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 BACKGROUND The greatest prevalence of asthma is in preschool children ; however , the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index , long-term tolerability , and frequency and /or difficulty of administration .  Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma , although very young patients may have difficulty using inhalers , and dose delivery can be variable . Moreover , reduced compliance with inhaled therapy relative to orally administered therapy has been reported . One potential advantage of montelukast is the ease of administering a once-daily chewable tablet ; additionally , no tachyphylaxis or change in the safety profile has been evidence d after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years , respectively . To our knowledge , this represents the first large , multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma , as well as one of the few asthma studies that incorporated end points vali date d for use in preschool children . OBJECTIVE Our primary objective was to determine the safety profile of montelukast , an oral leukotriene receptor antagonist , in preschool children with persistent asthma . Secondarily , the effect of montelukast on exploratory measures of asthma control was also studied . DESIGN AND STATISTICAL ANALYSIS : We conducted a double-blind , multicenter , multinational study at 93 centers worldwide : including 56 in the United States , and 21 in countries in Africa , Australia , Europe , North America , and South America . In this study , we r and omly assigned 689 patients ( aged 2 - 5 years ) to 12 weeks of treatment with placebo ( 228 patients ) or 4 mg of montelukast as a chewable tablet ( 461 patients ) after a 2-week placebo baseline period . Patients had a history of physician-diagnosed asthma requiring use of beta-agonist and a predefined level of daytime asthma symptoms . Caregivers answered questions twice daily on a vali date d , asthma-specific diary card and , at specified times during the study , completed a vali date d asthma-specific quality -of-life question naire . Physicians and caregivers completed a global evaluation of asthma control at the end of the study . Efficacy end points included : daytime and overnight asthma symptoms , daily use of beta-agonist , days without asthma , frequency of asthma attacks , number of patients discontinued because of asthma , need for rescue medication , physician and caregiver global evaluations of change , asthma-specific caregiver quality of life , and peripheral blood eosinophil counts . Although exploratory , the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding . At screening and at study completion , a complete physical examination was performed . Routine laboratory tests were drawn at screening and weeks 6 and 12 , and su bmi tted to a central laboratory for analysis . Adverse effects were collected from caregivers at each clinic visit . An intention-to-treat approach , including all patients with a baseline measurement and at least 1 postr and omization measurement , was performed for all efficacy end points . An analysis -of-variance model with terms for treatment , study center and stratum ( inhaled/nebulized corticosteroid use , cromolyn use , or none ) was used to estimate treatment group means and between-group differences and to construct 95 % confidence intervals . Treatment-by-age , -sex , -race , -radioallergosorbent test , -stratum , and - study center interactions were evaluated by including each term separately . Fisher 's exact test was used for between-group comparisons of the frequency of asthma attacks , discontinuations from the study because of worsening asthma , need for rescue medication , and the frequencies of adverse effects . Because of an imbalance in baseline values for eosinophil counts for the 2 treatment groups , an analysis of covariance was performed on the eosinophil change from baseline with the patient 's baseline as covariate . STUDY PARTICIPANTS Of the 689 patients enrolled , approximately 60 % were boys and 60 % were white . Patients were relatively evenly divided by age : 21 % , 24 % , 30 % , and 23 % were aged 2 , 3 , 4 , and 5 years , respectively . For 77 % of the patients , asthma symptoms first developed during the first 3 years of life . During the placebo baseline period , patients had asthma symptoms on 6.1 days/week and used beta-agonist on 6.0 days/week . RESULTS In over 12 weeks of treatment of patients aged 2 to 5 years , montelukast administered as a 4-mg chewable tablet produced significant improvements compared with placebo in multiple parameters of asthma control including : daytime asthma symptoms ( cough , wheeze , trouble breathing , and activity limitation ) ; overnight asthma symptoms ( cough ) ; the percentage of days with asthma symptoms ; the percentage of days without asthma ; the need for beta-agonist or oral corticosteroids ; physician global evaluations ; and peripheral blood eosinophils . The clinical benefit of montelukast 
    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 BACKGROUND The greatest prevalence of asthma is in preschool children ; however , the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index , long-term tolerability , and frequency and /or difficulty of administration .  Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma , although very young patients may have difficulty using inhalers , and dose delivery can be variable . Moreover , reduced compliance with inhaled therapy relative to orally administered therapy has been reported . One potential advantage of montelukast is the ease of administering a once-daily chewable tablet ; additionally , no tachyphylaxis or change in the safety profile has been evidence d after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years , respectively . To our knowledge , this represents the first large , multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma , as well as one of the few asthma studies that incorporated end points vali date d for use in preschool children . OBJECTIVE Our primary objective was to determine the safety profile of montelukast , an oral leukotriene receptor antagonist , in preschool children with persistent asthma . Secondarily , the effect of montelukast on exploratory measures of asthma control was also studied . DESIGN AND STATISTICAL ANALYSIS : We conducted a double-blind , multicenter , multinational study at 93 centers worldwide : including 56 in the United States , and 21 in countries in Africa , Australia , Europe , North America , and South America . In this study , we r and omly assigned 689 patients ( aged 2 - 5 years ) to 12 weeks of treatment with placebo ( 228 patients ) or 4 mg of montelukast as a chewable tablet ( 461 patients ) after a 2-week placebo baseline period . Patients had a history of physician-diagnosed asthma requiring use of beta-agonist and a predefined level of daytime asthma symptoms . Caregivers answered questions twice daily on a vali date d , asthma-specific diary card and , at specified times during the study , completed a vali date d asthma-specific quality -of-life question naire . Physicians and caregivers completed a global evaluation of asthma control at the end of the study . Efficacy end points included : daytime and overnight asthma symptoms , daily use of beta-agonist , days without asthma , frequency of asthma attacks , number of patients discontinued because of asthma , need for rescue medication , physician and caregiver global evaluations of change , asthma-specific caregiver quality of life , and peripheral blood eosinophil counts . Although exploratory , the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding . At screening and at study completion , a complete physical examination was performed . Routine laboratory tests were drawn at screening and weeks 6 and 12 , and su bmi tted to a central laboratory for analysis . Adverse effects were collected from caregivers at each clinic visit . An intention-to-treat approach , including all patients with a baseline measurement and at least 1 postr and omization measurement , was performed for all efficacy end points . An analysis -of-variance model with terms for treatment , study center and stratum ( inhaled/nebulized corticosteroid use , cromolyn use , or none ) was used to estimate treatment group means and between-group differences and to construct 95 % confidence intervals . Treatment-by-age , -sex , -race , -radioallergosorbent test , -stratum , and - study center interactions were evaluated by including each term separately . Fisher 's exact test was used for between-group comparisons of the frequency of asthma attacks , discontinuations from the study because of worsening asthma , need for rescue medication , and the frequencies of adverse effects . Because of an imbalance in baseline values for eosinophil counts for the 2 treatment groups , an analysis of covariance was performed on the eosinophil change from baseline with the patient 's baseline as covariate . STUDY PARTICIPANTS Of the 689 patients enrolled , approximately 60 % were boys and 60 % were white . Patients were relatively evenly divided by age : 21 % , 24 % , 30 % , and 23 % were aged 2 , 3 , 4 , and 5 years , respectively . For 77 % of the patients , asthma symptoms first developed during the first 3 years of life . During the placebo baseline period , patients had asthma symptoms on 6.1 days/week and used beta-agonist on 6.0 days/week . RESULTS In over 12 weeks of treatment of patients aged 2 to 5 years , montelukast administered as a 4-mg chewable tablet produced significant improvements compared with placebo in multiple parameters of asthma control including : daytime asthma symptoms ( cough , wheeze , trouble breathing , and activity limitation ) ; overnight asthma symptoms ( cough ) ; the percentage of days with asthma symptoms ; the percentage of days without asthma ; the need for beta-agonist or oral corticosteroids ; physician global evaluations ; and peripheral blood eosinophils . The clinical benefit of montelukast 
    Output:
    