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: 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 BACKGROUND In vitro the long acting β2 agonist salmeterol can , in contrast to formoterol , behave as a partial agonist and become a partial antagonist to other β2 agonists . To study this in vivo , the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists . METHODS A r and omised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second ( FEV1 ) of 88.4 % predicted and median concentration of methacholine provoking a fall in FEV1 of 20 % or more ( PC20 ) of 0.62 mg/ml at entry . One hour after the last dose of 2 weeks of treatment with formoterol ( 24 μg twice daily by Turbuhaler ) , salmeterol ( 100 μg twice daily by Diskhaler ) , or placebo a methacholine provocation test was performed and continued until there was at least a 30 % decrease in FEV1 . Salbutamol ( 50 μg ) was administered immediately thereafter , followed by ipratropium bromide ( 40 μg ) after a further 30 minutes . Lung function was monitored for 1 hour after provocation . RESULTS There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment . The dose of methacholine needed to provoke a fall in FEV1 of ⩾30 % was higher after pretreatment with formoterol ( 2.48 mg ) than with salmeterol ( 1.58 mg ) or placebo ( 0.74 mg ) . The difference between formoterol and salmeterol was statistically significant : 0.7 doubling dose steps ( 95 % CI 0.1 to 1.2 , p=0.016 ) . The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs ( p<0.0003 for both ) . Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8 % , 7.3 % , and 5.5 % for placebo , formoterol and salmeterol , respectively ( equivalent to increases of 26 % , 14 % , and 12 % , respectively , from the lowest FEV1after methacholine ) . At 30 minutes significant differences remained , but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups . CONCLUSION Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent , indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo . Irrespective of this , prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally , indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol . Patients on regular treatment with long acting β2 agonists  should be made aware that an additional single dose of a short acting β2 agonist may become less effective Salmeterol is a beta-agonist with bronchodilator properties that last for at least 12 h after inhalation . However , the onset of action of salmeterol immediately after inhalation has not been sufficiently investigated . In the present study , the onset of action and tremor-inducing effect of two doses of inhaled salmeterol ( 50 and 100 microg ) were compared with inhaled salbutamol ( 200 and 400 microg ) and placebo .  Lung function was measured using forced expiratory volume in 1 s ( FEV1 ) , and tremor was measured using a linear accelerometer . With salbutamol there was rapid bronchodilation , both doses producing more than 15 % improvement in mean FEV1 within 2 mins of inhalation . With salmeterol , on the other h and , significant bronchodilation was delayed until 7 mins versus placebo , and the full bronchodilation effect was not achieved until 60 mins after inhalation . There was a much more rapid onset of tremor with salbutamol ( 400 microg ) than salmeterol . There was a much slower onset of bronchodilation with salmeterol than salbutamol . Therefore , salmeterol can not be recommended to relieve acute symptoms BACKGROUND The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity . The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects . METHODS A double blind , r and omised , crossover study was carried out in 16 healthy subjects who inhaled formoterol 24 , 48 and 96 μg ( via Turbuhaler ® ) , salmeterol 100 , 200 and 400 μg ( via Diskhaler ® ) , or placebo on separate days . Heart rate , systolic and diastolic blood pressure , and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose . Mean maximum ( or minimum ) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs . Lunch was taken after the four hour readings and , since this caused additional changes to the main outcome measures , data from the first four hours are also presented in a post hoc analysis . RESULTS Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration ; formoterol also caused an early increase in systolic blood pressure . The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol , apart from the glycaemic response . The effects of salmeterol were slightly more prolonged than those of formoterol , although some dose related effects were apparent at eight hours with both drugs . The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values . Relative dose potencies ( 95 % CI ) for maximum heart rate and plasma potassium concentrations were 4.1 ( 3.0 to 5.6 ) and 5.8 ( 4.1 to 8.6 ) over four hours and 2.4 ( 1.2 to 3.8 ) and 3.0 ( 1.2 to 5.7 ) over eight hours . CONCLUSIONS Formoterol and salmeterol cause dose related changes in heart rate , diastolic blood pressure , and plasma glucose and potassium concentrations . Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity . Both drugs have a relatively modest therapeutic window . The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses . Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained BACKGROUND Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear . Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects . A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow ( FBF ) as a measure of peripheral vasodilatation . METHODS Eight men with mild asthma underwent the following treatments : normoxia + placebo ( NP ) , normoxia + salbutamol ( NS ) , hypoxia + placebo ( HP ) , and hypoxia + salbutamol ( HS ) . The period of mask breathing started at t=0 minutes , lasted for 60 minutes , and at 30 minutes 800 μg salbutamol was inhaled . The experiment was completed 30 minutes after the inhalation ( t=60 minutes ) . For the hypoxia treatment the Spo 2 level was 82 % . Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value . RESULTS There were no significant differences in blood pressure and potassium levels between the treatments . After 60 minutes the increase in FBF was 13 % ( 95 % CI –12 to 39 ) more for HP treatment than for NP , 21 % ( 95 % CI –5 to 46 ) more for NS than for NP , and 32 % ( 95 % CI 7 to 58 ) more for HS than for HP ( p=0.016 ) . The inhalation of salbutamol during hypoxia result ed in a significant increase in FBF of 45 % ( 95 % CI 20 to 71 ) compared with NP ( p=0.001 ) . CONCLUSION Patients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death BACKGROUND Nocturnal worsening of asthma is a common problem in asthma and is associated with increased morbidity and mortality . Long acting beta-2 agonists are considered long-term symptom control medications , especially for nocturnal symptoms . OBJECTIVE To compare efficacy of an extended release oral beta-2 agonist , albuterol sulfate ( Volmax ) , to a long-acting inhaled agent , salmeterol ( Serevent ) in the treatment of nocturnal asthma . METHODS This was a multicenter double-blind , double-dummy , r and omized , crossover design with a 1-week baseline period and two 3-week treatment periods separated by a 7 to 9-day washout . An optional 2-week , open-label phase was conducted to evaluate patient preference . RESULTS A total of 46 patients were included in the efficacy analysis . For the primary outcome variable of morning peak expiratory flow , there were similar and significant improvements over the 3-week treatment period for both medications compared with baseline ( P < .001 ) . Similar improvements were seen in the overnight change in PEF values ( P < .001 ) . The morning and overnight changes in FEV1 were not significantly different between treatment arms ( P > .05 ) . There were significant improvements in both treatment periods in regard to the percentage of nights without awakenings ( baseline 53.6+/-5.3 % ) , extended release albuterol 83.3+/-3.0 % ( P < .001 ) , and salmeterol 88.8+/-2.4 % . The percentage of patients who had no awakenings during treatment did not differ significantly for the two medications . Both treatments also result ed in a decrease in the use of rescue albuterol ( extended release 2.66+/-0.35 puffs per day , salmeterol 1.85+/-0.29 ) from baseline ( 4.57+/-0.41 , P < .001 ) . There was a significant difference between groups ( P = .001 ) . The reasons why patients preferred one medication over the other varied . CONCLUSION Both extended release albuterol tablets and inhaled salmeterol result ed in similar bronchodilation and good control of nocturnal asthma symptoms AIMS Inhalers combining long acting beta2-adrenoceptor agonists ( LABA ) and corticosteroids ( ICS ) are indicated at Step 3 of current asthma guidelines . We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function , bronchoprotection , acute salbutamol recovery following methacholine bronchial challenge , and surrogate inflammatory markers in patients with moderate persistent asthma . METHODS Twenty-nine patients with mean FEV1 ( + /- SEM ) of 78 + /- 3 % predicted completed a r and omized , double-blind , double-dummy , cross-over study . Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg ( BUD + FM ) combination twice daily followed by 1 week of BUD 400 microg alone twice daily , or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg ( FP + SM ) combination twice daily followed by 1 week of FP 250 microg alone twice daily . Measurements were made at baseline and following each r and omized treatment . RESULTS FEV1 increase from pretreatment baseline as mean ( + /- SEM ) % predicted was significantly higher ( P < 0.05 ) for BUD + FM ( 8 + /- 1 % ) vs BUD ( 2 + /- 1 % ) , and for FP + SM ( 8 + /- 1 % ) vs FP ( 2 + /- 1 % ) . The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups ; BUD + FM ( 22 + /- 1 % ) , BUD ( 24 + /- 1 % ) , FP + SM ( 23 + /- 1 % ) and FP ( 23 + /- 1 % ) . Salbutamol recovery over 30 min following methacholine challenge as area under curve ( AUC % .min ) was significantly blunted ( 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: 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 BACKGROUND In vitro the long acting β2 agonist salmeterol can , in contrast to formoterol , behave as a partial agonist and become a partial antagonist to other β2 agonists . To study this in vivo , the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists . METHODS A r and omised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second ( FEV1 ) of 88.4 % predicted and median concentration of methacholine provoking a fall in FEV1 of 20 % or more ( PC20 ) of 0.62 mg/ml at entry . One hour after the last dose of 2 weeks of treatment with formoterol ( 24 μg twice daily by Turbuhaler ) , salmeterol ( 100 μg twice daily by Diskhaler ) , or placebo a methacholine provocation test was performed and continued until there was at least a 30 % decrease in FEV1 . Salbutamol ( 50 μg ) was administered immediately thereafter , followed by ipratropium bromide ( 40 μg ) after a further 30 minutes . Lung function was monitored for 1 hour after provocation . RESULTS There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment . The dose of methacholine needed to provoke a fall in FEV1 of ⩾30 % was higher after pretreatment with formoterol ( 2.48 mg ) than with salmeterol ( 1.58 mg ) or placebo ( 0.74 mg ) . The difference between formoterol and salmeterol was statistically significant : 0.7 doubling dose steps ( 95 % CI 0.1 to 1.2 , p=0.016 ) . The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs ( p<0.0003 for both ) . Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8 % , 7.3 % , and 5.5 % for placebo , formoterol and salmeterol , respectively ( equivalent to increases of 26 % , 14 % , and 12 % , respectively , from the lowest FEV1after methacholine ) . At 30 minutes significant differences remained , but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups . CONCLUSION Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent , indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo . Irrespective of this , prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally , indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol . Patients on regular treatment with long acting β2 agonists  should be made aware that an additional single dose of a short acting β2 agonist may become less effective Salmeterol is a beta-agonist with bronchodilator properties that last for at least 12 h after inhalation . However , the onset of action of salmeterol immediately after inhalation has not been sufficiently investigated . In the present study , the onset of action and tremor-inducing effect of two doses of inhaled salmeterol ( 50 and 100 microg ) were compared with inhaled salbutamol ( 200 and 400 microg ) and placebo .  Lung function was measured using forced expiratory volume in 1 s ( FEV1 ) , and tremor was measured using a linear accelerometer . With salbutamol there was rapid bronchodilation , both doses producing more than 15 % improvement in mean FEV1 within 2 mins of inhalation . With salmeterol , on the other h and , significant bronchodilation was delayed until 7 mins versus placebo , and the full bronchodilation effect was not achieved until 60 mins after inhalation . There was a much more rapid onset of tremor with salbutamol ( 400 microg ) than salmeterol . There was a much slower onset of bronchodilation with salmeterol than salbutamol . Therefore , salmeterol can not be recommended to relieve acute symptoms BACKGROUND The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity . The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects . METHODS A double blind , r and omised , crossover study was carried out in 16 healthy subjects who inhaled formoterol 24 , 48 and 96 μg ( via Turbuhaler ® ) , salmeterol 100 , 200 and 400 μg ( via Diskhaler ® ) , or placebo on separate days . Heart rate , systolic and diastolic blood pressure , and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose . Mean maximum ( or minimum ) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs . Lunch was taken after the four hour readings and , since this caused additional changes to the main outcome measures , data from the first four hours are also presented in a post hoc analysis . RESULTS Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration ; formoterol also caused an early increase in systolic blood pressure . The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol , apart from the glycaemic response . The effects of salmeterol were slightly more prolonged than those of formoterol , although some dose related effects were apparent at eight hours with both drugs . The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values . Relative dose potencies ( 95 % CI ) for maximum heart rate and plasma potassium concentrations were 4.1 ( 3.0 to 5.6 ) and 5.8 ( 4.1 to 8.6 ) over four hours and 2.4 ( 1.2 to 3.8 ) and 3.0 ( 1.2 to 5.7 ) over eight hours . CONCLUSIONS Formoterol and salmeterol cause dose related changes in heart rate , diastolic blood pressure , and plasma glucose and potassium concentrations . Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity . Both drugs have a relatively modest therapeutic window . The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses . Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained BACKGROUND Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear . Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects . A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow ( FBF ) as a measure of peripheral vasodilatation . METHODS Eight men with mild asthma underwent the following treatments : normoxia + placebo ( NP ) , normoxia + salbutamol ( NS ) , hypoxia + placebo ( HP ) , and hypoxia + salbutamol ( HS ) . The period of mask breathing started at t=0 minutes , lasted for 60 minutes , and at 30 minutes 800 μg salbutamol was inhaled . The experiment was completed 30 minutes after the inhalation ( t=60 minutes ) . For the hypoxia treatment the Spo 2 level was 82 % . Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value . RESULTS There were no significant differences in blood pressure and potassium levels between the treatments . After 60 minutes the increase in FBF was 13 % ( 95 % CI –12 to 39 ) more for HP treatment than for NP , 21 % ( 95 % CI –5 to 46 ) more for NS than for NP , and 32 % ( 95 % CI 7 to 58 ) more for HS than for HP ( p=0.016 ) . The inhalation of salbutamol during hypoxia result ed in a significant increase in FBF of 45 % ( 95 % CI 20 to 71 ) compared with NP ( p=0.001 ) . CONCLUSION Patients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death BACKGROUND Nocturnal worsening of asthma is a common problem in asthma and is associated with increased morbidity and mortality . Long acting beta-2 agonists are considered long-term symptom control medications , especially for nocturnal symptoms . OBJECTIVE To compare efficacy of an extended release oral beta-2 agonist , albuterol sulfate ( Volmax ) , to a long-acting inhaled agent , salmeterol ( Serevent ) in the treatment of nocturnal asthma . METHODS This was a multicenter double-blind , double-dummy , r and omized , crossover design with a 1-week baseline period and two 3-week treatment periods separated by a 7 to 9-day washout . An optional 2-week , open-label phase was conducted to evaluate patient preference . RESULTS A total of 46 patients were included in the efficacy analysis . For the primary outcome variable of morning peak expiratory flow , there were similar and significant improvements over the 3-week treatment period for both medications compared with baseline ( P < .001 ) . Similar improvements were seen in the overnight change in PEF values ( P < .001 ) . The morning and overnight changes in FEV1 were not significantly different between treatment arms ( P > .05 ) . There were significant improvements in both treatment periods in regard to the percentage of nights without awakenings ( baseline 53.6+/-5.3 % ) , extended release albuterol 83.3+/-3.0 % ( P < .001 ) , and salmeterol 88.8+/-2.4 % . The percentage of patients who had no awakenings during treatment did not differ significantly for the two medications . Both treatments also result ed in a decrease in the use of rescue albuterol ( extended release 2.66+/-0.35 puffs per day , salmeterol 1.85+/-0.29 ) from baseline ( 4.57+/-0.41 , P < .001 ) . There was a significant difference between groups ( P = .001 ) . The reasons why patients preferred one medication over the other varied . CONCLUSION Both extended release albuterol tablets and inhaled salmeterol result ed in similar bronchodilation and good control of nocturnal asthma symptoms AIMS Inhalers combining long acting beta2-adrenoceptor agonists ( LABA ) and corticosteroids ( ICS ) are indicated at Step 3 of current asthma guidelines . We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function , bronchoprotection , acute salbutamol recovery following methacholine bronchial challenge , and surrogate inflammatory markers in patients with moderate persistent asthma . METHODS Twenty-nine patients with mean FEV1 ( + /- SEM ) of 78 + /- 3 % predicted completed a r and omized , double-blind , double-dummy , cross-over study . Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg ( BUD + FM ) combination twice daily followed by 1 week of BUD 400 microg alone twice daily , or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg ( FP + SM ) combination twice daily followed by 1 week of FP 250 microg alone twice daily . Measurements were made at baseline and following each r and omized treatment . RESULTS FEV1 increase from pretreatment baseline as mean ( + /- SEM ) % predicted was significantly higher ( P < 0.05 ) for BUD + FM ( 8 + /- 1 % ) vs BUD ( 2 + /- 1 % ) , and for FP + SM ( 8 + /- 1 % ) vs FP ( 2 + /- 1 % ) . The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups ; BUD + FM ( 22 + /- 1 % ) , BUD ( 24 + /- 1 % ) , FP + SM ( 23 + /- 1 % ) and FP ( 23 + /- 1 % ) . Salbutamol recovery over 30 min following methacholine challenge as area under curve ( AUC % .min ) was significantly blunted ( P 
    Output:
    