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: The oral , selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy and safety of roflumilast used concomitantly with long-acting & bgr;2-agonists ( LABAs ) to reduce exacerbations , and the influence of exacerbation history . Pooled data were analysed from two 12-month , placebo-controlled roflumilast ( 500 μg once daily ) studies involving 3,091 patients with severe-to-very severe COPD . Approximately half of patients used concomitant LABAs ; 39 % used concomitant short-acting muscarinic antagonists ( SAMAs ) ; 27 % were frequent exacerbators ( two or more exacerbations per year ) . Roflumilast  reduced the rate of moderate or severe exacerbations , with LABA ( rate ratio ( RR ) 0.79 , 95 % CI 0.69–0.91 ; p=0.001 ) or without LABA ( RR 0.85 , 95 % CI 0.74–0.99 ; p=0.039 ) and prolonged time both to first ( p=0.035 with LABA , p=0.300 without LABA ) and second ( p=0.018 with LABA , p=0.049 without LABA ) exacerbations . Frequent exacerbators experienced a reduction in moderate or severe exacerbations ( RR 0.78 , 95 % CI 0.66–0.91 ; p=0.002 ) . Similarly , roflumilast remained effective with concomitant SAMA . No differences arose in adverse events between these subgroups . Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function , without increasing adverse events in COPD patients receiving concomitant LABAs Background The oral selective phosphodiesterase-4 inhibitor roflumilast ( ROF ) reduces exacerbations in patients with severe COPD . Adverse events ( AEs ) can cause early ROF discontinuation . Alternative dosing strategies may help patients continue their therapy . Methods In this multicenter , double-blind trial , 1,321 patients with severe COPD were r and omized 1:1:1 to 4 weeks ’ treatment with ROF 250 µg once daily ( OD ) , 500 µg every other day ( EOD ) , or 500 µg OD , each followed by ROF 500 µg OD for 8 weeks , plus st and ard therapy . The primary end point was the percentage of patients prematurely discontinuing study treatment . Results Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations ( odds ratio [ OR ] 0.66 [ 95 % CI 0.47–0.93 ] , p=0.017 ) and lower rates of AEs of interest such as diarrhea , nausea , headache , decreased appetite , insomnia and abdominal pain ( OR 0.63 [ 95 % CI 0.47–0.83 ] , p=0.001 ) compared with those in the 500 µg OD group . Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD , the difference was not significant ( OR 0.76 , p=0.114 , and OR 0.78 , p=0.091 , respectively ) compared with ROF 500 µg OD . Conclusion A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD result ed in reduced treatment discontinuation and improved tolerability Cilomilast ( Ariflo ) , a new oral phosphodiesterase-4 selective inhibitor , improves lung function in chronic obstructive pulmonary disease ( COPD ) . We have evaluated its antiinflammatory effects in 59 patients with COPD r and omized to receive cilomilast , 15 mg two times a day , or placebo for 12 weeks . Induced sputum differential cell counts were obtained at baseline and at five further visits . Interleukin-8 and neutrophil elastase were measured in sputum supernatant . Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils , CD8 + and CD4 + T-lymphocyte subsets , and CD68 + macrophages . Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified . Compared with placebo , analysis of variance ( ANOVA ) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1 . However , bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8 + ( p = 0.001 ; ANOVA ) and CD68 + cells ( p < 0.05 ; ANOVA ) . In addition , by Poisson analysis , comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8 + ( 48 % p < 0.01 ) and CD68 + ( 47 % p = 0.001 ) cells . This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD . Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease Background Many patients with chronic obstructive pulmonary disease ( COPD ) continue to suffer exacerbations , even when treated with maximum recommended therapy ( eg , inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids , with or without a long-acting anticholinergic [ long-acting muscarinic antagonist ] ) . Roflumilast is approved to treat severe COPD in patients with chronic bronchitis – and a history of frequent exacerbations – as an add-on to bronchodilators . Purpose The REACT ( Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment ) study ( identification number RO-2455 - 404-RD , clinical trials . gov identifier NCT01329029 ) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations . Patients and methods REACT is a 1-year r and omized , double-blind , multicenter , phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination . A concomitant long-acting muscarinic antagonist will be allowed at stable doses . The primary outcome is the rate of moderate or severe COPD exacerbations . Using a Poisson regression model with a two-sided significance level of 5 % , a sample size of 967 patients per treatment group is needed for 90 % power . COPD patients with severe to very severe airflow limitation , symptoms of chronic bronchitis , and at least two exacerbations in the previous year will be recruited . Conclusion It is hypothesized that because roflumilast ( a phosphodiesterase-4 inhibitor ) has a different mode of action to bronchodilators and inhaled corticosteroids , it may provide additional benefits when added to these treatments in frequent exacerbators . REACT will be important to determine the role of roflumilast in COPD management . Here , the design and rationale for this important study is described BACKGROUND AND OBJECTIVE Roflumilast , an oral , selective phosphodiesterase 4 inhibitor , has been shown to reduce exacerbations and improve pulmonary function in patients with COPD . This study examined the efficacy , safety and tolerability of roflumilast in Asian patients with COPD . METHODS Patients with COPD were r and omized 1:1 to enter a 12-week treatment period and receive either oral roflumilast , 500 µg once daily , or placebo , following a single-blind , 4-week baseline period in which all patients received placebo . The primary end point was mean change in FEV₁ from baseline to each postr and omization visit during the treatment period . Other spirometric lung function measurements were evaluated as secondary end points . COPD exacerbations were monitored . Safety was assessed from clinical laboratory tests , vital signs , physical examination ( including electrocardiogram ) and monitoring of adverse events ( AEs ) . RESULTS Of 551 patients recruited , 410 were r and omized and received at least one dose of study medication ( roflumilast , n = 203 ; placebo , n = 207 ) . Superiority of roflumilast over placebo was demonstrated by a statistically significant difference in postbronchodilator FEV₁ ( 79 mL , P < 0.0001 ) . Other spirometry end points , including prebronchodilator FEV₁ , pre- and postbronchodilator FEV₆ , forced vital capacity and peak expiratory flow significantly favoured roflumilast over placebo . AEs were more common with roflumilast than with placebo , but were comparable with those reported in previous studies . CONCLUSIONS Roflumilast , 500 µg once daily , improves pulmonary function in Asian patients with COPD .  The safety and tolerability of roflumilast in this population was similar to that in a Caucasian population The purpose of this study was to investigate the effects of 500 & mgr;g roflumilast , taken once daily for 12 weeks , on airway physiology during rest and exercise in patients with moderate-to-severe chronic obstructive pulmonary disease . This r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 250 patients with a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of 30–80 % predicted and a functional residual capacity of ≥120 % pred .  Pre- and post-bronchodilator spirometry and body plethysmography , and pre-bronchodilator constant work rate cycle exercise at 75 % of peak work rate were evaluated . Exercise measurements included ventilation , breathing pattern , inspiratory capacity ( IC ) and arterial oxygen saturation measured by pulse oximetry ( Sp , O2 ) . Compared with placebo , 12 weeks of treatment with roflumilast was associated with : small but progressive increases in pre- and post-bronchodilator FEV1 and FEV1/forced vital capacity ; small decreases in specific airway resistance ; and no significant changes in resting vital capacity , IC or measurements of lung hyperinflation . There was no treatment effect on exercise endurance time . At a st and ardised exercise time after roflumilast , compared with  placebo , IC increased by 0.12 L ( p=0.008 ) and Sp , O2 increased by 0.7 % ( p=0.020 ) ; peak ventilation increased by 1.9 L·min−1 ( p=0.014 ) . Roflumilast treatment was associated with progressive improvement of airway function but not lung hyperinflation . Newly described non-bronchodilator effects of roflumilast included small but consistent improvements in air trapping and Sp , O2 during exercise Purpose Roflumilast is the only oral phosphodiesterase 4 inhibitor approved to treat chronic obstructive pulmonary disease ( COPD ) patients [ post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted ] with chronic bronchitis and a history of frequent exacerbations . This study evaluated the efficacy and safety of roflumilast in Korean patients with COPD and compared the efficacy based on the severity of airflow limitation . Material s and Methods A post-hoc subgroup analysis was performed in Korean COPD patients participating in JADE , a 12-week , double-blinded , placebo-controlled , parallel-group , phase III trial in Asia . The primary efficacy endpoint was the mean [ least-squares mean adjusted for covariates ( LSMean ) ] change in post-bronchodilator FEV1 from baseline to each post-r and omization visit . Safety endpoints included adverse events ( AEs ) and changes in laboratory values , vital signs , and electrocardiograms . Results A total of 260 Korean COPD patients were recruited , of which 207 were r and omized to roflumilast ( n=102 ) or placebo ( n=105 ) treatment . After 12 weeks , LSMean post-bronchodilator FEV1 increased by 43 mL for patients receiving roflumilast and decreased by 60 mL for those taking placebo .  Adverse events were more common in the roflumilast group than in the placebo group ; however , the types and frequency of AEs were comparable to those reported in previous studies . Conclusion Roflumilast significantly improved lung function with a tolerable safety profile in Korean COPD patients irrespective of the severity of airflow limitation Background Chronic obstructive pulmonary disease ( COPD ) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators , but above all , CD8 + T-lymphocytes , macrophages and neutrophils are important players in disease pathogenesis . Roflumilast , a first-in-class , potent and selective phosphodiesterase 4 ( P 
    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: The oral , selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy and safety of roflumilast used concomitantly with long-acting & bgr;2-agonists ( LABAs ) to reduce exacerbations , and the influence of exacerbation history . Pooled data were analysed from two 12-month , placebo-controlled roflumilast ( 500 μg once daily ) studies involving 3,091 patients with severe-to-very severe COPD . Approximately half of patients used concomitant LABAs ; 39 % used concomitant short-acting muscarinic antagonists ( SAMAs ) ; 27 % were frequent exacerbators ( two or more exacerbations per year ) . Roflumilast  reduced the rate of moderate or severe exacerbations , with LABA ( rate ratio ( RR ) 0.79 , 95 % CI 0.69–0.91 ; p=0.001 ) or without LABA ( RR 0.85 , 95 % CI 0.74–0.99 ; p=0.039 ) and prolonged time both to first ( p=0.035 with LABA , p=0.300 without LABA ) and second ( p=0.018 with LABA , p=0.049 without LABA ) exacerbations . Frequent exacerbators experienced a reduction in moderate or severe exacerbations ( RR 0.78 , 95 % CI 0.66–0.91 ; p=0.002 ) . Similarly , roflumilast remained effective with concomitant SAMA . No differences arose in adverse events between these subgroups . Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function , without increasing adverse events in COPD patients receiving concomitant LABAs Background The oral selective phosphodiesterase-4 inhibitor roflumilast ( ROF ) reduces exacerbations in patients with severe COPD . Adverse events ( AEs ) can cause early ROF discontinuation . Alternative dosing strategies may help patients continue their therapy . Methods In this multicenter , double-blind trial , 1,321 patients with severe COPD were r and omized 1:1:1 to 4 weeks ’ treatment with ROF 250 µg once daily ( OD ) , 500 µg every other day ( EOD ) , or 500 µg OD , each followed by ROF 500 µg OD for 8 weeks , plus st and ard therapy . The primary end point was the percentage of patients prematurely discontinuing study treatment . Results Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations ( odds ratio [ OR ] 0.66 [ 95 % CI 0.47–0.93 ] , p=0.017 ) and lower rates of AEs of interest such as diarrhea , nausea , headache , decreased appetite , insomnia and abdominal pain ( OR 0.63 [ 95 % CI 0.47–0.83 ] , p=0.001 ) compared with those in the 500 µg OD group . Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD , the difference was not significant ( OR 0.76 , p=0.114 , and OR 0.78 , p=0.091 , respectively ) compared with ROF 500 µg OD . Conclusion A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD result ed in reduced treatment discontinuation and improved tolerability Cilomilast ( Ariflo ) , a new oral phosphodiesterase-4 selective inhibitor , improves lung function in chronic obstructive pulmonary disease ( COPD ) . We have evaluated its antiinflammatory effects in 59 patients with COPD r and omized to receive cilomilast , 15 mg two times a day , or placebo for 12 weeks . Induced sputum differential cell counts were obtained at baseline and at five further visits . Interleukin-8 and neutrophil elastase were measured in sputum supernatant . Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils , CD8 + and CD4 + T-lymphocyte subsets , and CD68 + macrophages . Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified . Compared with placebo , analysis of variance ( ANOVA ) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1 . However , bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8 + ( p = 0.001 ; ANOVA ) and CD68 + cells ( p < 0.05 ; ANOVA ) . In addition , by Poisson analysis , comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8 + ( 48 % p < 0.01 ) and CD68 + ( 47 % p = 0.001 ) cells . This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD . Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease Background Many patients with chronic obstructive pulmonary disease ( COPD ) continue to suffer exacerbations , even when treated with maximum recommended therapy ( eg , inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids , with or without a long-acting anticholinergic [ long-acting muscarinic antagonist ] ) . Roflumilast is approved to treat severe COPD in patients with chronic bronchitis – and a history of frequent exacerbations – as an add-on to bronchodilators . Purpose The REACT ( Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment ) study ( identification number RO-2455 - 404-RD , clinical trials . gov identifier NCT01329029 ) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations . Patients and methods REACT is a 1-year r and omized , double-blind , multicenter , phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination . A concomitant long-acting muscarinic antagonist will be allowed at stable doses . The primary outcome is the rate of moderate or severe COPD exacerbations . Using a Poisson regression model with a two-sided significance level of 5 % , a sample size of 967 patients per treatment group is needed for 90 % power . COPD patients with severe to very severe airflow limitation , symptoms of chronic bronchitis , and at least two exacerbations in the previous year will be recruited . Conclusion It is hypothesized that because roflumilast ( a phosphodiesterase-4 inhibitor ) has a different mode of action to bronchodilators and inhaled corticosteroids , it may provide additional benefits when added to these treatments in frequent exacerbators . REACT will be important to determine the role of roflumilast in COPD management . Here , the design and rationale for this important study is described BACKGROUND AND OBJECTIVE Roflumilast , an oral , selective phosphodiesterase 4 inhibitor , has been shown to reduce exacerbations and improve pulmonary function in patients with COPD . This study examined the efficacy , safety and tolerability of roflumilast in Asian patients with COPD . METHODS Patients with COPD were r and omized 1:1 to enter a 12-week treatment period and receive either oral roflumilast , 500 µg once daily , or placebo , following a single-blind , 4-week baseline period in which all patients received placebo . The primary end point was mean change in FEV₁ from baseline to each postr and omization visit during the treatment period . Other spirometric lung function measurements were evaluated as secondary end points . COPD exacerbations were monitored . Safety was assessed from clinical laboratory tests , vital signs , physical examination ( including electrocardiogram ) and monitoring of adverse events ( AEs ) . RESULTS Of 551 patients recruited , 410 were r and omized and received at least one dose of study medication ( roflumilast , n = 203 ; placebo , n = 207 ) . Superiority of roflumilast over placebo was demonstrated by a statistically significant difference in postbronchodilator FEV₁ ( 79 mL , P < 0.0001 ) . Other spirometry end points , including prebronchodilator FEV₁ , pre- and postbronchodilator FEV₆ , forced vital capacity and peak expiratory flow significantly favoured roflumilast over placebo . AEs were more common with roflumilast than with placebo , but were comparable with those reported in previous studies . CONCLUSIONS Roflumilast , 500 µg once daily , improves pulmonary function in Asian patients with COPD .  The safety and tolerability of roflumilast in this population was similar to that in a Caucasian population The purpose of this study was to investigate the effects of 500 & mgr;g roflumilast , taken once daily for 12 weeks , on airway physiology during rest and exercise in patients with moderate-to-severe chronic obstructive pulmonary disease . This r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 250 patients with a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of 30–80 % predicted and a functional residual capacity of ≥120 % pred .  Pre- and post-bronchodilator spirometry and body plethysmography , and pre-bronchodilator constant work rate cycle exercise at 75 % of peak work rate were evaluated . Exercise measurements included ventilation , breathing pattern , inspiratory capacity ( IC ) and arterial oxygen saturation measured by pulse oximetry ( Sp , O2 ) . Compared with placebo , 12 weeks of treatment with roflumilast was associated with : small but progressive increases in pre- and post-bronchodilator FEV1 and FEV1/forced vital capacity ; small decreases in specific airway resistance ; and no significant changes in resting vital capacity , IC or measurements of lung hyperinflation . There was no treatment effect on exercise endurance time . At a st and ardised exercise time after roflumilast , compared with  placebo , IC increased by 0.12 L ( p=0.008 ) and Sp , O2 increased by 0.7 % ( p=0.020 ) ; peak ventilation increased by 1.9 L·min−1 ( p=0.014 ) . Roflumilast treatment was associated with progressive improvement of airway function but not lung hyperinflation . Newly described non-bronchodilator effects of roflumilast included small but consistent improvements in air trapping and Sp , O2 during exercise Purpose Roflumilast is the only oral phosphodiesterase 4 inhibitor approved to treat chronic obstructive pulmonary disease ( COPD ) patients [ post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted ] with chronic bronchitis and a history of frequent exacerbations . This study evaluated the efficacy and safety of roflumilast in Korean patients with COPD and compared the efficacy based on the severity of airflow limitation . Material s and Methods A post-hoc subgroup analysis was performed in Korean COPD patients participating in JADE , a 12-week , double-blinded , placebo-controlled , parallel-group , phase III trial in Asia . The primary efficacy endpoint was the mean [ least-squares mean adjusted for covariates ( LSMean ) ] change in post-bronchodilator FEV1 from baseline to each post-r and omization visit . Safety endpoints included adverse events ( AEs ) and changes in laboratory values , vital signs , and electrocardiograms . Results A total of 260 Korean COPD patients were recruited , of which 207 were r and omized to roflumilast ( n=102 ) or placebo ( n=105 ) treatment . After 12 weeks , LSMean post-bronchodilator FEV1 increased by 43 mL for patients receiving roflumilast and decreased by 60 mL for those taking placebo .  Adverse events were more common in the roflumilast group than in the placebo group ; however , the types and frequency of AEs were comparable to those reported in previous studies . Conclusion Roflumilast significantly improved lung function with a tolerable safety profile in Korean COPD patients irrespective of the severity of airflow limitation Background Chronic obstructive pulmonary disease ( COPD ) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators , but above all , CD8 + T-lymphocytes , macrophages and neutrophils are important players in disease pathogenesis . Roflumilast , a first-in-class , potent and selective phosphodiesterase 4 ( P 
    Output:
    