human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND 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 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 < 0.05 ) with BUD + FM ( 486.7 + /- 35.5 ) vs BUD ( 281.1 + /- 52.8 ) , and with FP + SM ( 553.1 + /- 34.1 ) vs FP ( 368.3 + /- 46.7 ) . There were no significant differences between respective combination inhalers or between respective ICS alone . Decreases in exhaled nitric oxide ( NO ) and serum eosinophilic cationic protein ( ECP ) from baseline were not significantly different between treatments . CONCLUSIONS Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone , but delay acute salbutamol recovery after bronchoconstriction To demonstrate the presence of functional cardiac β2-adrenoceptors in man , we studied the responses to intracoronary injections of salbutamol in three groups of six patients . We injected salbutamol , a selective β2-adrenoceptor agonist , into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly . Salbutamol injections caused a sinus tachycardia . The same doses of salbutamol injected into the aortic root caused no change in heart rate , ruling out a systemic effect . The mean dose required to cause an increase in heart rate of 30 beats/min ( IHR30 ) was 2.6 μg in the first group of six patients . In 12 other patients salbutamol was given after β-blockade to confirm the β2-selectivity of the responses . Doses of practolol ( β1,-selective blockade ) and of propranolol ( β1- and β2-blockade ) that had equal β1-blocking activity were used . In six patients who were given practolol  , the mean IHR30 dose was 2.1 μg . In six patients who were given propranolol , the mean IHR30 dose was significantly greater at 64 μg ( p < 0.001 , practolol vs. propranolol ) . This study demonstrates that direct cardiac β2-adrenoceptor stimulation in man has a positive chronotropic effect The relationship between asthma medication and the perception of asthma symptoms is of interest for daily practice . Poor perception of asthma symptoms might influence patients ' health care behavior and subsequently might lead to undertreatment and deterioration of their disease . This study investigated the influence of the chronic use of short-acting and long-acting beta(2)-agonists , compared with the additional use of inhaled corticosteroids on the perception of histamine-induced bronchoconstriction . Patients with asthma ( 33 male and 31 female , mean age 35 + /- 11 yr , FEV(1 ) 87 + /- 14 % of the reference value , PC(20 ) geometric mean 1.08 mg/ml ( 95 % CI : 0.76 - 1.52 ) were selected and r and omly allocated to the use of either a short-acting beta(2)-agonists ( salbutamol , n = 22 ) or a long-acting beta(2)-agonists ( formoterol , n = 22 ) or placebo ( n = 20 ) , which has been used for 12 wk . This medication treatment was repeated exactly 1 yr later , with patients receiving the same medication plus an inhaled corticosteroid .  Perception of histamine-induced bronchoconstriction was measured at the start of each treatment period and every 4 wk thereafter . Subjects quantified their sensation of respiratory discomfort during the challenge tests on a modified Borg scale . The perceptive " sensitivity " for changes in FEV(1 ) was analyzed by the linear regression slope ( alpha ) " Borg versus percentage fall in FEV(1 ) . " The " absolute perceptual magnitude " was determined by the perception score at the 20 % fall in FEV(1 ) ( PS(20 ) ) . The additional use of inhaled corticosteroids during the second year result ed in an improved perception of histamine-induced bronchoconstriction ( slope alpha ) compared with the first year for only the long-acting beta(2)-agonists group ( p value 0.036 ) . This improvement was not observed for the " absolute perceptual magnitude " ( PS(20 ) ) . The additional use of inhaled corticosteroids during chronic use of long-acting beta(2)-agonists improves the perceptive " sensitivity " for changes in FEV(1 ) during histamine-induced bronchoconstriction , which was not observed for short-acting bronchodilators . This result might indicate that the positive effects on perception of airway obstruction might be another reason ( besides the beneficial effects on the clinical condition ) for prescribing a combination of long-acting beta(2)-agonists and inhaled steroids BACKGROUND --Knowing the extent of the systemic effects of a new beta 2 agonist relative to an established drug is important for the prediction and interpretation of side effects . A recent study in which the effect of cumulative doses of salbutamol was compared with single doses of salmetreol suggested that , weight for weight , salmeterol may be up to 10 times more potent than salbutamol . This current study was design ed to investigate further the dose equivalence of salmeterol and salbutamol . METHODS --Twelve patients with mild asthma inhaled cumulative doses of placebo , salmeterol 25 , 50 , 100 , and 200 micrograms , and salbutamol 100 , 500 , 1000 , and 1000 micrograms on separate days at hourly intervals in a r and omised double blind crossover study . Changes in forced expiratory volume in one second ( FEV1 ) , heart rate , plasma potassium concentration , systolic and diastolic blood pressure were measured . Dose equivalence was determined as the dose ratio of salmeterol to salbutamol for the 50 % maximum response to salbutamol . RESULTS --No important changes occurred in any measurements following placebo . Salmeterol and salbutamol caused a near maximum increase in FEV1 following the first dose so the dose equivalence for the airway effects could not be estimated . Heart rate increased and plasma potassium concentration and diastolic blood pressure decreased in a dose dependent manner following salmeterol and salbutamol , with median dose equivalences for salmeterol compared with salbutamol of 17.7 , 7.8 , and 7.6 , respectively . CONCLUSIONS --These results confirm that the systemic activity of salmeterol compared with salbutamol is higher than would be expected from in vitro data , particularly for heart rate . Whether this is because of the relatively high dose of salmeterol used or pharmacokinetic differences between the two drugs is uncertain The airway response and cardiovascular and hypokalaemic effects of fenoterol , salbutamol , and terbutaline given in multiples of st and ard doses from metered-dose inhalers were studied in ten patients with mild asthma . In a double-blind , crossover , placebo-controlled study the subjects received 2 , 6 , and 18 puffs of each drug with intervals of 90 min , and forced expiratory volume in 1 s , heart rate , QTc interval , plasma potassium concentration , tremor , and bronchial reactivity to histamine were measured . All three drugs produced similar bronchodilatation . However , the rises in heart rate , QTc interval , and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline . The maximum mean ( SD ) increases in heart rate for fenoterol , salbutamol , and terbutaline were 29 ( 24 ) bpm , 8 ( 9 ) bpm , and 8 ( 14 ) bpm , respectively ; falls in plasma potassium were 0.76 ( 0.62 ) mmol/l , 0.46 ( 0.32 ) mmol/l , and 0.52 ( 0.39 ) mmol/l , respectively . Fenoterol afforded no additional protection against histamine compared with salbutamol . These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline . The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists ; fenoterol may in addition be less selective for beta 2 receptors Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction . This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist , formoterol . The modifying effect of intravenous corticosteroid was also studied . Ten asthmatic subjects ( using inhaled steroids ) participated in a r and omised , double-blind , placebo-controlled , cross-over study . Formoterol  
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND 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 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 < 0.05 ) with BUD + FM ( 486.7 + /- 35.5 ) vs BUD ( 281.1 + /- 52.8 ) , and with FP + SM ( 553.1 + /- 34.1 ) vs FP ( 368.3 + /- 46.7 ) . There were no significant differences between respective combination inhalers or between respective ICS alone . Decreases in exhaled nitric oxide ( NO ) and serum eosinophilic cationic protein ( ECP ) from baseline were not significantly different between treatments . CONCLUSIONS Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone , but delay acute salbutamol recovery after bronchoconstriction To demonstrate the presence of functional cardiac β2-adrenoceptors in man , we studied the responses to intracoronary injections of salbutamol in three groups of six patients . We injected salbutamol , a selective β2-adrenoceptor agonist , into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly . Salbutamol injections caused a sinus tachycardia . The same doses of salbutamol injected into the aortic root caused no change in heart rate , ruling out a systemic effect . The mean dose required to cause an increase in heart rate of 30 beats/min ( IHR30 ) was 2.6 μg in the first group of six patients . In 12 other patients salbutamol was given after β-blockade to confirm the β2-selectivity of the responses . Doses of practolol ( β1,-selective blockade ) and of propranolol ( β1- and β2-blockade ) that had equal β1-blocking activity were used . In six patients who were given practolol  , the mean IHR30 dose was 2.1 μg . In six patients who were given propranolol , the mean IHR30 dose was significantly greater at 64 μg ( p < 0.001 , practolol vs. propranolol ) . This study demonstrates that direct cardiac β2-adrenoceptor stimulation in man has a positive chronotropic effect The relationship between asthma medication and the perception of asthma symptoms is of interest for daily practice . Poor perception of asthma symptoms might influence patients ' health care behavior and subsequently might lead to undertreatment and deterioration of their disease . This study investigated the influence of the chronic use of short-acting and long-acting beta(2)-agonists , compared with the additional use of inhaled corticosteroids on the perception of histamine-induced bronchoconstriction . Patients with asthma ( 33 male and 31 female , mean age 35 + /- 11 yr , FEV(1 ) 87 + /- 14 % of the reference value , PC(20 ) geometric mean 1.08 mg/ml ( 95 % CI : 0.76 - 1.52 ) were selected and r and omly allocated to the use of either a short-acting beta(2)-agonists ( salbutamol , n = 22 ) or a long-acting beta(2)-agonists ( formoterol , n = 22 ) or placebo ( n = 20 ) , which has been used for 12 wk . This medication treatment was repeated exactly 1 yr later , with patients receiving the same medication plus an inhaled corticosteroid .  Perception of histamine-induced bronchoconstriction was measured at the start of each treatment period and every 4 wk thereafter . Subjects quantified their sensation of respiratory discomfort during the challenge tests on a modified Borg scale . The perceptive " sensitivity " for changes in FEV(1 ) was analyzed by the linear regression slope ( alpha ) " Borg versus percentage fall in FEV(1 ) . " The " absolute perceptual magnitude " was determined by the perception score at the 20 % fall in FEV(1 ) ( PS(20 ) ) . The additional use of inhaled corticosteroids during the second year result ed in an improved perception of histamine-induced bronchoconstriction ( slope alpha ) compared with the first year for only the long-acting beta(2)-agonists group ( p value 0.036 ) . This improvement was not observed for the " absolute perceptual magnitude " ( PS(20 ) ) . The additional use of inhaled corticosteroids during chronic use of long-acting beta(2)-agonists improves the perceptive " sensitivity " for changes in FEV(1 ) during histamine-induced bronchoconstriction , which was not observed for short-acting bronchodilators . This result might indicate that the positive effects on perception of airway obstruction might be another reason ( besides the beneficial effects on the clinical condition ) for prescribing a combination of long-acting beta(2)-agonists and inhaled steroids BACKGROUND --Knowing the extent of the systemic effects of a new beta 2 agonist relative to an established drug is important for the prediction and interpretation of side effects . A recent study in which the effect of cumulative doses of salbutamol was compared with single doses of salmetreol suggested that , weight for weight , salmeterol may be up to 10 times more potent than salbutamol . This current study was design ed to investigate further the dose equivalence of salmeterol and salbutamol . METHODS --Twelve patients with mild asthma inhaled cumulative doses of placebo , salmeterol 25 , 50 , 100 , and 200 micrograms , and salbutamol 100 , 500 , 1000 , and 1000 micrograms on separate days at hourly intervals in a r and omised double blind crossover study . Changes in forced expiratory volume in one second ( FEV1 ) , heart rate , plasma potassium concentration , systolic and diastolic blood pressure were measured . Dose equivalence was determined as the dose ratio of salmeterol to salbutamol for the 50 % maximum response to salbutamol . RESULTS --No important changes occurred in any measurements following placebo . Salmeterol and salbutamol caused a near maximum increase in FEV1 following the first dose so the dose equivalence for the airway effects could not be estimated . Heart rate increased and plasma potassium concentration and diastolic blood pressure decreased in a dose dependent manner following salmeterol and salbutamol , with median dose equivalences for salmeterol compared with salbutamol of 17.7 , 7.8 , and 7.6 , respectively . CONCLUSIONS --These results confirm that the systemic activity of salmeterol compared with salbutamol is higher than would be expected from in vitro data , particularly for heart rate . Whether this is because of the relatively high dose of salmeterol used or pharmacokinetic differences between the two drugs is uncertain The airway response and cardiovascular and hypokalaemic effects of fenoterol , salbutamol , and terbutaline given in multiples of st and ard doses from metered-dose inhalers were studied in ten patients with mild asthma . In a double-blind , crossover , placebo-controlled study the subjects received 2 , 6 , and 18 puffs of each drug with intervals of 90 min , and forced expiratory volume in 1 s , heart rate , QTc interval , plasma potassium concentration , tremor , and bronchial reactivity to histamine were measured . All three drugs produced similar bronchodilatation . However , the rises in heart rate , QTc interval , and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline . The maximum mean ( SD ) increases in heart rate for fenoterol , salbutamol , and terbutaline were 29 ( 24 ) bpm , 8 ( 9 ) bpm , and 8 ( 14 ) bpm , respectively ; falls in plasma potassium were 0.76 ( 0.62 ) mmol/l , 0.46 ( 0.32 ) mmol/l , and 0.52 ( 0.39 ) mmol/l , respectively . Fenoterol afforded no additional protection against histamine compared with salbutamol . These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline . The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists ; fenoterol may in addition be less selective for beta 2 receptors Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction . This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist , formoterol . The modifying effect of intravenous corticosteroid was also studied . Ten asthmatic subjects ( using inhaled steroids ) participated in a r and omised , double-blind , placebo-controlled , cross-over study . Formoterol  
    Output:
    