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Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. European Respiratory Study Group. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma. Comparison of salmeterol with disodium cromoglycate in the treatment of adult asthma. Oral Montelukast Compared with Inhaled Salmeterol To Prevent Exercise-Induced Bronchoconstriction Efficacy and Safety of Fluticasone Propionate/Salmeterol HFA 134A MDI in Patients with Mild‐to‐Moderate Persistent Asthma The Effects of Inhaled Albuterol and Salmeterol in 2- to 5-Year-Old Asthmatic Children as Measured by Impulse Oscillometry* Salmeterol versus sodium cromoglycate for the protection of exercise induced asthma in children--a randomised cross-over study. Comparison of powder and aerosol formulations of salmeterol in the treatment of asthma. Salmeterol compared with current therapies in chronic asthma. Salmeterol in two different doses in the treatment of nocturnal bronchial asthma poorly controlled by other therapies Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. Comparison of the short-term effects of salmeterol and formoterol on heart rate variability in adult asthmatic patients. Efficacy of salmeterol in the treatment of childhood asthma. Regular inhaled salbutamol and airway responsiveness to allergen A twelve-week comparison of salmeterol and salbutamol in the treatment of mild-to-moderate asthma: a Canadian multicenter study. Dose-response study of inhaled salmeterol in asthmatic patients with 24-hour spirometry and Holter monitoring. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Prevention of Exercise-induced Bronchospasm in Pediatric Asthma Patients: A Comparison of Two Salmeterol Powder Delivery Devices Efficacy, safety, and impact on quality of life of salmeterol in patients with moderate persistent asthma. Onset and duration of action of single doses of formoterol inhaled via Turbuhaler. A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma. Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis. Safety of salmeterol in the maintenance treatment of asthma. Twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients. European Study Group. A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. The cardiorespiratory response to submaximal exercise in subjects with asthma following pretreatment with controlled release oral salbutamol and high-dose inhaled salmeterol. Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children. Effect on airway responsiveness of six weeks treatment with salmeterol. Duration and magnitude of action of 50 and 100 micrograms of inhaled salmeterol in protecting against bronchoconstriction induced by hyperventilation of dry cold air in subjects with asthma. Bitolterol and albuterol metered-dose aerosols: comparison of two long-acting beta 2-adrenergic bronchodilators for treatment of asthma. Long-acting beta 2-agonist salmeterol compared with albuterol in maintenance asthma therapy. [Salmeterol improves the control of disease in patients with moderate asthma. A comparative study of inhaled salmeterol 50 mg and salbutamol depot tablets 8 mg, both administered twice daily]. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Acute effects of higher than customary doses of salmeterol and salbutamol in patients with acute exacerbation of COPD. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. Prevention of exercise-induced bronchospasm in pediatric asthma patients: a comparison of salmeterol powder with albuterol. Efficacy and duration of salmeterol powder inhalation in protecting against exercise-induced bronchoconstriction. Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Effects of long-acting bronchodilators and placebo on histamine-induced asthma symptoms and mild bronchusobstruction. A 4‐week comparison of salmeterol and terbutaline in adult asthma * A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge. Salmeterol: a four week study of a long-acting beta-adrenoceptor agonist for the treatment of reversible airways disease. Comparison of inhaled salmeterol and individually dose-titrated slow-release theophylline in patients with reversible airway obstruction. European Study Group. A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma. Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma. Pilgrim's progress: the effect of salmeterol in older children with chronic severe asthma. Potential masking effects of salmeterol on airway inflammation in asthma. Salmeterol does not cause tolerance during long-term asthma therapy. Effectiveness and safety of salmeterol in nonspecialist practice settings. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study. The efficacy and tolerability of inhaled salmeterol and individually dose-titrated, sustained-release theophylline in patients with reversible airways disease. Effect of a single dose of inhaled salmeterol on baseline airway caliber and methacholine-induced airway obstruction in asthmatic children. Salmeterol inhaler using a non-chlorinated propellant, HFA134a: systemic pharmacodynamic activity in healthy volunteers. [Therapy of nocturnal asthma: salmeterol versus nocturnal administration of retard theophylline--comparison of effectiveness and tolerance]. Salmeterol HFA is as effective as salmeterol CFC in children and adults with persistent asthma. A comparative study in atopic subjects with asthma of the effects of salmeterol and salbutamol on allergen-induced bronchoconstriction, increase in airway reactivity, and increase in urinary leukotriene E4 excretion. Long-term treatment of asthmatic patients with salmeterol vs slow-release theophylline. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration.
Brambilla C , Chastang C , Georges D , Bertin L. Salmeterol compared with slow‐release terbutaline in  nocturnal asthma .  A multicenter , r and omized , double‐blind , double‐dummy , sequential clinical trial BACKGROUND In vitro the long acting β2 agonist salmeterol can , in contrast to formoterol , behave as a partial agonist and become a partial antagonist to other β2 agonists . To study this in vivo , the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists . METHODS A r and omised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second ( FEV1 ) of 88.4 % predicted and median concentration of methacholine provoking a fall in FEV1 of 20 % or more ( PC20 ) of 0.62 mg/ml at entry . One hour after the last dose of 2 weeks of treatment with formoterol ( 24 μg twice daily by Turbuhaler ) , salmeterol ( 100 μg twice daily by Diskhaler ) , or placebo a methacholine provocation test was performed and continued until there was at least a 30 % decrease in FEV1 . Salbutamol ( 50 μg ) was administered immediately thereafter , followed by ipratropium bromide ( 40 μg ) after a further 30 minutes . Lung function was monitored for 1 hour after provocation . RESULTS There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment . The dose of methacholine needed to provoke a fall in FEV1 of ⩾30 % was higher after pretreatment with formoterol ( 2.48 mg ) than with salmeterol ( 1.58 mg ) or placebo ( 0.74 mg ) . The difference between formoterol and salmeterol was statistically significant : 0.7 doubling dose steps ( 95 % CI 0.1 to 1.2 , p=0.016 ) . The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs ( p<0.0003 for both ) . Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8 % , 7.3 % , and 5.5 % for placebo , formoterol and salmeterol , respectively ( equivalent to increases of 26 % , 14 % , and 12 % , respectively , from the lowest FEV1after methacholine ) . At 30 minutes significant differences remained , but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups . CONCLUSION Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent , indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo . Irrespective of this , prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally , indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol . Patients on regular treatment with long acting β2 agonists  should be made aware that an additional single dose of a short acting β2 agonist may become less effective Salmeterol is a beta-agonist with bronchodilator properties that last for at least 12 h after inhalation . However , the onset of action of salmeterol immediately after inhalation has not been sufficiently investigated . In the present study , the onset of action and tremor-inducing effect of two doses of inhaled salmeterol ( 50 and 100 microg ) were compared with inhaled salbutamol ( 200 and 400 microg ) and placebo .  Lung function was measured using forced expiratory volume in 1 s ( FEV1 ) , and tremor was measured using a linear accelerometer . With salbutamol there was rapid bronchodilation , both doses producing more than 15 % improvement in mean FEV1 within 2 mins of inhalation . With salmeterol , on the other h and , significant bronchodilation was delayed until 7 mins versus placebo , and the full bronchodilation effect was not achieved until 60 mins after inhalation . There was a much more rapid onset of tremor with salbutamol ( 400 microg ) than salmeterol . There was a much slower onset of bronchodilation with salmeterol than salbutamol . Therefore , salmeterol can not be recommended to relieve acute symptoms BACKGROUND The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity . The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects . METHODS A double blind , r and omised , crossover study was carried out in 16 healthy subjects who inhaled formoterol 24 , 48 and 96 μg ( via Turbuhaler ® ) , salmeterol 100 , 200 and 400 μg ( via Diskhaler ® ) , or placebo on separate days . Heart rate , systolic and diastolic blood pressure , and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose . Mean maximum ( or minimum ) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs . Lunch was taken after the four hour readings and , since this caused additional changes to the main outcome measures , data from the first four hours are also presented in a post hoc analysis . RESULTS Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration ; formoterol also caused an early increase in systolic blood pressure . The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol , apart from the glycaemic response . The effects of salmeterol were slightly more prolonged than those of formoterol , although some dose related effects were apparent at eight hours with both drugs . The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values . Relative dose potencies ( 95 % CI ) for maximum heart rate and plasma potassium concentrations were 4.1 ( 3.0 to 5.6 ) and 5.8 ( 4.1 to 8.6 ) over four hours and 2.4 ( 1.2 to 3.8 ) and 3.0 ( 1.2 to 5.7 ) over eight hours . CONCLUSIONS Formoterol and salmeterol cause dose related changes in heart rate , diastolic blood pressure , and plasma glucose and potassium concentrations . Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity . Both drugs have a relatively modest therapeutic window . The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses . Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained BACKGROUND Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear . Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects . A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow ( FBF ) as a measure of peripheral vasodilatation . METHODS Eight men with mild asthma underwent the following treatments : normoxia + placebo ( NP ) , normoxia + salbutamol ( NS ) , hypoxia + placebo ( HP ) , and hypoxia + salbutamol ( HS ) . The period of mask breathing started at t=0 minutes , lasted for 60 minutes , and at 30 minutes 800 μg salbutamol was inhaled . The experiment was completed 30 minutes after the inhalation ( t=60 minutes ) . For the hypoxia treatment the Spo 2 level was 82 % . Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value . RESULTS There were no significant differences in blood pressure and potassium levels between the treatments . After 60 minutes the increase in FBF was 13 % ( 95 % CI –12 to 39 ) more for HP treatment than for NP , 21 % ( 95 % CI –5 to 46 ) more for NS than for NP , and 32 % ( 95 % CI 7 to 58 ) more for HS than for HP ( p=0.016 ) . The inhalation of salbutamol during hypoxia result ed in a significant increase in FBF of 45 % ( 95 % CI 20 to 71 ) compared with NP ( p=0.001 ) . CONCLUSION Patients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death BACKGROUND Nocturnal worsening of asthma is a common problem in asthma and is associated with increased morbidity and mortality . Long acting beta-2 agonists are considered long-term symptom control medications , especially for nocturnal symptoms . OBJECTIVE To compare efficacy of an extended release oral beta-2 agonist , albuterol sulfate ( Volmax ) , to a long-acting inhaled agent , salmeterol ( Serevent ) in the treatment of nocturnal asthma . METHODS This was a multicenter double-blind , double-dummy , r and omized , crossover design with a 1-week baseline period and two 3-week treatment periods separated by a 7 to 9-day washout . An optional 2-week , open-label phase was conducted to evaluate patient preference . RESULTS A total of 46 patients were included in the efficacy analysis . For the primary outcome variable of morning peak expiratory flow , there were similar and significant improvements over the 3-week treatment period for both medications compared with baseline ( P < .001 ) . Similar improvements were seen in the overnight change in PEF values ( P < .001 ) . The morning and overnight changes in FEV1 were not significantly different between treatment arms ( P > .05 ) . There were significant improvements in both treatment periods in regard to the percentage of nights without awakenings ( baseline 53.6+/-5.3 % ) , extended release albuterol 83.3+/-3.0 % ( P < .001 ) , and salmeterol 88.8+/-2.4 % . The percentage of patients who had no awakenings during treatment did not differ significantly for the two medications . Both treatments also result ed in a decrease in the use of rescue albuterol ( extended release 2.66+/-0.35 puffs per day , salmeterol 1.85+/-0.29 ) from baseline ( 4.57+/-0.41 , P < .001 ) . There was a significant difference between groups ( P = .001 ) . The reasons why patients preferred one medication over the other varied . CONCLUSION Both extended release albuterol tablets and inhaled salmeterol result ed in similar bronchodilation and good control of nocturnal asthma symptoms AIMS Inhalers combining long acting beta2-adrenoceptor agonists ( LABA ) and corticosteroids ( ICS ) are indicated at Step 3 of current asthma guidelines . We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function , bronchoprotection , acute salbutamol recovery following methacholine bronchial challenge , and surrogate inflammatory markers in patients with moderate persistent asthma . METHODS Twenty-nine patients with mean FEV1 ( + /- SEM ) of 78 + /- 3 % predicted completed a r and omized , double-blind , double-dummy , cross-over study . Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg ( BUD + FM ) combination twice daily followed by 1 week of BUD 400 microg alone twice daily , or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg ( FP + SM ) combination twice daily followed by 1 week of FP 250 microg alone twice daily . Measurements were made at baseline and following each r and omized treatment . RESULTS FEV1 increase from pretreatment baseline as mean ( + /- SEM ) % predicted was significantly higher ( P < 0.05 ) for BUD + FM ( 8 + /- 1 % ) vs BUD ( 2 + /- 1 % ) , and for FP + SM ( 8 + /- 1 % ) vs FP ( 2 + /- 1 % ) . The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups ; BUD + FM ( 22 + /- 1 % ) , BUD ( 24 + /- 1 % ) , FP + SM ( 23 + /- 1 % ) and FP ( 23 + /- 1 % ) . Salbutamol recovery over 30 min following methacholine challenge as area under curve ( AUC % .min ) was significantly blunted ( P < 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 Twenty-eight patients aged 64 - 88 years with reversible airflow obstruction , showing a diurnal variation in peak expiratory flow rate ( PEFR ) of over 15 % or symptoms of airflow obstruction on 4 days of the last week of the run-in period , were entered into a r and omized , double-blind , placebo-controlled , cross-over study to evaluate the efficacy of salmeterol 50 microg twice daily by metered-dose inhaler . Salmeterol or matching placebo were each given for 28 days . Mean morning PEFR was 258.71/min on slameterol and 242 . 41/min on placebo ( adjusted mean difference = 16.31/min ; 95 % CI = 7 . 4 , 25.21/min;p = 0.0011 ) . Diurnal variation in PEFR was 7.31/min on salmeterol and 17.51/min on placebo ( adjusted mean difference = 10 . 31/min ; 95 % CI -2.0 , 0.5 actuations/day ; p = 0.0015 ) . After 28 days of treatment the patients ' assessment of efficacy was statistically significantly in favour of salmeterol ( p = 0.05 ) . Salmeterol was well tolerated as assessed by pulse , blood pressure , haematological and biochemical variables and number of adverse events . Salmeterol 50 microg bd is an effective and well-tolerated therapy for elderly patients with reversible airflow obstruction 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 BACKGROUND Salmeterol xinafoate is a long-acting , highly selective , beta2-adrenergic agonist that produces bronchodilation and clinical ly significant improvement in pulmonary function for up to 12 hours in patients with asthma . OBJECTIVE To evaluate the impact on asthma-specific quality of life , efficacy , and safety of salmeterol versus albuterol in adult patients with mild-to-moderate persistent asthma . METHODS A r and omized , double-blind , double-dummy , parallel-group , multicenter study was conducted in 539 adult asthma patients over 12 weeks . Patients were r and omized to receive either salmeterol 42 microg via metered-dose inhaler twice daily or albuterol 180 microg four times daily . Upon entry into the study , 46 % of patients were being treated with an inhaled  corticosteroid and were allowed to continue treatment throughout the study . Pulmonary function and asthma symptoms were monitored daily , and patients completed the Asthma Quality of Life Question naire ( AQLQ ) at baseline and after 4 , 8 , and 12 weeks of treatment . RESULTS Treatment with salmeterol twice daily produced significantly greater improvements from baseline in all quality of life domain ( " Activity Limitation , " " Asthma Symptoms , " " Emotional Function , " " Environmental Exposure " ) scores and in the global AQLQ score at 12 weeks ( P < or = .038 ) compared with albuterol treatment four times daily . Pulmonary function and asthma symptoms were also significantly improved with salmeterol compared with albuterol . CONCLUSIONS Salmeterol 42 microg administered twice daily is significantly more effective than albuterol 180 microg four times daily for improving asthma-specific quality of life , controlling asthma symptoms , and improving pulmonary function in patients with mild-to-moderate persistent asthma . Furthermore , those improvements were maintained over a 12-week period The development of tolerance to the bronchodilator effects of beta2-agonists used in asthma therapy has been the subject of debate . We conducted two placebo-controlled crossover studies to assess the bronchodilator response to a short-acting beta2-agonist before and after chronic therapy with salmeterol .  Patients in one study were corticosteroid-naive ; patients in the other study were using inhaled corticosteroids .  Changes in FEV1 after cumulative doubling doses of inhaled albuterol were assessed after a 2-wk beta-agonist washout period , before administering study medication on Day 1 , and again after 28 d of therapy . Ipratropium bromide was provided as rapid-relief treatment for asthma , and use of any beta2-agonist except the study treatment was prohibited . On both assessment days for salmeterol , and during placebo administration periods , significant increases from predose FEV1 values were observed beginning with the lowest dose of albuterol and continuing throughout the dose-response assessment ( p < /= 0.001 ) . These increases in FEV1 were maintained for 6 h after the last dose of albuterol ( p < 0.05 ) . There were no statistically significant differences in the albuterol dose response following salmeterol or placebo . These studies indicate that irrespective of concurrent corticosteroid treatment , chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol 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 BACKGROUND Poor adherence with inhaled corticosteroids is an important problem in asthma management . Previous approaches to improving adherence have had limited success . AIM To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids . DESIGN OF STUDY R and omised , parallel group , open-label trial . SETTING Forty-four general practice s in Nottinghamshire . METHOD Participants who used less than 70 % of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were r and omised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required ( control group ) , or budesonide/formoterol 200/6 microg one puff once daily and as required ( active group ) for 6 months . The primary outcome was inhaled corticosteroid dose . RESULTS Seventy-one participants ( 35 control , 36 active group ) were r and omised . Adherence with budesonide in the control group was approximately 60 % of the prescribed dose . Participants in the active group used approximately 80 % more budesonide than participants in the control group ( 448 versus 252 microg/day , mean difference 196 mug , 95 % confidence interval 113 to 279 ; P<0.001 ) and were less likely to withdraw from the study ( 3 versus 13 ; P<0.01 ) . No safety issues were identified . CONCLUSION Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken , suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids BACKGROUND Polymorphisms of the β2 adrenoceptor influence receptor function in vitro and asthma phenotypes in vivo . However , their importance in determining responses to inhaled β agonist treatment has not been clearly defined . METHODS In a retrospective analysis of previously published data we have examined relationships between polymorphisms at codons 16 and 27 of the β2 adrenoceptor and clinical outcomes in a r and omised , placebo controlled , crossover trial of regularly scheduled salbutamol and salmeterol in 115 patients with mild to moderate asthma . Genotyping was obtained for positions 16 and 27 in 108 and 107 patients , respectively . For position 16 , 17 patients ( 16 % ) were homozygous Arg-Arg , 40 ( 37 % ) were heterozygous Arg-Gly , and 51 ( 47 % ) were homozygous Gly-Gly . RESULTS Within the homozygous Arg-16 group major exacerbations were more frequent during salbutamol treatment than with placebo ( 1.91 ( 95 % CI 1.07 to 3.12 ) per year versus 0.81 ( 95 % CI 0.28 to 1.66 ) per year ; p = 0.005 ) . No significant treatment related differences occurred for heterozygous Arg-Gly patients  ( salbutamol 0.11 ( 95 % CI 0.01 to 0.40 ) , placebo 0.54 ( 95 % CI 0.26 to 1.00 ) exacerbations per year ) or homozygous Gly-16 patients  ( salbutamol 0.38 ( 95 % CI 0.17 to 0.73 ) , placebo 0.30 ( 95 % CI 0.12 to 0.61 ) exacerbations per year ) . No adverse changes occurred for any position 16 subgroup with salmeterol . There was no significant relationship between position 27 genotypes and treatment related outcomes . CONCLUSION Homozygous Arg-16 patients are susceptible to clinical ly important increases in asthma exacerbations during chronic dosing with the short acting β2 agonist salbutamol 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 effect of adding inhaled salmeterol to inhaled corticosteroids was studied in patients with poorly controlled nocturnal asthma . In a double-blind , cross-over study , 20 patients were r and omized to receive either salmeterol 50 micrograms twice daily or placebo via a Diskhaler after a 1-week run-in period . After 4 weeks of treatment , patients were subsequently crossed over to receive the other treatment for a further 4 weeks with a 2-week wash-out period in between . The response to treatment was assessed by peak expiratory flow rates ( PEF ) measured in the morning and evening , symptom scores of asthma , number of bronchodilators used , forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) at regular intervals . Patients ' preference for the Diskhaler or metered-dose inhaler was assessed at the last visit . The results showed that morning PEF was significantly higher while on salmeterol than on placebo ( 296.9 + /- 70.2 vs 274.6 + /- 77.4 L/min ) . Evening PEF showed a trend towards a higher value while on salmeterol than on placebo ( 321.1 + /- 73.4 vs 288.7 + /- 79.4 L/min ) , but the difference was not significant . There was no statistically significant improvement in symptom scores , number of rescue bronchodilators used and FEV1 or FVC between the two treatment groups . The occurrence of side effects in terms of tremors and palpitations between treatment and placebo were similar . There were more patients who preferred Diskhaler to metered-dose inhaler ( 70 % vs 30 % ) . We conclude that salmeterol 50 micrograms twice daily produces significant improvement in morning PEF and is well tolerated in patients with nocturnal asthma . Diskhaler is a device which is easy to use and preferred to a metered-dose inhaler Ninety-six patients with nocturnal asthma ( FEV1 = 60 - 90 % pred , reversibility greater than or equal to 15 % , at least 2 awakenings in the week preceding the trial ) were included in a double-blind , r and omized , crossover , multicenter study which compared the efficacy and side effects of inhaled salmeterol ( 50 micrograms morning and evening ) to the association theophylline-ketotifen ( 300 mg and 1 mg morning and evening , respectively ) . The trial included a run-in period of 14 days and 2 periods of successive treatment of 28 days each . The efficacy was expressed in terms of therapeutic success , defined by the total disappearance of nocturnal symptoms during the treatment week . A statistically significant difference ( p less than 0.01 ) was found between salmeterol and the association for this criteria : during the first period , 46 % of subjects treated by salmeterol did not present nocturnal awakenings during the last treatment week by comparison with 15 % of subjects taking the association ; during the second period , corresponding figures were 39 % for salmeterol by comparison with 26 % for the association . Differences were also significant , favoring salmeterol , for other criteria ( lung function tests , extra-need for salbutamol ) . Side effects were 5 times more frequent for the association ( p less than 0.004 ) . Salmeterol is clearly superior to the association theophylline-ketotifen in the treatment of nocturnal asthma Abstract Objectives : To determine the effect of adding salmeterol 50 μg twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan . Design : A double blind , r and omised crossover study . Setting : Nottingham . Subjects : 101 subjects with mild or moderate asthma taking at least 200 μg twice daily of beclomethasone dipropionate or budesonide .  Interventions : Salmeterol 50 μg twice daily and placebo for six months each , with a one month washout . Subjects adjusted inhaled steroid dose according to guidelines . Main outcome measure : Reduction in inhaled steroid use , exacerbations of asthma , and use of oral steroids . Results : Data were available for 87 subjects . When compared with placebo salmeterol treatment was associated with a 17 % reduction in inhaled steroid use ( 95 % confidence interval 12 % to 22 % ) with no significant difference in the number of subjects who had an exacerbation ( placebo 25 % , salmeterol 16 % ) or use of oral steroids . For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second ; a reduction in symptoms , bronchodilator use , and airway responsiveness to methacholine ; and no effect on serum potassium concentration , 24 hour heart rate , or the final forced expiratory volume in one second achieved during a salbutamol dose-response study . Conclusions : In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 μg twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control . Key messages One hundred and one subjects with mild or moderate asthma  took salmeterol 50 μg and placebo for six months each in a crossover study Subjects adjusted their inhaled steroid dose according to a management plan based on peak flow recordings and symptoms The dose of inhaled steroids was reduced by 17 % with salmeterol , with no change in exacerbations or use of oral steroids Despite the reduction in inhaled steroid dose , salmeterol was associated with bronchodilatation and a reduction in symptoms The efficacy of salmeterol was maintained over the six Salmeterol xinafoate is an inhaled long-acting beta2-adrenoceptor agonist recently introduced for the treatment of asthma . Both in vitro and animal studies suggest that it may have anti-inflammatory activities of benefit in this disease . To assess this directly , the effects of 6 weeks ' treatment with salmeterol on indices of clinical activity , airway dysfunction and inflammation in subjects with stable atopic asthma were investigated . In a double blind study , asthmatic patients were r and omized to 6 weeks ' treatment with either salmeterol 50 microg twice daily ( n=14 ) or placebo ( n=12 ) . They underwent bronchoscopy with bronchoalveolar lavage ( BAL ) and bronchial biopsy immediately before starting treatment and again after 6 weeks . Treatment with salmeterol improved clinical indices of asthma activity , but there were no changes in BAL differential cell counts or mediator levels , and no change in T-cell numbers or activation status . In the biopsy specimens there were no changes in numbers of inflammatory cells , sub-basement membrane collagen deposition or mast cell degranulation . Regular treatment with salmeterol improves clinical indices of asthma but has no effect on the underlying inflammatory process . These findings strengthen guideline recommendations that long-acting beta2-agonists should not be prescribed as sole antiasthma medication 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 This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma . A total of 243 children , aged 4 - 11 years , with mild-to-moderate asthma were enrolled in a r and omized , double-blind , placebo-controlled , parallel-group , multicenter study evaluating salmeterol xinafoate 21 micrograms and 42 micrograms administered via metered-dose inhaler ( MDI ) twice daily for 1 week . Patients were allowed to use albuterol MDI as needed for relief of acute symptoms . Inhaled corticosteroids and /or cromolyn at fixed dosages could be continued during the study , but theophylline and oral beta-agonists were not allowed . Twelve-hour serial spirometry ( for patients aged 6 - 11 years ) and serial peak expiratory flow rate ( PEFR ) ( all patients ) were performed on days 1 and 8 of treatment ; morning and evening PEFR were recorded each day prior to inhalation of the study drug . Safety was assessed by monitoring adverse events , clinical laboratory values , vital signs , electrocardiogram ( ECG ) , and 24-hr ECG ( Holter ) monitoring . Both the 21-micrograms and 42-micrograms doses of salmeterol produced significantly greater bronchodilation , as measured by 12-hr serial forced expiratory volume in 1 sec ( FEV1 ) ( p < or = 0.02 ) and PEFR ( p < or = 0.001 ) , than did placebo on days 1 and 8 . A small dose-response was observed , with the 42-micrograms dosage producing consistently higher serial FEV1 and PEFR than did the 21-micrograms dosage , although the differences were not statistically significant . Morning and evening PEFR increased significantly ( p < or = 0.008 ) with both dosages of salmeterol compared with placebo . Twelve patients ( 5 % ) experienced potentially drug-related adverse events , with headache ( 4 % in each salmeterol group ) being the most common . There were no clinical ly significant changes in heart rate as measured by Holter monitoring , ECGs , vital signs , or clinical laboratory values following treatment with either dose of salmeterol . Salmeterol 21 micrograms or 42 micrograms twice daily was effective in producing bronchodilation in children aged 4 - 11 years , and both dosages had good safety profiles . Patients treated with salmeterol 42 micrograms twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 micrograms The efficacy and tolerability of salmeterol , 50 micrograms b.i.d . was compared for three months with salbutamol , 200 micrograms q.i.d . , administered from metered-dose inhaler . For the following nine months , safety and clinic lung function was monitored on salmeterol , 50 micrograms b.i.d . , compared with salbutamol , 200 micrograms b.i.d . This comparison was made in a multicentre , double-blind , parallel-group study of 667 moderate asthmatics , who had a forced expiratory volume in one second ( FEV1 ) or peak expiratory flow rate ( PEFR ) > 50 % predicted , a 15 % reversibility to inhaled salbutamol and who were experiencing symptoms . Throughout the first three month treatment period , both morning and evening PEFR were significantly higher on treatment with salmeterol than salbutamol ( mean differences between the treatments 30 l.min-1 for morning , p < 0.001 , and 11 l.min-1 for evening , p < 0.01 ) . In addition , the diurnal variation in PEFR , nocturnal and daytime symptoms and use of additional  salbutamol were significantly lower in the salmeterol treated group . This improvement was also apparent in the separate sub population s of patients taking no concurrent glucocorticosteroid or concurrent inhaled and /or oral glucocorticosteroids . Both treatments were well-tolerated throughout the 12 months of treatment . There was a lower incidence of asthma and related events during salmeterol treatment compared to salbutamol treatment subgroups . The results of the study clearly demonstrate that salmeterol , 50 micrograms b.i.d . , is well-tolerated and more effective than salbutamol , 200 micrograms q.i.d . , in the treatment of moderate asthma STUDY OBJECTIVE A dose-ranging study was conducted to evaluate the efficacy and safety of a new long-acting , selective beta 2-adrenoceptor agonist , salmeterol . DESIGN Adolescents and adults ( N = 160 ) with mild-to-moderate asthma received salmeterol ( 10.5 , 21 , 42 , or 84 micrograms ) or placebo by metered-dose inhaler twice daily for 1 week . Twelve-hour serial spirometry measurements were performed on the first and last days of treatment , and patients recorded their peak expiratory flow ( PEF ) twice daily on diary cards . RESULTS On day 1 , salmeterol produced greater bronchodilation than placebo ( p = 0.001 ) , and both the 42-micrograms and 84-micrograms doses of salmeterol were significantly more effective in improving FEV1 responses than the two lower doses of salmeterol ( p < 0.05 ) . After 1 week of treatment , all but the 21-micrograms dose of salmeterol remained statistically superior to placebo ( p < 0.01 ) , but significant differences between salmeterol doses were no longer evident , despite an apparent dose-response effect . Only the 42-micrograms and 84-micrograms doses of salmeterol sustained bronchodilation for 12 h in the majority of patients at both treatment days . The degree of improvement in morning and evening PEF was also found to be dose related . There was no significant difference among treatment groups in the overall incidence of adverse events ; however , pharmacologically predictable events ( eg , tremor ) occurred significantly more often with salmeterol , 84 micrograms . CONCLUSIONS Salmeterol , 42 micrograms , was similar in efficacy to 84 micrograms but was associated with a lower incidence of adverse events . Salmeterol , 42 micrograms twice daily , is a safe and effective dosage for patients with mild-to-moderate asthma who are persistently symptomatic and require maintenance bronchodilator therapy Objective : To assess the effect of a long-acting inhaled β2-agonist , salmeterol ( SM ) , compared to a short-acting inhaled β2-agonist , salbutamol ( or albuterol , SB ) , on the occurrence of morning dip ( MD ) in patients recovering from an acute severe asthma attack ( ASA ) . Design : Prospect i ve study Setting : 18-bed , medical intensive care unit ( ICU ) in a university hospital . Patients : 19 patients suffering from an ASA . Interventions : Serial measurements of the peak expiratory flow rate ( PEFR ) , arterial blood gases , vital capacity and forced expiratory volume in one second ( FEV1 ) were performed from admission . All patients were first treated with i. v. methyl prednisolone and i.v . SB . Once the PEFR was stable and > 35 % of predicted value , i. v. SB was stopped while i. v. steroids were maintained , and patients were r and omised to either inhaled SB ( 9 patients , 400 μg every 4 h ) or inhaled SM ( 10 patients , 100 μg every 12 h ) . Results : The mean admission PEFR was 26.1 ± 11.7 % of the predicted value and was not different between the two groups . MD was more frequent with SB ( 6/9 patients ) than with SM ( 4/10 ) . The severity of MD , expressed in 1/min fall in PEFR , was higher in SB than in SM ( 106 ± 25 vs 55±37;p<0.05 ) . Discussion : MD is frequent in ASA . In ASA , SM appears to reduce the frequency and the severity of MD more than SB . The clinical implication s of this observation , particularly a lowering of mortality and a shortening of the ICU stay , remain to be investigated BACKGROUND Although theophylline is recommended by current guidelines for the management of asthma in patients with persistent symptoms , theophylline has a narrow therapeutic index , requiring individual dose titration and regular monitoring of serum theophylline concentrations to avoid adverse effects . OBJECTIVE To compare the inhaled long-acting bronchodilator , salmeterol , with the oral bronchodilator , theophylline , in the maintenance treatment of asthma . METHODS In two multicenter , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group studies , patients received salmeterol aerosol 42 micrograms , extended-release theophylline capsules , or placebo twice daily for 12 weeks . RESULTS Of 638 adult and adolescent patients with moderate asthma who entered the prebaseline theophylline titration period , 154 were withdrawn prior to r and omization ( 71 due to theophylline-related adverse effects ) ; 484 patients comprised the intent-to-treat population . The mean serum theophylline concentration measured approximately seven hours postdose during the titration period in the theophylline group was 12.7 mg/L ( 70 mumol/L ) . The same dose during the treatment period result ed in a mean serum theophylline concentration between 7.6 to 7.9 mg/L ( 42 - 44 mumol/L ) when measured approximately 12 hours postdose . Salmeterol was significantly more effective than theophylline or placebo in improving mean morning PEF over the entire 12 weeks ( P < or = .02 ) . Mean predose FEV1 improved significantly with salmeterol compared with placebo ( P < .001 ) ; there was no difference between theophylline and placebo . Salmeterol was also significantly more effective than theophylline or placebo ( P < .02 ) in improving asthma symptoms , reducing nighttime awakenings , and reducing the daily use of albuterol . After 12 weeks of treatment , patients in the salmeterol group expressed significantly greater overall satisfaction with their asthma medication than did patients who received theophylline ( P < .01 ) . Patients in the theophylline group experienced more gastrointestinal adverse events than did patients in the salmeterol group ( P < .05 ) . CONCLUSION Salmeterol , 42 mg twice daily , was better tolerated and significantly more effective than extended-release theophylline twice daily in the maintenance treatment of asthma In a multicentre , double-blind , r and omized , parallel study , 426 asthmatic children aged 5 - 15 years old received salmeterol 50 micrograms b.i.d . or placebo b.i.d . via the Diskhaler . All patients had access to inhaled salbutamol to be used on an ' as required ' ( p.r.n . ) basis for symptomatic relief . The study design comprised a 2-week baseline , a 12-month treatment period incorporating a 2-week ' off treatment ' after 6 months , and a 2-week follow-up period at the end of the trial . At the end of 12 months of treatment with salmeterol , the adjusted change from baseline for morning and evening peak expiratory flow rate ( PEF ) was 56 and 47 l min-1 , respectively , and this was significantly greater than placebo ( P < 0.01 ; P < 0.05 ) . Exacerbation rates did not differ between groups and results were not dependent upon concurrent inhaled steroid use . Neither treatment caused a change of > or = 1 doubling dose in PC20/PD20 either during or on stopping treatment . Treatment with regular salmeterol 50 micrograms b.i.d . over a 12-month treatment period provides a significant , rapid and well-maintained improvement in lung function without increasing bronchial reactivity or asthma exacerbation rates compared to p.r.n . salbutamol BACKGROUND The adverse effects of long term treatment of asthma with the short acting β agonist fenoterol have been established in both epidemiological and clinical studies . A study was undertaken to investigate the efficacy and safety of long term treatment with salbutamol and salmeterol in patients with mild to moderate bronchial asthma . METHODS In a two centre double dummy crossover study 165 patients were r and omly assigned to receive salbutamol 400 μg qid , salmeterol 50 μg bid , or placebo via a Diskhaler . All patients used salbutamol as required for symptom relief . The study comprised a four week run in and three treatment periods of 24 weeks , each of which was followed by a four week washout . Asthma control was assessed by measuring mean morning and evening peak expiratory flow rate ( PEFR ) , a composite daily asthma score , and minor and major exacerbation rates . Washout assessment s included methacholine challenge and bronchodilator dose response tests . Analysis was by intention to treat . RESULTS Data from 157 patients were analysed . Relative to placebo , the mean morning PEFR increased by 30 l/min ( 95 % CI 26 to 35 ) for salmeterol but did not change for salbutamol . Evening PEFR increased by 25 l/min ( 95 % CI 21 to 30 ) and 21 l/min ( 95 % CI 17 to 26 ) , respectively ( p<0.001 ) . Salmeterol improved the asthma score compared to placebo ( p<0.001 ) , but there was no overall difference with salbutamol . Only daytime symptoms were improved with salbutamol . The minor exacerbation rates were 0.29 , 0.88 , and 0.97 exacerbations/patient/year for salmeterol , salbutamol and placebo , respectively ( p<0.0001 for salmeterol ) . The corresponding major exacerbation rates were 0.22 , 0.51 and 0.40 , respectively ( p<0.03 for salmeterol ) . For salbutamol the asthma score deteriorated over time ( p<0.01 ) , and the time spent in major exacerbation was significantly longer compared with placebo ( 12.3 days ( 95 % CI 4.2 to 20.4 ) ) versus 8.4 days ( 95 % CI 5.2 to 11.6 ) , p = 0.02 ) . There was no evidence of rebound deterioration in asthma control , lung function , or bronchial hyperresponsiveness following cessation of either active treatment , and no evidence of tolerance to salbutamol or salmeterol . CONCLUSIONS Regular treatment with salmeterol is effective in controlling asthma symptoms and reduces minor more than major exacerbation rates .  Salbutamol was associated with improved daytime symptoms but subtle deterioration in asthma control occurred over time . Salbutamol should therefore be used only as required Salmeterol is a new beta 2-selective agonist with a long duration of action . We compared the effect of 50 micrograms salmeterol administered by metered dose inhaler ( MDI ) and dry powder inhaler ( DPI ) , with 200 micrograms albuterol ( by MDI ) on FEV1 and histamine-induced bronchoconstriction in 12 asthmatic subjects in a double-blind , placebo-controlled crossover study . Subjects were studied for 12 h on four occasions with a histamine challenge test at 1 , 4 , 8 , and 12 h , the response being measured as the dose of histamine causing a 20 % fall in FEV1 ( PD20 ) . There was no difference in the mean + /- st and ard error of the mean maximum increase in FEV1 between salmeterol MDI , salmeterol DPI , or albuterol ( 0.57 + /- 0.078 , 0.54 + /- 0.089 , and 0.49 + /- 0.081 L , respectively ) ; the increase following placebo was 0.25 + /- 0.082 L. The area under the 12-h time-response curve for FEV1 was greater for both formulations of salmeterol ( MDI and DPI ) than for albuterol . The three active drugs protected against histamine-induced bronchoconstriction . The increase in PD20 at 1 and 12 h and the area under the 12-h time-response curve for PD20 were greater following both formulations of salmeterol than after albuterol . The greater change in geometric mean PD20 values at 1 h after both formulations of salmeterol ( 2.21 and 1.88 mumol ) relative to albuterol ( 0.98 mumol ) suggests that despite similar effects on FEV1 the doses used do not have an equivalent effect on the airways . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVES To compare the efficacy , safety , and effects on sleep quality of salmeterol and extended-release theophylline in patients with nocturnal asthma . DESIGN R and omized , double-blind , double-dummy , three-period crossover . SETTING Out patients at a single center . Patients spent 1 night during screening and 2 nights during each study period in a sleep laboratory for completion of sleep studies . PATIENTS Male and female patients who were at least 18 years old with nocturnal asthma ( baseline FEV1 , 50 to 90 % of predicted ) and who required regular bronchodilator therapy . Patients on inhaled corticosteroids , cromolyn , and nedocromil were allowed into the study if their dosing remained constant throughout the study . INTERVENTIONS Inhaled salmeterol ( 42 microg per actuation ) , extended-release oral theophylline ( titrated to serum levels of 10 to 20 microg/mL ) , and placebo taken twice daily . MEASUREMENTS AND RESULTS Efficacy measurements included nocturnal spirometry , nocturnal polysomnography , sleep question naires , and daily measurements of lung function and symptoms . Salmeterol was superior to theophylline ( p < or = 0.05 ) in maintaining nocturnal FEV1 levels and was superior to placebo ( p < or = 0.05 ) in improving morning and evening peak expiratory flow ( PEF ) and in decreasing nighttime albuterol use . The use of salmeterol significantly increased the percentage of days and nights with no albuterol use and decreased daytime albuterol use compared with theophylline and placebo ( p < or = 0.05 ) . Sleep quality global scores significantly improved with salmeterol and placebo ( p < 0.001 ) but not with theophylline . The effects on sleep architecture were similar across treatment groups . CONCLUSIONS Salmeterol ( but not theophylline ) was associated with sustained improvements in morning PEF , protection from nighttime lung function deterioration , reductions in albuterol use , and improvements in patient perceptions of sleep . No differences were seen in polysomnographic measures of sleep quality Salmeterol is an original molecule with a selective-beta-2-sympathomimetic effect which is intended to a prolonged treatment of asthma . This inhaled preparation has a long duration of action which points to its use on a BID regimen . Results of the phase III development has been assessed in 2,277 subjects .  Salmeterol administered at a dose of 50 micrograms morning and evening results in a marked increase in FEV1 , which remains superior to 15 % by comparison with baseline 12 hours after the last dose in the majority of subjects . In the specific case of more severe asthma ( FEV1 less than 50 % of predicted ) , the use of 100 micrograms morning and evening allows for an extra-improvement in FEV1 . In the majority of studies , salmeterol has result ed in an almost complete remission of the clinical symptomatology : disappearance or major diminution in the use of inhaled salbutamol  administered as a rescue medication on a PRN basis ( during the day and at night ) and of nocturnal awakenings , global improvement of clinical scores . Daily peak expiratory flow rates ( morning and night values ) are considerably improved ( greater than or equal to 50 l/min ) with a significant reduction of daily swings . Lung function tests are also very significantly improved . Salmeterol has proved to be largely superior to the comparison medications , salbutamol taken at a dose of 200 micrograms four times a day , and optimal therapy with theophylline .  Clinical acceptability of salmeterol is good and is not different from salbutamol STUDY OBJECTIVES To determine the effect of long-term salmeterol aerosol therapy on  airway hyperresponsiveness  measured by methacholine challenge . DESIGN R and omized , double-blind , placebo-controlled , multicenter study . SETTING Thirty-one clinical centers in the United States . PATIENTS Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70 % of predicted values . Patients were not using inhaled corticosteroids . INTERVENTIONS Twice-daily salmeterol aerosol , 42 microg , or placebo via metered-dose inhaler for 24 weeks . Backup albuterol was available . MEASUREMENTS AND RESULTS Pulmonary function tests were performed before , during , and after treatment . Subjects recorded asthma-related symptoms , morning and evening peak expiratory flow ( PEF ) levels , and use of supplemental albuterol daily on diary cards .  Methacholine challenges were performed 10 to 14 h postdose at weeks 4 , 12 , and 24 , and 3 and 7 days posttreatment . Over 24 weeks of treatment , salmeterol provided significant ( p < 0.001 ) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection . A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy . Salmeterol treatment result ed in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo ( p < 0.001 ) . The use of salmeterol significantly reduced combined daytime asthma symptoms by 20 % when compared to placebo ( p = 0.005 ) . A total of 34 and 48 exacerbations , respectively , were reported in the Salmeterol and placebo groups , and no evidence was present for a difference in the severity of asthma exacerbations between groups . Adverse event profiles were similar for the salmeterol and placebo groups . CONCLUSIONS Regular long-term use of salmeterol aerosol result ed in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period . There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy . There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment . Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks The aim of this study was to compare the effects of salmeterol and beclomethasone on lung function and symptoms in children with mild to moderate asthma . Sixty-seven children not treated with inhaled corticosteroids were r and omized in a double-blind parallel study either to salmeterol 50 micrograms b.i.d . or beclomethasone 200 micrograms b.i.d . After one year , FEV1 significantly increased in the beclomethasone group , whereas in the salmeterol group there was a small reduction . Differences between groups were 14.2 % predicted ( p < 0.0001 ) and 7.0 % predicted ( p = 0.007 ) for pre- and postbronchodilator FEV1 values , respectively . PD20 methacholine decreased by 0.73 DD ( p = 0.05 ) in the salmeterol group and increased by 2.02 DD ( p < 0.0001 ) in the beclomethasone group . Morning and evening PEF and symptom scores improved in both groups , although more in the beclomethasone group . Asthma exacerbations , for which prednisolone was needed , were more frequent in the salmeterol group ( 17 versus two ) , as were the number of withdrawals due to exacerbations ( six versus one ) . However , growth was significantly slower in the beclomethasone group ( -0.28 SDS ) compared with that in the salmeterol group ( -0.03 SDS ) ( p = 0.001 ) . We conclude that treatment with a moderate dose of beclomethasone is superior to salmeterol in children with mild to moderate asthma and recommend that salmeterol should not be used as monotherapy It has been shown that asthmatics have nocturnal symptoms associated with impaired cognitive performance . We explored more carefully different therapeutic approaches on this performance in relation to lung function in 46 atopics with mild to moderate asthma and with a circadian variation in peak expiratory flow ( PEF ) > or = 15 % . In a double-blind , parallel study they inhaled salmeterol 50 microg or fluticasone 250 microg or a combination of both twice daily for 6 wk . The psychometric tests used informed about focused attention , mental flexibility , concentration , and attention . The results of the psychometric tests were compared with those in healthy control subjects . The PASAT score and the finishing time of the color-word chart subtest were significantly lower in these asthmatics than in the control subjects . Circadian PEF variation was the only independent factor significantly associated with impaired cognitive performance before the treatment period . The three treatment groups were equally effective in reducing circadian PEF variation below 10 % and in improving FEV1 and bronchial hyperresponsiveness to methacholine ( MCh ) both day and night . After 6 wk of therapy , the daytime cognitive performance was improved to levels comparable to those of the healthy control subjects no matter which drug was inhaled . We conclude that a high level of circadian PEF variation ( > or = 20 % ) has been associated with lower daytime cognitive performance in asthmatics . Reduction of circadian PEF variation to below 10 % is an important goal of treatment in asthmatics STUDY OBJECTIVES This study investigates the long-term cardiovascular safety of salmeterol powder vs placebo in adolescent and adult patients with mild persistent asthma . DESIGN Multicenter , r and omized , double-blind , placebo-controlled , parallel-group study . SETTING Eighteen US clinical centers . PATIENTS Three hundred fifty-two patients ( > or = 12 years ) with mild persistent asthma ( duration > or = 6 months ) requiring pharmacotherapy ; with FEV1 of 70 to 90 % of predicted and without abnormal ECG/continuous ambulatory ECG ( Holter ) . INTERVENTIONS R and omized to twice-daily salmeterol powder ( 50 microg ) or placebo via breath-actuated device for 52 weeks . Backup albuterol was available to control asthma symptoms . MEASUREMENTS AND RESULTS Cardiovascular safety was regularly assessed by 12-lead ECG with a 15-s lead II rhythm strip , 24-h continuous ambulatory ECG ( Holter ) monitoring , serial vital sign measurements , and review of adverse cardiovascular events . No deaths occurred during the study . No clinical ly significant between-group differences were observed in pulse rate , ECG QTc interval , median number of ventricular or supraventricular ectopic events , incidence of ventricular ectopic couplets and runs , or incidence of > 100 ventricular or supraventricular ectopic events in 24 h. No clinical ly significant between-group differences were observed in arterial BP or incidence of adverse cardiovascular events . Salmeterol was well tolerated throughout the 52-week study period , with a cardiovascular safety profile similar to that of placebo . CONCLUSIONS Long-term , twice-daily pharmacotherapy with salmeterol powder is safe and is not associated with unfavorable clinical ly significant changes in cardiac function or increases in cardiovascular adverse effects RATIONALE Long-acting beta-agonists ( LABAs ) and inhaled corticosteroids administered together appear to be complementary in terms of effects on  asthma control .  The elements of asthma control achieved by LABAs ( improved lung function ) and leukotriene receptor antagonists ( LTRAs ; protection against exacerbations ) may be complementary as well . OBJECTIVE We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma . METHODS AND MEASUREMENTS In a r and omized , placebo-controlled , crossover study of 192 subjects with moderate asthma , we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma . The primary efficacy outcome was time to treatment failure . MAIN RESULTS Three months after the r and omization of the last subject , the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial . The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures ( p = 0.0008 ) , lung function ( 26 L/min difference in a.m. peak expiratory flow rate , p = 0.011 ) , asthma control score ( 0.22 difference in Asthma Control Question naire score , p = 0.038 ) , and markers of inflammation and airway reactivity . CONCLUSIONS Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA BACKGROUND Vesicoureteral reflux and urinary incontinence are frequently observed among myelodysplastic patients . Since the conservative therapy is not always effective to improve these pathologies , surgical intervention is necessary for some of the patients . METHODS Thirty-eight myelodysplastic patients were divided into 2 groups : Group A comprised 17 patients who had been operated by anti-reflux surgery ( crossover method ) alone and Group B 21 patients who had undergone anti-reflux surgery ( Orikasa 's method ) and augmentation enterocystoplasty with or without sling operation .  Cessation rate of reflux , bladder capacity , bladder compliance and operative complications were analyzed in the 2 groups . A question naire was sent to the patient asking to answer frequency of clean intermittent catheterization ( CIC ) , severity of urinary incontinence , satisfaction rate for operation and so on . Mean followed-up periods were 11.7 ( 5.3 - 13.6 ) years for Group A and 3.7 ( 0.6 - 6.9 ) years for Group B , respectively . RESULTS Reflux was successfully eradicated in 19 of 24 ureters ( 79 % ) of Group A and in 25 of 29 ureters ( 86 % ) of Group B , which was not significantly different . In Group A , bladder capacity and compliance slightly improved . The latter , however , remained less than 10 ml/cmH2 O. Bladder capacity and compliance of Group B increased more than twice the original value with statistical significance . Operative complication in Group A was ureteral obstruction in 1 patient , which eventually necessitated peritoneal dialysis . In Group B revision of ventriculoperitoneal shunt was necessary in 4 patients , incomplete ileus was conservatively treated in 3 , and a bladder stone was formed in 1 . The patients assessed that frequency of pyelonephritis was less in Group B compared to Group A. Other subjective parameters , however , such as frequency of CIC , severity of urinary incontinence , postoperative changes in the amount of urinary incontinence , and satisfaction rate for operation , were not different between the 2 groups . COMMENTS Though operation-related complications occurred more frequently in those of Group B , these patients enjoyed significant improvement in bladder capacity and bladder compliance . We conclude when the conservative therapy fails to cure and improve vesicoureteral reflux and urinary incontinence , surgical interventions including anti-reflux surgery and augmentation cystoplasty with or without sling operation are recommended as a treatment option In severe chronic asthma , long-term oral steroids may be necessary to control symptoms . In patients in whom such treatment was under consideration , the efficacy and safety of salmeterol xinafoate 100 micrograms b.i.d . was investigated in a r and omized , double-blind , placebo-controlled parallel-group , multicentre study . One hundred and nineteen chronic symptomatic asthmatics were r and omized to receive either salmeterol , 100 micrograms b.i.d . ( n = 55 ; baseline % predicted morning peak expiratory flow ( PEF ) 59 % ; forced expiratory volume in one second ( FEV1 ) 66 % ) or placebo ( n = 64 ; baseline % predicted morning PEF 63 % ; FEV1 66 % ) both via the Diskhaler . Morning and evening PEF and asthma symptoms were recorded in daily record booklets by the patient over a 12 week period . A significant improvement in morning PEF was achieved after 1 month in the salmeterol treated group ; this persisted throughout the treatment period ( estimated treatment difference 22 L.min-1 ) . There was a significant increase in the proportion of symptom-free nights experienced by the salmeterol treated group ( 33 ( SD 32 ) % ) compared with placebo ( 13 ( 26 ) % ) , and a significant decrease in daily use of relief medication ( mean decrease 5.1 ( 4.7 ) doses per day with salmeterol , 2.5 ( 4.0 ) doses with placebo ) . Both treatments were well-tolerated , with no evidence of any difference in the side-effects associated with beta 2-agonists . In conclusion , the addition of salmeterol ( 100 micrograms daily ) to the existing treatment of chronic asthmatics under consideration for maintenance oral corticosteroid therapy is well-tolerated , improves lung function and provides additional symptom control This study aim ed to investigate and compare the incidence of metered-dose inhaler (MDI)-associated bronchoconstriction in an asthmatic population , following the use of three different MDIs . Two different placebo metered-dose inhaler preparations containing the same chlorofluorocarbons but differing in dispersant chemicals , one containing oleic acid ( MDI-OA ) and the other lecithin NF ( MDI-L ) , were compared with a MDI containing salmeterol xinafoate ( 25 micrograms ) and lecithin NF ( MDI-S ) . The study population comprised 11,850 asthmatic patients , who were assigned to receive two puffs from one of the three inhalers : MDI-S ( n = 3,948 ) ; MDI-L ( n = 3,942 ) ; or MDI-OA ( n = 3,960 ) . Peak expiratory flow ( PEF ) was measured before and 5 min after inhalation . A 20 % fall in PEF was defined as a clinical ly significant bronchoconstriction . Overall 180 ( 1.5 % ) patients demonstrated bronchoconstriction , 43 ( 1.1 % ) in the MDI-S group , 67 ( 1.7 % ) in the MDI-L group and 70 ( 1.8 % ) in the MDI-OA . A significantly lower incidence of bronchoconstriction was seen with the salmeterol xinafoate MDI compared to either of the other two preparations . The risk of acute bronchoconstriction was also shown to increase with age and with decreasing pretreatment PEF . The study has shown that acute bronchoconstriction is an uncommon adverse reaction following the use of metered-dose inhalers . In addition , the study suggests that one of the inert constituents currently within metered-dose inhalers is the likely source of the irritant leading to bronchoconstriction BACKGROUND --Beta-2 agonists protect against non-specific bronchoconstricting agents such as methacholine , but it has been suggested that the protection afforded by long acting beta 2 agonists wanes rapidly with regular treatment . METHODS --The changes in airway responsiveness were investigated during and after eight weeks of regular treatment with salmeterol 50 micrograms twice daily in 26 adult asthmatic patients , 19 of whom were receiving maintenance inhaled corticosteroids . The study was of a r and omised , placebo controlled , double blind design . Airway responsiveness to methacholine  was measured as PD20 by a st and ardised dosimeter technique 12 hours after the first dose , at four weeks and eight weeks during treatment ( 12 hours after the last dose of test medication ) , and at 60 hours , one week and two weeks after stopping treatment . RESULTS --There were no significant differences between the baseline characteristics of the two groups . A significant improvement in PD20 was seen at all points during treatment with salmeterol compared with the placebo group , with no significant fall off with time . PD20 measurements returned to baseline values after cessation of treatment with no significant difference from the placebo group . CONCLUSIONS --Salmeterol gave significant protection against methacholine induced bronchoconstriction 12 hours after administration . This protection was of small magnitude , but there was no significant attenuation with eight weeks of regular use and no rebound increase in airway responsiveness on stopping treatment in a group of moderate asthmatic patients , the majority of whom were receiving inhaled corticosteroids It has been hypothesized that regular inhaled beta2-agonist therapy causes desensitization of beta2-receptors . The aim of this study was to define whether beta2-receptor desensitization occurs after treatment with the long-acting beta2-agonist salmeterol , assessed by measuring the bronchodilator response to cumulative repeated doses of inhaled salbutamol before and after treatment . Forty nine stable adult patients with asthma were r and omized to receive either salmeterol 50 microg b.d . or placebo b.d . from an Accuhaler for 4 weeks after an initial 2 week run-in period without beta2-agonists . All patients were receiving inhaled corticosteroids .  Bronchodilator responsiveness to cumulative repeated doses of inhaled salbutamol were measured before and 12 and 36 h after the last dose of study treatment . The primary efficacy endpoint was the peak forced expiratory volume in one second ( FEV1 ) response before and after treatment . There were no significant differences between the two treatment groups in the absolute peak FEV1 or maximal peak expiratory flow ( PEF ) results 12 or 36 h after the last dose of study treatment . Significantly higher clinic lung function and diary card parameters were noted in the salmeterol group when compared to the placebo-treated patients , demonstrating the beneficial effects of regular salmeterol . Regular salmeterol usage did not lead to reduced efficacy of usual or higher than usual doses of salbutamol OBJECTIVE Using a model of natural allergen exposure , we examined the effect of regular treatment with salmeterol on allergen-induced  changes in airway responsiveness and exhaled nitric oxide ( ENO ) . DESIGN Double-blind , r and omized , parallel-group study . SETTING Specialist allergy unit in a university hospital . PATIENTS Asthmatic patients sensitized to pollen allergens were r and omly allocated to monotherapy with salmeterol ( n = 14 ) or placebo ( n = 13 ) . INTERVENTIONS Salmeterol , 25 micro g , and placebo inhalers , two puffs bid , for 6 weeks . MEASUREMENTS Spirometry , the level of a provocative concentration of a substance ( methacholine ) causing a 20 % fall in FEV(1 ) ( PC(20 ) ) , the PC(20 ) level for adenosine 5'-monophosphate ( AMP ) , and ENO were measured before the pollen season and were repeated at the height of the pollen season after 6 weeks of treatment with salmeterol or placebo . RESULTS The decrease in FEV(1 ) during the pollen season was significantly larger in the placebo group than in the salmeterol group , the mean difference in the change between the groups being 0.20 L ( 95 % confidence interval , 0.03 to 0.35 ; p = 0.047 ) . Changes in PC(20 ) for methacholine , PC(20 ) for AMP , and ENO levels were not significantly different between treatment groups . However , a mean ( + /- SEM ) decrease in the PC(20 ) for methacholine of -1.0 + /- 0.4 doubling concentrations was observed within the placebo group ( p = 0.03 ) , whereas no significant changes were observed within the salmeterol group . A significant decrease in PC(20 ) for AMP ( doubling concentrations ) was observed within the placebo group ( -2.1 + /- 0.6 ; p = 0.003 ) and the salmeterol group ( -1.5 + /- 0.4 ; p = 0.003 ) . ENO concentrations increased significantly among the placebo and the salmeterol groups during natural pollen exposure . CONCLUSION These observations indicate that natural allergen exposure and the regular use of salmeterol are not associated with a greater increase in ENO and airway responsiveness than allergen exposure alone 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 STUDY OBJECTIVE To determine whether a spacer device design ed as a valved holding chamber with a flow signal increases the efficacy of the long-acting beta(2)-agonist , salmeterol , in patients who use incorrect technique with metered-dose inhaler ( MDI ) alone . DESIGN Double-blind , r and omized , placebo-controlled study . SETTING University hospital outpatient rooms . PATIENTS Twenty adult out patients with stable persistent asthma , receiving a daily anti-inflammatory drug . INTERVENTIONS Patients were r and omized to either salmeterol MDI ( incorrect use : 1 s after actuating MDI , inhale rapidly ) and placebo plus spacer ( correct use : inhale slowly as MDI is actuated , continue to inhale slowly and deeply ) or placebo MDI ( incorrect use ) and salmeterol plus spacer ( correct use ) . The following week , patients received the opposite treatment . The dose was two puffs from each device on each treatment day ; each puff was separated by 1 min . MEASUREMENTS AND RESULTS After baseline peak expiratory flow ( PEF ) , salmeterol was administered and serial PEF determined ( 0.5 , 1 , 2 , 3 , 4 , 6 , 8 , 10 , and 12 h ) . Administration of salmeterol MDI plus spacer result ed in significantly greater increases in PEF from baseline vs MDI at 4 h ( 44 L/min vs 10 L/min ; p < 0.01 ) and 6 h ( 49 L/min vs 24 L/min ; p < 0.05 ) . Both methods of administration were equally well tolerated . CONCLUSION We conclude that patients who have poor timing and rapid inhalation with salmeterol MDI alone will have greater increases in PEF at 4 h and 6 h and no additional side effects if the dose is administered with a valved holding chamber that is used correctly . Further study is needed regarding other errors in MDI technique with salmeterol BACKGROUND Montelukast , a leukotriene receptor antagonist , and salmeterol , a long-acting beta(2)-receptor agonist , each have demonstrated benefits in the treatment of exercise-induced bronchoconstriction ( EIB ) in short-term studies . Direct comparisons between these agents in long-term studies are limited . OBJECTIVE We sought to compare montelukast and salmeterol in the long-term treatment of EIB . METHODS One hundred ninety-seven patients with mild asthma and a postexercise fall in FEV(1 ) of at least 18 % were r and omized ( double-blind ) to receive montelukast 10 mg once daily or salmeterol 50 microg twice daily for 8 weeks . Exercise challenge was repeated at day 3 , week 4 , and week 8 after r and omization near the end of the dosing interval for both drugs . The primary efficacy endpoint was the maximal percent fall in postexercise FEV(1 ) at week 8 . RESULTS Montelukast was effective in treating EIB without inducing tolerance and provided superior ( P < /=.001 ) protection than salmeterol at weeks 4 and 8 , with comparable protection at day 3 . The frequency of respiratory clinical adverse events ( P = .046 ) and discontinuations because of clinical adverse events ( P = .052 ) were less with montelukast . CONCLUSION The effect of montelukast was greater than that of salmeterol in the chronic treatment of EIB over a period of 8 weeks in patients with mild asthma as demonstrated by effect size , maintenance of effect , and fewer respiratory clinical adverse events during the study period . Montelukast may be a better alternative to salmeterol as a controller agent for the chronic treatment of EIB 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 Traditional clinical outcomes have demonstrated that salmeterol improves pulmonary function and reduces asthma symptoms . However , they do not evaluate how patients perceive the effect of therapeutic intervention on day-to-day functioning and well-being . OBJECTIVE We sought to evaluate the impact of salmeterol on disease-specific quality of life with the Asthma Quality -of-Life Question naire , as well as the efficacy and safety of salmeterol in patients with stable asthma who were symptomatic despite daily use of inhaled corticosteroids . METHODS This was a r and omized , double-blind , placebo-controlled , parallel-group study of 506 patients . Patients were treated with 42 microg salmeterol or placebo twice daily for 12 weeks delivered through a metered dose inhaler . RESULTS Mean change from baseline in asthma quality -of-life scores was significantly greater ( p < or = 0.006 ) after 12 weeks of treatment with salmeterol compared with placebo ( " as-needed " albuterol ) in global scores ( 1.08 vs 0.61 ) and individual domains ( activity limitations , 0.91 vs 0.54 ; asthma symptoms , 1.28 vs 0.71 ; emotional function , 1.17 vs 0.65 ; and environmental exposure , 0.84 vs 0.47 ) . Patients treated with salmeterol experienced significantly greater improvements from baseline to week 12 compared with placebo in FEV1 ( 0.42 L vs 0.15 L , p < 0.001 ) , morning peak expiratory flow ( 47 L/min vs 14 L/min , p < 0.001 ) , evening peak expiratory flow ( 29 L/min vs 11 L/min , p < 0.001 ) , and asthma symptom scores ( daytime scores reduced by 0.55 vs 0.30 , p < 0.001 ) . Patients treated with salmeterol used significantly less supplemental albuterol ( reduced by 3 puffs/day vs 1 puff/day , p < 0.001 ) . CONCLUSION Salmeterol provided significantly greater improvement in quality -of-life outcomes in patients whose asthma symptoms are not well controlled with inhaled corticosteroids . These results demonstrate that the benefits of salmeterol are not limited to conventional clinical measures of efficacy 1 Although the clinical effects of the tulobuterol patch have been reported to include an increase in morning peak expiratory flow ( PEF ) values and a decrease of symptoms and the frequency of the rescue use of inhaled short‐acting b2‐adrenoceptor agonists , no trials comparing the efficacy of the tulobuterol patch to other st and ard inhaled long‐acting b2‐adrenoceptor agonists have yet been conducted . The aim of the present study was to compare the clinical effects of the patch formulation of tulobuterol with those of inhaled salmeterol in moderate to severe asthma . 2 Fifty‐four patients with moderate to severe asthma , whose conditions were suboptimally controlled despite receiving inhaled corticosteroids , were recruited . The study was a prospect i ve , r and omized trial of cross‐over design comparing the effects of 4 weeks treatment with tulobuterol patch , 2 mg once daily , and salmeterol , 50 mg twice daily . The mean prebronchodilator morning PEF during the last 14 days of each treatment period and health‐related quality of life ( HRQoL ) were the primary outcome variables . The HRQoL was assessed using the St George 's Respiratory Question naire . 3 Forty‐four patients ( 81.5 % ) completed the trial and were included in the analysis . The mean morning PEF and HRQoL score were significantly improved in both the salmeterol ( P < 0.0001 and P < 0.05 , respectively ) and the tulobuterol patch ( P < 0.01 and P < 0.05 , respectively ) treatment periods compared with the run‐in period . Although the mean morning PEF was significantly higher in the salmeterol‐treated group than in the tulobuterol‐treated group ( P < 0.001 ) , the HRQoL scores were comparable . 4 The tulobuterol patch may be useful as a controller medication in addition to inhaled corticosteroids in moderate to severe asthma 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 The airway response and cardiovascular effects of salmeterol ( SM ) and salbutamol ( SB ) given as a single dose from metered-dose inhalers were studied in 10 patients with mild asthma . In a double-blind , r and omized , cross-over , placebo-controlled study , the subjects received SM 100 micrograms ( four puffs , 25 micrograms per actuation ) , SB 200 micrograms ( four puffs , 50 micrograms per actuation ) or placebo ( P ) ( four puffs ) . SM caused a greater and longer lasting increase of peak expiratory flow rate ( PEFR ) value than SB and P. There was no significant difference either with P or the study drugs in heart rate , PR interval , QT interval corrected for heart rate ( QTc ) , incidence of ventricular and supraventricular ectopics , and in echocardiogram evaluation . These findings show that at dosages based on those used in clinical practice salmeterol causes cardiovascular effects comparable to those induced by salbutamol and confirm the favourable cardiac safety profile of this drug BACKGROUND Current UK and international guidelines on asthma management recommend that , in pediatric patients still symptomatic on treatment with high-dose inhaled corticosteroids , consideration should be given to the introduction of regular twice daily long-acting beta 2-agonists . OBJECTIVE The purpose of this study was to assess the efficacy and safety of inhaled salmeterol xinafoate 50 micrograms bid via the Diskhaler when added to the existing treatment of children with moderate to severe asthma . METHODS A 12-week multicenter , double-blind , placebo-controlled , parallel group study was conducted at 78 hospital centers throughout the United Kingdom , involving 210 asthmatic children aged between 4 and 16 years of age .  Morning peak expiratory flow ( PEF ) , evening PEF , night-time and daytime symptoms and relief medication usage were recorded daily by the patient or parent over a 12-week treatment period . RESULTS Compared with placebo , the addition of salmeterol xinafoate to existing high dose inhaled corticosteroid treatment significantly improved mean morning PEF expressed as percent predicted ( PEF-PP ) during the first 4 weeks of treatment ( median increase 6.5 percentage points P < .001 ) . This effect persisted throughout the 12-week treatment period ( P < .05 ) . Both groups demonstrated an overall improvement in mean morning PEF-PP , 7.5 percentage points for salmeterol xinafoate and 4 percentage points for placebo .  The mean evening PEF-PP followed a similar although less pronounced trend which was significant only during the first 4 weeks of treatment ( P = .014 ) . Daytime relief medication and recorded symptoms were reduced significantly in both groups . There was a greater improvement in the number of symptom-free days during the first 4 weeks ( P < .01 ) and the last 4 weeks ( P < .05 ) of treatment for salmeterol xinafoate . The overall incidence and nature of minor adverse events was similar in both groups . CONCLUSIONS This study demonstrates that the addition of salmeterol xinafoate to inhaled corticosteroid therapy in symptomatic asthmatic children significantly improves morning PEF-PP , and reduces their symptoms and use of relief medication 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 : Patients with severe asthma require multiple therapies to improve lung function and reduce symptoms . The use of long-acting inhaled β2-agonists plus theophylline in addition to high doses of inhaled corticosteroids ( ICSs ) for the treatment of severe asthma has not been extensively studied . Objective : The purpose of this study was to investigate the efficacy and safety of salmeterol combined with high-dose ICSs plus theophylline in severe asthma . Methods : We undertook a r and omized , placebo-controlled , crossover study to compare the effect of a single dose of inhaled salmeterol ( 50 µg ) or a placebo in patients with severe asthma whose conditions were not being adequately controlled by therapies with high-dose ICSs plus oral theophylline with or without leukotriene receptor antagonists .  Results : Twenty patients took part in the trial . Compared with the placebo , the inhalation of salmeterol significantly increased the FEV1 . Even in the 9 patients treated with high-dose ICSs plus theophylline plus a leukotriene receptor antagonist , the FEV1 increased significantly more after salmeterol than after the placebo . Conclusion : Patients with severe asthma receiving high-dose  ICSs plus theophylline may benefit from the addition of salmeterol BACKGROUND Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli . Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach , but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents . We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma . METHODS In a parallel , double-blind study , 24 patients with mild asthma were r and omly assigned to treatment with either inhaled salmeterol ( 50 micrograms , twice daily ) ( n = 12 ) or placebo ( n = 12 ) during an eight-week trial . Methacholine challenge was performed before , during , and after the treatment period . Methacholine responsiveness was measured as the provocative concentration ( PC20 ) that caused a 20 percent decrease in the forced expiratory volume in one second ( FEV1 ) . RESULTS There was a significant increase in FEV1 one hour after the inhalation of salmeterol ( P = 0.006 ) , which did not differ significantly on days 0 , 28 , and 56 of the treatment period ( increase , 9.8 , 9.4 , and 8.8 percent of predicted FEV1 , respectively ; P = 0.91 ) . On the first treatment day , salmeterol afforded significant protection against methacholine-induced bronchoconstriction , as shown by a 10-fold increase in the PC20 as compared with the value at entry ( P less than 0.001 ) . After four and eight weeks of treatment , however , the salmeterol-induced change in the PC20 was significantly attenuated ( P less than 0.001 ) to only a twofold increase . Two and four days after treatment ended , the PC20 was not significantly different from the value before treatment ( P = 0.15 ) . CONCLUSIONS Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus , in this case inhaled methacholine , despite well-maintained bronchodilation . This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma BACKGROUND An effective , long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs . We compared a new long-acting , inhaled beta 2-adrenoceptor agonist , salmeterol , with a short-acting beta 2-agonist , albuterol , in the treatment of mild-to-moderate asthma . METHODS We r and omly assigned 234 patients ( 150 male and 84 female patients 12 to 73 years old ) to one of three treatment groups : one group received 42 micrograms of salmeterol twice daily , one received 180 micrograms of albuterol four times daily , and one received placebo . Treatment was assigned in a double-blind fashion , and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period . RESULTS Measurements of the forced expiratory volume in one second , performed hourly for 12 consecutive hours , showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart ( 6.3 vs. 4.9 liter.hr , P < 0.05 ) . The difference was significant on day 1 and at week 4 of the study , but not at week 8 or 12 . Salmeterol was also more effective than albuterol or placebo ( with albuterol taken as needed ) in increasing the morning peak expiratory flow rate : salmeterol induced a mean increase of 24 liters per minute over the pretreatment values , as compared with a decrease of 6 liters per minute with albuterol ( P < 0.001 ) and an increase of 1 liter per minute with placebo ( P = 0.002 ) . The mean overall symptom score was improved most by salmeterol treatment ( P < 0.05 ) , with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent , respectively ; there were no differences in results between albuterol treatment and placebo administration . We found no evidence of tolerance to the bronchodilating effects of salmeterol , and adverse reactions to all the treatments were infrequent and mild . CONCLUSIONS For the management of mild-to-moderate asthma , salmeterol given twice daily is superior to albuterol given either four times daily or as needed Two multicenter , r and omized , double-masked , placebo-controlled studies involving 451 adolescent and adult patients with mild-to-moderate asthma compared the efficacy and safety of salmeterol powder 50 micrograms twice daily with albuterol 180 micrograms four times daily or placebo ( with albuterol as needed ) for 12 weeks . Patients had forced expiratory volume in 1 second ( FEV1 ) of 50 % to 80 % . Throughout the 12-week treatment period , the mean change from baseline in percentage of predicted FEV1 was significantly greater with salmeterol than with placebo ;  mean area under the curve for FEV1 was significantly greater with salmeterol than with albuterol or placebo . Significant improvements in morning and evening peak expiratory flow , percentage of nights without awakening , and asthma symptoms were observed with salmeterol . Salmeterol was well tolerated , and no clinical ly significant changes in electrocardiographic activity were observed BACKGROUND An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children . The role of long-acting beta2-adrenergic-receptor agonists , such as salmeterol , needs to be defined . METHODS We conducted a r and omized , double-blind , placebo-controlled , parallel-group , one-year study of 241 children ( mean [ + /-SD ] age , 9.3+/-2.4 years ) with clinical ly stable asthma and less than one month of prior glucocorticoid use . We compared inhaled beclomethasone dipropionate ( 200 microg twice daily ) with salmeterol xinafoate ( 50 microg twice daily ) and placebo ( lactose ) . The primary outcome measure , airway responsiveness ( as assessed with a methacholine challenge ) was evaluated before treatment ; after 3 , 6 , 9 , and 12 months of treatment ( 12 and 36 hours after study medications had been withheld ) ; and 2 weeks after the end of treatment . Spirometry , symptoms , use of rescue medication ( 200 microg of albuterol inhaled as needed ) , and adverse effects were also assessed . RESULTS During months 1 through 12 overall , beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol ( P= 0.003 ) or placebo ( P<0.001 ) . This effect was lost two weeks after treatment had been stopped . As compared with placebo , beclomethasone was associated with less variability between morning and evening in the peak expiratory flow ( P=0.002 ) , as was salmeterol ( P=0.02 ) . Beclomethasone was also associated with a reduced need for albuterol as rescue therapy ( P<0.001 ) and fewer withdrawals because of asthma exacerbations ( P=0.03 ) , but salmeterol was not ( P=0.09 and 0.55 , respectively ) . During months 1 through 12 , linear growth was 3.96 cm in the children receiving beclomethasone , as compared with 5.40 cm in the salmeterol group ( P=0.004 ) and 5.04 cm in the placebo group ( P=0.018 ) . Height was not measured after treatment ended . CONCLUSIONS Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma , but it was associated with decreased linear growth . Salmeterol was not as effective as beclomethasone in reducing airway hyperresponsiveness or in controlling symptoms ; however , it was an effective bronchodilator and was not associated with rebound airway hyperresponsiveness , masking of symptoms , or adverse effects CONTEXT Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid ( ICS ) therapy . OBJECTIVE To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen . DESIGN AND SETTING A 24-week r and omized , controlled , blinded , double-dummy , parallel-group trial conducted at 6 National Institutes of Health-sponsored , university-based ambulatory care centers from February 1997 through January 1999 . PARTICIPANTS One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide ( 400 microg twice per day ) . INTERVENTION Patients continued triamcinolone therapy and were r and omly assigned to receive add-on therapy with either placebo ( placebo-minus group , n = 21 ) or salmeterol xinafoate , 42 microg twice per day ( n = 154 ) for 2 weeks . The entire placebo-minus group was assigned and half of the salmeterol group ( salmeterol-minus group ) was r and omly assigned to reduce by 50 % ( for 8 weeks ) then eliminate ( for 8 weeks ) triamcinolone treatment . The other half of the salmeterol group ( salmeterol-plus group ) was r and omly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks ( active control group ) . MAIN OUTCOME MEASURE Time to asthma treatment failure in patients receiving salmeterol . RESULTS Treatment failure occurred in 8.3 % ( 95 % confidence interval [ CI ] , 2%-15 % ) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8 % ( 95 % CI , 0%-7 % ) of the salmeterol-plus group during the same period . Treatment failure occurred in 46.3 % ( 95 % CI , 34%-59 % ) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7 % ( 95 % CI , 5%-22 % ) of the salmeterol-plus group . The relative risk ( 95 % CI ) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 ( 2.0 - 9.2 ) compared with the salmeterol-plus group ( P<.001 ) . CONCLUSIONS Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol , a substantial reduction ( 50 % ) in triamcinolone dose can occur without a significant loss of asthma control . However , total elimination of triamcinolone therapy results in a significant deterioration in asthma control and , therefore , can not be recommended BACKGROUND The efficacy and safety of salmeterol powder have not previously been evaluated in children with asthma in the United States . OBJECTIVE The efficacy and safety of salmeterol powder versus placebo were compared in children between the ages of 4 and 11 years with chronic persistent asthma . METHODS A r and omized , double-blind , placebo-controlled , parallel group trial was performed at 11 clinical centers . Two hundred seven patients were r and omly assigned to receive 50 microg salmeterol powder or placebo ( and albuterol as needed ) twice daily via a breath-actuated device for 12 weeks . Twelve-hour serial pulmonary function assessment s were conducted on day 1 and at week 12 . Daily recordings of morning and evening peak expiratory flow ( PEF ) , supplemental albuterol use , asthma symptoms , and nocturnal awakenings were assessed . RESULTS On day 1 and at week 12 , weighted mean percent of predicted PEF ( P < .001 , day 1 and P=.008 , week 12 ) and weighted mean forced expiratory volume in one second ( P < .001 , day 1 and week 12 ) were significantly higher at all timepoints evaluated over the 12-hour postdosing period in patients treated with salmeterol powder compared with placebo . Overall reductions in supplemental albuterol use and mean asthma symptom scores were also significantly greater in children administered salmeterol compared with placebo ( P=.004 and P=.006 , respectively ) . The frequency of adverse events was similar in the two treatment groups . CONCLUSION Salmeterol powder ( 50 microg twice daily ) is effective and safe in producing bronchodilation and relieving symptoms in children with chronic persistent asthma during 12 weeks of treatment The aim of this study was to assess the efficacy and safety of inhaled salmeterol 100 micrograms b.d . ( SM ) versus inhaled salbutamol 400 micrograms q.d.s . ( SB ) , both via the Diskhaler , when added to concurrent treatment , in asthmatic patients who were not controlled on high doses of inhaled steroids ( > or = 1,500 micrograms beclomethasone dipropionate ( BDP ) or equivalent daily ) . This was a multicentre , parallel group , double-blind study in which 190 patients with a forced expiratory volume in one second ( FEV1 ) or peak expiratory flow rate ( PEFR ) of 30 - 75 % predicted and 15 % reversibility to inhaled bronchodilator were r and omized to treatment for 6 weeks . In the SM group , morning PEFR increased from 281 to 315 L-min-1 during treatment and in the SB group from 311 to 315 L.min-1 ( p < 0.001 ) . The SM group showed significantly better reduction in diurnal variation , from 39 to 22 L.min-1 during treatment , than the SB group ( 34 to 37 L.min-1 ) ( p < 0.001 ) . There was a significantly greater improvement in FEV1 in the SM group ( from 1.63 to 1.85 L ) than in the SB group ( from 1.79 to 1.84 L ) . The SM group had significantly more symptom-free nights than the SB group ( p < 0.001 ) , and also more " rescue-free " nights ( p = 0.04 ) . The adverse event profile was similar in both groups . This study indicates that in asthmatic patients , not controlled on high-dose inhaled steroids , inhaled salmeterol 100 micrograms b.d . significantly improves lung function and reduces asthma symptoms 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 We have investigated the ability of salbutamol to protect against bronchoconstriction induced by methacholine , histamine , and adenosine 5'-monophosphate ( AMP ) in nine subjects with asthma . In a double-blind , placebo-controlled study , salbutamol , 2.5 mg administered by nebulization , increased the geometric mean provocation concentrations of methacholine , histamine , and AMP required to produce a 20 % decrease in FEV1 from 0.3 to 2.2 , 0.4 to 3.8 , and 4.0 to 106.7 mg/ml after placebo and active treatment , respectively ( p less than 0.01 ) . Thus , this dose of beta 2-adrenoceptor agonist displaced the concentration-response curves for methacholine , histamine , and AMP to the right in a parallel fashion by 8.8 ( 0.6 to 29.3)- , 10.3 ( 1.4 to 33)- , and 26.6 ( 1.5 to 76.6)-fold , respectively , the difference between the results for AMP and those for histamine and methacholine being statistically significant ( p less than 0.01 ) . For six of the nine subjects studied , salbutamol displaced the concentration-response curve for AMP to the right by greater than 50-fold . There was no correlation between bronchodilatation and protection against bronchoconstriction induced by any of the agonists . We conclude that salbutamol protects against bronchoconstriction provoked by methacholine and histamine by functional antagonism , whereas with AMP , an additional activity is demonstrable , possibly involving inhibition of mast cell-mediator release BACKGROUND Disodium cromoglycate and salmeterol , a long acting beta 2-agonist , achieve their therapeutic effects through different mechanisms but both are used as maintenance therapies in asthma . OBJECTIVES It was the purpose of this study to assess the comparative efficacy and safety of both drugs when used as prophylactic therapy for adults with symptomatic mild to moderate asthma . METHODS In this 8-week , double-blind , double-dummy , parallel group , multicenter study , 134 adult patients with a forced expiratory volume in one second ( FEV1 ) ranging from 60 % to 90 % predicted , reversibility in FEV1 of greater than 15 % and a total daily symptom score of at least 2 or a diurnal variation in peak expiratory flow ( PEF ) of greater than 15 % on three of the seven days of the run-in period , were r and omized to either salmeterol , 50 microgram twice daily ( via metered-dose inhaler ) , or disodium cromoglycate , 20 mg four times daily ( via Spinhaler ) , plus corresponding placebo . Approximately 50 % of the total population were concurrently receiving inhaled corticosteroids . RESULTS Salmeterol was significantly better than disodium cromoglycate in improving both morning ( mean difference between treatments = 31 L/min ; P = .007 ) and evening PEF ( mean difference between treatments = 29 L/min ; P = .008 ) . Both treatments were however , associated with significant improvement in FEV1 , daytime and night-time symptoms score and use of rescue salbutamol ( P < .001 ) . Although salmeterol tended to produce greater improvement than disodium cromoglycate in all these parameters only the difference in rescue salbutamol achieved statistical significance ( P = .021 ) . Salmeterol was the preferred treatment of both the patients and the physicians ( P = .002 ) . Both treatments were well tolerated with a similarly low incidence of adverse event reports , the majority of which were related to underlying disease . CONCLUSION Salmeterol , 50 microgram twice daily , provides better control of symptomatic mild to moderate asthma than disodium cromoglycate , 20 mg four times daily Exercise-induced bronchoconstriction is common in patients with chronic asthma ( 1 ) . Airway cooling or desiccation during exercise may trigger activation of mast cells and release of such mediators as histamine and cysteinyl leukotrienes , result ing in bronchospasm ( 1 , 2 ) . Cysteinyl leukotrienes ( LTC4 , LTD4 , and LTE4 ) , synthesized from arachidonic acid through the 5-lipoxygenase pathway , are potent bronchoconstrictors , with an effect greater than 1000 times that of histamine ( 3 - 5 ) . Several research ers have demonstrated an increase in urinary concentrations of LTE4 after exercise ( 6 , 7 ) . Prophylaxis against exercise-induced bronchoconstriction with inhaled mast cell-stabilizing agents and short-acting -agonists must be administered 15 to 30 minutes before exercise . The long-acting inhaled -agonist salmeterol protects against exercise-induced bronchoconstriction for up to 12 hours , thus providing more flexibility in the dosing schedule for active patients with asthma ( 8 , 9 ) . However , in some patients , tolerance to salmeterol develops with long-term use , and the level of bronchoprotection diminishes by 6 to 9 hours ( 10 - 12 ) . Montelukast sodium , a leukotriene receptor antagonist , is a potent oral medication for the treatment of asthma . The leukotriene receptor antagonists have demonstrated a significant bronchoprotective effect with exercise after one or two doses ( 13 , 14 ) . In patients with exercise-induced bronchoconstriction , short-term treatment with montelukast ( Singulair , Merck & Co. , Inc. , Whitehouse Station , New Jersey ) given once daily diminished the postexercise response , as described by the area under the FEV1 time curve ( AUC0 - 60 min ) , by more than 50 % , even at the end of the dosing interval ( 20 to 24 hours after administration ) ( 15 , 16 ) . Furthermore , tolerance to the bronchoprotective effects of montelukast did not occur with long-term administration ( 17 ) . We sought to test the hypothesis that the bronchoprotective effects of montelukast were greater than those of salmeterol in patients with chronic asthma who experienced exercise-induced bronchoconstriction . Methods Design We conducted a r and omized , parallel-group study consisting of a 2-week , single-blind placebo baseline period followed by an 8-week , double-blind treatment period with montelukast sodium ( 10-mg tablet taken orally once in the evening ) or inhaled salmeterol ( 50-g aerosol formulation [ 2 puffs ] taken twice daily ) . Seventeen clinical study sites participated in the trial . To mask formulation differences , a double-dummy treatment regimen was used . Each patient received one tablet daily ( active agent or matching placebo ) or one inhaler twice daily ( active agent or matching placebo ) for both the single-blind and double-blind treatment periods . A computer-generated allocation schedule with a blocking factor of 4 was produced by the statistician . Each center was given a block of allocation numbers that were assigned sequentially to consecutive r and omly assigned patients . Spirometric measurements were obtained before and after st and ardized exercise challenges at the beginning and end of the baseline period , within the first 3 days of the double-blind treatment period , and at weeks 4 and 8 of the treatment period . Additional measurements were physical examination , vital signs , electrocardiography , chest radiography , and laboratory tests ( hematology , chemistry profile , and urinalysis ) . At each visit , all spontaneously reported adverse events were recorded . The protocol was approved by the institutional review board of each site , and written informed consent was obtained from each patient . Inclusion Criteria Male and female patients 15 to 45 years of age with a history of chronic asthma were enrolled . All patients had an FEV1 of at least 65 % of the predicted value at rest and a decrease in FEV1 of at least 20 % after a st and ardized exercise challenge on two occasions during the baseline period . All patients had been nonsmokers for at least 1 year and had a smoking history of less than 15 pack-years . Exclusion Criteria Persons who had upper respiratory infection or exacerbation of asthma requiring emergency care within the past month or were hospitalized for asthma in the past 3 months were excluded . Use of oral or inhaled corticosteroids , theophylline , cromolyn sodium , nedocromil , oral -agonist , and long-acting antihistamines was prohibited before and during the study . Use of inhaled albuterol for symptomatic relief of asthma and use of short-acting antihistamines were permitted . Evaluations A st and ard spirometer ( Puritan-Bennett PB100/PB110 , Puritan-Bennett , Wilmington , Massachusetts ) was used to obtain all spirometric measurements according to American Thoracic Society st and ard criteria ( 18 ) . Patients had to have discontinued use of inhaled short-acting -agonists for 6 hours before the visit . Exercise testing was done in the early afternoon near the trough of effect for both drugs according to a method described elsewhere ( 17 ) . Measurements were obtained 20 and 5 minutes before exercise ( prechallenge period ) . Exercise challenge was performed only if the average FEV1 in the prechallenge period was greater than 65 % of predicted ; otherwise , the test was rescheduled . Patients  exercised on a treadmill while inhaling room temperature , compressed , dry air . During the first test , the speed and gradient of the treadmill were adjusted to achieve 80 % to 90 % of the patient 's age-predicted maximum heart rate . The setting s were maintained for a total of 6 minutes ; the same setting s were used for future tests . This level of exercise has been used to quantify the level of bronchoconstriction associated with regular exercise ( 19 ) . Serial spirometric measurements were obtained at 0 , 5 , 10 , 15 , 30 , 45 , and 60 minutes after exercise ( postexercise period ) . Additional measurements were carried out at 15-minute intervals for up to 90 minutes if the patient 's FEV1 had not returned to within 5 % of the prechallenge value by 60 minutes . If the patient 's FEV1 did not return to the prechallenge value by 90 minutes after exercise , a rescue dose of inhaled -agonist was administered at the discretion of the study investigator . Statistical Analysis An all- patients -treated analysis , which included patients with a baseline visit and at least one post-r and omization visit , was performed . The change from baseline in the maximal percentage decrease in FEV1 after exercise at the end of 8 weeks of treatment was the primary end point . Analysis of variance was used to compare the two treatment groups . The analysis of variance model included terms for treatment , center , and the interaction of treatment and center . Ninety-five percent CIs for within-group means and the difference between groups were constructed to assess the magnitude of the treatment effect . Analysis of variance on the ranked data was used to analyze percentage inhibition for all end points . In the event of early termination of the exercise challenge because of administration of rescue medication , the largest percentage decrease in FEV1 achieved before administration of rescue medication was used in the analysis . Secondary end points were change from baseline for maximal percentage decrease in FEV1 at days 1 to 3 and week 4 , the time required after maximal decrease in FEV1 to return within 5 % of prechallenge values ( time to recovery ) , and the AUC0 - 60 min at all visits . The mean of the 20- and 5-minute prechallenge measurements was used as the pre-exercise FEV1 value . If a patient required rescue with inhaled -agonist during the postexercise period , the last recorded FEV1 value was used and carried forward for all subsequent readings and 100 minutes was entered for the end point of time to recovery . The AUC0 - 60 min was calculated by using the trapezoidal method . If a patient 's FEV1 did not decrease below 95 % of the prechallenge value , the time to recovery was assigned a value of zero . The persistence of effect over time was assessed by using a repeated- measures fixed-effects model with terms for center , treatment group , time , and the interaction of treatment group and time to calculate the rate of change over the treatment period . Persistence of effect was defined as a slope of zero . The magnitude of the slopes for each treatment group was estimated , and 95 % CIs were calculated . An overall test of equal slopes between the treatment groups was examined , and a 95 % CI on the difference in slopes between treatment groups was provided . The number and percentage of patients requiring rescue medication  during or at the end of the exercise test were summarized by treatment group at each time point . In addition , the number and percentage of patients whose decrease in FEV1 from pre-exercise levels was less than 10 % , 10 % to 20 % , 20 % to 40 % , and greater than 40 % were summarized by treatment group for each visit . The overall incidence of adverse events and laboratory abnormalities was assessed by using the Fisher exact test , and within-group changes in the number of laboratory abnormalities were assessed by using the McNemar test . Descriptive statistics were provided by treatment group for patient demographic characteristics , clinical characteristics , and baseline profile . The study was design ed with a sample size of 160 patients ( 80 patients per treatment group ) to have 95 % power ( two-sided test at = 0.05 ) to detect a 7 % difference in the mean change in maximal percentage decrease in FEV1 between treatments . All statistical analyses were performed by using SAS software , version 6 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding Source Funding for this trial was provided by Merck & Co. , Inc. , Whitehouse Station , New Jersey . Personnel from Merck U.S. Human Health , Clinical Development department played a significant role in the design , conduct , and analysis of the trial . The trial was conducted in accordance with guidelines for clinical trials of investigational agents established by U.S. regulatory authorities . Results The objective of this study was to compare the efficacy and safety of fluticasone propionate ( FP ) ( 44 µg)/salmeterol ( 21 µg ) delivered as two inhalations twice daily via a single hydrofluoroalkane ( HFA 134a ) metered dose inhaler ( MDI ) ( FSC ) with that of placebo HFA 134a ( PLA ) , fluticasone propionate 44 µg chlorofluorocarbon ( CFC ) alone and salmeterol 21 µg CFC alone ( S ) in patients ( n = 360 ) with persistent asthma previously treated with β2‐agonists ( short‐ or long‐acting ) or inhaled corticosteroids ( ICS ) . After 12 weeks of treatment , patients treated with FSC had a significantly greater increase ( p ≤ 0.006 ) in mean FEV1 AUC(bl ) compared with PLA , FP , or S. At end point , mean change from baseline in morning predose FEV1 for FSC ( 0.58 L ) was significantly ( p ≤ 0.004 ) greater than PLA ( 0.14 L ) , FP ( 0.36 L ) , and S ( 0.25 L ) . Patients treated with FSC also had a significantly higher probability of remaining in the study without being withdrawn due to worsening asthma ( 2 % ) compared with those in the PLA ( 29 % ) and S ( 25 % ) groups ( p < 0.001 ) . Finally , treatment with FSC result ed in significantly ( p ≤ 0.007 ) greater improvements in morning and evening peak expiratory flow , need for rescue albuterol , and asthma symptom scores compared with FP , S , and PLA . The safety profile of FSC was also similar to FP or S alone . Initial maintenance treatment of the two main components of asthma , inflammation , and smooth muscle dysfunction ( e.g. , bronchoconstriction ) , with FSC results in greater overall improvements in asthma control compared with treatment of either individual component alone The functional assessment of the response to bronchodilators in 2- to 5-year-old asthmatic children is technically difficult . For this reason , there have been no reports on the effects of long-acting bronchodilators , such as salmeterol , in this age group . Of the several techniques available for measuring resistance to airflow , forced oscillation remains the most adaptable to young children and the most practical for research and clinical use . In this study we used the Jaeger MasterScreen Impulse Oscillometry System to assess the response of 2 to 5 year-old asthmatic children to an inhaled long-acting bronchodilator , salmeterol , by comparing it to the effect of a st and ard dose of the short-acting bronchodilator , albuterol . We performed a placebo-controlled , r and omized , crossover study in 10 children aged 2 to 5 years who had a history of physician-diagnosed asthma and who were not on regular controller therapy . At weekly intervals after baseline measurements of reversibility , each child received two inhalations from an albuterol metered-dose inhaler ( MDI ) with a spacer ( 200 µg ) , or placebo MDI with spacer , or two inhalations from a salmeterol MDI ( 50 µg ) , or 50 µg from a salmeterol Diskus ® . Measurements were obtained at 5 , 30 , 60 , 360 , and 540 min , the last time interval only on the salmeterol days . Based on previous studies , total respiratory system reactance at 5 Hz ( X5 ) , calculated by the MasterScreen computer from mouth pressure and flow data , was used as the primary efficacy variable . The mean intra-individual variability in X5 was 10.5 % ( range 3.6 % to 17.9 % ) . The mean ( SE ) changes from baseline X5 at each time point were as follows : for placebo , 9.6 ( 3.0 ) , 10.1 ( 2.6 ) , 5.1 ( 2.9 ) , 6.1 ( 3.5 ) , p=0.36 vs. baseline ; after treatment with albuterol , 32.7 ( 3.8 ) , 53.9 ( 1.2 ) , 47.3 ( 5.4 ) , 18.1 ( 5.8 ) , p<0.01 vs. baseline at all time points ; after salmeterol MDI , 16 ( 6.4 ) , 28.9 ( 5.2 ) , 32.7 ( 3.9 ) , 34.6 ( 4.4 ) , 31.2 ( 4.8 ) , p<0.05 at 60 , 360 , and 540 min ; and after salmeterol Diskus ® , 16.4 ( 4.0 ) , 16.9 ( 6.6 ) , 27.8 ( 5.9 ) , 28.6 ( 5.6 ) , 33.8 ( 4.0 ) , p<0.05 at 540 min . No significant adverse events or electrocardiographic changes were noted at any time . Impulse oscillometry is an acceptable method of assessing airway responses to bronchoactive drugs in this age group . Compared to albuterol and to its effect in older children and adults , the response to salmeterol Diskus ® appears to be somewhat blunted in this age group . The MasterScreen system is well suited for pharmacodynamic studies and clinical investigations in pre-school-aged children OBJECTIVE Physical activity is an important and frequent trigger of airways obstruction in asthmatic children . We aim ed to compare the efficacies of 50 microg salmeterol twice daily and 2 mg SCG four times daily with respect to protection from exercise induced bronchoconstriction ( EIB ) . METHODS Twenty seven children and adolescents aged 4 to 16 years with mild or moderate exercise induced asthma ( FEV1 70 % to 90 % predicted ) were admitted to the study .  Exercise challenge was performed on a treadmill using a predefined protocol in order to produce 10 minutes of exercise at near-maximum targets . The trial had a r and omised , cross-over design comprising a 3-day run-in period and two 7-day treatment periods , separated by a one-week washout period . RESULTS The mean protective efficacy of salmeterol was larger than that of SCG . A difference between treatments of 39.7 % ( 95 % CI , - 0,8 to 68.9 % ) in favour of salmeterol was calculated using a Hodges-Lehmann-estimate . The maximum post-challenge fall in FEV subset 1 was significantly lower ( p<0.001 ) after salmeterol than after SCG ( - 5.6 + /- 6.4 % vs. -12.1 + /- 9.3 % , respectively ) . In addition , salmeterol improved base-line lung function to a greater degree than SCG . FEV1 increased by 0.4 l/sec after salmeterol , whereas no improvement was observed after SCG . CONCLUSIONS A one-week treatment with salmeterol 50 microg b.i.d in asthmatic children and adolescents provided better protection against EIB and improved baseline lung function as compared to SCG four times daily BACKGROUND The efficacy and safety of the aerosol metered-dose inhaler ( MDI ) formulation of salmeterol for asthma symptoms have been established . Recently , salmeterol has been introduced as a micronized powder formulation administered via a breath-activated multidose powder inhaler ( Diskus ) . OBJECTIVE A multicenter , r and omized , double-blind , double-dummy , parallel-group , placebo-controlled study involving 498 adolescents and adults with mild-to-moderate asthma was conducted to compare the efficacy and safety of salmeterol powder 50 microg twice daily via Diskus , salmeterol aerosol 42 microg twice daily via MDI , and placebo . METHODS Patients were r and omized to one of the three treatment groups for 12 weeks . Efficacy was assessed by serial measurements of forced expiratory volume in one second ( FEV1 ) over 12 hours , daily peak expiratory flow ( PEF ) , self-rated asthma symptom scores , nighttime awakenings , and supplemental albuterol use . Safety of each treatment was evaluated by monitoring vital signs , electrocardiograms , Holter monitoring , and occurrence of adverse events . RESULTS As compared with placebo , both salmeterol powder and aerosol produced significant improvement in FEV1 and PEF and decreased nighttime awakenings and supplemental albuterol use . There were no significant differences in the efficacy of the two salmeterol formulations . The magnitude of improvement in pulmonary function was undiminished over the 12-week study . Both formulations of salmeterol were well tolerated , with safety profiles not significantly different from placebo . CONCLUSION Results of this study indicate that salmeterol , administered either as a powder 50 microg twice daily via Diskus or as an aerosol 42 microg twice daily via MDI , produces clinical ly significant and comparable improvement in pulmonary function and is well tolerated in patients with mild-to-moderate persistent asthma BACKGROUND Therapy with salmeterol , a long-acting , selective , inhaled beta 2-adrenergic agonist , is effective and safe for patients with persistent asthma ; however , few long-term studies comparing salmeterol with current combination treatment regimens have been reported . METHODS A multicenter , r and omized , placebo-controlled , double-blind study was conducted in 386 patients over 41 to 46 weeks in 27 medical centers ( two thirds of the investigators were primary care physicians ) . Patients were r and omized to receive either salmeterol or placebo , and further r and omized to weaning or nonweaning from current asthma therapies ( except inhaled corticosteroids ) . Treatment groups were : salmeterol/weaning ( S + W ) , placebo/weaning ( P + W ) , salmeterol/no weaning ( S + NW ) , and placebo/no weaning ( P + NW ) . Attempts at active weaning were carried out at the discretion of the investigator for 2 to 6 weeks . Pulmonary function , albuterol use , and asthma symptoms were measured . RESULTS The clinical benefits of salmeterol occurred despite weaning off existing nonsteroidal asthma medications . The mean morning peak expiratory flow rate was significantly increased in the S + W group ( 32.3 L/min ) compared with both the P + W ( 4.9 L/min ) and P + NW ( 6.8 L/min ) groups ( P < .001 ) . Compared with the P + W and P + NW groups , the S + W group experienced significant ( P < .05 ) improvements in overall mean asthma symptom scores , mean number of puffs of supplemental albuterol , the percentage of days with no supplemental albuterol use , and the mean number of awakenings caused by asthma ( except for the P + NW comparison , P = .090 ) . No significant differences were noted between treatment groups in any safety evaluation , including 12-lead electrocardiograms . CONCLUSIONS The addition of salmeterol in the treatment of persistent asthma result ed in sustained improvement in pulmonary function and symptoms . The long-term use of salmeterol is safe and improves the clinical course and stability of asthma following reductions in nonsteroidal asthma therapy This study compared the efficacy of inhaled salmeterol ( SM ) 50 μmg twice a day with SM 100 μmg once a day ( at night ) and placebo in patients with poorly controlled nocturnal asthma despite treatment with corticosteroids , oral long‐acting bronchodilators , or both . This was a two‐center , double‐blind , r and omized , crossover study with three treatment periods , each of 3 weeks ’ duration . The first treatment period was preceded by two 1‐week run‐in periods , and the last treatment period was followed by a 2‐week follow‐up period . In the three treatment periods , patients received either SM 50 μmg twice a day , SM 100 μmg nightly , or placebo , in r and omized order . Salbutamol metered‐dose inhaler was given as relief medication . Of the 41 r and omized patients , 38 were evaluable for more than one treatment period . Efficacy and safety were determined by daily record card data : morning and evening peak expiratory flow rates ( PEFR ) , daytime and nighttime asthma symptom scores , and rescue salbutamol use . At clinic visits , FEV1 and FVC were measured , and the physicians ’ and the patients ’ respective assessment s of the study mediation were noted . The study showed that the two doses , SM 50 μmg twice a day and SM 100 μmg nightly , were equally effective in controlling nocturnal asthma symptoms and were significantly better than placebo . SM was well tolerated , and no unexpected problems were revealed . The adverse events reported during this study were related either to the patient 's underlying disease or to an intercurrent respiratory infection OBJECTIVE --To compare safety of salmeterol and salbutamol in treating asthma . DESIGN --Double blind , r and omised clinical trial in parallel groups over 16 weeks . SETTING --General practice s throughout the United Kingdom . SUBJECTS--25,180 patients with asthma considered to require regular treatment with bronchodilators who were recruited by their general practitioner ( n = 3516 ) . INTERVENTIONS --Salmeterol ( Serevent ) ( 50 micrograms twice daily ) or salbutamol ( 200 micrograms four times a day ) r and omised in the ratio of two patients taking salmeterol to one taking salbutamol . All other drugs including prophylaxis against asthma were continued throughout the study . MAIN OUTCOME MEASURES --All serious events and reasons for withdrawals ( medical and non-medical ) whether or not they were considered to be related to the drugs . RESULTS --Fewer medical withdrawals due to asthma occurred in patients taking salmeterol than in those taking salbutamol ( 2.91 % v 3.79 % ; chi 2 = 13.6 , p = 0.0002 ) . Mortality and admissions to hospital were as expected . There was a small but non-significant excess mortality in the group taking salmeterol and a significant excess of asthma events including deaths in patients with severe asthma on entry . Use of more than two canisters of bronchodilator a month was particularly associated with the occurrence of an adverse asthma event . CONCLUSIONS --Treatment over 16 weeks with either salmeterol or salbutamol was not associated with an incidence of deaths related to asthma in excess of that predicted . Overall control of asthma was better in patients allocated to salmeterol . Serious adverse events occurred in patients most at risk on entry and were probably due to the disease rather than treatment 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 The aim of the clinical study reported here was to investigate the efficacy of salmeterol , a new long-acting selective beta 2-agonist , in patients with bronchial asthma . Twenty-four children with moderate asthma were enrolled in the longitudinal study , consisting of a run-in period of 2 weeks followed by a treatment period of 4 weeks . Maintenance treatment consisted of inhaled corticosteroid and disodium cromoglycate , or both , at the same daily dose throughout the study . During the run-in period , the patients continued to inhale salbutamol when needed and some of them ( 37 % ) also received theophylline . They were subsequently treated with salmeterol 50 micrograms twice daily and prn salbutamol for 4 weeks . Efficacy was evaluated using symptom scores and pulmonary function tests including forced vital capacity parameters , pulmonary volumes , airway resistance and specific airway conductance that were measured sensitively by a whole body plethysmograph . As a result , salmeterol produced significant improvement in morning and evening peak expiratory flow rates , vital capacity , airway resistance , conductance and asthma symptoms versus salbutamol and theophylline .  Adverse reactions were judged to be mild and few 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 BACKGROUND A long-acting inhaled bronchodilator that is both well tolerated and effective could allow for improved control of both daytime and nighttime symptoms in patients with asthma who use frequent as-needed short-acting bronchodilators despite antiinflammatory treatment . OBJECTIVE AND METHODS We compared the efficacy and safety of inhaled salmeterol , 50 micrograms twice daily , with inhaled salbutamol , 200 micrograms four times daily , delivered through a metered-dose inhaler for 3 months in a multicenter , r and omized , double-blind , parallel-group study of 228 patients ( aged 12 to 76 years ) with mild-to-moderate asthma . RESULTS A single morning dose of salmeterol produced improvement in FEV1 that was significantly greater ( p < or = 0.012 ) than that produced by two doses of salbutamol ( taken 6 hours apart ) when patients were assessed 3 to 6 hours and 10 to 12 hours after the dose . This greater bronchodilation was present on day 1 of the study and after 4 , 8 , and 12 weeks of regular treatment . Over the 12 weeks , compared with salbutamol , salmeterol treatment was associated with a greater mean improvement in morning peak expiratory flow ( 35 L/min vs -3 L/min , p < 0.001 ) , a higher percentage of days with no symptoms ( 29 % vs 15 % ; p = 0.012 ) , and a higher percentage of nights with no awakenings ( 14 % vs -1 % ; p < 0.001 ) . Adverse events were similar for both treatments . CONCLUSIONS In this study salmeterol , 50 micrograms twice daily , was well tolerated and more effective than salbutamol , 200 micrograms four times daily , in improving symptoms and lung function in patients with mild-to-moderate asthma Salmeterol is a new long-acting beta 2-selective adrenoceptor agonist . In this double-blind , 6-way crossover study , four single doses of salmeterol by metered dose inhaler ( 12.5 , 25 , 50 , 100 micrograms ) were compared with albuterol aerosol 200 micrograms and placebo in 24 patients with moderate asthma with 24-hour pulmonary function testing and Holter monitoring .  Salmeterol was an effective bronchodilator at each dose evaluated and demonstrated a greater increase in FEV1 above baseline , a slightly slower onset and a longer duration of bronchodilation than albuterol . Median duration s of bronchodilation were 9.0 , 15.6 , 13.4 , and 18.4 hours with increasing doses of salmeterol in comparison to 4.2 hours for albuterol . Holter monitoring showed ( 1 ) a mean maximum heart rate 2 to 5 bpm higher after salmeterol 50 and 100 micrograms compared with placebo and ( 2 ) supraventricular premature beats ( > 30 per hour or > 100 per 24 hours ) more often in the salmeterol 100-micrograms group ( 13 % to 17 % of patients ) than in the placebo ( 4 % ) , albuterol ( 4 % to 8 % ) , or other salmeterol groups ( 4 % to 9 % ) . These differences were not statistically significant . Tremor and palpitations were the most frequently reported drug-related adverse events and their frequencies increased with increasing doses of salmeterol . This study demonstrated that single doses of salmeterol given by metered dose inhaler over an 8-fold range possess substantial , long-lasting bronchodilator activity 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 Background . A powder formulation of salmeterol has been shown to prevent exercise-induced bronchospasm ( EIB ) in asthmatic children and adults ; however , the delivery device ( Diskhaler ; Glaxo Wellcome Inc , Research Triangle Park , NC ) must be reloaded after 4 doses . A new multidose powder inhaler ( Diskus ) provides 60 doses of salmeterol in a blister pack presentation with a dose counter . Objective . To evaluate the safety and efficacy of 50-μg salmeterol powder via two different delivery systems ( Diskhaler and Diskus ) in preventing EIB in asthmatic children . Study Design . A r and omized , double-blind , double-dummy , single-dose , placebo-controlled , three-way crossover study was conducted in 24 children 4 to 11 years of age demonstrating EIB and mild to moderate asthma . Serial forced expiratory volume in 1 second ( FEV1 ) was measured before and after treadmill exercise challenges conducted at 1 , 6 , and 12 hours after study drug administration . Adverse events were also assessed . Results . During all exercise challenges , EIB-mediated reductions in FEV1 were minimized or prevented in patients receiving single doses of salmeterol powder compared with placebo . Single doses of salmeterol powder delivered via either system were equally effective in preventing EIB . There were no drug-related adverse events , cardiovascular , or other clinical ly relevant safety concerns . Conclusions . Single doses of salmeterol powder delivered by either delivery system are safe and effective in preventing EIB for ≥12 hours in asthmatic children OBJECTIVE To evaluate the efficacy , safety , and impact on asthma-specific quality of life of salmeterol , a highly selective , long-acting beta 2-agonist , compared with that of placebo ( i.e. , " as-needed " albuterol ) . STUDY DESIGN R and omized , double-blind , placebo-controlled , parallel-group , multicenter study . PATIENTS AND METHODS Five hundred thirty-eight nonsmoking symptomatic patients 12 years of age and older meeting American Thoracic Society asthma criteria were enrolled at 55 outpatient clinics ; 443 patients completed the study . Patients were r and omly assigned to treatment with either salmeterol aerosol 42 micrograms twice daily or placebo ( as-needed albuterol ) for 12 weeks . We assessed changes in quality of life using the Asthma Quality of Life Question naire ( AQLQ ) . Efficacy measurements included daily peak expiratory flow ( PEF ) rate , daytime and nighttime asthma symptoms , results of pulmonary function tests , and supplemental albuterol use . Patients recorded their PEF rate , supplemental albuterol use , and asthma-related symptoms daily . Pulmonary function tests and AQLQ assessment s were performed at baseline and after 4 , 8 , and 12 weeks of treatment . Safety measurements included vital signs , physical examination , and reports of clinical adverse events at baseline and after 4 , 8 , and 12 weeks of treatment . RESULTS Mean changes from baseline in AQLQ global and domain scores were significantly greater in the salmeterol group compared with the placebo group ( P < 0.001 ) . Patients treated with salmeterol also had significant improvements in mean PEF rates , supplemental albuterol use , asthma symptom scores , and forced expiratory volume in 1 second compared with those given placebo . Both salmeterol and placebo were well tolerated and were not associated with any clinical ly significant changes in vital signs or physical examination findings . CONCLUSIONS Salmeterol 42 micrograms twice daily result ed in significantly greater improvements in asthma-specific quality of life , pulmonary function , and asthma symptoms compared with placebo ( as-needed albuterol ) in patients with moderate persistent asthma The aim of the study was to investigate the time of onset and the duration of the bronchodilating effect of different doses of formoterol administered via Turbuhaler in patients with moderate asthma . Thirty-one patients ( five women ) with a mean forced expiratory volume in 1 s ( FEV1 ) of 1.97 + /- 0.54 1 and a mean reversibility of 31 + /- 14 % of baseline were included in this double-blind , r and omized , placebo-controlled and cross-over study . The patients inhaled single doses of placebo , i.e. 6 , 12 , 24 , or 48 micrograms formoterol fumarate , on 5 separate days . Serial measurements of specific airways conductance ( SGAW ) and FEV1 were performed at regular time intervals for 12 h. The majority of the patients had at least a 50 % increase in SGAW within 1 - 4 min after administration of all active treatments . The maximum increase in FEV1 over placebo was dose-dependent : 12 % ( 6 micrograms ) , 18 % ( 12 micrograms ) , 19 % ( 24 micrograms ) , and 26 % ( 48 micrograms ) ( P < 0.001 ) . Twelve hours after administration of 6 , 12 , 24 , and 48 micrograms formoterol , the mean increase in FEV1 was still 7 % , 15 % , 18 % , and 27 % , respectively , above the value following placebo .  Headache was the most frequently reported adverse event in all treatments including placebo . After inhalation of 48 micrograms , three patients experienced mild tremor lasting for less than 1 h ; likewise , one patient experienced the same event for 3 h after placebo . Formoterol administered via Turbuhaler10 gave a rapid and dose-related bronchodilating effect lasting for 12 h and was well tolerated STUDY OBJECTIVES To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma . DESIGN A prospect i ve , double-blind , r and omized placebo-controlled trial . SETTING Medical wards of a large university-based hospital . PATIENTS Forty-three patients admitted for an acute exacerbation of asthma . INTERVENTIONS Salmeterol ( 42 microg ) or two puffs of placebo every 12 h in addition to st and ard therapy ( short-acting beta-agonists , corticosteroids , and anticholinergic agents ) . RESULTS No clinical ly adverse effects were seen with the addition of salmeterol to conventional therapy . After salmeterol , there was no difference in pulse , respiratory rate , oxygen saturation by pulse oximetry , severity of symptoms , or dyspnea score . Patients receiving salmeterol had greater FEV(1 ) percent improvements than the placebo group at 12 , 24 , 36 , and 48 h. These findings were not statistically significant . By paired Student 's t tests , there were significant improvements in FEV(1 ) ( p = 0.03 ) and FVC ( p = 0.03 ) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group . In a subgroup analysis of patients with an initial FEV(1 ) < or = 1.5 L , the absolute FEV(1 ) percent improvement for salmeterol vs placebo was 51 % vs 16 % at 24 h and 54 % vs 40 % at 48 h. The relative FEV(1 ) percent improvement for salmeterol vs placebo was 17 % vs 8 % at 24 h and 18 % vs 14 % at 48 h. CONCLUSION The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma . Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma Salmeterol ( SM ) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients . In the present study , evaluating efficacy and possible development of tachyphylaxis after SM , 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15 % to 200 micrograms salbutamol ( SB ) or 20 % to 500 micrograms SB . At inclusion all patients were receiving treatment with inhaled beta 2-agonists , and 11 of the 12 patients were also receiving inhaled corticosteroids .  The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day , following a double-blind , double-dummy , r and omized design . The treatment periods were separated by a washout period of 1 wk . Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period . On each of these days , basal FEV1 , tremor , heart rate , and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve . During the treatment periods , as well as during the washout week after each treatment , the patients recorded their morning and evening peak expiratory flow ( PEF ) each day before the inhalation of the study drug . Subjective asthma symptoms were monitored by a visual analog scale after each treatment period . The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments , but significant increases in basal FEV1 and FVC were seen after the SM period ( p less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Salmeterol is the first long-acting inhaled beta 2-agonist available in the US for the maintenance treatment of asthma . OBJECTIVE To compare the safety of salmeterol with that of the short-acting beta 2-agonist albuterol . METHODS Two identically design ed , prospect i ve , r and omized , double-blind , parallel studies were conducted comparing salmeterol 42 micrograms twice daily , albuterol 180 micrograms four times daily , and placebo over 12 weeks in 556 patients ( 12 to 73 years old ) with mild-to-moderate chronic asthma . Patients in each treatment group could use albuterol as needed to control acute symptoms . RESULTS The incidence of potentially drug-related adverse events was similar among the treatment groups ( range : 22 % to 23 % ) , with headache being the most commonly reported ( range : 9 % to 10 % ) . No deaths occurred during the studies . Concomitant use of > 4 puffs of supplemental albuterol per day in the salmeterol group produced no increase in the incidence of adverse events either in general or of a cardiovascular nature . There were no statistically significant differences among treatment groups or clinical ly significant changes from pretreatment values in mean pulse rate , systolic/diastolic blood pressure , or clinical laboratory values after 12 weeks . There were no clinical ly significant differences among groups in heart rates nor were there differences in the frequency of supraventricular or ventricular ectopic beats during 24-hr Holter monitoring . The frequency of asthma exacerbations was lowest among patients receiving salmeterol ( and highest among those who received placebo ) , and this rate did not increase over the 12 weeks . Asthma exacerbations were treated successfully with nebulized albuterol ( 2.5 mg ) , with no evidence of any increased risk of cardiovascular events . CONCLUSIONS Salmeterol 42 micrograms twice daily is well-tolerated in patients with asthma , having a similar safety profile as that of albuterol 180 micrograms inhaled four times daily or placebo ( plus as-needed albuterol ) . Concomitant use of albuterol , either by MDI or nebulization , did not affect the safety of salmeterol . Extensive cardiovascular monitoring revealed no significant cardiovascular adverse effects or arrhythmogenic effects associated with salmeterol over 12 weeks BACKGROUND : Salmeterol is a potent selective beta 2 agonist that has been shown to have a duration of action in excess of 12 hours . In this study salmeterol and salbutamol were compared over a three month period with a further extension of nine months . METHODS : Three hundred and eighty eight patients with mild to moderate reversible airways obstruction ( forced expiratory volume in one second ( FEV1 ) > 50 % predicted ) were r and omised to receive salmeterol ( 50 micrograms ) twice daily or salbutamol ( 400 micrograms ) four times daily , both by dry powder , in a double blind parallel group study . During the first three months detailed assessment of efficacy was made with recording of morning and evening peak expiratory flow rates ( PEF ) , asthma symptoms , and bronchodilator use when necessary for the relief of symptoms . Patients continued in the study for a further nine months with the salbutamol dose reduced to 400 micrograms twice daily . Lung function was measured at the clinic and safety data were collected during this period . RESULTS : Salmeterol produced a significantly higher mean morning PEF ( mean difference compared with salbutamol 21 ( 95 % CI 12 - 31 ) l/min ) , and a significant reduction in mean diurnal variation in PEF ( from 30 l/min at baseline to 11 34 l/min at baseline to 32 l/min during salbutamol treatment ) . Salmeterol also reduced day and night symptoms and use of rescue bronchodilator . FEV1 increased with both salmeterol and salbutamol treatment over the 12 month treatment period . For both treatments the number of patients reporting exacerbations of asthma and the frequency of these exacerbations remained constant during the study . Thirty six patients in the salmeterol and 49 in the salbutamol group withdrew during the 12 months of the study . CONCLUSIONS : In this study salmeterol ( 50 micrograms twice daily ) was more effective than salbutamol ( 400 micrograms four times daily ) in the control of asthma over three months , and more effective than salbutamol ( 400 micrograms twice daily ) over a further nine months . Neither salmeterol nor salbutamol was associated with any worsening of control of asthma BACKGROUND Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma . It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens . Moreover , it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists . METHODS Asthmatic patients ( n = 145 ) allergic to house dust mite ( HDM ) were r and omly allocated to monotherapy with a short-acting beta(2)-agonist ( SA ; n = 48 ) , a long-acting beta(2)-agonist ( LA ; n = 50 ) , or placebo ( n = 47 ) , double blind , double dummy . The study covered three periods : ( 1 ) a 4-week run-in period , in which no changes took place ; followed by ( 2 ) cessation of treatment with asthma medication including inhaled corticosteroids , introduction of allergen avoidance measures ( active/placebo treatment ) to lower HDM exposure in the active group , and an 8-week washout period to adjust patients to these changes ; followed by ( 3 ) a 12-week study medication period . At the start of the 12-week medication period , and every 4 weeks thereafter , spirometric measurements ( FEV(1 ) and provocative concentration of histamine causing a 20 % fall in FEV(1 ) [ PC(20 ) ] ) were performed . Peak flow and asthma symptoms were recorded daily . Additionally , at the start and every 6 weeks thereafter , dust sample s were collected from mattresses and living room and bedroom floors to assess HDM ( der p 1 ) concentrations . Effects on FEV(1 ) , PC(20 ) , peak flow , and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens . RESULTS There were no significant differences among the three medication groups after 12 weeks for FEV(1 ) . However , a significant decrease in mean FEV(1 ) percent predicted ( 95 % confidence interval [ CI ] ) was observed within the SA group : - 6.6 ( - 10.4 to - 2.8 ) ( p = 0.0002 ) . A decrease in geometric mean PC(20 ) ( 95 % CI ) of - 1.2 ( - 1.96 to - 0.44 ) doubling concentration was observed within the SA group ( p = 0.05 ) . No significant changes in FEV(1 ) and PC(20 ) were observed > 12 weeks within the LA group or the placebo group . There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups . Moreover , none of the parameters showed interactive effects with allergen exposure . CONCLUSION There were no significant differences among the three medication groups for FEV(1 ) and PC(20 ) . The within-treatment group comparison showed a significant small decline in FEV(1 ) for the SA group ( but not for the LA group ) , which could indicate that monotherapy with SAs might have negative effects on FEV(1 ) . This was not seen during regular use of LAS : No clear pathophysiologic mechanism can explain these findings at the moment . Relatively high or low exposure to allergens did not alter these findings BACKGROUND Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control . OBJECTIVE Our purpose was to compare the efficacy and safety of salmeterol 50 microg combined with fluticasone 100 microg ( in a combination dry powder product ) with that of placebo , fluticasone , or salmeterol alone . METHODS A 12-week r and omized , double-blind , multicenter study was conducted in 356 patients aged 12 years or older with asthma . After a 14-day screening period , patients were r and omized to treatment with salmeterol 50 microg combined with fluticasone 100 microg ( combination product ) , salmeterol 50 microg , fluticasone 100 microg , or placebo administered in the Diskus dry powder inhaler ( GlaxoWellcome , UK ) twice daily . RESULTS Mean change in FEV(1 ) at end point was significantly ( P < or = .003 ) greater with the combination product ( 0.51 L ) compared with placebo ( 0.01 L ) , salmeterol ( 0.11 L ) , and fluticasone ( 0.28 L ) . The combination product significantly increased ( P < or = .013 ) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo , salmeterol , and fluticasone at week 1 and week 12 . Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups ( P < or = .020 ) . The combination product significantly increased ( P < or = .012 ) morning PEF ( combination , 52.5 L/min ; placebo , -23.7 L/min ; salmeterol , -1.7 L/min ; fluticasone , 17.3 L/min ) and evening PEF at end point compared with the other groups . The combination product significantly ( P < or = .025 ) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol . All treatments were equally well tolerated . CONCLUSION Salmeterol 50 microg and fluticasone 100 microg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses Treatment for exercise induced asthma ( EIA ) in sporting competition is controlled to prevent the use of agents which might enhance physical performance . There is little information concerning the effects of the long-acting inhaled , and oral , sustained release type bronchodilators on the cardiorespiratory effects of submaximal exercise . The aim of this study was to compare the cardiorespiratory effects of submaximal exercise in patients with EIA before and after pretreatment with high-dose inhaled salmeterol xinafoate ( SX ) and controlled release oral salbutamol ( CR ) .  Patients were treated with SX ( 100 micrograms b.d . ) and CR ( 8 mg b.d . ) for > or = 3 days in a double-blind r and omized cross-over design , with a 5 - 14 day washout period between treatments . A submaximal exercise test ( total exercise time 6 min , final 3 min at 60 % of VEpeak ) was performed prior to each treatment period , and repeated at 1 , 6 , and 12 h postdose at the end of the treatment period . Two subjects were withdrawn from the study . Three subjects required relief medication after 1 h ( CR ) and one subject after 6 h ( SX ) and they did not perform further exercise tests . Both treatments increased baseline FEV1 , with SX producing significantly greater pre-exercise bronchodilation than CR ( P = 0.04 ) . Following CR , there were no significant differences from the pretreatment values for VO2 , VE , respiratory exchange ratio , heart rate , ventilatory equivalents for VO2 , and oxygen pulse during the submaximal exercise challenge . Following SX , there were no significant differences for any of the exercise variables except for VE at 6 and 12 h ( mean increase 4.27 l min-1 at 6 h , P < 0.01 and 4.69 l min-1 at 12 h , P = 0.05 ) . The changes in ventilation following SX did not have an effect on oxygen consumption , and the ventilatory efficiency ( VE/VO2 ) remained unchanged . The findings from this study demonstrate that , despite exercising from a higher baseline FEV1 , short pretreatment periods with controlled release oral salbutamol and with inhaled salmeterol do not confer any cardiorespiratory advantage during submaximal exercise in subjects with EIA The effects of therapeutic 4 weeks ' inhaled salmeterol treatment on the cardiovascular and respiratory autonomic nervous regulation was studied in 11 asthmatic children using inhaled corticosteroid medication . The study followed a r and omized , double-blind , placebo-controlled cross-over design . The salmeterol dose was 50 micrograms twice daily . The 4-week salmeterol treatment increased baseline heart rate , low-frequency/high-frequency ( LF/HF ) variability ratio of R-R intervals , LF variability of systolic arterial pressure ( SAP ) and maximum tidal volume during the deep breathing test , as well as morning and evening peak expiratory flow ( PEF ) values . The 4-week salmeterol treatment decreased baseline HF variability of R-R intervals . As a response to the acute 600 micrograms of salbutamol , the changes in heart rate , HF variability of R-R intervals and diastolic blood pressure were significantly smaller after 4 weeks ' salmeterol treatment . In conclusion , 4 weeks ' therapeutic salmeterol treatment decreases basal cardiovagal reactivity , increases sympathetic dominance in the cardiovascular autonomic balance and improves pulmonary function . A tolerance develops in the cardiovascular response but not in the bronchodilatory response It has been suggested that the new long-acting beta 2-agonist , salmeterol , has anti-inflammatory properties -- properties which should improve airway responsiveness ( AR ) . Conversely , several recent studies have suggested that regular beta 2-agonist treatment may worsen asthma and AR . Furthermore , a short-lived rebound increase in AR has been described following cessation of regular treatment with these agents . We have consequently assessed the effects on AR of regular treatment with either salmeterol or salbutamol at conventional doses over 6 weeks . FEV1 and AR were measured five times in 20 asthmatic subjects r and omly allocated to one or other treatment regimen ; twice during a 2-week run-in period ; and 24 h , 72 h , and 2 weeks after the last dose of the study medication . Peak expiratory flow rate ( PEFR ) was also recorded throughout the study period . There were no statistically significant changes in FEV1 or AR between the run-in period and any of the post treatment measurements for either of the treatments used . Mean PEFR was significantly higher during the treatment period than the run-in period for the salmeterol group , but not the salbutamol group , confirming that therapeutically adequate doses of salmeterol had been given . We conclude that if the regular use of salmeterol is associated with beneficial or adverse effects on AR , this is not apparent after a treatment period of 6 weeks Salmeterol is a new long-acting and highly selective & -agonist agent . Clinical studies have shown that it has a very long ( at least 12 hours ) duration of action in terms of its bronchodilator effect1 and that its effect on bronchial hyperresponsiveness may even be longer . In a recent study we showed that salmeterol administered in a single dose of 50 pg still had a complete blocking effect on hyperventilation-induced asthma in four of 12 subjects ( one third ) who were tested up to 12 hours later . ’ The recommended dose of this preparation varies between 50 and 100 pg every 12 hours . The aim of this study was to exp and our previous work on characterizing the magnitude and duration of action of inhaled salmetereol  on hyperventilation-induced bronchoconstriction in a more detailed way , especially on the interval between 12 and 24 hours and later after its administration . We also wanted to compare the efficacy of two different doses , 50 and 100 pg . recent modification in their need for a bronchodilator ) were included in the study . The project was accepted by a local ethics committee , and a written consent form was obtained from each participant In this double-blind , parallel , single-dose study , bitolterol mesylate aerosol ( three sprays , 1.11 mg ) and albuterol aerosol ( two sprays , 180 mcg ) were compared for efficacy of bronchodilation in 120 adolescent and young adult patients with moderate to severe asthma . All patients required regular medications for asthma control . None was steroid dependent . Both medications gave effective bronchodilation within 5 min with maximum effect at 30 to 60 min . Mean percent increase in forced expiratory volume in 1 sec ( FEV1 ) over baseline was higher for bitolterol than for albuterol at all test times up to 8 hr after a dose at which time 20 % mean percent increase of FEV1 over baseline was still present in the bitolterol-treated patients . With albuterol mean percent increase in FEV1 fell to 15 % over baseline at 5 hr after a dose . Differences in FEV1 increase between the two treatment groups were statistically significant at 4 to 8 hr after a dose . Patients with baseline FEV1 less than 50 % of predicted normal had a response to bitolterol that was higher than that observed with albuterol treatment ( p less than 0.1 ) . Mean maximum percent increase in FEV1 and median duration of bronchodilation were greater with bitolterol than with albuterol , but the differences were not statistically significant . Both bitolterol aerosol and albuterol aerosol were demonstrated to be safe , effective , and long-acting bronchodilating agents . Both bitolterol and albuterol administered by aerosol had a rapid onset , and the maximum degree of bronchodilation was comparable . However , at the doses studied , bitolterol produced significantly higher increase in FEV1 over baseline at longer times after medication than did albuterol BACKGROUND Salmeterol is the first long-acting inhaled bronchodilator available in the United States . This paper summarizes the combined results of the two pivotal US studies evaluating the efficacy of this beta 2-agonist in the maintenance treatment of asthma . METHODS Salmeterol ( 42 micrograms twice daily ) was compared with the short-acting beta 2-agonist albuterol ( 180 micrograms four times daily ) in two double-blind , r and omized studies involving 556 patients with mild-to-moderate asthma . All patients could use supplemental inhaled albuterol as needed for breakthrough symptoms , and patients were allowed to continue to use inhaled corticosteroids during the study . RESULTS Salmeterol , 42 micrograms bid , was more effective than albuterol , 180 micrograms qid , or placebo in maintaining bronchodilation , as measured by FEV1 over 12-hour periods and morning and evening peak expiratory flow rates . Patients who received salmeterol also experienced significantly greater increases in the number of days without asthma symptoms and the percentage of nights without awakenings compared with either the albuterol or placebo group . There was no difference between patients who received concomitant inhaled corticosteroids and those who did not with respect to pulmonary-function measurements or improvements in symptoms . There was no loss of asthma control with salmeterol over the 12-week period . CONCLUSIONS Salmeterol , 42 micrograms twice daily , was more effective than albuterol , 180 micrograms four times daily , or placebo ( plus as-needed albuterol ) in improving pulmonary function and controlling asthma symptoms In a r and omized , double-blind , double-dummy , cross-over study the efficacy and safety of inhaled salmeterol 50 mcg ( b.i.d . ) was compared with oral salbutamol controlled release 8 mg ( b.i.d . ) . Fifty-nine patients with moderate asthma were r and omized to two four-week periods of treatment with a two-week washout period . During the study period the patients were allowed to use inhaled Salbutamol on a prn . basis . Inhaled steroids , if any , were continued . On diary cards patients recorded peak expiratory flow rate ( PEFR ) morning and evening before medication , asthma symptom score , and use of inhaled salbutamol .  Salmeterol was more effective than salbutamol CR in decreasing daily symptoms ( p = 0.001 ) and increasing morning-PEFR ( p = 0.004 ) . Salmeterol result ed in significantly more days without symptoms ( p = 0.0004 ) and days and nights without need for rescue medication ( p = 0.01 and p = 0.01 ) . Salmeterol was better tolerated than salbutamol CR 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 Worsening of underlying bronchospasm may be associated with acute exacerbations of chronic obstructive pulmonary disease ( COPD ) . As airway obstruction becomes more severe , the therapeutic option is to add salbutamol , but not salmeterol , as needed to cause rapid relief of bronchospasm . Unfortunately the most effective dosage of beta2-agonists may increase above that recommended during acute exacerbations . In this study , we compared the acute effects of higher than customary doses of salmeterol and salbutamol in 20 patients with acute exacerbation of COPD . A dose-response curve to salmeterol pMDI , 25 microg/puff or salbutamol pMDI , 100 microg/puff , was constructed using 1 , 1 , and 2 puff ' i.e. , a total cumulative dose of 100 microg salmeterol or 400 microg salbutamol on 2 consecutive days . After baseline measurements , dose increments were given at 30-min intervals with measurements being made 25 min after each dose . Hear rate ( HR ) and pulse-oximetry ( SpO2 ) measurements were then taken . Both salmeterol and salbutamol induced a larg and significant ( P < 0.05 ) dose-dependent increase in FEV1 [ mean differences from baseline ( L ) = after 100 microg salmeterol 0.174 ( 95 % CI : 0.112 to 0.237 ) ; after 400 microg salbutamol : 0.165 ( 95 % CI : 0.080 to 0.249 ) ] , in IC [ mean differences from baseline ( L ) = after 100 microg salmeterol : 0.332 ( 95 % CI : 0.165 to 0.499 ) ; after 400 microg salbutamol : 0.281 ( 95 % CI : 0.107 to 0.456 ) ] ( Fig. 2 ) , and in FVC mean differences from baseline ( L ) = after 100 microg salmeterol : 0.224 ( 95 % CI : 0.117 to 0.331 ) ; after 400 microg salbutamol : 0.242 ( 95 % CI : 0.090 to 0.395 ) ] . There was no significant difference between the FEV1 values ( P=0.418 ) , the ICvalues ( P=0.585 ) , and the FVCvalue ( P=0.610 ) after 100 microg salmeterol and 400 microg salbutamol . HR [ mean differences from baseline ( beats/min ) = after 100 microg salmeterol : 3.15 ( 95 % CI : -0.65 to 6.96 ) ; after 400 microg salbutamol : 2.30 ( 95 % CI : -0.91 to 5.51 ) ] and SpO2 [ mean differences from baseline ( % ) = after 100 microg salmeterol : -0.20 ( 95 % CI : -1.00 to 0.60 ) ; after 400 microg salbutamol : -0.11 ( 95 % CI : -1.00 to 0.79 ) ] did not change significantly from baseline ( P > 0.05 ) . These data indicate that salmeterol is effective and safe in the treatment of acute exacerbation of COPD and support its use in this clinical condition BACKGROUND Salmeterol , a long-acting beta2 -agonist , and zafirlukast , a leukotriene receptor antagonist , are both indicated for the treatment of asthma in adolescent and adult patients . OBJECTIVE We sought to compare the effect of 4 weeks of treatment with inhaled salmeterol xinafoate versus oral zafirlukast in the treatment of persistent asthma . METHODS This was a r and omized , double-blind , double-dummy , parallel-group , multicenter clinical trial . Patients , over 80 % of whom were on a concurrent inhaled corticosteroid regimen , were treated for 4 weeks with either inhaled salmeterol xinafoate 42 microgram twice daily administered by means of a metered-dose inhaler or oral zafirlukast 20 mg twice daily . The primary efficacy measure was morning peak expiratory flow ( PEF ) ; secondary efficacy measures included evening PEF , asthma symptom scores , supplemental albuterol use , nighttime awakenings , sleep symptoms , asthma exacerbations , and FEV1 . RESULTS Both inhaled salmeterol and oral zafirlukast result ed in within-group improvements from baseline in measures of pulmonary function , asthma symptoms , and supplemental albuterol use . Salmeterol treatment result ed in significantly greater improvements from baseline compared with zafirlukast for most efficacy measurements , including morning PEF ( 29.6 vs 13.0 L/min ; P < /= .001 ) , percentage of symptom-free days ( 22.4 % vs 8.8 % ; P < /= .001 ) , and percentage of days and nights with no supplemental albuterol use ( 30.5 % vs 11.3 % ; P < /= .001 ) . There were no differences in safety profiles as assessed by adverse event monitoring . CONCLUSION In patients with persistent asthma , most of whom were concurrently using inhaled corticosteroids , treatment with inhaled salmeterol provided significantly greater improvement than oral zafirlukast in overall asthma control over the 4-week treatment period 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 BACKGROUND Exercise-induced bronchospasm ( EIB ) is a common problem in children with asthma . Pretreatment with the beta2 ( beta 2)-adrenoreceptor agonist albuterol is effective for preventing EIB , but is recognized as providing only short-term ( 2 to 3 hour ) protection . OBJECTIVE To evaluate the 12-hour efficacy and safety of single doses of 25 micrograms and 50 micrograms of salmeterol powder administered via Diskus inhaler versus albuterol aerosol via pressurized metered-dose inhaler and placebo in preventing EIB in asthmatic children . METHODS A r and omized , double-blind , placebo-controlled , double-dummy , single-dose , four-way crossover study was conducted in pediatric patients ( 4 to 11 years of age ) demonstrating EIB and mild-to-moderate asthma .  Serial forced expiratory volume in 1 second ( FEV1 ) was measured before and after st and ard treadmill exercise at hour 1 , hour 6 , and hour 12 after administration of 25 micrograms or 50 micrograms salmeterol powder , 180 micrograms albuterol aerosol , or placebo .  Adverse events were recorded . RESULTS After completion of the hour 1 exercise challenge , mean minimum % predicted FEV1 was significantly higher following albuterol ( 91.3 % ) than for placebo ( 75.3 % ) and for both dosages of salmeterol ( 86.9 % and 85.8 % for salmeterol 25 micrograms and 50 micrograms , respectively ; P < or = .026 ) . After completion of both the hour 6 and hour 12 exercise challenges , the 50-microgram salmeterol treatment produced a significantly higher mean minimum percent of predicted FEV1 ( 90.6 % and 87.3 % predicted , respectively ) than the mean minimum percent of predicted FEV1 for placebo or albuterol ( 73.8 % to 78.4 % of predicted ; P < or = .041 ) . At hour 6 , the 25-microgram salmeterol treatment was not significantly different from albuterol or placebo . At hour 12 , the 25-microgram salmeterol treatment mean minimum percent of predicted was significantly higher than albuterol ( 87.9 % versus 73.8 % of predicted ; P = .006 ) and there was also a trend toward significance over placebo ( 76.9 % predicted ; P = .056 ) . At all exercise periods , no statistically significant differences in spirometry values were observed between the two salmeterol treatment groups . Safety profiles were similar among treatments , including placebo . No drug-related adverse events or withdrawals due to adverse events occurred . Changes in laboratory values , vital signs , 12-lead ECGs , and physical examinations were unremarkable . CONCLUSIONS A single 50-microgram dose of salmeterol powder provided effective and safe protection against EIB for at least 12 hours in asthmatic children and provided a significantly more prolonged effect than albuterol aerosol ( 180 micrograms ) BACKGROUND The protective effect of a new long acting beta 2-agonist , salmeterol , against exercise-induced bronchoconstriction has been documented when given as inhaled aerosol . OBJECTIVE The aim of the present study was to examine the duration of the protective effect of a single dose of salmeterol , 50 micrograms , inhaled as dry powder , against exercise-induced bronchoconstriction . METHODS Sixteen patients with reproducible exercise-induced bronchoconstriction were challenged on a treadmill on two pre study visits and six study days . The patients were challenged 4 , 8 , and 12 hours postdosing . The study was design ed as a double blind placebo-controlled r and omized crossover trial . RESULTS Statistically significant differences in % maximum fall in PEFR were found at four and eight hours postdosing , in favor of salmeterol . At 12 hours postdosing , no clear statistical inference was possible , owing to the presence of a statistical carry-over effect ; however , significant differences in area under curve in favor of salmeterol were found at 4 , 8 , and 12 hours postdosing . CONCLUSION Salmeterol , 50 micrograms , dry powder inhalation had a protective effect against exercise-induced bronchoconstriction up to 12 hours postdosing , as compared with placebo . No adverse effects were identified Salmeterol inhaled twice-daily is now being used more frequently as additional treatment in asthma insufficiently controlled by inhaled corticosteroids . We compared oral bambuterol in a dose of 20 mg taken once daily in the evening with inhaled salmeterol at 50 microgram taken twice daily in 126 asthmatic patients ( 60 bambuterol , 66 salmeterol ) aged 18 to 74 yr who were treated for at least 4 wk with inhaled corticosteroids at a constant dose of 400 to 2,000 microgram/d or with oral corticosteroids at < /= 20 mg/d . The patients were able to use a pressurized metered dose inhaler ( pMDI ) efficiently , and had an  FEV1  of 40 to 85 % of the predicted normal value . During a run-in period , patients had to show at least one nocturnal or early awakening caused by asthma symptoms that required rescue medication , and a > /= 15 % overnight decrease in peak expiratory flow ( PEF ) on 3 of the preceding 7 d , in order to be r and omized into this double-blind , double dummy , multicenter parallel group study ( 2-wk run-in period and 6 wk of treatment ) . There was no significant difference between bambuterol and salmeterol in morning change from baseline in PEF ( p = 0.53 ) . The median increases in morning PEF were 50 L/min for bambuterol and 55 L/min for salmeterol . Other variables ( evening PEF , percent of overnight decrease in PEF , number of awakenings , percent of nights with an awakening , number of puffs of rescue medication , asthma symptoms during the day and night , and mean tremor score ) also showed no significant difference between bambuterol and salmeterol . Both treatments , at the doses given , were well tolerated . Once-daily oral bambuterol is a convenient , effective , and less expensive alternative to twice-daily inhaled salmeterol for treating nocturnal asthma 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 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 This was a 4‐week , open‐label , parallel‐group study design ed to compare the efficacy and safety of the long‐acting inhaled bronchodilator , salmeterol , with the established inhaled bronchodilator , terbutaline , in the treatment of patients with mild to moderate asthma . A total of 243 adult patients was r and omized to receive treatment with either salmeterol 50 μg bd via a DiskhalerTM ( Glaxo ) inhaler ( n=121 ) or terbutaline 500 μg qds via a reservoir powder inhaler device ( n=122 ) . Apart from all bronchodilator treatment which was withdrawn at the start of the run‐in period and replaced by inhaled salbutamol to be used as required for symptom relief , all concurrent medications were kept constant throughout the study . Salmeterol produced a significantly greater increase in mean morning peak expiratory flow ( PEF )  than terbutaline ( difference in adjusted means after treatment=28 l/min ; 95 % CI=19–37 l/min ; P<0.001 ) . Likewise , the increase in mean evening PEF was significantly greater following treatment with salmeterol than with terbutaline ( difference in adjusted means=9 l/min ; 95 % CI=0–17 l/min ; P=0.045 ) . Salmeterol was associated with a significant reduction in diurnal variation in PEF by comparison with terbutaline ( difference in adjusted means=−18 l/min ; 95 % CI=−24 , −12 l/min ; P<0.001 ) . Significant improvements with salmeterol by comparison with terbutaline were also observed in daytime and night‐time asthma scores , percentage of symptom‐free days and nights , use of additional inhaled bronchodilator , and percentage of days and nights when no additional inhaled bronchodilator was needed . The greater overall improvement in the control of asthma and its symptoms after treatment with salmeterol was further evident from the lower incidence of asthma‐related adverse events in patients taking salmeterol compared with those taking terbutaline ( 2 % and 15 % , respectively ) . While both treatments were well tolerated , more patients withdrew from the terbutaline group than from the salmeterol group ( 12 and 3 patients , respectively ) and terbutaline was associated with a higher incidence of drug‐related adverse events ( 26 % and 9 % in the terbutaline‐ and salmeterol‐treated groups , respectively ) . This study demonstrated that salmeterol 50 mUg bd via a Diskhaler was significantly more effective and associated with fewer adverse events than terbutaline 500 μg qds via a reservoir powder inhaler device OBJECTIVES To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids ( ICS ) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction . METHODS A double-blind , placebo-controlled study was performed at 16 centers in the United States . Patients with asthma ( n = 122 , ages 15 - 58 ) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were r and omized to receive either montelukast ( 10 mg once daily ) , salmeterol ( 50microg twice daily ) , or placebo for 4 weeks . St and ardized spirometry  after exercise challenge and beta2-agonist rescue was performed at baseline , week 1 and 4 . RESULTS Maximum achievable forced expiratory volume in 1 s ( FEV1 ) percent predicted after rescue beta2-agonist improved in the montelukast ( + 1.5 % ) and placebo ( + 1.2 % ) groups at 4 weeks , but diminished in the salmeterol ( -3.9 % ) group ( P < 0.001 ) . Although pre-exercise FEV1 was greatest with salmeterol ( P = 0.10 ) , patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol ( P < 0.001 ) . Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol ( P < 0.001 ) . Five minutes after rescue beta2-agonist , 92 % of patients taking montelukast and 68 % of those taking placebo had recovered to pre-exercise levels , whereas only 50 % of those taking salmeterol had recovered to pre-exercise levels . CONCLUSION In patients whose asthma symptoms remain uncontrolled using ICS , addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinical ly meaningful protection against exercise-induced bronchoconstriction A total of 1,068 patients , aged 18 - 70 yrs , with mild to moderate reversible airways disease , were recruited into a multicentre , double-blind , parallel group study in 76 European centres . Following a 2 week run-in period , the 692 patients fulfilling the entry criteria were r and omized to 4 weeks treatment with either salmeterol 12.5 , 50 or 100 micrograms or placebo b.d . all given by pressurized inhaler , with assessment s of symptoms and ventilatory lung function prior to dosing . All three doses of salmeterol had significant efficacy , manifested by increased morning and evening peak expiratory flow rate ( PEFR ) ( by 35 - 59 l.min-1 and 11 - 38 l.min-1 , respectively ) , by reduced diurnal variation in PEFR , and by reduced requirement for additional bronchodilator for symptomatic relief . These effects were dose-related . Daytime asthma symptoms and nocturnal awakenings were significantly reduced by salmeterol treatment , although these reductions were not dose-related . The incidence of adverse events was low . Pharmacologically predictable events ( e.g. tremor ) were more frequent after treatment with 100 micrograms b.d . than with placebo . On the basis of the efficacy and side-effect information , 50 micrograms b.d . is considered to be the optimum dose for the treatment of this group of asthmatics The aim of this study was to compare the clinical efficacy of salmeterol versus theophylline in the treatment of moderate-to-severe asthma . One hundred and eighty nine asthmatic patients ( forced expiratory volume in one second ( FEV1 ) or peak expiratory flow ( PEF ) > 50 % of predicted ) were r and omized to receive either salmeterol dry powder , 50 microg b.i.d . via a Diskhaler ( n=92 ) or dose-titrated slow-release theophylline capsules ( " Theo-Dur " ) b.i.d . ( n=97 ) , in a double-blind , double-dummy , parallel group study for 4 weeks . Patients had previously been titrated with theophylline to a serum theophylline level of 10 - 20 microg x mL-1 . The median percentage of nights with no asthma symptoms rose from 14 % in both groups at baseline to 71 % with salmeterol and to 46 % with theophylline ( p=0.044 ) . There was also a significant increase for salmeterol in the median percentage of nights with no rescue salbutamol use ( from 36 to 86 % ) compared with theophylline ( from 71 to 78 % ; p=0.002 ) . The mean morning PEF increased from 337 L x min-1 in the salmeterol group and 332 L x min-1 in the theophylline group to 372 and 357 L x min-1 , respectively . No significant difference between the two treatments was observed for PEF , symptoms or additional salbutamol medication during the day . The incidence of gastrointestinal symptoms ( gastric irritation , nausea and vomiting ) was greater among patients receiving theophylline ( 11 % ) than with salmeterol ( 3 % ) . These findings suggest that inhaled salmeterol is more effective in relieving symptoms of asthma , and better tolerated than theophylline in patients with moderate-to-severe asthma BACKGROUND There is a paucity of data comparing the long-term safety and efficacy of long-acting inhaled beta2-agonists versus low-dose inhaled corticosteroids in the treatment of asthma . OBJECTIVE To compare the safety and efficacy of salmeterol xinafoate , beclomethasone dipropionate ( BDP ) , and placebo over a 6-month treatment period in patients with persistent asthma . METHODS Salmeterol ( 42 microg twice daily ) , BDP ( 84 microg four times daily ) , or placebo was administered via metered-dose inhaler to 386 adolescent and adult inhaled corticosteroid-naive patients in a r and omized , double-blind , double-dummy , parallel-group study . Eligible patients demonstrated a forced expiratory volume in 1 second ( FEV1 ) from 65 % to 90 % of predicted values .  Pulmonary function , symptom control , frequency of asthma exacerbations , bronchial hyperresponsiveness ( BHR ) to methacholine challenge , and adverse events were assessed . RESULTS There were few statistically significant differences between the two active treatments over 6 months of therapy . Asthma symptoms and lung function were significantly improved with both salmeterol and BDP compared with placebo ( changes from baseline in FEV1 of 0.28 L ( SE = 0.04 ) and 0.23 L ( SE = 0.04 ) , respectively , compared with 0.08 L ( SE = 0.04 ) ; P < or = .014 ) . There were no significant differences among the treatment groups with respect to the distribution of asthma exacerbations over time . Both salmeterol and BDP significantly reduced BHR compared with placebo ( P < or = .033 ; changes from baseline of 1.29 ( SE = 0.26 ) and 1.42 ( SE = 0.24 ) doubling doses at 6 months , respectively , compared with 0.24 ( SE = 0.29 ) doubling dose for placebo ) . No rebound effect in BHR was seen upon cessation of any of the three treatment regimens . There were no clinical ly important differences in the safety profiles among the three treatments . CONCLUSIONS Both salmeterol and BDP are effective and well-tolerated when administered for 6 months to inhaled corticosteroid-naive patients with persistent asthma OBJECTIVE To compare the efficacy and safety of inhaled salmeterol xinafoate , a long-acting beta 2-adrenoceptor agonist , with that of albuterol , a short-acting inhaled beta 2-agonist , in the treatment of asthma . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Eleven outpatient clinical centers . SUBJECTS A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy . INTERVENTION Patients were treated with salmeterol xinafoate ( 42 micrograms inhaled twice daily ) , albuterol ( 180 micrograms inhaled four times daily ) , or placebo ( four times a day ) for 12 weeks ; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms . MAIN OUTCOME MEASURES Serial 12-hour forced expiratory flow in 1 second ( FEV1 ) , peak expiratory flow ( PEF ) , asthma symptoms , nocturnal awakenings due to asthma , episodes of asthma exacerbations , and electrocardiography . RESULTS The mean area under the curve for FEV1 throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart ( P < .001 ) , with the difference ranging from 3.1 to 4.3 L.h . Salmeterol produced an average increase in morning and evening PEF of 26 and 29 L/min , respectively , over pretreatment values compared with decreases of -13 and -3 L/min , respectively , in the albuterol group and -2 L/min both in the morning and evening in the placebo group ( P < .001 ) . Patients in the salmeterol group had significantly fewer days and nights with symptoms than did either the albuterol or placebo group ( P < .001 ) . Responses to salmeterol were similar at day 1 and at week 12 . Adverse events in all treatment groups were equally infrequent , and no clinical ly significant change in cardiac rhythm was observed with salmeterol treatment . CONCLUSION Salmeterol inhaled twice daily is more effective than albuterol inhaled four times a day ( or as needed ) in patients with asthma requiring maintenance therapy . No deterioration of asthma control was observed with the use of salmeterol over a 3-month period Twenty-four children aged 12 - 17 years entered a r and omized , double-blind placebo-controlled study investigating the use of salmeterol in chronic severe asthma . In addition to their usual medication , the children were given either placebo or 100 micrograms salmeterol b.d . by dry powder inhalation . Treatment was continued throughout one term at a residential school for asthma . Symptom scores , peak expiratory flow rates , spirometry and quality -of-life scores were compared between the two treatment groups . One child withdrew during the run-in period . Twelve pupils received placebo and 11 pupils received salmeterol . There were consistent improvements in favour of salmeterol , reaching statistical significance for morning and evening peak flow rates and spirometry when measured on four occasions during the study period . There were no medication-related adverse events recorded and no pulse rate changes . Salmeterol ( 100 micrograms b.d . ) is well tolerated and efficacious in older children with chronic severe asthma 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 Controversy regarding tolerance to [ 32-agonist asthma therapy has surfaced periodically over the past 20 years , and recently it has again become a focus of attention . Although there is evidence that tolerance develops to the nonpulmonary effects of [ 3z_agonist,1,2 there is still uncertainty among many clinicians who treat patients with asthma as to whether any clinical ly significant tolerance develops to the pulmonary effects of these drugs , particularly to the recently introduced long-acting 132-agonist salmeterol . This report , which represents results from the largest data base of patients receiving salmeterol in clinical studies in the United States , supports the growing body of evidence that patients with asthma do not show any loss of bronchodilator effect after regular exposure to 132-agonist , 3-~ although some loss of the bronchoprotectiv e effect has been reported in a few exercise-induced bronchospasm and methacholine challenge studies . 6 , STUDY OBJECTIVES To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice setting s. DESIGN A r and omized , double-blind , 6-month , parallel-group study involving 253 centers . SETTING Primarily nonspecialist practice s ( n = 232 ) . PATIENTS A total of 911 subjects ( 417 men ; 494 women ) who met American Thoracic Society asthma criteria were enrolled and r and omized to treatment with either twice-daily salmeterol aerosol ( 50 microg ; n = 455 ) or matching placebo twice daily ( n = 456 ) . Both groups were allowed to take salbutamol as needed . All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study . MEASUREMENTS AND RESULTS The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization , emergency department visit , or use of prednisone during the treatment period . A total of 712 subjects competed the study . There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups ( 20.8 % vs 20.9 % , respectively ; p = 0.935 ; power > 88 % ) . Peak expiratory flow was significantly higher in the salmeterol group ( 398 L/min vs 386 L/min for placebo ; p < 0.01 ) . Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo ( p < 0.001 ) . The proportion of subjects sleeping through the night was significantly higher in the salmeterol group ( 74 % ) as compared to placebo ( 68 % ; p = 0.028 ) . CONCLUSIONS Salmeterol treatment is effective in subjects typically cared for in the primary -care setting and does not increase the frequency of severe exacerbations BACKGROUND The current stepwise approach to pharmacotherapy in the treatment of asthma includes the initiation of an inhaled corticosteroid with the addition of a long-acting inhaled bronchodilator if low dose inhaled corticosteroid fails to control asthma symptoms . OBJECTIVE To determine whether initiation of salmeterol and fluticasone propionate treatment together improves asthma control greater than initiation of monotherapy with the individual agents alone with no additional safety risk in patients with asthma who had not previously been treated with inhaled corticosteroids . METHODS A total of 136 male and female patients at least 12 years of age with asthma [ forced expiratory volume in 1 second ( FEV ) between 50 % and 80 % of predicted ] were r and omized to twice daily salmeterol 42 microg , fluticasone propionate 88 microg , fluticasone propionate 220 microg , salmeterol 42 microg plus fluticasone propionate 88 microg , salmeterol 42 microg plus fluticasone propionate 220 microg , or placebo for 4 weeks . RESULTS Patients treated with salmeterol combined with fluticasone propionate had improvements over baseline in FEV at endpoint that were at least twice as great ( 0.6 to 0.7 L ) as improvements in patients treated with salmeterol ( 0.3 L ) or fluticasone propionate alone ( 0.3 L ) ( P < .05 ) . Patient-rated data ( peak expiratory flow , asthma symptom scores , percent of days with no asthma symptoms ) confirmed greater ( P < .05 ) mean change from baseline improvements after combined treatment compared with fluticasone propionate alone . No clinical ly significant differences were noted between treatment groups in any safety measurement . CONCLUSION Initiation of maintenance therapy with salmeterol and fluticasone propionate in patients with asthma treated with short-acting beta2-agonists alone provides greater improvements in pulmonary function and symptom control than initiation of maintenance therapy with fluticasone propionate alone 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 OBJECTIVE This study compared the efficacy and tolerability of the combination of fluticasone propionate ( FP ) and salmeterol ( SAL ) delivered via a single hydrofluoroalkane ( HFA ) 134a metered-dose inhaler ( MDI ) with those of its 2 components alone delivered via a chlorofluorocarbon ( CFC ) MDI and placebo ( PLA ) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses ( equivalent to FP 440 - 660 microg/d ) of inhaled corticosteroids ( ICSs ) . METHODS This was a r and omized , double-blind , placebo-controlled , parallel-group study consisting of a 2-week , single-blind , placebo run-in period followed by a 12-week , double-blind treatment period . Participants had to be > or = 12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study . Patients had to have used ICS therapy for > or =3 months before the study and at a consistent dose for the previous month . Lack of asthma control was defined as a forced expiratory volume in 1 second ( FEV(1 ) ) that was 40 % to 85 % of the predicted value . Patients could not enter the double-blind treatment period if they had 3 days when they required > 12 puffs of rescue albuterol per day or > 3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the r and omization visit . Patients were r and omized to receive one of the following treatments delivered via MDI twice daily for 12 weeks : FSC 220/42 microg HFA ( 2 inhalations of FSC 110/21 microg ; 125 microg/21 microg ex-valve ) ; FP 220 microg CFC ( 2 inhalations of FP 110 microg ) ; SAL 42 microg CFC ( 2 inhalations of 21 microg ) ; or 2 inhalations of PLA HFA . The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV(1 ) curve relative to the prer and omization baseline ( FEV(1 ) AUC(bl ) ) . The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV(1 ) at end point and the probability of not being withdrawn from the study due to worsening asthma . Tolerability assessment s included electrocardiograms , routine clinical laboratory tests , vital signs , oropharyngeal examinations , and physical examinations . Adverse events were assessed at each clinic visit . RESULTS Thirty-two adolescent and 333 adult patients were r and omly assigned to receive double-blind treatment . The treatment groups were comparable at baseline with respect to demographic characteristics ( mean age , 38 - 41 years ; white race , 78%-88 % ) and pulmonary function ( mean percent predicted FEV(1 ) , 68%-69 % ; mean asthma symptom score , 1.6 [ scale 0 - 5 ] ; and mean daily albuterol use , 3.1 puffs ) . After 12 weeks of treatment , the mean FEV(1 ) AUC(bl ) was significantly greater in patients who received FSC compared with those who received FP , SAL , or PLA ( 7.0 , 3.6 , 5.3 , and 1.4 L-h , respectively ; all comparisons , P < or = 0.020 ) . At end point , the mean change from baseline in morning predose FEV(1 ) for FSC was significantly greater than that for FP , SAL , and PLA ( 0.41 , 0.19 , 0.15 , and -0.12 L ; all comparisons , P < or = 0.001 ) . During 12 weeks of treatment , 7 % of patients receiving FSC were withdrawn due to worsening asthma , compared with 24 % of patients receiving SAL and 54 % of patients receiving PLA ( P < 0.001 ) ; 11 % of patients receiving FP were withdrawn due to worsening asthma . Treatment with FSC result ed in significant improvements in morning and evening peak expiratory flow compared with FP , SAL , and PLA ( both , P < 0.001 ) ; need for rescue albuterol compared with FP and PLA ( P < or = 0.005 ) ; and asthma symptom scores compared with PLA ( P < 0.001 ) . The tolerability of FSC was similar to that of FP or SAL alone . The incidence of possibly drug-related adverse events was generally similar across treatment groups , and the most common ( occurring in > or= 2 % of patients ) were headache ( 1%-4 % ) , throat irritation ( 1%-2 % ) , c and idiasis of the mouth/throat ( 0%-2 % ) , unspecified oropharyngeal plaques ( 0%-2 % ) , and palpitations ( 0%-2 % ) . CONCLUSIONS In these adolescent and adult patients whose asthma was not controlled by medium doses of an ICS , FSC delivered via HFA 134a MDI ( 2 inhalations of 110/21-microg strength administered BID ) was more effective in improving lung function than FP or SAL monotherapy or PLA . All treatments were well tolerated In a double-blind , double-dummy , cross-over , multicentre study , 141 patients with moderate reversible airways disease were r and omized to receive either 50 micrograms salmeterol via a metered dose inhaler or individually dose-titrated oral theophylline , both twice daily for a 2-week period . Just over half ( n = 77 ) the patients had received theophylline before , but 64 patients were new to theophylline therapy .  Efficacy was based on lung function data and symptom scores . Salmeterol produced significantly higher increase in mean morning peak expiratory flow ( PEF ) of 161 min-1 ( P < 0.001 ; 95 % Confidence Interval ( CI ) ; 8 - 241 min-1 ) and mean evening PEF of 151 min-1 ( p < 0.001 ; 95 % CI ; 7 - 221 min-1 ) compared with theophylline therapy . Further analysis of the data revealed that the increase in PEF with salmeterol compared with theophylline was highest in a sub-group of patients new to theophylline therapy . Patients on salmeterol had significantly less night-time awakenings than those on theophylline ( P = 0.011 ) and significantly less daytime symptoms ( P = 0.017 ) . There was also a significant increase in the number of nights ( P = 0.013 ) and days ( P < 0.001 ) on salmeterol when no additional salbutamol was required compared with theophylline . Theophylline produced a higher incidence of adverse events compared with salmeterol . The results of this study show that inhaled salmeterol is more effective and better tolerated than individually dose-titrated oral theophylline over a 2-week study period in patients with moderate asthma BACKGROUND Salmeterol is a new inhaled selective beta 2-adrenergic receptor agonist with a long duration of action . We studied the duration of the bronchodilation and the protective effect against methacholine-induced airway obstruction of a single dose of salmeterol in a double-blind , r and omized , placebo-controlled , crossover design . METHODS Seventeen boys and three girls with mild-to-moderate asthma participated in the study . On two separate days either 50 micrograms salmeterol or placebo was inhaled . FEV1 and PD20 methacholine were determined before and 1 , 4 , 8 , 12 , and 24 hours after inhalation . RESULTS Salmeterol result ed in a significant bronchodilation compared with placebo , up to 12 hours ( p = 0.0001 ) . At 24 hours there was a residual effect that approached significance ; mean FEV1 being 8.3 % + /- 2.4 % above baseline ( p = 0.06 ) . Significant protection against airway sensitivity to methacholine after salmeterol inhalation was found at all time points ( p < 0.005 ) . Twenty-four hours after administration mean PD20 was still 1.22 + /- 0.29 doubling dose above baseline . No important adverse effects were noted . CONCLUSION We conclude that a single dose of 50 micrograms salmeterol in children with asthma gives a long-lasting bronchodilation , exceeding 12 hours , which is comparable to the results in adult studies . The duration of the protection against airway sensitivity to methacholine exceeds 24 hours BACKGROUND --Metered dose inhalers for the treatment of asthma use chlorofluorocarbons as propellants . These face an international ban due to their effect on the ozone layer . Salmeterol has been reformulated using the non-chlorinated propellant Glaxo inhalation grade HFA134a . METHODS --The safety , tolerability and systemic pharmacodynamic activity of the salmeterol/HFA134a inhaler , the current salmeterol inhaler , and placebo ( HFA134a ) were compared in 12 healthy volunteers in a double blind , r and omised crossover study using a cumulative dosing design . RESULTS --Safety and tolerability were similar and the response was related to the dose over the range used ( 50 - 400 micrograms ) with both salmeterol inhalers . The salmeterol/HFA134a inhaler showed no differences from the current inhaler for pulse rate , blood pressure , tremor , QTc interval , and plasma glucose levels . The salmeterol/HFA134a inhaler had significantly less effect on plasma potassium levels . CONCLUSIONS --In healthy volunteers the salmeterol/HFA134a inhaler is at least as safe and well tolerated as the current salmeterol inhaler , and has similar systemic pharmacodynamic activity The aim of the present study was to compare the efficacy and the tolerability of salmeterol and theophylline in patients with nocturnal asthma . 16 patients were entered into a r and omized , double-blind , crossover trial . Using a double-dummy technique , salmeterol ( 50 micrograms b.i.d . by MDI ) or theophylline ( Uniphyllin ; 600 mg nocte orally ) were given for periods of 7 days with a wash-out period of 7 days between treatment periods . With salmeterol the number of nights with an overnight fall in peak expiratory peak flow rate ( PEFR ) of at least 20 % was reduced by about 20 % compared to about 10 % with theophyllin ( p < 0.05 for the difference between salmeterol and theophylline ) . With respect to nocturnal symptoms 62.6 % of the patients had rare or non symptoms without and 84.7 % with salmeterol , compared to 46.5 % without and 67.3 % with theophylline ( p < 0.05 ) . With respect to the improvement of early morning symptoms , the increase of nights with none or rare symptoms was 46.2 % with salmeterol compared to 25.8 % with theophylline . The overall parameter of efficacy defined as a ) the number of nights with an overnight fall in PEFR or less than 20 % als well as b ) none or rare nocturnal symptoms and c ) none or rare early morning symptoms increased from 23.4 % at baseline to 75.1 % during treatment with salmeterol compared to an increase from 24.5 % at baseline with 54.8 % during treatment with theophylline ( p < 0.05 ) . 12 patients preferred salmeterol over theophylline ( p < 0.05 ) . 3 patients had gastrointestinal disturbances during theophylline treatment . It can be concluded that both salmeterol and theophylline are effective in the treatment of nocturnal asthma . With respect to the overall efficacy and the tolerability salmeterol is superior to theophylline In accordance with the Montreal Protocol 1987 , initiatives to phase out and replace ozone-depleting chlorofluorocarbon ( CFC ) propellants with non-ozone-depleting propellants in metered-dose inhalers ( MDIs ) in the treatment of asthma and chronic obstructive pulmonary disease are underway . In view of this , two multi-centre , r and omised , parallel-group , double-blind studies were conducted to compare the safety and efficacy of salmeterol xinafoate delivered by an MDI using the hydrofluoroalkane ( HFA ) 134a propellant with the licensed CFC formulation ( Serevent ) in asthmatic population s of children ( 4 - 11 years ) and adults ( 12 years ) . Patients on a stable dose of inhaled corticosteroids with a scope for improvement based on mean morning peak expiratory flow ( PEF ) and symptoms were r and omised to receive salmeterol HFA MDI 50 microg twice daily or salmeterol CFC MDI 50 microg twice daily for 12 weeks . The primary efficacy variable was mean morning PEF and secondary variables included other lung function parameters , symptom scores , use of relief medication and safety assessment s. The difference between the treatments in adjusted mean morning PEF ( salmeterol HFA-salmeterol CFC ) were 2.5 and -3.2 L/min for per- protocol population s of children and adults , respectively . The lower limit of 95 % confidence intervals for both population s was within the pre-defined limit ( -15 L/min ) set for non-inferiority . Similar results were observed in intent-to-treat ( ITT ) population s. In children , the two formulations result ed in a lack of any statistically significant difference in secondary efficacy parameters . A significant difference at endpoint in clinic forced expiratory volume in 1s was reported in favour of the HFA formulation in the adult population , although the magnitude of this effect was not considered clinical ly significant . The incidences of adverse events ( AEs ) were similar for both formulations and population s , and no safety concerns were generated . Together these data demonstrate salmeterol HFA MDI to be as effective as salmeterol CFC MDI in adults and children Salmeterol ( SM ) is a novel beta 2-adrenoceptor agonist with a duration of action in excess of 12 hours . Evidence from in vitro studies has also demonstrated that , unlike the short-acting beta 2-agonists , such as salbutamol ( SB ) , it may have some anti-inflammatory properties . With a r and omized , double-blind , crossover design , we have compared the inhibitory effects of SM ( 50 micrograms ) and SB ( 200 micrograms ) delivered by metered-dose inhaler on allergen-induced bronchoconstriction , changes in airway reactivity , and urinary leukotriene ( LT ) E4 excretion in 12 atopic subjects with mild asthma . The immediate bronchoconstriction to allergen was significantly reduced by both beta 2-agonists ( p less than 0.005 ) , when reduction was expressed either in terms of maximum fall in FEV1 at 15 minutes after allergen ( percent fall in FEV1 , mean + /- SEM : 6.2 + /- 4.9 , SM ; 5.7 + /- 2.5 , SB ; 40.4 + /- 6.3 , placebo ) or the area under the FEV1 time curve ( AUC ) for the first 120 minutes after allergen . Four hours after challenge , results in the SB-treated and placebo-treated groups were not significantly different and demonstrated a small persistent bronchoconstriction compared to bronchodilatation in the SM-treated group ( percent fall in FEV1 , respectively , 9.3 + /- 3.7 , 14.3 + /- 7.1 , and -6.3 + /- 2.7 ; p less than 0.005 , SM versus SB ; p less than 0.02 , SM versus placebo ) . Expressed in terms of AUC , only SM significantly reduced bronchoconstriction in the period 120 to 240 minutes after allergen ( p less than 0.01 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The aim of the present multicentre , open , r and omized , parallel group study was to evaluate the efficacy and safety of salmeterol versus theophylline in asthmatic patients . A total of 112 patients were r and omized : 56 received inhaled salmeterol ( 50 micrograms twice daily ) and 50 oral dose titrated theophylline twice daily . The study lasted 12 months . The efficacy of both drugs was evaluated for the first 3 months of the study and the safety for a further 9 months . Spirometric measurements were carried out for the total duration of the study . Salmeterol showed a greater and more significant efficacy than theophylline in reducing both day- and night-time symptoms ( P < 0.001 ) and in reducing additional salbutamol requirement ( P < 0.001 ) . The subjective assessment of efficacy by physicians and patients was in favour of salmeterol from the first month of treatment ( P < 0.001 ) . Both drugs improved the quality of life as measured by the specific question naire ' Living with Asthma ' with no significant differences . The total number of adverse events was slightly higher in the theophylline group compared with salmeterol ( 18 vs 9 ; P n.s . ) . Both salmeterol and theophylline increased morning and evening PEFR with no significant difference . FEV1 and FVC increased in both groups of patients ; the difference between the effects of the two treatment was not statistically significant at 12 months . Our study suggests that salmeterol has higher efficacy and safety than theophylline in long-term treatment of asthmatic patients 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
BACKGROUND Epidemiological evidence has suggested a link between beta-agonists and increases in  asthma mortality .
There has been much debate about possible causal links for this association , and whether regular ( daily ) long-acting beta(2)-agonists are safe .
OBJECTIVES The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that r and omised patients with chronic asthma to regular salmeterol versus placebo or regular short-acting beta(2)-agonists .