Efficacy and tolerability of formoterol Turbuhaler in children. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. Intracoronary Injections of Salbutamol Demonstrate the Presence of Functional ft-Adrenoceptors in the Human Heart Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma. Systemic effects of salbutamol and salmeterol in patients with asthma. Cost-Effectiveness Analysis of Formoterol Versus Salmeterol in Patients with Asthma A comparison of the speeds of action of salmeterol and salbutamol in reversing methacholine-induced bronchoconstriction. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma Tolerance to beta-agonists during acute bronchoconstriction. Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol. Dose-related efficacy and safety of formoterol (Oxis) Turbuhaler compared with salmeterol Diskhaler in children with asthma. The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists. Eformoterol Turbohaler compared with salmeterol by dry powder inhaler in asthmatic children not controlled on inhaled corticosteroids. Cost-effectiveness of eformoterol Turbohaler versus salmeterol Accuhaler in children with symptomatic asthma. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. [Changes in specific airway resistance after powder inhalation of formoterol or salmeterol in moderate bronchial asthma]. Comparison of the short-term effects of salmeterol and formoterol on heart rate variability in adult asthmatic patients. Regular inhaled salbutamol and airway responsiveness to allergen Relief of dyspnoea by beta2-agonists after methacholine-induced bronchoconstriction. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Hypokalemia from beta2-receptor stimulation by circulating epinephrine. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. A 6-month comparison between formoterol and salmeterol in patients with reversible obstructive airways disease. Effects of long-acting bronchodilators and placebo on histamine-induced asthma symptoms and mild bronchusobstruction. Potential masking effects of salmeterol on airway inflammation in asthma. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. Regular inhaled beta-agonist treatment in bronchial asthma
A r and omised , double-blind trial was undertaken to investigate the efficacy and tolerability of formoterol Turbuhaler in children with mild to moderate asthma . After a two-week run-in , 248 children aged 6 - 17 years were r and omised to receive formoterol 4.5 and 9 pmicro b.i.d . or placebo for 12 weeks . Morning PEF ( primary variable ) , was significantly improved versus placebo only in the formoterol 9 pmicro b.i.d . group ( 13 l/min , 95 % CCI 1.9 , 24.2 % ; p = 0 .02 ) . Both formoterol 4.5 and 9 pmicro significantly increased the pre-bronchodilator FEV1 by 5.2 - 6.7 % ( p < 0 .05 ) and reduced use of daytime relief medication versus placebo ( p < 0 .05 ) . Formoterol 9 pmicro significantly reduced night-time reliever use and awakenings due to asthma versus placebo ( p < 0.05 ) . Both doses of formoterol were as well tolerated as placebo . In conclusion , formoterol 4.5 and 9 micro b.i.d . is effective and well tolerated as maintenance therapy in children with mild to moderate asthma 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 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 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 Abstract Objective : The aim of this study was to determine the relative economic consequences of treating asthmatics with twice daily dry powder formoterol 12 mg as compared with salmeterol 50 mg from a societal perspective . Design and Setting : A r and omised , 6-month , open-label study including 482 patients with asthma was conducted in Italy , Spain , France , Switzerl and , the UK and Sweden .  Medical costs included the costs of medications , physician services , emergency room visits , hospital admissions and lung function and other tests . Travel costs and costs of production loss were also calculated . Unit prices were estimated from external sources . To pool the costs of the 6 countries , European currencies were converted to US dollars using 1995 exchange rates . Outcome measures were the number of episode-free days ( EFDs ) and the number of patients reaching a clinical ly relevant improvement in quality of life as measured using the St. Georges Respiratory Question naire . Main outcome measures and results : There were no significant differences between the 2 treatment arms in the frequency of emergency room visits , hospital admissions , use of rescue medication or contacts with general practitioners ( GPs ) , specialists or nurses . Median medical costs over 6 months were $ US828 per patient with formoterol and $ US850 with salmeterol . This difference was not statistically significant . In both groups , about 60 % of all days were episode-free . Average costs per EFD were about $ US9 for both treatments . The average cost per patient reaching a clinical ly relevant improvement in quality of life was between $ US1300 and $ US1400 . Incremental cost-effectiveness ratios were not calculated because both costs and outcomes were not significantly different . Asthma-related absenteeism ranged between 3 days and 6 months per patient in both groups . Conclusions : There was no evidence to suggest that either treatment was more cost effective than the other We compared the speed of action of the long acting beta-agonist salmeterol with that of salbutamol in order to assess whether reported in vitro differences are likely to have clinical significance . We used methacholine tests to produce a st and ardized level of bronchoconstriction and then observed the rate of recovery of FEV1 towards baseline after the administration by metered dose inhaler of salmeterol 50 micrograms or salbutamol 200 micrograms -- doses which are considered to have similar bronchodilator potency . Twenty asthmatic subjects participated , and a double-blind , r and omized , cross-over study design was followed . Salmeterol showed a significantly slower speed of action with median recovery to 90 % and 95 % of the baseline FEV1 ( pre-methacholine ) occurring after 9.6 and 19.4 min , respectively , compared with 4.8 and 8.3 min , respectively , for salbutamol ( P less than 0.01 ) . These observations are consistent with in vitro findings and suggest that salmeterol is likely to be less satisfactory than salbutamol as a ' rescue medication ' for the treatment of acute episodes of bronchoconstriction 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 Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects . However , most studies have been conducted in stable asthma . This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction . Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline ( 1 mg q.i.d . ) , budesonide ( 400 microg , b.i.d . ) , both drugs or placebo in a r and omized , double-blind , cross-over study . After each treatment methacholine was administered to induce a 20 % fall in the forced expiratory volume in one second ( FEV1 ) . The response to inhaled salbutamol 100 , 100 , 200 microg at 5 min intervals ) was then measured . Dose-response curves were compared using an analysis of covariance . Pre-methacholine FEV1 , the highest pre-methacholine FEV1 , the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20 % fall in FEV1 ( PD20 ) were used as covariates . There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment : the mean ( 95 % confidence intervals ( CI ) ) area under the dose-response curve was reduced by 36 % ( 24 , 47 ) compared to placebo ( p<0.0001 ) . The reduction in bronchodilator response was not affected by concomitant treatment with budesonide . Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction . Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations 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 12 microg b.i.d . or matching placebo was given for 10 - 14 days with > 2 weeks washout . Following each treatment , patients underwent a methacholine challenge to induce a fall in forced expired volume in one second ( FEV1 ) of at least 20 % , then salbutamol 100 microg , 100 microg , and 200 microg was inhaled via a spacer at 5 min intervals , with a further 400 microg at 45 min . After a third single-blind formoterol treatment period , hydrocortisone 200 mg was given intravenously prior to salbutamol . Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry . Regular formoterol result ed in a significantly lower FEV1 after salbutamol at each time point compared to placebo ( p<0.01 ) . The area under the curves ( AUCs ) for 15 ( AUC0 - 15 ) and 45 ( AUC0 - 45 ) min were 28.8 % and 29.5 % lower following formoterol treatment ( p<0.001 ) . Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration . It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol . This bronchodilator tolerance is evident in circumstances of acute bronchconstriction To compare the dose-related bronchodilator efficacy and tolerability of formoterol ( Oxis ) Turbuhaler with salmeterol Diskhaler and placebo in children with asthma . A single-dose , r and omized , double-blind , incomplete crossover study of 68 children ( 7 - 17 years ) , with moderate-to-severe asthma , 82 % receiving inhaled corticosteroids .  Patients received four of six treatments [ 4.5 , 9 , 18 , or 36 microg formoterol ( 6 , 12 , 24 or 48 microg metered doses ) , 50 microg salmeterol ( metered dose ) or placebo ] at 12-h visits , separated by > or =3 days . Forced expiratory volume in 1 s ( FEV1 ) , pulse , blood pressure , electrocardiogram , adverse events and urine formoterol  were assessed . The therapeutic ratio of formoterol vs. salmeterol was estimated from the efficacy and systemic effects results . All active treatments significantly improved FEV1 compared with placebo . Formoterol 9 - 36 microg provided dose-related increases over salmeterol in lung function : average 12-h FEV1 ( increases of 4.9 - 8.7 % , p < 0.001 ) and FEV1 at 12 h post-dose ( 7.0 - 12.2 % , p < 0.001 ) . The onset of effect of formoterol was also significantly faster than salmeterol for doses > or = 9 microg . Salmeterol 50 microg was estimated to be equieffective to 3.3 microg formoterol for 12-h average FEV1 and the estimated equieffective dose for a variety of systemic effects was 7.8 - 13.5 microg formoterol . All treatments were well tolerated .  Formoterol ( Oxis ) Turbuhaler 4.5 - 36 microg provided dose-related improvements in bronchodilator efficacy in children with asthma . Formoterol > or = 9 microg provided superior bronchodilator efficacy over 12 h compared with salmeterol Diskhaler 50 microg with no increase in systemic effects BACKGROUND Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma . However , approximately one-third of patients show little or no initial response to this partial beta(2)-agonist . METHODS We conducted a r and omized , double-blind , proof-of-concept study to investigate whether a full beta(2)-agonist , isoproterenol , offers a therapeutic advantage in adults presenting with acute severe asthma ( FEV(1)<50 % ) who fail to respond to an initial treatment of the partial beta(2)-agonist , albuterol . Study subjects were r and omized to receive a 2-h continuous nebulization of either albuterol ( 7.5mg/h ) ( n=10 , mean FEV(1)=37 % predicted ) or isoproterenol ( 7.5mg/h ) ( n=9 , mean FEV(1)=33 % predicted ) . Respiratory symptoms , vital signs and pulmonary function measures were collected . RESULTS Subjects from both treatment groups had similar baseline characteristics . The percent improvements from baseline FEV(1 ) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol ( 44 vs. 17 % and 63 vs. 24 % , respectively , P<0.05 ) . The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol ( P<0.01 ) . Both treatments were well tolerated , though the mean increase in pulse rate at 60 and 120min ( 21 vs. 1 and 23 vs. 6beats/min , respectively , P<0.05 ) and the mean change in serum potassium at 120min ( -0.52 vs. -0.07meq/L , P<0.05 ) from baseline were significantly greater in the isoproterenol group . CONCLUSIONS Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol , the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms We evaluated the profile of the bronchodilatory effect of three inhaled beta2-agonists , 24 microg formoterol , 50 microg salmeterol and 200 microg salbutamol , in patients with stable , moderately severe asthma . Thirty asthmatics ( mean+/-SD age 54+/-8 yrs ; forced expiratory volume in one second ( FEV1 ) 58+/-12 % predicted ; reversibility of FEV1 21+/-8 % from baseline ) participated in a single-centre , double-blind , r and omized , single-dose , cross-over study . FEV1 was obtained in baseline condition and 10 , 20 , 30 , 60 min , and every hour up to 12 h after inhalation of the trial drug . Specific airway conductance ( sGaw ) was measured at baseline condition and 1 , 3 , 5 , 7 , 10 , 20 , 30 , 60 min , and every hour up to 12 h after inhalation . Formoterol produced a mean increase in sGaw ( as % of baseline ) of 44 % after 1 min , maximal ( 135 % ) after 2 h , and 56 % after 12 h. The mean increase in FEV1 was maximal ( 27 % ) after 2h , and 10 % after 12 h. After salmeterol , mean increase in sGaw amounted to 16 % after 3 min , maximal ( 111 % ) after 2 - 4 h , and 58 % after 12 h. The mean increase in FEV1 was maximally 25 % after 3h , being 11 % after 12 h. After salbutamol , mean increase in sGaw was 44 % after 1 min and maximal ( 100 % ) after 30 min . The peak increase in FEV1 was 25 % . We conclude that formoterol ( 24 microg ) and salmeterol ( 50 microg ) had an equal bronchodilatory capacity , which was similar to that of 200 microg salbutamol and lasted for at least 12 h in patients with asthma . However , formoterol had a more rapid onset of action than salmeterol , equal to that of salbutamol BACKGROUND Beta2-adrenergic agonists are frequently used for the prevention and relief of bronchospasm in patients with reversible obstructive airway disease .  Formoterol and salmeterol are long-acting beta2-agonists . In addition to its long duration of action , formoterol has been reported to have an onset of action similar to that of albuterol . OBJECTIVE This study compared the effects on lung function of regular twice-daily inhalation of formoterol or salmeterol in adults with moderate to moderately severe persistent asthma who were receiving daily inhaled corticosteroids . METHODS In this 6-month , multicenter , open-label , parallel-group study , patients with moderate or moderately severe asthma were r and omized to receive either formoterol 12 microg BID or salmeterol 50 microg BID . The primary end point was mean morning peak expiratory flow ( PEF ) measured 5 minutes after dosing and entered in a patient diary each day during the first 4 weeks of treatment . Secondary end points included mean morning and evening predose PEF and number of episode-free days recorded in the patient diaries during the first 4 weeks of treatment , use and time of rescue medication , symptom scores , and overall mean morning predose PEF ( spirometric measurements made by the physician during scheduled visits ) for the entire treatment period . Safety assessment s included spontaneously reported adverse events and vital signs . RESULTS A total of 528 patients were r and omized to study treatment , 262 to formoterol and 266 to salmeterol .  There were no significant differences in demographic or baseline characteristics between treatment groups , except in the proportion of current smokers in the formoterol group ( 4.6 % ) compared with the salmeterol group ( 1.5 % ; P = 0.039 ) . Based on the information recorded in patients ' diaries , those receiving formoterol showed significant improvement in mean morning PEF measured 5 minutes after dosing ( P < 0.001 ) , reduced use of rescue medication ( P < 0.03 ) , and an increased number of episode-free days ( P < 0.04 ) compared with patients receiving salmeterol .  Mean predose morning and evening PEF and symptom scores based on diary data and mean morning predose PEF based on measurements obtained during office visits were comparable between the 2 treatment groups throughout the study . CONCLUSIONS In this open-label trial , patients r and omized to formoterol treatment had greater improvement in mean PEF 5 minutes after dosing , required significantly less rescue medication ( fewer actuations of albuterol ) , and experienced more episode-free days compared with patients receiving salmeterol . Thus , although both formoterol and salmeterol are long-acting beta2-agonists , formoterol had a more rapid onset of action In vitro data suggest that salmeterol , contrary to formoterol , can partly antagonise the effect of short-acting beta(2)-agonist rescue medication . To explore whether this occurs in vivo , we compared the effects of increasing doses ( 200 - 3200 microg ) of fenoterol on the recovery of methacholine induced bronchoconstriction as well as PD(20 ) methacholine in 23 asthmatic patients , during two-week treatment periods with placebo , and st and ard doses of salmeterol or formoterol in a double blind , double-dummy , crossover study . Salmeterol showed a slightly higher propensity for the development of bronchodilator tolerance . The recovery of methacholine induced bronchoconstriction was more complete during regular use of formoterol relative to salmeterol . During regular use of both long-acting beta(2)-agonists the bronchoprotective efficacy of fenoterol was attenuated , but this was more pronounced during salmeterol than during formoterol . The mean maximum increase in PD(20 ) metacholine after the highest dose of fenoterol was 3.97 DD during placebo , 2.47 DD during formoterol ( p<0.001 ) and 1.81 DD during salmeterol treatment ( p<0.001 ) . We conclude that in asthmatic patients the efficacy of short-acting beta(2)-adrenoceptor agonists can be significantly attenuated during regular use of long-acting beta(2)-agonists . In this respect , differences were observed between salmeterol and formoterol that may represent the expression of partial antagonism by salmeterol The aim of the study was to compare the efficacy of the inhaled long-acting beta2-agonists eformoterol and salmeterol when added to existing inhaled corticosteroid ( ICS ) therapy in symptomatic asthmatic children . This r and omized , 12-week , parallel-group study , performed in a primary care setting , included 156 children and adolescents ( aged 6 - 17 years ) with moderate persistent asthma . Patients were r and omized to open-label eformoterol ( Oxis ) Turbohaler 9 microg ( delivered dose ) or salmeterol Accuhaler 50 microg , both b.i.d , added to current ICS . Assessment s included : changes in daytime reliever beta2-agonist therapy ( primary variable ) , total 24-h reliever use , lung function , clinic and diary symptom scores , patient and carer health-related quality of life ( HRQL ) and adverse events . Daytime reliever use decreased significantly ( p < 0.001 ) from baseline by 65 % and 52 % , respectively in the eformoterol and salmeterol treatment groups . Compared with salmeterol , eformoterol produced a greater decrease in daytime ( -0.46 inhalations/day ; p = 0.081 ) and 24-h ( -0.70 inhalations/day ; p = 0.043 ) reliever use . The percentage of patients who did not require any reliever medication during the study was significantly higher in the eformoterol group ( p < 0.05 vs. salmeterol at weeks 8 and 12 ) . Clinic and diary card peak expiratory flow and symptom measures all improved from baseline in both treatment arms . There was a significantly greater effect in favour of eformoterol for the reduction in clinic-assessed overall night-time symptoms ( p < 0.05 vs. salmeterol ) . Clinical ly relevant improvements in patient-assessed HRQL occurred during treatment with eformoterol and salmeterol , but carer-assessed HRQL was improved to a clinical ly relevant extent , only with eformoterol . Both treatments were well tolerated . In children and adolescents with moderate persistent asthma , add-on therapy with eformoterol was well tolerated and at least as effective as salmeterol We conducted an economic evaluation in a UK setting based on a 12-week prospect i ve r and omized open-label parallel-group comparison of eformoterol Turbohaler 12 microg b. i.d . with salmeterol Accuhaler 50 microg b. i.d . in children aged 6 - 17 with symptomatic asthma receiving inhaled corticosteroids and short-acting beta2-agonists .  The principal effectiveness measure was percentage of symptom-free days with no short-acting beta2-agonist use during the study period . Asthma-related medication , unscheduled physician contacts and hospitalizations were collected prospect ively and cost to the UK NHS calculated using year 2,000 prices . The economic evaluation included 73 patients in the eformoterol group and 72 patients in the salmeterol group . The mean age of patients was 11.6 years ( eformoterol ) and 11.8 years ( salmeterol ) . The mean percentage of symptom-free days with no short-acting beta2-agonist use was 39 % in the eformoterol group and 30 % in the salmeterol group . Mean per patient daily cost was 1.15 pounds in the eformoterol group and 1.39 pounds in the salmeterol group . Both cost and effectiveness differences favoured eformoterol ( P < 0.05 ; one-sided ) . Sensitivity analysis confirmed the results to be robust to changes in effectiveness , price and re source utilisation parameters . Eformoterol delivered by Turbohaler was found to be significantly more effective and less expensive than salmeterol Accuhaler in this study There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli . Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists . In a double-blind placebo-controlled crossover study in 12 patients with mild asthma , we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol ( 200 micrograms ) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol .  Patients were r and omized to be treated for 3 wk with inhaled budesonide ( 800 micrograms twice a day ) or placebo ; salmeterol ( 50 micrograms twice a day ) was added during the third week . Airway responsiveness to methacholine was measured 15 min after albuterol , both before and exactly 12 h [ corrected ] after the last salmeterol dose . Mean FEV1 increased significantly after 2 wk of budesonide ( p < 0.05 ) and increased further after salmeterol ( p < 0.05 ) compared with placebo . After 2 wk , the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo ( 3.4 versus 2.4 doubling dilutions ; p < 0.05 ) , consistent with an improvement in airway hyperresponsiveness with budesonide therapy . However , regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge , both with budesonide and with placebo ( -1.1 + /- 0.42 and -1.41 + /- 0.30 doubling dilutions , respectively ) . There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods . Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy Formoterol and salmeterol are two long acting beta 2 agonists available for the treatment of asthma which show differences in onset of action . In a multicentre parallel group study , patients with moderate asthma were investigated by measuring the specific airway resistance ( sRaw ) , a more sensitive parameter than FEV1 . A total of 99 patients were r and omised for open treatment with either 12 micrograms formoterol delivered via Turbohaler or 50 micrograms salmeterol via Diskus . The patients were between 18 and 66 years of age , had a medium FEV1 of 68.8 % ( + /- 17.8 % ) predicted and showed a medium reversibility of 28.8 % ( + /- 16.5 % ) . The patients response to one inhalation of the study drug was investigated by sRaw measurements 2 , 5 , 10 , 20 and 60 minutes after inhalation of the formulation . Additionally , FEV1 was measured . The results show a significant decrease in specific airway resistance of 29 % within the first two minutes in patients who had received 12 micrograms formoterol via Turbohaler . However , patients on salmeterol showed no change ( sRaw + /- 1 % ) . This difference is statistically highly significant ( p < 0.0001 ) . Furthermore , in 49 % of the patients treated with salmeterol an increase in sRaw was seen immediately after inhalation of the drug . This increase was + 16.4 % in an average of 2 minutes after inhalation . One hour after inhalation the differences between the groups were small and not significant neither between formoterol and salmeterol-treated patients nor within the salmeterol group . In the following week patients were treated with 12 micrograms formoterol Turbohaler b.i.d . or 50 micrograms salmeterol Diskus b.i.d . , respectively . A further sRaw measurement was performed 11 + /- 1 hours after the last inhalation of the drug . The results for sRaw and FEV1 show no differences between both study drugs indicating a similar duration of action for both formoterol Turbohaler and Salmeterol Diskus in moderate asthma . No serious adverse events were reported . The adverse event profile observed in both study groups was comparable . Thus , this study shows once again that formoterol delivered via Turbohaler has a more rapid onset of bronchodilating action compared with salmeterol Diskus . Furthermore the inhalation of salmeterol via Diskus in one-half of the patients led to an increase in specific airway resistance within the first minutes after inhalation . It is worth discussing whether an unspecific reaction to the relatively large lactose particles which are components of the salmeterol Diskus formulation are responsible for this observation STUDY OBJECTIVES We investigated the effects of beta2-adrenergic agonists salmeterol and formoterol on heart rate variability ( HRV ) in adult asthmatic patients using time-domain measures of HRV . PATIENTS Thirty-nine adult patients with asthma were studied . All patients showed a mild-to-moderate decrease in baseline FEV1 .  Any diseases that might have influenced the autonomic function were excluded . All patients underwent a complete physical examination and medical history that revealed no cardiovascular disease or medication . METHODS The beta2-adrenergic inhaled agonists salmeterol , 50 microg , and formoterol , 12 microg , were used in the study . HRV analysis was performed for each 5-min segment : 5 min and 10 min before inhalation of the study drug , and 5 , 10 , 15 , 20 , 25 , and 30 min after inhalation . Time-domain parameters of HRV were calculated : ( 1 ) the SD all normal-to-normal intervals ; ( 2 ) the SD of the mean of all normal-to-normal intervals in all 5-min segments of the entire recording ; ( 3 ) the root mean square of differences between adjacent normal-to-normal intervals ; ( 4 ) the mean of the SD of all normal-to-normal intervals in all the 5-min intervals ; and ( 5 ) the SD of the SD of all normal-to-normal intervals in all the 5-min intervals . RESULTS Baseline HRV parameters were not significantly different between formoterol and salmeterol groups . There were no significant differences in HRV parameters after formoterol and salmeterol inhalation . The HRV parameters in each 5-min segment in the formoterol group were not statistically significant different when compared to the same segment in the salmeterol group . CONCLUSION Salmeterol and formoterol have no short-term adverse effects on HRV Regular inhaled beta 2 agonist causes tolerance to the acute protective effect of beta 2 agonist against bronchoconstriction induced by chemical stimuli such as AMP , histamine , and methacholine . We examined a more clinical ly relevant stimulus , inhaled allergen , in a double-blind , cross-over , r and om-order trial in 13 mild atopic asthmatics , who had not used beta 2 agonist for at least 4 weeks . We compared regular inhaled salbutamol ( 200 micrograms four times daily for 2 weeks ) with placebo ( 2 weeks ) for effects on bronchodilator response , baseline methacholine , and allergen airway responsiveness , and on the acute protective effect of salbutamol against both stimuli . Baseline forced expiratory volume in 1 s ( FEV1 ) , bronchodilator response , and methacholine responsiveness were the same during both treatment periods . After regular salbutamol , the allergen PC20 ( provocation concentration producing a 20 % FEV1 decrease ) fell by 0.91 ( SD 0.66 ) ( p = 0.0009 ) doubling doses , and the protective effects of salbutamol  on methacholine and allergen were both significantly reduced ( p = 0.026 and 0.025 , respectively ) . Taking into account the reduced baseline allergen PC20 , the post-salbutamol allergen PC20 was almost 2 doubling doses ( 1.94 [ 1.43 ] , p < 0.01 ) lower during salbutamol treatment . Thus , 2 weeks of regular inhaled salbutamol increased airway responsiveness to allergen but not to methacholine , and caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both stimuli . These effects of inhaled beta 2 agonist provide further evidence to support detrimental effects of their regular use Virtually all asthma patients use brorichodilators . Formoterol and salbutamol have a rapid onset of bronchodilating effect , whereas salmeterol acts slower . We studied the onset of improvement of dyspnoea sensation after inhalation with these bronchodilators and placebo to reverse a methacholine-induced bronchoconstriction as a model for an acute asthma attack . Seventeen patients with asthma completed this r and omised , double-blind , crossover , double-dummy study . On 4 test days , forced expiratory volume in 1 s ( FEV1 ) and Borg score were recorded and patients were challenged with methacholine until FEV1 fell with > or = 30 % of baseline value . Thereafter , formoterol 12 microg via Turbuhaler , salbutamol 50 microg via Turbuhaler , salmeterol 50 microg via Diskhaler , or placebo was inhaled . FEV1 and Borg scores were assessed during the following 60 min . The first sensed improvement of Borg score was significantly ( P<0.05 ) faster achieved with formoterol ( geometric mean ( Gmean ) ( range ) 1.5 ( 1 - 40 ) min ) and salbutamol 1.8 ( 1 - 10 ) min than with salmeterol 4.5 ( 1 - 30 ) min and placebo 3.4 ( 1 - 40 ) min . The Borg score returned significantly faster to the baseline value with formoterol , salbutamol  , and salmeterol  ( Gmean time 13.8 ( 1 - 75 ) , 13.4 ( 1 - 60 ) , and 18.0 ( 1 - 75 ) min , respectively ) than with placebo ( 33.6 ( 1 - 75 min ) . Formoterol and salbutamol act significantly faster than salmeterol in relieving dyspnoea induced by methacholine-induced bronchoconstriction , in patients with asthma Studies performed on airway smooth muscle in vitro have indicated that salmeterol is a partial agonist on the beta2-receptor in comparison to formoterol . In the present study we evaluated whether these pharmacological differences between salmeterol and formoterol also are applicable to asthmatic patients . The protective effects by increasing cumulative doses of formoterol ( 12 , 60 , 120 micrograms ) and salmeterol ( 50 , 250 , 500 micrograms ) on methacholine-induced bronchoconstriction were evaluated in a double-blind , crossover , placebo-controlled design . Patients were regularly treated with salbutamol 200 micrograms twice daily during the study period , to avoid variability in beta2-adrenoceptor tolerance . S-potassium , heart rate corrected Q-T interval ( Q-Tc ) , and tremor score were followed as measures of systemic effects .  Formoterol dose-dependently protected against methacholine responsiveness ( 4.6 doubling doses after 120 micrograms ) . Salmeterol , however , showed a flatter dose-response curve , and a significantly weaker maximal protective effect ( 2.8 doubling doses after 250 micrograms ) . Formoterol caused a significantly higher tremor score and a larger drop in S-potassium than salmeterol at the highest doses . These data show that salmeterol is a partial agonist on the beta2-receptor in relation to formoterol in human airways in vivo . Further studies are required to document the clinical consequences of this finding , for example in severe asthmatic patients To determine whether epinephrine-induced hypokalemia is due to beta2-adrenoceptor stimulation , and whether hypokalemia can occur at physiologic concentrations of the agonist , epinephrine was infused into six normal volunteers at a rate of 0.1 microgram per kilogram of body weight per minute . The circulating  epinephrine concentration was increased to 1.74 + /- 0.65 ng per milliliter , plasma potassium was reduced by 0.82 + /- 0.19 meq per liter , plasma insulin fell by 12 + /- 4 mU per liter , plasma renin activity was elevated , and tachycardia occurred . Isoproterenol infused at 0.02 micrograms per kilogram per minute caused similar tachycardia ( 25 beats per minute ) and elevation in plasma renin activity ( 6.0 to 6.5 ng per milliliter per hour ) , but no hypokalemia . The difference in responses to the two catecholamines was ascribed to the relative beta2-selectivity of epinephrine . This hypothesis was tested in six subjects given infusions of epinephrine ( 0.05 micrograms per kilogram per minute ) after administration of either 2.5 or 5 mg of ICI 118551 - -a selective beta2-receptor antagonist -- or placebo . After placebo , epinephrine infusion elevated the circulating epinephrine concentration and reduced plasma potassium ; hypokalemia was prevented by the beta2-antagonist . This drug only partially inhibited the rises in plasma renin and glucose and the shortening of systolic time intervals ; there was no tachycardia . Fifteen-fold to 30-fold increases in circulating epinephrine concentration appear to cause hypokalemia by a specific beta2-receptor effect distinct from other actions of epinephrine . This phenomenon may be of physiologic importance after severe myocardial infa rct ion , when similar increases in plasma epinephrine have occurred Evidence of bronchodilator subsensitivity was sought in studies using the specific beta2 adrenergic agonist , albuterol . After a period of 1 or 2 weeks off all oral sympathomimetic agents , the mean response of the patients to the first dose of albuterol was consistently greater than the response after a period during which the drug had been administered regularly . Maximal decrease in response occurred after 2 weeks ' of treatment , and there was no further decrease after prolonged treatment with the same dose of albuterol for periods as long as 1 year High doses of inhaled salbutamol produce substantial improvements in airway response in patients with asthma , and are associated with dose-dependent systemic beta-adrenoceptor responses . The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol .  Twelve asthmatic patients ( FEV1 , 81 + /- 4 % predicted ) , requiring only occasional inhaled beta-agonists as their sole therapy , were given a 14-day treatment with high dose inhaled salbutamol ( HDS ) , 4,000 micrograms daily , low dose inhaled salbutamol ( LDS ) , 800 micrograms daily , or placebo ( PI ) by metered-dose inhaler in a double-blind , r and omized crossover design . During the 14-day run-in and during washout periods , inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purpose s. At the end of each 14-day treatment , a dose-response curve ( DRC ) was performed , and airway ( FEV1 , FEF25 - 75 ) chronotropic ( HR ) , tremor , and metabolic ( K , Glu ) responses were measured at each step ( from 100 to 4,000 micrograms ) . Treatment had no significant effect on baseline values . There were dose-dependent increases in FEV1 and FEF25 - 75 ( p less than 0.001 ) , and pretreatment with HDS did not displace the DRC to the right . DRC for HR ( p less than 0.001 ) , K ( p less than 0.001 ) , and Glu ( p less than 0.005 ) were attenuated after treatment with HDS compared with PI . There were also differences between HDS and LDS for HR ( p less than 0.001 ) and Glu ( p less than 0.05 ) responses . Frequency and severity of subjective adverse effects were also reduced after HDS : tremor ( p less than 0.001 ) , palpitations ( p less than 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVE To compare the safety of salmeterol xinafoate or placebo added to usual asthma care . DESIGN A 28-week , r and omized , double-blind , placebo-controlled , observational study . SETTING Study subjects were seen once in the study physician 's office for screening and were provided all blinded study medication for the entire study period . Follow-up by telephone was scheduled every 4 weeks . PARTICIPANTS Subjects ( > 12 years old ) with asthma as judged by the study physician were eligible . Individuals with a history of long-acting beta2-agonist use were excluded . INTERVENTIONS Salmeterol , 42 mug bid via metered-dose inhaler ( MDI ) , and placebo bid via MDI . MEASUREMENTS AND RESULTS Following an interim analysis in 26,355 subjects , the study was terminated due to findings in African Americans and difficulties in enrollment . The occurrence of the primary outcome , respiratory-related deaths , or life-threatening experiences was low and not significantly different for salmeterol vs placebo ( 50 vs 36 ; relative risk [ RR ] = 1.40 ; 95 % confidence interval [ CI ] , 0.91 to 2.14 ) . There was a small , significant increase in respiratory-related deaths ( 24 vs 11 ; RR , 2.16 ; 95 % CI , 1.06 to 4.41 ) and asthma-related deaths ( 13 vs 3 ; RR , 4.37 ; 95 % CI , 1.25 to 15.34 ) , and in combined asthma-related deaths or life-threatening experiences ( 37 vs 22 ; RR , 1.71 ; 95 % CI , 1.01 to 2.89 ) in subjects receiving salmeterol vs placebo . The imbalance occurred largely in the African-American sub population : respiratory-related deaths or life-threatening experiences ( 20 vs 5 ; RR , 4.10 ; 95 % CI , 1.54 to 10.90 ) and combined asthma-related deaths or life-threatening experiences ( 19 vs 4 ; RR , 4.92 ; 95 % CI , 1.68 to 14.45 ) in subjects receiving salmeterol vs placebo . CONCLUSIONS For the primary end point in the total population , there were no significant differences between treatments . There were small , but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol . Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects . Whether this risk is due to factors including but not limited to a physiologic treatment effect , genetic factors , or patient behaviors leading to poor outcomes remains unknown The aim of this r and omized , open , parallel group study was to compare the clinical efficacy of formoterol dry powder capsule 12 micrograms b.i.d . and salmeterol dry powder 50 micrograms b.i.d . in the treatment of patients with reversible obstructive airways disease . The 6-month treatment was preceded by a 2 week run-in period . Morning pre-dose peak expiratory flow ( PEF ) during the last 7 days of treatment was the primary variable . Throughout the study , patients recorded morning and evening pre-dose PEF , use of rescue medication , respiratory symptoms and adverse events . Clinic visits were scheduled at monthly intervals . Of the 482 patients r and omized ( equal numbers in the two treatment groups ) , 428 completed the study . Four hundred and twenty-five patients were included in the efficacy analysis for the primary variable . For mean morning pre-dose PEF during the last 7 days of treatment , the 95 % confidence interval ( CI ) for the treatment contrast formoterol minus salmeterol was included entirely in the pre-defined range of equivalence ( CI limits = -8.69 , + 9.841 min-1 ) . This was also the case for the morning PEF during the last week before each clinic visit . For mean evening pre-dose PEF , the estimated treatment contrasts showed a trend towards superiority of formoterol over salmeterol , which became statistically significant at 2 , 3 and 4 months ( P < 0.05 ; estimated contrasts 7.27 , 10.45 and 10.511 min-1 , respectively ) . No treatment group differences were found in use of rescue medication and respiratory symptom scores . The incidence of adverse events was similar in the two groups . These findings demonstrate that formoterol 12 micrograms b.i.d . and salmeterol 50 micrograms b.i.d . , both formulated as dry powders , have similar long-term efficacy and safety profiles in patients with reversible obstructive airways disease STUDY OBJECTIVE Accurate perception of airway caliber remains an important issue in asthma management . The way bronchodilation is perceived is partly related to the perception of the efficacy of bronchodilators in relieving complaints . In the present study , we compared the effects of salmeterol , formoterol and placebo on relief of histamine-induced asthma symptoms and mild bronchusobstruction . METHODS In this r and omized controlled , double blind study , 30 asthmatics were challenged with histamine until forced expiratory volume in 1s ( FEV(1 ) ) fell with > or = 20 % . Subjects received salmeterol , formoterol or placebo after the histamine provocation . Pulmonary function ( FEV(1 ) ) and asthma symptoms ( Asthma Symptom Checklist , Borg Dyspnea Scale ) were assessed 5 and 20 min later . RESULTS FEV(1 ) improved significantly more in the salmeterol and formoterol group than in the placebo group ( P<0.001 , P<0.001 and P<0.05 , respectively ) . Salmeterol and formoterol were not different with regard to the pulmonary function recovery . No significant differences were found between the effects of salmeterol , formoterol and placebo on any of the symptom responses at the different time points . CONCLUSIONS We conclude that after a histamine-induced mild bronchusobstruction , a similar asthma symptom recovery occurred when inhaling salmeterol , formoterol or placebo , despite better recovery of pulmonary function in the active drug conditions We hypothesized that regular use of long-acting beta-agonists could delay recognition of ( " mask " ) increasing airway inflammation . We studied steroid-sparing and " masking " effects of salmeterol versus placebo in 13 asthmatic individuals requiring > = 1,500 microgram inhaled corticosteroid daily .  Corticosteroid doses were reduced weekly until criteria were met for an exacerbation or the corticosteroid was fully withdrawn . Subjects were restabilized on their original dose of inhaled corticosteroid for 4 wk before crossover to the alternative treatment . Subjects maintained symptom and peak expiratory flow ( PEF ) diaries , and underwent weekly spirometric , methacholine challenge , sputum eosinophil , and serum eosinophil cationic protein ( ECP ) measurements . Mean corticosteroid dose was reduced by 87 % during salmeterol treatment , versus 69 % with placebo ( p = 0.04 ) . Sputum eosinophils increased before exacerbation despite stable symptoms , FEV1 , and PEF . In the week before clinical exacerbation , sputum eosinophil counts were higher in the salmeterol-treatment arm ( 19.9 + /- 29.8 % [ mean + /- SD ] , versus placebo 9.3 + /- 17.6 % ; p = 0.006 ) . Five subjects showed > 10 % sputum eosinophilia before exacerbation during salmeterol treatment , as compared with two receiving placebo . In this model , salmeterol controlled symptoms and lung function until inflammation became significantly more advanced . We conclude that the bronchodilating and symptom-relieving effects of salmeterol can mask increasing inflammation and delay awareness of worsening asthma BACKGROUND There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting beta(2)-agonists . OBJECTIVES The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol , and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid . MATERIAL S AND METHODS Twelve patients ( mean [ SD ] age , 43 [ 15 ] years ; FEV(1 ) , 57 [ 17 ] % predicted ) with stable , moderate to severe persistent asthma who were all taking inhaled corticosteroids  were evaluated in a r and omized , placebo-controlled , double-blind , double-dummy , crossover study . Patients received treatments each for 2 weeks followed by a bolus ( IV/inhaled ) of corticosteroid or placebo : ( 1 ) placebo inhaler bid + bolus placebo ; ( 2 ) formoterol Turbuhaler 24 microg metered dosage bid ( delivered dosage 18 microg bid ) + placebo ; ( 3 ) formoterol 24 microg bid + bolus IV hydrocortisone , 200 mg ; or ( 4 ) formoterol 24 microg bid + bolus inhaled budesonide , 1,600 microg .  Bronchodilator response to repeated puffs of albuterol ( 200 to 1,600 microg ) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid . The study was powered at the 80 % level to detect a 20 % difference in area under curve between 20 and 80 min ( AUC ) for FEV(1 ) response to albuterol as change from baseline ( primary end point ) . RESULTS There was significant subsensitivity ( p = 0.01 ) of the mean albuterol FEV(1 ) response ( as AUC , L x s ) after formoterol alone ( 737 ) as compared to placebo ( 1,453 ) along with partial reversal by steroid administration : formoterol + hydrocortisone ( 1 , 050 ) , and formoterol + budesonide ( 942 ) . There was a similar pattern of subsensitivity ( p = 0.03 ) for the mean albuterol forced expiratory flow between 25 % and 75 % of vital capacity response ( as AUC , L ) : placebo ( 2,149 ) , formoterol alone ( 1,002 ) , formoterol + hydrocortisone ( 1,402 ) , and formoterol + budesonide ( 1,271 ) . CONCLUSION Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol , which was partially reversed by a bolus dose of systemic or inhaled corticosteroid The peak response and the duration of bronchodilator effect were measured after four inhalations at 20 min intervals of 250 micrograms of aerosolized terbutaline in 13 patients with bronchial asthma . Patients were initially studied after strict avoidance of all adrenergic agents for 2 wk ; they were then studied at 2 wk intervals for 12 wk while receiving 500 micrograms of aerosolized terbutaline q.i.d . The initial testing ( TI ) and the testing at the end of 12 wk ( TII ) were double blind . Both peak response and duration of action decreased significantly between TI and TII . Cumulative dose-response curves showed that further improvement occurred after each inhalation during TI but that there was significant improvement only after the first inhalation during TII 89 subjects with stable asthma took part in a double-blind , placebo-controlled , r and omized , crossover study of the effects of regular versus on-dem and inhaled bronchodilator therapy . The subjects inhaled fenoterol or placebo by a dry powder delivery system for 24 weeks . Control of asthma was judged by daily morning and evening peak expiratory flow rates , symptom diaries , use of additional inhaled bronchodilator , and requirement for short courses of prednisone . Of 64 subjects who completed the trial , 57 showed a clear difference in degree of control of asthma between the fenoterol and placebo periods : in 17 ( 30 % [ 95 % confidence interval 18.4 - 43.4 % ] ) asthma was better controlled during regular inhaled bronchodilator treatment , whereas in 40 ( 70 % [ 56.6 - 81.6 % ] ) control was better during placebo treatment with bronchodilator for symptom relief only . Mean airway responsiveness to methacholine increased slightly during the fenoterol period . The adverse effect of regular bronchodilator inhalation occurred not only among subjects who used a bronchodilator as sole treatment ( 2 were better and 10 were worse during regular bronchodilator treatment ) but also among those who took inhaled corticosteroids ( 14 were better and 29 were worse ) . Thus , regular inhalation of a beta-sympathomimetic agent was associated with deterioration of asthma control in the majority of subjects . The trends to use of regular , higher doses or longer-acting inhaled beta-sympathomimetic treatment may be an important causal factor in the worldwide increase in morbidity from asthma
BACKGROUND An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in previous Cochrane review s. OBJECTIVES We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have r and omised patients with chronic asthma to regular formoterol versus regular salmeterol .