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 aim of this study was to test the hypothesis that use of tiotropium , a new long-acting anticholinergic bronchodilator , would be associated with sustained reduction in lung hyperinflation and , thereby , would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease . A r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 187 patients ( forced expiratory volume in one second 44±13 % pred ) : 96 patients received 18 µg tiotropium and 91 patients received placebo once daily for 42 days . Spirometry , plethysmographic lung volumes , cycle exercise endurance and exertional dyspnoea intensity at 75 % of each patient 's maximal work capacity were compared . On day 42 , the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to  placebo : vital capacity and inspiratory capacity ( IC ) increased , with inverse decreases in residual volume and functional residual capacity  . Tiotropium  increased post-dose exercise endurance time by 105±40 s ( 21 % ) as compared to placebo on day 42 . At a st and ardised time near end-exercise ( isotime ) , IC , tidal volume and minute ventilation all increased , whilst dyspnoea decreased by 0.9±0.3 Borg scale units . In conclusion , the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise . Result ant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance Background : The benefits of pharmacotherapy with tiotropium H and iHaler 18 μg for patients with chronic obstructive pulmonary disease ( COPD ) have been previously demonstrated . However , few data exist regarding the treatment of moderate disease ( Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stage II ) . Aims : To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy . Methods : A r and omised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily ( via H and iHaler ) was performed in maintenance therapy – naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity ( FVC ) ratio < 0.7 and post-bronchodilator FEV1 ⩾50 and < 80 % . Results : A total of 457 patients were r and omised ( 238 tiotropium , 219 placebo ; mean age 62 years ; FEV1 1.93 l ( 66 % predicted ) )  . Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h ( AUC0–3h ) at week 24 ( primary endpoint ) : 0.19 vs. −0.03 l ( least-squares mean difference 0.23 l , P<0.001 ) . FVC AUC0–3h , trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo ( P<0.001 ) . Compared with placebo , tiotropium  provided numerical improvements in physical activity ( P = NS ) . Physician ’s Global Assessment ( health status ) improved ( P=0.045 ) with less impairment on the Work Productivity and Activity Impairment question naire ( P=0.043 ) at week 24 . The incidence of exacerbations , cough , bronchitis and dyspnoea was lower with tiotropium than placebo . Conclusions : Tiotropium  improved lung function and patient-reported outcomes in maintenance therapy – naive patients with GOLD stage II COPD , suggesting benefits in initiating maintenance therapy early Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules  taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT This was a multicenter , r and omized , double-blind within device , parallel-group , dose-ranging study . COPD patients ( n = 202 ; 86 % male ; mean age : 61 years ) were r and omized to receive tiotropium 1.25 μg , 2.5 μg , 5 μg , 10 μg , or 20 μg Respimat ® SMI ( a novel , propellant-free device ) ; tiotropium 18 μg H and iHaler ® ; placebo Respimat ® ; or placebo H and iHaler ® for 3 weeks . The primary endpoint was trough FEV1 on Day 21 . Other assessment s included FVC , PEFR , rescue medication use , safety , and pharmacokinetics . In general , all active treatments improved the primary and secondary endpoints on Day 21 ( steady state ) compared with placebo . Tiotropium 5 μg Respimat ® , 20 μg Respimat ® , and tiotropium 18 μg H and iHaler ® were statistically significantly higher than placebo for the primary endpoint ( mean change in trough FEV1 was 150 mL ( both Respimat ® doses ) versus 20 mL ( placebo Respimat ® ) ; p < 0.05 ; and 230 mL ( H and iHaler ® ) versus −90 mL ( placebo H and iHaler ® ) ; p ≤ 0.001 ) . The urinary excretion ( up to 2 hours post-dose ) of tiotropium 5–10 μg Respimat ® was comparable with tiotropium 18 μg H and iHaler ® ; the overall incidence of adverse events was comparable across treatment groups . Tiotropium 5 and 10 μg Respimat ® improve lung function in COPD patients and appear to be comparable with tiotropium 18 μg H and iHaler ® STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction 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 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 
    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 aim of this study was to test the hypothesis that use of tiotropium , a new long-acting anticholinergic bronchodilator , would be associated with sustained reduction in lung hyperinflation and , thereby , would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease . A r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 187 patients ( forced expiratory volume in one second 44±13 % pred ) : 96 patients received 18 µg tiotropium and 91 patients received placebo once daily for 42 days . Spirometry , plethysmographic lung volumes , cycle exercise endurance and exertional dyspnoea intensity at 75 % of each patient 's maximal work capacity were compared . On day 42 , the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to  placebo : vital capacity and inspiratory capacity ( IC ) increased , with inverse decreases in residual volume and functional residual capacity  . Tiotropium  increased post-dose exercise endurance time by 105±40 s ( 21 % ) as compared to placebo on day 42 . At a st and ardised time near end-exercise ( isotime ) , IC , tidal volume and minute ventilation all increased , whilst dyspnoea decreased by 0.9±0.3 Borg scale units . In conclusion , the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise . Result ant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance Background : The benefits of pharmacotherapy with tiotropium H and iHaler 18 μg for patients with chronic obstructive pulmonary disease ( COPD ) have been previously demonstrated . However , few data exist regarding the treatment of moderate disease ( Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stage II ) . Aims : To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy . Methods : A r and omised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily ( via H and iHaler ) was performed in maintenance therapy – naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity ( FVC ) ratio < 0.7 and post-bronchodilator FEV1 ⩾50 and < 80 % . Results : A total of 457 patients were r and omised ( 238 tiotropium , 219 placebo ; mean age 62 years ; FEV1 1.93 l ( 66 % predicted ) )  . Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h ( AUC0–3h ) at week 24 ( primary endpoint ) : 0.19 vs. −0.03 l ( least-squares mean difference 0.23 l , P<0.001 ) . FVC AUC0–3h , trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo ( P<0.001 ) . Compared with placebo , tiotropium  provided numerical improvements in physical activity ( P = NS ) . Physician ’s Global Assessment ( health status ) improved ( P=0.045 ) with less impairment on the Work Productivity and Activity Impairment question naire ( P=0.043 ) at week 24 . The incidence of exacerbations , cough , bronchitis and dyspnoea was lower with tiotropium than placebo . Conclusions : Tiotropium  improved lung function and patient-reported outcomes in maintenance therapy – naive patients with GOLD stage II COPD , suggesting benefits in initiating maintenance therapy early Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules  taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT This was a multicenter , r and omized , double-blind within device , parallel-group , dose-ranging study . COPD patients ( n = 202 ; 86 % male ; mean age : 61 years ) were r and omized to receive tiotropium 1.25 μg , 2.5 μg , 5 μg , 10 μg , or 20 μg Respimat ® SMI ( a novel , propellant-free device ) ; tiotropium 18 μg H and iHaler ® ; placebo Respimat ® ; or placebo H and iHaler ® for 3 weeks . The primary endpoint was trough FEV1 on Day 21 . Other assessment s included FVC , PEFR , rescue medication use , safety , and pharmacokinetics . In general , all active treatments improved the primary and secondary endpoints on Day 21 ( steady state ) compared with placebo . Tiotropium 5 μg Respimat ® , 20 μg Respimat ® , and tiotropium 18 μg H and iHaler ® were statistically significantly higher than placebo for the primary endpoint ( mean change in trough FEV1 was 150 mL ( both Respimat ® doses ) versus 20 mL ( placebo Respimat ® ) ; p < 0.05 ; and 230 mL ( H and iHaler ® ) versus −90 mL ( placebo H and iHaler ® ) ; p ≤ 0.001 ) . The urinary excretion ( up to 2 hours post-dose ) of tiotropium 5–10 μg Respimat ® was comparable with tiotropium 18 μg H and iHaler ® ; the overall incidence of adverse events was comparable across treatment groups . Tiotropium 5 and 10 μg Respimat ® improve lung function in COPD patients and appear to be comparable with tiotropium 18 μg H and iHaler ® STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction 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 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 
    Output:
    