human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors , with formoterol being a full agonist . The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40 % of patients and is known to predispose to agonist-induced downregulation and desensitization . OBJECTIVES To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction ( the primary end point ) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism . METHODS Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were r and omized to completion ( mean [ SEM ] age , 35.8 [ 3.2 ] years ; mean FEV(1 ) , 76.9 [ 2 . 5]% predicted ) . Patients received three different treatments for 1 week in r and omized , double-blind , crossover fashion , with a 1-week washout period between treatments : formoterol , 12 microg bid ; salmeterol , 50 microg bid ; and placebo . For each of the r and omized treatment periods , there were three separate methacholine challenges : baseline after washout , 12 h after the first dose , and 12 h after the last dose . RESULTS Both salmeterol and formoterol exhibited significantly ( p < 0.05 ) greater bronchoprotection than placebo for their effects after single or repeated dosing , although there was no significant difference between the two drugs . The geometric mean fold protection vs placebo ( 95 % confidence interval [ CI ] ) for the first dose was 1.6-fold ( 95 % CI , 1.1 to 2.2 ) for salmeterol and 1.9-fold ( 95 % CI , 1.1 to 3.2 ) for formoterol , and for last dose was 1.6-fold ( 95 % CI , 1.2 to 2.3 ) for salmeterol and 1 . 9-fold ( 95 % CI , 1.2 to 2.8 ) for formoterol . Salmeterol and formoterol produced significant ( p < 0.05 ) increases in FEV(1 ) and forced expiratory flow after 25 to 75 % of vital capacity has been expelled , after the first but not the last dose compared to placebo , while there were significant ( p < 0.05 ) improvements in domiciliary peak flows during treatment with both drugs . CONCLUSION Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype . There was a significant residual degree of bronchoprotection after 1 week of treatment , which was not significantly different compared to the first-dose effect Brambilla C , Chastang C , Georges D , Bertin L. Salmeterol compared with slow‐release terbutaline in  nocturnal asthma .  A multicenter , r and omized , double‐blind , double‐dummy , sequential clinical trial The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers , serum levels of eosinophil cationic protein ( ECP ) , serum eosinophil chemotactic activity ( ECA ) , and serum neutrophil chemotactic activity ( NCA ) were studied in two groups of patients with allergic asthma . Group 1 ( n = 8) had a circadian variation of peak expiratory flow ( PEF ) 15 % or greater , and group 2 ( n = 9 ) had a circadian PEF variation less than 15 % . Both groups were r and omized and crossover treated for 4 weeks with ( A ) 0.4 mg budesonide at 8 AM and 8 PM , ( B ) 20 mg bambuterol at 8 PM , and ( C ) placebo . At the end of each period blood eosinophil numbers , ECP , ECA , and NCA were measured during 24 hours at 4-hour intervals . No significant differences in the inflammatory parameters could be observed between the groups , although eosinophil numbers tended to be higher in group 1 than in group 2 . Highest eosinophil numbers were observed at night . Budesonide reduced both eosinophil numbers and ECP levels , especially at night ; bambuterol had no effect on both variables . No circadian variation or treatment effects were observed for ECA and NCA . This study suggests a role for the eosinophil in the nocturnal worsening of asthma , and it demonstrates that budesonide produces , in contrast to bambuterol , a reduction of ( nocturnal ) eosinophil numbers and activity The asthmatic inflammatory response can be attenuated by corticosteroids and in part by beta(2)-agonists . We investigated if these effects are accompanied by a downregulation in nuclear factor kappa B ( NF-kappaB ) , a transcription factor regulating many of the cytokine and adhesion molecule genes expressed in allergic inflammation . Bronchial biopsies were taken before and after 8 wk treatment with formoterol , budesonide , or placebo from atopic asthmatics . Biopsies were processed into glycol methacrylate and stained immunohistochemically for eosinophils ( as an index of inflammation ) , activated and total NF-kappaB , adhesion molecules , and cytokines . After budesonide treatment there was a significant decrease in the number of submucosal cells staining for total NF-kappaB , granulocyte macrophage colony-stimulating factor ( GM-CSF ) and tumor necrosis factor-alpha ( TNF-alpha ) , accompanied by a significant decrease in mucosal eosinophils and expression of vascular cell adhesion molecule-1 ( VCAM-1 ) in the endothelium and interleukin-8 ( IL-8 ) in the epithelium . After formoterol treatment there was a significant decrease in eosinophils and the epithelial expression of activated NF-kappaB , but these changes were not accompanied by reduced immunoreactivity for adhesion molecules or cytokines . We conclude that at least some of the therapeutic efficacy of inhaled corticosteroids is mediated through inhibition of NF-kappaB-regulated gene expression , whereas the reduction in airway eosinophilia by long-acting beta(2)-agonists probably operates through alternative pathways Inhalation of on-dem and salbutamol ( ODS ) several times daily is sometimes the only beta2-agonist prescribed in moderate persistent asthma , whereas a long-acting beta2-agonist should be added . This trial aim ed to compare the efficacy of formoterol dry-powder capsule 12 microg b.i.d . ( Foradil ) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids , in the conditions of real practice . Two hundred and fifty-nine patients were r and omized ( formoterol ; 130 ; ODS : 129 ) in this open , parallel-group trial . The mean increases in morning peak expiratory flow ( PEF primary variable ) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol : + 25.7 and + 24.1 l min(-1 ) , respectively vs. + 4.5 and + 0.5 l min(-1 ) respectively with ODS . The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3 . Formoterol  reduced the use of salbutamol as rescue medication by two-thirds . The percentages of symptom-free days and nights statistically significantly increased with formoterol ( + 20 % and + 33 % respectively ) , but did not significantly change with ODS  .  Clinical ly relevant and statistically significant improvement in the mean total score of the St George 's Hospital Respiratory Question naire was observed in the formoterol group . Adverse events were similar in the two groups . The results show that treatment with formoterol has significant advantages over ODS  in patients with moderate persistent asthma Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone . Design and setting A 52 week , two period , double blind , multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were r and omised to add montelukast or salmeterol .  Participants Patients ( 15 - 72 years ; n = 1490 ) had a clinical history of chronic asthma for ≥ 1 year , a baseline forced expiratory volume in one second ( FEV 1 ) value 50 - 90 % predicted , and a β agonist improvement of ≥ 12 % in FEV 1 . Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation . Results 20.1 % of the patients in the group receiving montelukast and fluticasone  had an asthma exacerbation compared with 19.1 % in the group receiving salmeterol and fluticasone ; the difference was 1 % ( 95 % confidence interval -3.1 % to 5.0 % ) . With a risk ratio ( montelukast-fluticasone/salmeterol-fluticasone ) of 1.05 ( 0.86 to 1.29 ) , treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone . Salmeterol and fluticasone  significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone ( P ≤ 0.001 ) , whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups . Montelukast and fluticasone significantly ( P = 0.011 ) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone . Both treatments were generally well tolerated . Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol BACKGROUND The greatest prevalence of asthma is in preschool children ; however , the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index , long-term tolerability , and frequency and /or difficulty of administration .  Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma , although very young patients may have difficulty using inhalers , and dose delivery can be variable . Moreover , reduced compliance with inhaled therapy relative to orally administered therapy has been reported . One potential advantage of montelukast is the ease of administering a once-daily chewable tablet ; additionally , no tachyphylaxis or change in the safety profile has been evidence d after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years , respectively . To our knowledge , this represents the first large , multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma , as well as one of the few asthma studies that incorporated end points vali date d for use in preschool children . OBJECTIVE Our primary objective was to determine the safety profile of montelukast , an oral leukotriene receptor antagonist , in preschool children with persistent asthma . Secondarily , the effect of montelukast on exploratory measures of asthma control was also studied . DESIGN AND STATISTICAL ANALYSIS : We conducted a double-blind , multicenter , multinational study at 93 centers worldwide : including 56 in the United States , and 21 in countries in Africa , Australia , Europe , North America , and South America . In this study , we r and omly assigned 689 patients ( aged 2 - 5 years ) to 12 weeks of treatment with placebo ( 228 patients ) or 4 mg of montelukast as a chewable tablet ( 461 patients ) after a 2-week placebo baseline period . Patients had a history of physician-diagnosed asthma requiring use of beta-agonist and a predefined level of daytime asthma symptoms . Caregivers answered questions twice daily on a vali date d , asthma-specific diary card and , at specified times during the study , completed a vali date d asthma-specific quality -of-life question naire . Physicians and caregivers completed a global evaluation of asthma control at the end of the study . Efficacy end points included : daytime and overnight asthma symptoms , daily use of beta-agonist , days without asthma , frequency of asthma attacks , number of patients discontinued because of asthma , need for rescue medication , physician and caregiver global evaluations of change , asthma-specific caregiver quality of life , and peripheral blood eosinophil counts . Although exploratory , the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding . At screening and at study completion , a complete physical examination was performed . Routine laboratory tests were drawn at screening and weeks 6 and 12 , and su bmi tted to a central laboratory for analysis . Adverse effects were collected from 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors , with formoterol being a full agonist . The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40 % of patients and is known to predispose to agonist-induced downregulation and desensitization . OBJECTIVES To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction ( the primary end point ) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism . METHODS Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were r and omized to completion ( mean [ SEM ] age , 35.8 [ 3.2 ] years ; mean FEV(1 ) , 76.9 [ 2 . 5]% predicted ) . Patients received three different treatments for 1 week in r and omized , double-blind , crossover fashion , with a 1-week washout period between treatments : formoterol , 12 microg bid ; salmeterol , 50 microg bid ; and placebo . For each of the r and omized treatment periods , there were three separate methacholine challenges : baseline after washout , 12 h after the first dose , and 12 h after the last dose . RESULTS Both salmeterol and formoterol exhibited significantly ( p < 0.05 ) greater bronchoprotection than placebo for their effects after single or repeated dosing , although there was no significant difference between the two drugs . The geometric mean fold protection vs placebo ( 95 % confidence interval [ CI ] ) for the first dose was 1.6-fold ( 95 % CI , 1.1 to 2.2 ) for salmeterol and 1.9-fold ( 95 % CI , 1.1 to 3.2 ) for formoterol , and for last dose was 1.6-fold ( 95 % CI , 1.2 to 2.3 ) for salmeterol and 1 . 9-fold ( 95 % CI , 1.2 to 2.8 ) for formoterol . Salmeterol and formoterol produced significant ( p < 0.05 ) increases in FEV(1 ) and forced expiratory flow after 25 to 75 % of vital capacity has been expelled , after the first but not the last dose compared to placebo , while there were significant ( p < 0.05 ) improvements in domiciliary peak flows during treatment with both drugs . CONCLUSION Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype . There was a significant residual degree of bronchoprotection after 1 week of treatment , which was not significantly different compared to the first-dose effect Brambilla C , Chastang C , Georges D , Bertin L. Salmeterol compared with slow‐release terbutaline in  nocturnal asthma .  A multicenter , r and omized , double‐blind , double‐dummy , sequential clinical trial The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers , serum levels of eosinophil cationic protein ( ECP ) , serum eosinophil chemotactic activity ( ECA ) , and serum neutrophil chemotactic activity ( NCA ) were studied in two groups of patients with allergic asthma . Group 1 ( n = 8) had a circadian variation of peak expiratory flow ( PEF ) 15 % or greater , and group 2 ( n = 9 ) had a circadian PEF variation less than 15 % . Both groups were r and omized and crossover treated for 4 weeks with ( A ) 0.4 mg budesonide at 8 AM and 8 PM , ( B ) 20 mg bambuterol at 8 PM , and ( C ) placebo . At the end of each period blood eosinophil numbers , ECP , ECA , and NCA were measured during 24 hours at 4-hour intervals . No significant differences in the inflammatory parameters could be observed between the groups , although eosinophil numbers tended to be higher in group 1 than in group 2 . Highest eosinophil numbers were observed at night . Budesonide reduced both eosinophil numbers and ECP levels , especially at night ; bambuterol had no effect on both variables . No circadian variation or treatment effects were observed for ECA and NCA . This study suggests a role for the eosinophil in the nocturnal worsening of asthma , and it demonstrates that budesonide produces , in contrast to bambuterol , a reduction of ( nocturnal ) eosinophil numbers and activity The asthmatic inflammatory response can be attenuated by corticosteroids and in part by beta(2)-agonists . We investigated if these effects are accompanied by a downregulation in nuclear factor kappa B ( NF-kappaB ) , a transcription factor regulating many of the cytokine and adhesion molecule genes expressed in allergic inflammation . Bronchial biopsies were taken before and after 8 wk treatment with formoterol , budesonide , or placebo from atopic asthmatics . Biopsies were processed into glycol methacrylate and stained immunohistochemically for eosinophils ( as an index of inflammation ) , activated and total NF-kappaB , adhesion molecules , and cytokines . After budesonide treatment there was a significant decrease in the number of submucosal cells staining for total NF-kappaB , granulocyte macrophage colony-stimulating factor ( GM-CSF ) and tumor necrosis factor-alpha ( TNF-alpha ) , accompanied by a significant decrease in mucosal eosinophils and expression of vascular cell adhesion molecule-1 ( VCAM-1 ) in the endothelium and interleukin-8 ( IL-8 ) in the epithelium . After formoterol treatment there was a significant decrease in eosinophils and the epithelial expression of activated NF-kappaB , but these changes were not accompanied by reduced immunoreactivity for adhesion molecules or cytokines . We conclude that at least some of the therapeutic efficacy of inhaled corticosteroids is mediated through inhibition of NF-kappaB-regulated gene expression , whereas the reduction in airway eosinophilia by long-acting beta(2)-agonists probably operates through alternative pathways Inhalation of on-dem and salbutamol ( ODS ) several times daily is sometimes the only beta2-agonist prescribed in moderate persistent asthma , whereas a long-acting beta2-agonist should be added . This trial aim ed to compare the efficacy of formoterol dry-powder capsule 12 microg b.i.d . ( Foradil ) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids , in the conditions of real practice . Two hundred and fifty-nine patients were r and omized ( formoterol ; 130 ; ODS : 129 ) in this open , parallel-group trial . The mean increases in morning peak expiratory flow ( PEF primary variable ) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol : + 25.7 and + 24.1 l min(-1 ) , respectively vs. + 4.5 and + 0.5 l min(-1 ) respectively with ODS . The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3 . Formoterol  reduced the use of salbutamol as rescue medication by two-thirds . The percentages of symptom-free days and nights statistically significantly increased with formoterol ( + 20 % and + 33 % respectively ) , but did not significantly change with ODS  .  Clinical ly relevant and statistically significant improvement in the mean total score of the St George 's Hospital Respiratory Question naire was observed in the formoterol group . Adverse events were similar in the two groups . The results show that treatment with formoterol has significant advantages over ODS  in patients with moderate persistent asthma Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone . Design and setting A 52 week , two period , double blind , multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were r and omised to add montelukast or salmeterol .  Participants Patients ( 15 - 72 years ; n = 1490 ) had a clinical history of chronic asthma for ≥ 1 year , a baseline forced expiratory volume in one second ( FEV 1 ) value 50 - 90 % predicted , and a β agonist improvement of ≥ 12 % in FEV 1 . Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation . Results 20.1 % of the patients in the group receiving montelukast and fluticasone  had an asthma exacerbation compared with 19.1 % in the group receiving salmeterol and fluticasone ; the difference was 1 % ( 95 % confidence interval -3.1 % to 5.0 % ) . With a risk ratio ( montelukast-fluticasone/salmeterol-fluticasone ) of 1.05 ( 0.86 to 1.29 ) , treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone . Salmeterol and fluticasone  significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone ( P ≤ 0.001 ) , whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups . Montelukast and fluticasone significantly ( P = 0.011 ) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone . Both treatments were generally well tolerated . Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol BACKGROUND The greatest prevalence of asthma is in preschool children ; however , the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index , long-term tolerability , and frequency and /or difficulty of administration .  Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma , although very young patients may have difficulty using inhalers , and dose delivery can be variable . Moreover , reduced compliance with inhaled therapy relative to orally administered therapy has been reported . One potential advantage of montelukast is the ease of administering a once-daily chewable tablet ; additionally , no tachyphylaxis or change in the safety profile has been evidence d after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years , respectively . To our knowledge , this represents the first large , multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma , as well as one of the few asthma studies that incorporated end points vali date d for use in preschool children . OBJECTIVE Our primary objective was to determine the safety profile of montelukast , an oral leukotriene receptor antagonist , in preschool children with persistent asthma . Secondarily , the effect of montelukast on exploratory measures of asthma control was also studied . DESIGN AND STATISTICAL ANALYSIS : We conducted a double-blind , multicenter , multinational study at 93 centers worldwide : including 56 in the United States , and 21 in countries in Africa , Australia , Europe , North America , and South America . In this study , we r and omly assigned 689 patients ( aged 2 - 5 years ) to 12 weeks of treatment with placebo ( 228 patients ) or 4 mg of montelukast as a chewable tablet ( 461 patients ) after a 2-week placebo baseline period . Patients had a history of physician-diagnosed asthma requiring use of beta-agonist and a predefined level of daytime asthma symptoms . Caregivers answered questions twice daily on a vali date d , asthma-specific diary card and , at specified times during the study , completed a vali date d asthma-specific quality -of-life question naire . Physicians and caregivers completed a global evaluation of asthma control at the end of the study . Efficacy end points included : daytime and overnight asthma symptoms , daily use of beta-agonist , days without asthma , frequency of asthma attacks , number of patients discontinued because of asthma , need for rescue medication , physician and caregiver global evaluations of change , asthma-specific caregiver quality of life , and peripheral blood eosinophil counts . Although exploratory , the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding . At screening and at study completion , a complete physical examination was performed . Routine laboratory tests were drawn at screening and weeks 6 and 12 , and su bmi tted to a central laboratory for analysis . Adverse effects were collected from 
    Output:
    