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: UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed Background : The combination of salmeterol and fluticasone propionate ( SFC ) and tiotropium bromide ( TIO ) are commonly used treatments in chronic obstructive pulmonary disease ( COPD ) but there are few data on their effectiveness when used together . We compared the effects of SFC 50/500 μg twice daily in addition to TIO 18 μg once daily with the individual treatments alone . Methods : 41 patients with COPD participated in a r and omised , double blind , double dummy , three way crossover study with 2 week washout periods between treatments . Lung function assessment included plethysmography and spirometry . The primary end point was post-dose specific airways conductance ( sGaw ) area under the curve ( AUC0–4 h ) on day 14 . Results : AUC0–4 h sGaw was significantly higher on day 14 after SFC+TIO compared with TIO ( 22 % ) or SFC alone ( 27 % ) ( both p<0.001 ) . SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone ( 212 ml , p<0.001 ) and SFC alone ( 110 ml , p = 0.017 ) on day 14 . Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14 . Subjects receiving SFC+TIO had clinical ly relevant improvements in Transition Dyspnoea Index ( TDI ) total score of 2.2 compared with TIO alone ( p<0.001 ) ( but not SFC alone , 0.7 ; NS ) and used significantly less rescue medication ( 1.0 occasion less daily than TIO ( p<0.001 ) and 0.6 less than SFC ( p = 0.01 ) ) . Conclusion : SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone . The advantages of triple therapy are observed across a range of physiologically important parameters , including airway conductance and lung volumes . Triple therapy also led to patient related benefits by improving TDI and use of rescue medication . Trial registration number : NCT00325169 RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) Background : In chronic obstructive pulmonary disease ( COPD ) , the degree of circadian variation in forced expiratory volume in 1 second ( FEV1 ) and the influence of anticholinergic blockade is not known . Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD . We hypothesised that tiotropium would modify the overnight change in FEV1 , and this would be unaffected by the timing of drug administration . Methods : A double blind , r and omised , placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning ( 09.00 hours ) , evening ( 21.00 hours ) , or an identical placebo .  Patients with stable COPD ( n=121 , FEV1=41 % predicted ) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment . Results : There were no significant differences at baseline between the groups . Tiotropium improved mean ( SE ) FEV1 ( over 24 hours ) in the morning ( 1.11 ( 0.03 ) l ) and evening ( 1.06 ( 0.03 ) l ) groups compared with placebo ( 0.90 ( 0.03 ) l ) , and nocturnal FEV1 ( mean of 03.00 and 06.00 hours ) in the morning ( 1.03 ( 0.03 ) l ) and evening ( 1.04 ( 0.03 ) l ) groups compared with placebo ( 0.82 ( 0.03 ) l ) at the 6 week visit ( p<0.01 ) . FEV1 before morning or evening dosing was similar , while the peak FEV1 moved later in the day with active treatment . The mean percentage change in FEV1 from 09.00 hours to 03.00 hours ( the nocturnal decline in FEV1 ) was −2.8 % in the morning group , −1.0 % in the evening group , and −12.8 % in the placebo group . The magnitude of the peak to trough change in FEV1 was not statistically different . Conclusions : Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation .  Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency .  Patients ( n5142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr .  Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level .  Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations?yr ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients BACKGROUND International guidelines recommend the long-acting anticholinergic , tiotropium , or long-acting beta 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease ( COPD ) . The efficacy of long-acting beta(2)-agonists combined with inhaled corticosteroids ( ICS ) in the treatment of COPD has also been confirmed for severe and very severe COPD , but data comparing tiotropium with the combination of a long-acting beta 2-agonist and an ICS are lacking . METHODS This 6-week multicentre , r and omised , double-blind , triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 microg once daily ( n=56 ) vs. the combination of salmeterol 50 microg plus fluticasone 250 microg twice daily ( n=51 ) in patients with moderate-to-very severe COPD . Serial spirometry was performed over 12h after 6 weeks of treatment . The primary endpoint was forced expiratory volume in 1s ( FEV1 ) area under the curve from 0 to 12h ( AUC0 - 12h ) on Day 43 . RESULTS R and omization failed to provide treatment groups with comparable baseline characteristics for smoking history , current smokers , duration of COPD , FEV1 , forced vital capacity ( FVC ) and reversibility . Mean+/-SD FEV1 was 1.31+/-0.47 l in the tiotropium group vs. 1.46+/-0.53 l in the salmeterol plus fluticasone group . Fewer patients 
    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: UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed Background : The combination of salmeterol and fluticasone propionate ( SFC ) and tiotropium bromide ( TIO ) are commonly used treatments in chronic obstructive pulmonary disease ( COPD ) but there are few data on their effectiveness when used together . We compared the effects of SFC 50/500 μg twice daily in addition to TIO 18 μg once daily with the individual treatments alone . Methods : 41 patients with COPD participated in a r and omised , double blind , double dummy , three way crossover study with 2 week washout periods between treatments . Lung function assessment included plethysmography and spirometry . The primary end point was post-dose specific airways conductance ( sGaw ) area under the curve ( AUC0–4 h ) on day 14 . Results : AUC0–4 h sGaw was significantly higher on day 14 after SFC+TIO compared with TIO ( 22 % ) or SFC alone ( 27 % ) ( both p<0.001 ) . SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone ( 212 ml , p<0.001 ) and SFC alone ( 110 ml , p = 0.017 ) on day 14 . Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14 . Subjects receiving SFC+TIO had clinical ly relevant improvements in Transition Dyspnoea Index ( TDI ) total score of 2.2 compared with TIO alone ( p<0.001 ) ( but not SFC alone , 0.7 ; NS ) and used significantly less rescue medication ( 1.0 occasion less daily than TIO ( p<0.001 ) and 0.6 less than SFC ( p = 0.01 ) ) . Conclusion : SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone . The advantages of triple therapy are observed across a range of physiologically important parameters , including airway conductance and lung volumes . Triple therapy also led to patient related benefits by improving TDI and use of rescue medication . Trial registration number : NCT00325169 RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) Background : In chronic obstructive pulmonary disease ( COPD ) , the degree of circadian variation in forced expiratory volume in 1 second ( FEV1 ) and the influence of anticholinergic blockade is not known . Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD . We hypothesised that tiotropium would modify the overnight change in FEV1 , and this would be unaffected by the timing of drug administration . Methods : A double blind , r and omised , placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning ( 09.00 hours ) , evening ( 21.00 hours ) , or an identical placebo .  Patients with stable COPD ( n=121 , FEV1=41 % predicted ) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment . Results : There were no significant differences at baseline between the groups . Tiotropium improved mean ( SE ) FEV1 ( over 24 hours ) in the morning ( 1.11 ( 0.03 ) l ) and evening ( 1.06 ( 0.03 ) l ) groups compared with placebo ( 0.90 ( 0.03 ) l ) , and nocturnal FEV1 ( mean of 03.00 and 06.00 hours ) in the morning ( 1.03 ( 0.03 ) l ) and evening ( 1.04 ( 0.03 ) l ) groups compared with placebo ( 0.82 ( 0.03 ) l ) at the 6 week visit ( p<0.01 ) . FEV1 before morning or evening dosing was similar , while the peak FEV1 moved later in the day with active treatment . The mean percentage change in FEV1 from 09.00 hours to 03.00 hours ( the nocturnal decline in FEV1 ) was −2.8 % in the morning group , −1.0 % in the evening group , and −12.8 % in the placebo group . The magnitude of the peak to trough change in FEV1 was not statistically different . Conclusions : Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation .  Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency .  Patients ( n5142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr .  Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level .  Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations?yr ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients BACKGROUND International guidelines recommend the long-acting anticholinergic , tiotropium , or long-acting beta 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease ( COPD ) . The efficacy of long-acting beta(2)-agonists combined with inhaled corticosteroids ( ICS ) in the treatment of COPD has also been confirmed for severe and very severe COPD , but data comparing tiotropium with the combination of a long-acting beta 2-agonist and an ICS are lacking . METHODS This 6-week multicentre , r and omised , double-blind , triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 microg once daily ( n=56 ) vs. the combination of salmeterol 50 microg plus fluticasone 250 microg twice daily ( n=51 ) in patients with moderate-to-very severe COPD . Serial spirometry was performed over 12h after 6 weeks of treatment . The primary endpoint was forced expiratory volume in 1s ( FEV1 ) area under the curve from 0 to 12h ( AUC0 - 12h ) on Day 43 . RESULTS R and omization failed to provide treatment groups with comparable baseline characteristics for smoking history , current smokers , duration of COPD , FEV1 , forced vital capacity ( FVC ) and reversibility . Mean+/-SD FEV1 was 1.31+/-0.47 l in the tiotropium group vs. 1.46+/-0.53 l in the salmeterol plus fluticasone group . Fewer patients 
    Output:
    