmatic children taking regular inhaled steroids . Any complementary effects would be relevant to the choice between these alternatives . Exhaled nitric oxide ( FeNO ) may reflect these effects . OBJECTIVE To compare the control of FeNO provided by salmeterol or montelukast add-on therapy in asthmatic children undergoing regular maintenance treatment with a daily dose of 400 microg of budesonide .  METHODS The study included children with increased FeNO despite regular treatment with budesonide , 400 microg/d , and normal lung function .  Montelukast , 5 mg/d , salmeterol , 50 microg twice daily , or placebo was compared as add-on therapy to budesonide , 400 microg , in a r and omized , double-blind , double-dummy , crossover study . RESULTS Twenty-two children completed the trial . The geometric mean FeNO level was 20 ppb ( 95 % confidence interval [ CI ] , 15 - 27 ppb ) after salmeterol , which was significantly higher than after montelukast ( mean , 15 ppb ; 95 % CI , 11 - 18 ppb ; P = 0.002 ) and placebo ( mean , 15 ppb ; 95 % CI , 10 - 21 ppb ; P = 0.03 ) . There was no difference in FeNO between the montelukast and placebo groups . Mean forced expiratory volume in 1 second ( FEV1 ) was significantly increased after salmeterol ( mean , 2.63 L ; 95 % CI , 2.34 - 2.91 L ) compared with placebo ( mean , 2.48 L ; 95 % CI , 2.19 - 2.77 L ) . Montelukast ( mean , 2.57 L ; 95 % CI , 2.33 - 2.80 L ) was no different than placebo . CONCLUSIONS The FeNO levels were significantly higher after salmeterol add-on treatment compared with both placebo and montelukast add-on treatment . Salmeterol significantly improved lung function ( FEV1 ) compared with placebo and nonsignificantly compared with montelukast . Montelukast failed to reduce FeNO and improve lung function compared with placebo in this group of children taking regular budesonide , 400 microg Using BAL , we studied the effects of 8 wk of treatment with salmeterol on airway inflammation in nine asthmatic subjects in a double-blind crossover placebo-controlled protocol . The study patients were all receiving regular inhaled corticosteroid therapy ( 400 to 1,000 micrograms beclomethasone dipropionate per day ) and inhaled albuterol for symptomatic relief , i.e. , subjects who might be considered suitable for treatment with salmeterol . The asthmatic group had significant differences in numbers of epithelial cells and eosinophils in BAL compared with a group of 15 normal control subjects ( p < 0.01 ) . During salmeterol treatment mean morning and evening peak flow rates were increased ( p < 0.05 ) . There was no significant change in BAL cell profile and no change in percentages of CD4 and CD8 lymphocytes or proportion of lymphocytes expressing HLA-DR after salmeterol . In conclusion , we were unable to demonstrate any significant anti-inflammatory effect of regular salmeterol therapy on airway inflammation using BAL in these asthmatic patients . At the same time , there was equally no evidence of a deterioration in the underlying inflammatory disease process AIMS Inhaled corticosteroids alone or in combination with long acting beta2-agonists are indicated for use in mild persistent asthmatics . We set out to evaluate effects on airway hyperresponsiveness ( AHR ) and airway calibre using hydrofluoroalkane fluticasone/salmeterol ( FP/SM ) vs. double the dose of fluticasone alone ( FP ) . METHODS Fourteen mild persistent asthmatics completed a r and omized double-blind crossover study with 1-week run-in and washout periods prior to treatments . Subjects received 3 weeks of FP 250 microg or FP 125 microg/SM 25 microg as 1 puff twice daily .  Methacholine PD20 and lung function were measured after both baseline and treatment periods . RESULTS There were no significant differences in baseline values prior to r and omized treatments . Compared with pooled baseline , FP/SM and FP conferred improvements ( P < 0.05 ) on methacholine PD20 : 2.5 ( 95 % confidence interval 1.7 , 3.2 ) and 1.6 ( 0.8 - 2.3 ) doubling dose improvements , respectively ; between FP/SM vs. FP there was a 0.9 ( 0.4 , 1.4 ) doubling dose difference ( P < 0.05 ) . For forced expiratory volume in 1 s ( FEV1 ) , forced mid-expiratory flow ( FEF25 - 75 ) and morning peak expiratory flow ( PEF ) , FP/SM but not FP conferred improvements ( P < 0.05 ) compared with pooled baseline , with FP/SM being greater than FP ( P < 0.05 ) : differences in FEV1 of 7.2 % ( 3.8 , 10.6 ) predicted , FEF25 - 75 of 11.2 % ( 6.3 , 16.1 ) predicted , and morning PEF of 17 L x min(-1)(1 - 32 ) . CONCLUSIONS FP/SM conferred improvements on AHR and airway calibre , while twice the dose of FP improved only AHR in patients with mild asthma . The differential effects of FP/SM and FP suggest separate but complementary actions of the two moieties on airway inflammation and smooth muscle stabilization . This may explain the beneficial effects of combination inhalers on exacerbations Levels of pro-allergic cytokine IL-4 are increased in asthmatic airways , contributing to allergic inflammation . The purpose of this study was to define the effect of treatment with triamcinolon , montelukast , and formoterol on serum level of IL-4 and IgE , clinical parameters ( symptom score , FEV1 ) and bronchial hyperreactivity ( BHR ) in children with moderate asthma . It was 8 week , placebo-controlled and r and omized , double blind trial of 99 children with moderate atopic asthma allergic to dust mite . Patients were r and omly allocated to receive 400 mg triamcinolon ( n = 20 ) , 5 or 10 mg ( according to age ) montelukast ( n = 18 ) , 24 mg formoterol ( n = 19 ) , or placebo ( n = 42 ) . 80 children completed the study . After treatment with triamcinolon , montelukast , and formoterol the level of IL-4 in blood serum in all study groups significantly decreased , and all clinical parameters improved ; treatment with triamcinolon , formoterol , and montelukast had no effect on IgE level in serum . Mean IL-4 levels in serum before and after treatment with triamcinolon were 0.129 pg/ml with 95 % Cl , 0.1 - 0.145 pg/ml and 0.086 pg/ml with 95 % Cl , 0.023 - 0.109 pg/ml respectively ( p = 0.02 ) ; with montelukast were 0.123 pg/ml with 95 % Cl , 0.57 - 0.82 pg/ml and 0.102 pg/ml with 95 % Cl , 0.62 - 0.82 pg/ml respectively ( p < 0.001 ) ; with formoterol were 0.128 pg/ml with 95 % Cl , 0.108 - 0.164 pg/ml and 0.113 pg/ml with 95 % Cl , 0.096 - 0.146 pg/ml respectively ( p = 0.002 ) . No correlations have been found between changes in serum IL-4 and any other clinical parameters after treatment . This study demonstrates that one of the possible ways by which triamcinolon , montelukast , and formoterol contribute to inhibition of allergic inflammation is by decreasing IL-4 levels The present study was design ed to observe the effects of 8 wk of treatment with formoterol ( Foradil ) 24 microgram , budesonide 400 microgram , and matched placebo inhaled twice a day on inflammatory indices in the bronchial mucosa of 64 patients with mild atopic asthma . Biopsies were obtained at the start and 1 wk before stopping a 9-wk period of treatment , and inflammatory cell numbers were assessed in the submucosa and epithelium by immunohistochemistry . Regular formoterol significantly reduced the number of submucosal mast cells , with a similar trend for eosinophils but not activated T cells . A subgroup analysis conducted in biopsies with > = 10 eosinophils per mm2 revealed a significant reduction in eosinophil numbers when compared with both pretreatment baseline ( p < 0.01 ) and changes after placebo ( p < 0.01 ) . Parallel , but less pronounced , effects were observed on mast cell but not on CD25(+ ) T cell numbers . There was no effect of any of the three treatments on BAL levels of mast cell or eosinophil mediators . We conclude that regular treatment with inhaled formoterol reduces rather than increases inflammatory cells in the mucosa of asthmatic patients . It is possible that these cellular effects of formoterol may contribute to the therapeutic efficacy of this drug when used regularly in the STUDY OBJECTIVES Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations . Long-acting beta2-agonists ( LABAs ) , such as formoterol , reduce the number of asthma exacerbations . While beta2-agonists may affect neutrophil function in vitro , it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo . DESIGN In a double-blind r and omized crossover study , we evaluated the effects of 4 weeks of treatment with formoterol ( Turbuhaler ) , 24 microg bid , compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients .  Therapy with budesonide ( administered via Turbuhaler ) , 400 microg bid for 4 weeks , was added at the end as a " gold st and ard " antiinflammatory effect comparison . PATIENTS We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma . RESULTS Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo . There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils , indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production . CONCLUSIONS Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations 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 PURPOSE In the United Kingdom , about 40 % of patients with asthma are homozygous for the glycine-16 beta(2)-adrenoceptor polymorphism , which predisposes them to agonist-induced down-regulation and desensitization of the beta(2)-adrenoceptor . We assessed the effects of adding treatment with either a long-acting beta(2)-agonist ( inhaled formoterol , 12 microg twice daily ) or a leukotriene receptor antagonist ( oral zafirlukast , 20 mg twice daily ) to inhaled corticosteroid therapy in patients with this genotype . SUBJECTS AND METHODS We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids . Patients were r and omly assigned to receive one of three treatments ( placebo , zafirlukast , or formoterol in addition to inhaled corticosteroids ) for 1 week each in a crossover fashion , separated by a 1-week placebo run-in and washout period . Measurements of bronchoprotection ( measured as the provocative dose of methacholine that produced a 20 % decline in forced expiratory volume in 1 second [ FEV(1 ) ] ) , exhaled nitric oxide ( a surrogate marker of airway inflammation ) , and symptoms were made before each treatment and 12 hours after the last dose of each treatment . RESULTS Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo : the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold ( 95 % confidence interval [ CI ] : 1.1- to 2.2-fold ) for zafirlukast and 1.9-fold ( 95 % CI : 1.2- to 2.9-fold ) for formoterol . As compared with placebo , zafirlukast caused a significant suppression in exhaled nitric oxide ( 1.7-fold difference in geometric mean values , 95 % CI : 1.1- to 2.6-fold ) but formoterol did not ( 1.2-fold difference , 95 % CI : 0.8- to 1.9-fold ) . Diary cards showed significant ( P < 0.05 ) improvements in the peak flow with formoterol ( morning and evening ) and zafirlukast ( evening ) as compared with placebo . CONCLUSIONS Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta(2)-agonists . The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids beta 2-Adrenergic agonists are widely prescribed for the symptomatic relief of asthma , but are not thought to alter the underlying pathogenesis . However , it has been suggested that salmeterol , a new beta-agonist with prolonged bronchodilatory action , may have anti-inflammatory properties . A double-blind crossover study of 4 weeks of inhaled salmeterol versus placebo  was performed using a chemiluminescence assay to measure peripheral phagocyte function before and after each treatment period . Circulating cytokines [ interleukin-1 beta ( IL1 beta ) , IL4 , IL6 , IL2 receptor ( IL2R ) ] were also measured . Although salmeterol caused a significant improvement in spirometry , there was no apparent modulation of phagocyte or cytokine activity . No evidence was obtained to support a clinical ly significant anti-inflammatory action of salmeterol
BACKGROUND Long-acting beta(2)-agonists ( LABAs ) are recommended as add-on therapy to antiinflammatory treatment in patients with chronic persistent asthma .
Results from individual studies evaluating the in vivo antiinflammatory effect of LABAs are conflicting .
The purpose of this meta analysis was to determine whether LABAs have an in vivo antiinflammatory effect compared to placebo and whether the addition of a LABA to therapy with inhaled corticosteroids ( ICSs ) has a synergistic or additive antiinflammatory effect .