Efficacy and tolerability of formoterol Turbuhaler in children. Comparison between formoterol 12 microg b.i.d. and on-demand salbutamol in moderate persistent asthma. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. A three-month comparison of twice daily inhaled formoterol versus four times daily inhaled albuterol in the management of stable asthma. Intracoronary Injections of Salbutamol Demonstrate the Presence of Functional ft-Adrenoceptors in the Human Heart Formoterol Delivered via the Dry Powder Aerolizer® Inhaler Versus Albuterol MDI and Placebo in Mild-to-Moderate Asthma: A Randomized, Double-Blind, Double-Dummy Trial Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma. Formoterol, a new long-acting beta 2 agonist, inhaled twice daily, in stable asthmatic subjects. Potential masking effect on dyspnoea perception by short- and long-acting β2-agonists in asthma Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma. Formoterol fumarate inhalation powder vs albuterol nebulizer for the treatment of asthma in the acute care setting. Systemic effects of salbutamol and salmeterol in patients with asthma. Relative therapeutic index between inhaled formoterol and salbutamol in asthma patients. A comparison of the speeds of action of salmeterol and salbutamol in reversing methacholine-induced bronchoconstriction. Efficacy, tolerability, and effect on asthma-related quality of life of formoterol bid via multidose dry powder inhaler and albuterol QID via metered dose inhaler in patients with persistent asthma: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. Formoterol Turbuhaler as reliever medication in patients with acute asthma Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma Evidence of the Rapid Protective Effect of Formoterol Dry-Powder Inhalation against Exercise-Induced Bronchospasm in Athletes with Asthma Comparison of second controller medications in addition to inhaled corticosteroid in patients with moderate asthma. Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma. Tolerance to beta-agonists during acute bronchoconstriction. Formoterol as dry powder inhalation. A dose finding study in comparison with formoterol metered dose inhaler and placebo. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Inhaled formoterol in the prevention of exercise-induced bronchoconstriction in asthmatic children. Protection against cold air and exercise-induced bronchoconstriction while on regular treatment with Oxis. Formoterol, a new inhaled beta-2 adrenergic agonist, has a longer blocking effect than albuterol on hyperventilation-induced bronchoconstriction. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial Safety of formoterol Turbuhaler® at cumulative dose of 90 µg in patients with acute bronchial obstruction Assessment of a relative therapeutic index between inhaled formoterol and salbuterol in asthma patients. Formoterol compared with beclomethasone and placebo on allergen-induced asthmatic responses. Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Rapid onset of action of inhaled formoterol in asthmatic patients. Effect of formoterol on clinical parameters and lung functions in patients with bronchial asthma: a randomised controlled trial Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial Formoterol used as needed improves health-related quality of life in asthmatic patients uncontrolled with inhaled corticosteroids. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma. Traditional and patient-centred outcomes with three classes of asthma medication Protective effect and duration of action of formoterol aerosol on exercise-induced asthma. Improved lung function and symptom control with formoterol on demand in asthma Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol. Dose-related efficacy and safety of formoterol (Oxis) Turbuhaler compared with salmeterol Diskhaler in children with asthma. The Episode-Free Day as a Composite Measure of Effectiveness Prolonged bronchodilating effect of formoterol versus procaterol in bronchial asthma. Tolerability of a high dose of budesonide/formoterol in a single inhaler in patients with asthma. The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma. Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Is the increase in bronchial responsiveness or FEV1 shortly after cessation of beta2-agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting beta2-agonists. Randomised trial comparing as-needed versus regular treatment with formoterol in patients with persistent asthma. Formoterol used as needed in patients with intermittent or mild persistent asthma. A Randomized, Double-Blind, Double-Dummy, Safety Crossover Trial Comparing Cumulative Doses up to 96 μg of Formoterol Delivered via an HFA-134a-Propelled pMDI vs. Same Cumulative Doses of Formoterol DPI and Placebo in Asthmatic Patients Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Formoterol, a new long-acting bronchodilator for inhalation. A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists. A randomised, double-blind, placebo-controlled study to evaluate the role of formoterol in the management of acute asthma Long duration of airway but not systemic effects of inhaled formoterol in asthmatic patients. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Safety of formoterol by Turbuhaler® as reliever medication compared with terbutaline in moderate asthma Comparable Efficacy and Tolerability of Formoterol (Foradil®) Administered via a Novel Multi-Dose Dry Powder Inhaler (Certihaler™) or the Aerolizer® Dry Powder Inhaler in Patients with Persistent Asthma Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma. Onset of action following formoterol Turbuhaler and salbutamol pMDI in reversible chronic airway obstruction. Sustained improvement in asthma with long-term use of formoterol fumarate. Comparison of the short-term effects of salmeterol and formoterol on heart rate variability in adult asthmatic patients. Efficacy and Safety of Formoterol Delivered Via a New Multidose Dry Powder Inhaler (Certihaler™) in Adolescents and Adults with Persistent Asthma Regular inhaled salbutamol and airway responsiveness to allergen Twelve hours' bronchodilating effect of inhaled formoterol in children with asthma: a double‐blind cross‐over study versus salbutamol Dose-response study of inhaled salmeterol in asthmatic patients with 24-hour spirometry and Holter monitoring. Relief of dyspnoea by beta2-agonists after methacholine-induced bronchoconstriction. The extrapulmonary effects of increasing doses of formoterol in patients with asthma Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Formoterol delivered via a new multi-dose dry powder inhaler (Certihaler) is as effective and well tolerated as the formoterol dry powder inhaler (Aerolizer) in children with persistent asthma. Regular formoterol treatment in mild asthma. Effect on bronchial responsiveness during and after treatment. [Bronchial asthma treated with long-acting beta 2 agonist. Comparison between formoterol (12 mu/g) inhaled twice daily and salbutamol (200 mu/g) inhaled 4 times daily]. Addition of Formoterol or Montelukast to Low-Dose Budesonide: An Efficacy Comparison in Short- and Long-Term Asthma Control Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Long-term efficacy of formoterol compared to salbutamol Onset and duration of action of single doses of formoterol inhaled via Turbuhaler. Safety of formoterol after cumulative dosing via Easyhaler and Aerolizer. Effect of inhaled formoterol versus terbutaline on respiratory function in moderate bronchial asthma Long-term effects of formoterol and salbutamol on bronchial hyperreactivity and beta-adrenoceptor density on lymphocytes in children with bronchial asthma. A 3-month comparison of formoterol with terbutaline via turbuhaler. A placebo-controlled study. Double-Blind, Double-Dummy, Multinational, Multicenter, Parallel-Group Design Clinical Trial of Clinical Non-Inferiority of Formoterol 12 μg/Unit Dose in a b.i.d. Regimen Administered via an HFA-Propellant-pMDI or a Dry Powder Inhaler in a 12-Week Treatment Period of Moderate to Severe Stable Persis A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients. Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose Comparison of bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and chlorofluorocarbon aerosols and dry powder in a double blind, placebo-controlled, crossover study. A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler. Bioequivalence of inhaled formoterol fumarate assessed from pharmacodynamic, safety and urinary pharmacokinetic data. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. * Inhaled formoterol dry powder in the treatment of patients with reversible obstructive airway disease Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. Efficacy and safety of formoterol Turbuhaler when added to inhaled corticosteroid treatment in children with asthma. Formoterol suspension aerosol. Comparison with formoterol solution aerosol for 12 weeks in asthmatic patients. Formoterol, 24 microg bid, and serious asthma exacerbations: similar rates compared with formoterol, 12 microg bid, with and without extra doses taken on demand, and placebo. The effect of formoterol over 24 h in patients with asthma: the role of enantiomers. 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. Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. The Canadian FO/OD1 Study Group. [Formoterol as inhalation powder in the treatment of patients with reversible obstructive lung diseases. A 3-month placebo-controlled comparison of the effects of formoterol and salbutamol, followed by a 12-month period with formoterol alone]. Formoterol provides long-lasting protection against exercise-induced bronchospasm. Cost-effectiveness analysis of budesonide/formoterol compared with fluticasone in moderate-persistent asthma. Low-dose formoterol Turbuhaler (Oxis) b.i.d., a 3-month placebo-controlled comparison with terbutaline (q.i.d.). One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Quality of life during formoterol treatment: comparison between asthma-specific and generic questionnaires. Canadian and the Dutch Formoterol Investigators. Potential masking effects of salmeterol on airway inflammation in asthma. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Tolerability to high doses of formoterol and terbutaline via Turbuhaler for 3 days in stable asthmatic patients. Safety and tolerability of high-dose formoterol (Aerolizer) and salbutamol (pMDI) in patients with mild/moderate, persistent asthma. Evaluation of different doses of formoterol from a newly developed powder inhalation device in asthmatic patients. Efficacy and safety of formoterol delivered through the Novolizer, a novel dry powder inhaler (DPI) compared with a standard DPI in patients with moderate to severe asthma. [The effect of a single dose of formoterol using an aerosol inhaler in asthmatic children. A randomized, controlled, double-blind study]. Formoterol induces tolerance to the bronchodilating effect of Salbutamol following methacholine-provocation test in asthmatic children. The safety and efficacy of formoterol (Oxis) turbuhaler plus budesonide (Pulmicort) turbuhaler in mild to moderate asthma: a comparison with budesonide Turbuhaler alone and current non-corticosteroid therapy in Russia. Effect of solution and suspension type aerosol of formoterol on tremor response and airways in patients with asthma. Actions other than smooth muscle relaxation may play a role in the protective effects of formoterol on the allergen-induced late asthmatic reaction. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. Regular inhaled beta-agonist treatment in bronchial asthma
A r and omised , double-blind trial was undertaken to investigate the efficacy and tolerability of formoterol Turbuhaler in children with mild to moderate asthma . After a two-week run-in , 248 children aged 6 - 17 years were r and omised to receive formoterol 4.5 and 9 pmicro b.i.d . or placebo for 12 weeks . Morning PEF ( primary variable ) , was significantly improved versus placebo only in the formoterol 9 pmicro b.i.d . group ( 13 l/min , 95 % CCI 1.9 , 24.2 % ; p = 0 .02 ) . Both formoterol 4.5 and 9 pmicro significantly increased the pre-bronchodilator FEV1 by 5.2 - 6.7 % ( p < 0 .05 ) and reduced use of daytime relief medication versus placebo ( p < 0 .05 ) . Formoterol 9 pmicro significantly reduced night-time reliever use and awakenings due to asthma versus placebo ( p < 0.05 ) . Both doses of formoterol were as well tolerated as placebo . In conclusion , formoterol 4.5 and 9 micro b.i.d . is effective and well tolerated as maintenance therapy in children with mild to moderate asthma Inhalation of on-dem and salbutamol ( ODS ) several times daily is sometimes the only beta2-agonist prescribed in moderate persistent asthma , whereas a long-acting beta2-agonist should be added . This trial aim ed to compare the efficacy of formoterol dry-powder capsule 12 microg b.i.d . ( Foradil ) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids , in the conditions of real practice . Two hundred and fifty-nine patients were r and omized ( formoterol ; 130 ; ODS : 129 ) in this open , parallel-group trial . The mean increases in morning peak expiratory flow ( PEF primary variable ) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol : + 25.7 and + 24.1 l min(-1 ) , respectively vs. + 4.5 and + 0.5 l min(-1 ) respectively with ODS . The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3 . Formoterol  reduced the use of salbutamol as rescue medication by two-thirds . The percentages of symptom-free days and nights statistically significantly increased with formoterol ( + 20 % and + 33 % respectively ) , but did not significantly change with ODS  .  Clinical ly relevant and statistically significant improvement in the mean total score of the St George 's Hospital Respiratory Question naire was observed in the formoterol group . Adverse events were similar in the two groups . The results show that treatment with formoterol has significant advantages over ODS  in patients with moderate persistent asthma BACKGROUND In vitro the long acting β2 agonist salmeterol can , in contrast to formoterol , behave as a partial agonist and become a partial antagonist to other β2 agonists . To study this in vivo , the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists . METHODS A r and omised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second ( FEV1 ) of 88.4 % predicted and median concentration of methacholine provoking a fall in FEV1 of 20 % or more ( PC20 ) of 0.62 mg/ml at entry . One hour after the last dose of 2 weeks of treatment with formoterol ( 24 μg twice daily by Turbuhaler ) , salmeterol ( 100 μg twice daily by Diskhaler ) , or placebo a methacholine provocation test was performed and continued until there was at least a 30 % decrease in FEV1 . Salbutamol ( 50 μg ) was administered immediately thereafter , followed by ipratropium bromide ( 40 μg ) after a further 30 minutes . Lung function was monitored for 1 hour after provocation . RESULTS There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment . The dose of methacholine needed to provoke a fall in FEV1 of ⩾30 % was higher after pretreatment with formoterol ( 2.48 mg ) than with salmeterol ( 1.58 mg ) or placebo ( 0.74 mg ) . The difference between formoterol and salmeterol was statistically significant : 0.7 doubling dose steps ( 95 % CI 0.1 to 1.2 , p=0.016 ) . The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs ( p<0.0003 for both ) . Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8 % , 7.3 % , and 5.5 % for placebo , formoterol and salmeterol , respectively ( equivalent to increases of 26 % , 14 % , and 12 % , respectively , from the lowest FEV1after methacholine ) . At 30 minutes significant differences remained , but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups . CONCLUSION Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent , indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo . Irrespective of this , prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally , indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol . Patients on regular treatment with long acting β2 agonists  should be made aware that an additional single dose of a short acting β2 agonist may become less effective BACKGROUND The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity . The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects . METHODS A double blind , r and omised , crossover study was carried out in 16 healthy subjects who inhaled formoterol 24 , 48 and 96 μg ( via Turbuhaler ® ) , salmeterol 100 , 200 and 400 μg ( via Diskhaler ® ) , or placebo on separate days . Heart rate , systolic and diastolic blood pressure , and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose . Mean maximum ( or minimum ) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs . Lunch was taken after the four hour readings and , since this caused additional changes to the main outcome measures , data from the first four hours are also presented in a post hoc analysis . RESULTS Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration ; formoterol also caused an early increase in systolic blood pressure . The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol , apart from the glycaemic response . The effects of salmeterol were slightly more prolonged than those of formoterol , although some dose related effects were apparent at eight hours with both drugs . The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values . Relative dose potencies ( 95 % CI ) for maximum heart rate and plasma potassium concentrations were 4.1 ( 3.0 to 5.6 ) and 5.8 ( 4.1 to 8.6 ) over four hours and 2.4 ( 1.2 to 3.8 ) and 3.0 ( 1.2 to 5.7 ) over eight hours . CONCLUSIONS Formoterol and salmeterol cause dose related changes in heart rate , diastolic blood pressure , and plasma glucose and potassium concentrations . Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity . Both drugs have a relatively modest therapeutic window . The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses . Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained BACKGROUND Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear . Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects . A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow ( FBF ) as a measure of peripheral vasodilatation . METHODS Eight men with mild asthma underwent the following treatments : normoxia + placebo ( NP ) , normoxia + salbutamol ( NS ) , hypoxia + placebo ( HP ) , and hypoxia + salbutamol ( HS ) . The period of mask breathing started at t=0 minutes , lasted for 60 minutes , and at 30 minutes 800 μg salbutamol was inhaled . The experiment was completed 30 minutes after the inhalation ( t=60 minutes ) . For the hypoxia treatment the Spo 2 level was 82 % . Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value . RESULTS There were no significant differences in blood pressure and potassium levels between the treatments . After 60 minutes the increase in FBF was 13 % ( 95 % CI –12 to 39 ) more for HP treatment than for NP , 21 % ( 95 % CI –5 to 46 ) more for NS than for NP , and 32 % ( 95 % CI 7 to 58 ) more for HS than for HP ( p=0.016 ) . The inhalation of salbutamol during hypoxia result ed in a significant increase in FBF of 45 % ( 95 % CI 20 to 71 ) compared with NP ( p=0.001 ) . CONCLUSION Patients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death AIMS Inhalers combining long acting beta2-adrenoceptor agonists ( LABA ) and corticosteroids ( ICS ) are indicated at Step 3 of current asthma guidelines . We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function , bronchoprotection , acute salbutamol recovery following methacholine bronchial challenge , and surrogate inflammatory markers in patients with moderate persistent asthma . METHODS Twenty-nine patients with mean FEV1 ( + /- SEM ) of 78 + /- 3 % predicted completed a r and omized , double-blind , double-dummy , cross-over study . Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg ( BUD + FM ) combination twice daily followed by 1 week of BUD 400 microg alone twice daily , or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg ( FP + SM ) combination twice daily followed by 1 week of FP 250 microg alone twice daily . Measurements were made at baseline and following each r and omized treatment . RESULTS FEV1 increase from pretreatment baseline as mean ( + /- SEM ) % predicted was significantly higher ( P < 0.05 ) for BUD + FM ( 8 + /- 1 % ) vs BUD ( 2 + /- 1 % ) , and for FP + SM ( 8 + /- 1 % ) vs FP ( 2 + /- 1 % ) . The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups ; BUD + FM ( 22 + /- 1 % ) , BUD ( 24 + /- 1 % ) , FP + SM ( 23 + /- 1 % ) and FP ( 23 + /- 1 % ) . Salbutamol recovery over 30 min following methacholine challenge as area under curve ( AUC % .min ) was significantly blunted ( P < 0.05 ) with BUD + FM ( 486.7 + /- 35.5 ) vs BUD ( 281.1 + /- 52.8 ) , and with FP + SM ( 553.1 + /- 34.1 ) vs FP ( 368.3 + /- 46.7 ) . There were no significant differences between respective combination inhalers or between respective ICS alone . Decreases in exhaled nitric oxide ( NO ) and serum eosinophilic cationic protein ( ECP ) from baseline were not significantly different between treatments . CONCLUSIONS Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone , but delay acute salbutamol recovery after bronchoconstriction We compared the efficacy of inhaled formoterol , a long-acting beta 2-agonist , with inhaled albuterol in 145 stable adult asthmatics in a 12-wk multicenter trial . Patients were allocated in r and omized double-blind fashion to maintenance therapy with either formoterol 12 micrograms twice a day or albuterol 200 micrograms four times a day in addition to their other asthma medications . Patients were allowed to use " rescue " 100-micrograms albuterol puffs on an as-needed basis . Mean baseline FEV , in the morning before bronchodilator was 2.14 + /- 0.76 L and 1.98 + /- 0.71 L for the formoterol and albuterol groups , respectively , these values being used as baseline covariates in subsequent analysis of predrug and postdrug FEV1 . Measured at each clinic visit , morning predrug FEV1 rose significantly with formoterol treatment and was significantly greater at all visits than in the albuterol group , the greatest difference being in Week 8 ( 2.40 + /- 0.77 versus 1.92 + /- 0.66 L , p less than 0.001 ) . Morning FEV1 30 min postdrug was significantly higher in the formoterol group at Weeks 2 and 8 , the trend not reaching statistical significance at other times . Diurnal variation in prebronchodilator peak flow rates was significantly reduced in the formoterol group throughout the trial ( 17 versus 42 L/min at Week 12 , p less than 0.0001 ) . The number of asthma episodes per week was significantly less in the formoterol group during Weeks 4 , 8 , and 12 as were the number of sleep disruptions during Weeks 2 , 4 , 6 , 8 , and 12 . Significantly more rescue albuterol was required in the albuterol group by Week 2 and throughout the remainder of the study . ( ABSTRACT TRUNCATED AT 250 WORDS To demonstrate the presence of functional cardiac β2-adrenoceptors in man , we studied the responses to intracoronary injections of salbutamol in three groups of six patients . We injected salbutamol , a selective β2-adrenoceptor agonist , into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly . Salbutamol injections caused a sinus tachycardia . The same doses of salbutamol injected into the aortic root caused no change in heart rate , ruling out a systemic effect . The mean dose required to cause an increase in heart rate of 30 beats/min ( IHR30 ) was 2.6 μg in the first group of six patients . In 12 other patients salbutamol was given after β-blockade to confirm the β2-selectivity of the responses . Doses of practolol ( β1,-selective blockade ) and of propranolol ( β1- and β2-blockade ) that had equal β1-blocking activity were used . In six patients who were given practolol  , the mean IHR30 dose was 2.1 μg . In six patients who were given propranolol , the mean IHR30 dose was significantly greater at 64 μg ( p < 0.001 , practolol vs. propranolol ) . This study demonstrates that direct cardiac β2-adrenoceptor stimulation in man has a positive chronotropic effect The objectives of this study were to compare the efficacy and tolerability of twice-daily formoterol dry powder 12 µg and 24 µg ( Foradil ) delivered via Aerolizer inhaler with four times daily albuterol ( salbutamol ) 180 µg delivered via metered dose inhaler ( MDI ) and placebo .  A total of 554 adolescents and adults ( ages 12–75 years ) with mild-to-moderate asthma were r and omized to this 12-week , multicenter , double-blind , double-dummy , placebo-controlled , parallel-group study . Twelve-hour spirometry measurements were taken at weeks 0 , 4 , 8 , and 12 . A total of 484 patients completed the study ( 122 , 116 , 127 , and 119 given formoterol 12 µg , formoterol 24 µg , albuterol , and placebo , respectively ) . For the primary efficacy variable , the forced expiratory volume in 1 second ( FEV1 ) , both formoterol 12 µg and 24 µg were statistically superior to placebo at all time points on all test days ( p ≤ 0.017 ) and to albuterol at most time points on all test days ( p ≤ 0.001 ) . The onset of improvement in FEV1 was rapid , with 15 % increase within 5 min in 57 % , 71 % , and 65 % of formoterol 12 µg , formoterol 24 µg , and albuterol patients , respectively . Formoterol was also superior to placebo and albuterol in terms of secondary efficacy variables : FEV1 area under the curve , percentage of predicted FEV1 , forced vital capacity and forced expiratory flow , asthma symptom scores , and peak expiratory flows . In conclusion , both formoterol doses were superior to placebo in all lung function measurements . Overall , compared with  albuterol , both formoterol doses produced superior bronchodilation  . Formoterol and albuterol  were safe and well-tolerated 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 STUDY OBJECTIVE To determine whether formoterol , a new beta 2 agonist with experimentally documented long duration , is clinical ly more effective than salbutamol in the maintenance treatment of chronic asthma . DESIGN R and omized double-blind between-patient comparison between treatment with formoterol and with salbutamol during four weeks . SETTING Asthma/allergy department in a university hospital . PATIENTS Thirty-seven patients with chronic stable asthma , who during a two-week run-in period with inhaled salbutamol , 4 x 100 micrograms twice a day , used at least four additional doses ( 100 micrograms each ) daily , were r and omly assigned to use either formoterol or salbutamol .  Thirty-five patients were evaluated for efficacy . One early withdrawal and one dropout were found in the salbutamol group . The groups were similar with respect to demographic data and baseline lung function . INTERVENTIONS During the four-week study period , the patients used either formoterol ( 4 x 6 micrograms twice a day and as necessary , n = 19 ) or salbutamol ( 4 x 100 micrograms twice a day and as necessary , n = 16 ) . Inhaled steroids and orally administered theophylline were allowed if doses were kept constant . MEASUREMENTS AND MAIN RESULTS The median number of additional doses per 24 h ( median of two weeks ) of the test aerosols was 0 ( range , 0 to 6 ) for formoterol and 4 ( range , 0 to 14 ) for salbutamol ( p less than 0.01 ) . Morning and evening PEFRs were 422 ( SEM = 31 ) and 443 ( SEM = 30 ) , respectively , for formoterol , and 335 ( SEM = 30 ) and 360 ( SEM = 26 ) , respectively , for salbutamol ( p = 0.05 for both ) . Formoterol was superior ( p less than 0.05 ) to salbutamol with respect to control of asthma symptoms , estimated duration of action and patient preference . Side effects did not differ . CONCLUSIONS Inhaled formoterol administered twice a day and as necessary was clinical ly more effective than the same regimen of salbutamol Asthma patients evaluate the effect of medication treatment through the degree of their asthma symptoms , which might be affected by their ability to perceive these symptoms . It has been suggested that β2-agonists may mask the effects of an increase in airway inflammation . This study compared the perception of histamine-induced bronchoconstriction during monotherapy with short- or long-acting β2-agonists .  Asthmatic patients ( 68 male and 60 female , mean age 35±11 yrs , forced expiratory volume in one second ( FEV1 ) 86±15 % of the reference value , provocative concentration causing a 20 % fall in FEV1 ( PC20 ) geometric mean 0.97 mg·mL−1 ( 95 % confidence interval ( CI ) : 0.73–1.30 ) ) were selected and r and omly allocated to use either a short-acting ( salbutamol , n=41 ) or long-acting β2-agonist ( formoterol , n=46 ) or placebo ( n=41 ) for 12 weeks . Perception of dyspnoea provoked by histamine-induced bronchoconstriction was measured at the start and every 4 weeks thereafter . Subjects quantified their sensation of breathlessness during the challenge tests on a modified Borg scale at the start of the study and every 4 weeks thereafter . The sensitivity to changes in FEV1 was analysed by the linear regression slope ( α ) Borg versus % fall in FEV1 . The absolute perceptual magnitude ( PS20 ) was determined by the perception score at the 20 % fall in FEV1 . Although the geometric mean PC20 decreased significantly within the group using short-acting β2-agonists ( in the group with initial PC20 ≥2 mg·mL−1 there was a drop from 5.26–1.94 mg·mL−1 ; p=0.013 ) , repeated measurement analysis showed no difference in the course of time of perception ( both slope α and PS20 ) between the three medication groups . This study showed that chronic use of short- or long-acting β2-agonists in asthmatics for a period of 12 weeks , did not significantly change the perception of histamine-induced bronchoconstriction compared with placebo . Further investigation is required to establish whether this suggests that these drugs do not mask a deterioration of asthma BACKGROUND The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma . Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler ( pMDI ) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma , but it has not been assessed in patients with mild to moderate persistent asthma . OBJECTIVE The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI ( budesonide/formoterol pMDI ) , budesonide pMDI , formoterol dry powder inhaler ( DPI ) , and placebo . METHODS This 12-week , multicenter , double-blind , r and omized , placebo-controlled , double-dummy study was conducted at 56 centers across the United States . Patients aged > or = 12 years with mild to moderate persistent asthma treated with inhaled corticosteroids ( ICSs ) for > or = 4 weeks before screening and who had a forced expiratory volume in 1 second ( FEV(1 ) ) of > or = 60 % to < or = 90 % of predicted normal at screening were eligible . After 2 weeks ( current asthma therapy discontinued ) , patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations ( 160/9 microg ) , budesonide pMDI 80 microg x 2 inhalations ( 160 microg ) , formoterol DPI 4.5 microg x 2 inhalations ( 9 microg ) , or placebo . The co primary efficacy variables were changes from baseline in morning predose FEV(1 ) and 12-hour mean FEV(1 ) ( from serial spirometry ) after administration of the morning dose of study medication . Tolerability was assessed based on adverse events ( AEs ) ; routine laboratory assessment s ; electrocardiography ; 24-hour Holter monitor assessment s ; and physical examinations , including vital signs ( eg , systolic and diastolic blood pressure and heart rate ) . AEs were recorded manually by the patient in paper notebooks and review ed at each clinic visit by the investigator and during a final follow-up phone call . RESULTS A total of 480 patients were r and omized ( 299 females , 181 males ; mean age , 36 years ; mean FEV(1 ) , 2.4 L ; budesonide/formoterol pMDI , 123 patients ; budesonide pMDI , 121 ; formoterol DPI , 114 ; placebo , 122 ) . At end of treatment , the mean increases from baseline in predose FEV(1 ) were greater with budesonide/formoterol pMDI versus budesonide pMDI , formoterol DPI , and placebo ( 0.37 vs 0.23 , 0.17 , and 0.03 L , respectively ; all , P<0.005 ) . 0.005 ) . After administration of the first dose and at weeks 2 and 12 , mean increases in 12-hour mean FEV(1 ) were significantly greater with budesonide/formoterol pMDI ( 0.41 , 0.47 , and 0.50 L , respectively ) versus budesonide pMDI ( 0.17 , 0.30 , and 0.32 L ) and placebo ( 0.15 , 0.12 , and 0.12 L ) ( all , P < 0.001 ) . Fewer patients receiving budesonide/formoterol pMDI met criteria for ( 18.7 % ; P < 0.001 ) or withdrew because of ( 7.3 % ; P < or = 0.010 ) worsening asthma versus formoterol DPI ( 42.1 % and 18.4 % , respectively ) and placebo ( 56.6 % and 32.8 % ) ; results were similar between budesonide pMDI ( 21.5 % and 6.6 % , respectively ) and budesonide/formoterol pMDI . Three patients experienced serious AEs ; none was considered related to study medication . The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups . CONCLUSIONS In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs , twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents . All study drugs were generally well tolerated BACKGROUND Although albuterol remains the st and ard treatment for asthma in the emergency department , formoterol fumarate may be more advantageous , with its rapid and long-lasting bronchodilation . OBJECTIVE To compare formoterol fumarate with albuterol in controlling acute asthma exacerbation . METHODS Patients aged 18 to 65 years who presented to the emergency department with mild to moderate asthma exacerbation ( peak expiratory flow rate [ PEFR ] , 40%-60 % of predicted ) were r and omized to receive either formoterol fumarate aerolizer ( 12 microg ) or albuterol nebulizer ( 2.5 mg ) every 30 minutes up to 2 treatments . Symptom scores and PEFRs were measured at each treatment . RESULTS Thirty-four patients ( 19 in the albuterol arm and 15 in the formoterol fumarate arm ) were enrolled . At 30 and 60 minutes , the mean PEFR of the albuterol group increased from 43.7 % of predicted to 51.9 % of predicted and 54.6 % of predicted , respectively , and the formoterol fumarate group had changes in the mean PEFR from 49.3 % of predicted to 55.5 % of predicted and 57.3 % of predicted , respectively , and the mean change in the 2 groups was not significantly different at 30 and 60 minutes ( P = .64 and .57 , respectively , by t test ) . The albuterol group improved in symptom scores by 3.7 and 5.5 from 0 minutes to 30 and 60 minutes , respectively , and in the formoterol fumarate group these values were 3.1 and 4.9 at 30 and 60 minutes , respectively , and the mean change in the 2 groups was not significantly different at 30 and 60 minutes ( P = .61 and .76 , respectively , by t test ) . CONCLUSION Formoterol fumarate is as effective as albuterol inhalation for the treatment of adults with mild to moderate asthma exacerbations in the acute care setting 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 A double-blind , r and omized crossover study in 28 asthmatic patients assessed the relative therapeutic index for inhaled formoterol and salbutamol . Pre-drug administration FEV1 ( mean 2.08 l ) was 49 - 93 % of predicted and reversibility 16 - 82 % after inhalation of salbutamol . Patients inhaled single doses of formoterol ( Oxis ) ( 4.5,18 and 54 microg , delivered doses ) via Turbuhaler , salbutamol ( Ventolin ) ( 200 and 1800 microg ) via pressurized metered dose inhaler ( pMDI ) and placebo at intervals of 48 h or more . Individual maximum FEV1 and minimum S-K+ were calculated . Relative local ( maximum FEV1 ) and systemic ( minimum S-K+ ) dose potencies , and their ratio , the relative therapeutic index , were estimated using a non-linear mixed effect model . The drug effects were well tolerated and dose dependent . A log-linear approximation was used to describe the bronchodilatory effect , whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration . A bivariate dose-response model based on these principles was fitted simultaneously to all data . The mean relative therapeutic index between formoterol 4.5 - 54 microg given via Turbuhaler and salbutamol 200 - 1800 microg given via pMDI was estimated to be 2.5 in favour of formoterol ; this trend was not statistically significant 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 BACKGROUND Inhaled beta(2)-agonists are widely used in asthma treatment . The design limitations of pressurized metered dose inhalers ( pMDIs ) have prompted the development of dry powder inhalers ( DPIs ) for the delivery of asthma medications . OBJECTIVE The goal of this study was to evaluate the efficacy , tolerability , and effect on asthma-related quality of life ( QOL ) of a long-acting beta(2)-adrenoreceptor agonist , formoterol , delivered via multidose DPI , compared with albuterol delivered via pMDI or placebo in adolescents and adults with persistent asthma . METHODS This multicenter , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group study was conducted in outpatient clinics at 18 US centers . Adolescents and adults with persistent asthma received formoterol 10 pg BID via multidose DPI , albuterol 180 microg QID via pMDI , or placebo for 12 weeks . The primary efficacy variable was the 12-hour AUC of forced expiratory volume in 1 second ( FEV(1 ) ) after 12 weeks treatment . Secondary efficacy variables included asthma-related QOL , asthma symptom scores , rescue medication use , and other pulmonary function measures . RESULTS A total of 239 patients ( 147 females , 92 males ; age range , 13 - 85 years ) with persistent asthma were enrolled  ( formoterol , n = 80 ; albuterol , n = 79 ; placebo , n = 80 ) . Formoterol delivered via the multidose DPI result ed in clinical ly relevant and statistically significant increases in 12-hour AUC of FEV(1 ) after 12 weeks of treatment compared with albuterol pMDI and placebo ( P < 0.019 and P < 0.001 , respectively ) . Asthma-related QOL ( total score ) was significantly improved with formoterol treatment compared with placebo ( P < 0.015 ) . Nocturnal asthma symptom scores significantly improved with formoterol compared with albuterol and placebo ( P < 0.001 and P < 0.003 , respectively ) and rescue medication use was significantly less with formoterol compared with albuterol and placebo ( P < 0.004 and P < 0.002 , respectively ) . Treatment with formoterol was well tolerated . CONCLUSIONS In this study of adolescents and adults with persistent asthma , 12 weeks of treatment with formoterol 10 microg BID delivered via a multidose DPI provided significantly greater 24-hour bronchodilation compared with albuterol and placebo and result ed in significant improvements in asthma-related QOL compared with placebo . Formoterol was well tolerated in these patients The aim of this study was to compare the efficacy and safety of formoterol versus salbutamol as reliever medication in patients presenting at an emergency dept with acute asthma . A r and omised , double-blind , double-dummy , parallel group study was performed in four Australian emergency treatment centres . The study included a total of 78 adult patients ( mean baseline forced expiratory volume in one second ( FEV1 ) 1.83 L ; 59 % predicted ) with acute asthma . Based on the expected dose equivalence of formoterol Turbuhaler ® 4.5 µg ( delivered dose ) and salbutamol pressurised metered-dose inhaler 200 µg ( metered dose ) , patients received a total of formoterol Turbuhaler ® 36 µg ( delivered ) or salbutamol pressurised metered-dose inhaler with spacer 1,600 µg ( metered ) , divided into two equal doses at 0 and 30 min . FEV1 , peak expiratory flow and systemic β2-agonist effects were monitored for 4 h. The primary variable was FEV1 % pred at 45 min . At 45 min , mean increases in FEV1 expressed in % pred were 6.6 % and 9.3 % , respectively , with a small adjusted mean difference in favour of salbutamol ( 3.0 % , 95 % confidence interval −2.0–8.0 ) . Transient increases in systemic β2-agonist effects occurred predominantly with salbutamol , although no significant treatment differences were observed . Eight patients discontinued due to adverse events . In this study of patients presenting at emergency depts with acute asthma , formoterol Turbuhaler ® 36 µg was well tolerated and , as rescue therapy , had an efficacy that was not different from that of salbutamol pressurised metered-dose inhaler with spacer 1,600 µg in the number of patients studied 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 Background : Although formoterol , a new long-acting β2-adrenergic agonist , has a rapid bronchodilating action , no studies have previously examined whether it can provide equally rapid protection against exercise-induced bronchospasm ( EIB ) . Aim : The aim of the study was to assess the effect of inhaled formoterol against EIB 15 min and 4 h after administration in asthmatic athletes . Methods : The protective effect of a formoterol ( 12 µg ) dry-powder inhalation was evaluated in 14 EIB-positive asthmatic athletes ( 13 males , mean age 16.8 years ) , in a double-blind , placebo-controlled , two-period cross-over study . On each treatment day , the subjects underwent two cycloergometric exercise tests 15 min and 4 h after receiving formoterol or placebo . Results : Formoterol  induced significant bronchodilation in comparison with placebo both 15 min and 4 h after administration ( p = 0.007 and p = 0.004 ) ; placebo treatment had no effect on EIB , the maximum percent fall in FEV1 after exercise being 29.3 ± 14.3 % and 22.9 ± 13.7 % at 15 min and 4 h , respectively . Formoterol offered good protection against EIB in 12 athletes ( 86 % ) who experienced a decrease in FEV1 after exercise < 10 % both 15 min and 4 h after administration . The mean maximum percent fall in FEV1  after formoterol was 5.9±7.2 % at 15 min ( p < 0.0001 ) , and 5.8 ± 6.9 % at 4 h ( p < 0.0001 ) . There was no statistically significant difference in resting heart rate before and after medication with placebo or formoterol , nor was the heart rate at the end of exercise significantly different on the 2 treatment days . No side effect was observed in either group . Conclusions : This study demonstrates that formoterol dry powder inhalation is effective in protecting asthmatic athletes as early as 15 min after dosing . Furthermore , the data confirm the long duration of its protective effect and the absence of any significant adverse effects after acute administration The objective of this study was to compare the efficacy and safety of the second controller medications ( long-acting beta2-agonist , leukotriene receptor antagonist and sustained-release theophylline ) used in addition to inhaler corticosteroid treatment in moderate persistent asthma . A total of 64 patients with asthma , in the moderate persistent asthma category , were divided into three groups . Patients , all of whom were concurrently using inhaled corticosteroid ( Budesonide 400 microg twice daily ) , were treated for 3 months with either inhaled formoterol 9 microg twice daily ( first group ) , oral zafirlukast 20 mg twice daily ( second group ) , or sustained-release theophylline 400 mg once daily ( third group ) . All of the patients were subjected to assessment s on the subject of peak expiratory flow ( PEF ) variability , forced expiratory volume in 1 sec ( FEV1 ) , asthma symptom scores ( daytime and night-time ) , supplemental terbutalin use , asthma exacerbations and adverse events . Over the 3-month treatment period . In all of the three groups , significant improvements were recorded in the lung function , asthma symptom scores and supplemental terbutalin use criteria , as a result oftreatments applied . Formoterol treatment result ed in significantly greater and earlier improvements compared with the other two groups in several criteria : PEF variability ( 17.9 + /- 2.5 ; 21.9 + /- 3.2 ; 23.7 + /- 3.3 ; P < 0.001 ) ; asthma symptom score ( daytime ) ( 1.6 + /- 0.5 ; 1 + /- 0.5 ; 2.0 + /- 0,5 ; P < 0.05 ) ; asthma symptom score ( night-time ) ( 1.2 + /- 0.4 ; 2.2 + /- 0.5 ; 16 + /- 0.6 ; P < 0001 ) ; and supplement alter butalin  use ( 1.2 + /- 0.3 ; 1.8 + /- 0.5 ; 1.7 + /- 0.5 ; P < 0.05 ) . However , at the end of the treatment , in all of the three groups studied , improvements were attained in overall asthma control and there was no statistical difference among the groups . Although there were no side effects which required the discontinuation of the treatment , it was observed that the maximum side effect was in the second group ( 20 % , 31.6 % and 20 % , respectively ) . In conclusion , in patients who still have symptoms on treatment with inhaled corticosteroids , the addition of a long-acting beta2-agonist , leukotriene antagonists or sustained-release theophylline to the treatment is a logical approach , and , in addition to inhaled corticosteroids , any one of these second controller medications may be chosen in patients with moderate asthma STUDY OBJECTIVE To compare the acute bronchodilatory effect of the long-acting beta2-agonist formoterol against the short-acting beta2-agonist ( SABA ) terbutaline during exercise-induced bronchoconstriction ( EIB ) in children with asthma . DESIGN A r and omized , double-blind , placebo-controlled , crossover study of the immediate effect of formoterol , 9 microg , vs terbutaline , 0.5 mg , and placebo administered as dry powder at different study days . Exercise challenge test was used as a model of acute bronchoconstriction . PATIENTS Twenty-four 7- to 15-year-old children with persistent asthma . INTERVENTIONS The children performed st and ardized treadmill exercise tests , breathing dry air , with a submaximal workload . Study medication was administered 5 min after exercise if FEV1 dropped > or = 15 % within 5 min after exercise . FEV1 and forced expiratory flows were measured repeatedly until 60 min after dose . RESULTS Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dose compared with placebo ( p < 0.001 ) . There was no difference between formoterol and terbutaline in FEV1 5 min after dose ( p = 0.15 ) , with a mean increase from each predrug baseline of 62 % of the maximum increase for both . Median times to recovery within 5 % of baseline FEV1 were 5.0 min and 7.4 min for formoterol and terbutaline , respectively ( p = 0.33 ) . CONCLUSION Single-dose formoterol , 9 microg , via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB in schoolchildren with persistent asthma . Formoterol is at least as effective as SABA and may be considered an alternative in the treatment of acute bronchoconstriction in school children 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 We compared the bronchodilator effects and systemic tolerability of 12 , 24 and 48 micrograms formoterol DP capsules with 12 micrograms formoterol MDI and placebo in 30 patients with reversible obstructive airway disease . Pulmonary function tests were done and pulse rate and blood pressure were recorded . We observed significant differences between all active substances vs placebo regarding peak effect , duration of effect and AUC value . No significant difference was observed between either 12 or 24 micrograms formoterol DP and 12 micrograms from MDI in all mentioned parameters . With 48 micrograms DP , increased peak effect , AUC and duration of effect were noted . Heart rate Holter monitoring showed a slightly more pronounced effect with 48 micrograms . We conclude that 12 to 24 micrograms formoterol DP capsules are equivalent to 12 micrograms of formoterol MDI regarding efficacy and tolerability , while 48 micrograms formoterol DP capsules cause more profound effects in bronchodilation and on the heart rate BACKGROUND --There is controversy as to the role of long acting beta 2 agonists such as eformoterol and , in particular , whether bronchodilator tolerance occurs during continuous therapy . The purpose of this study was to extend previous observations of bronchodilator subsensitivity with metered dose eformoterol aerosol in order to assess whether tolerance also occurs with a dry powder formulation of the same drug . METHODS --Sixteen asthmatic patients of mean age 33 ( range 18 - 53 ) years and FEV1 ( % predicted ) of 64 (3)% , of whom 13 were receiving inhaled corticosteroids  , received regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily ( without beta 2 agonists ) given concurrently for four weeks in a r and omised double blind cross-over design . An initial two week run-in was used when beta 2 agonists were withdrawn and substituted with ipratropium bromide . Dose-response curves to eformoterol ( cumulative dose 6 - 102 micrograms ) for airways and systemic beta 2 responses were constructed at the end of each treatment period . RESULTS --Baseline values for airways and systemic responses were similar . The peak delta FEV1 response from the dose-response curve ( as change from baseline ) and the delta response for FEV1 and FEF25 - 75 at six hours after the last dose were attenuated after eformoterol compared with placebo :  peak delta FEV1 response 1.001 with placebo v 0.841 with eformoterol ( 95 % CI 0.04 to 0.28 ) ; at six hours 0.931 with placebo v 0.581 with eformoterol ( 95 % CI 0.20 to 0.50 ) ; and for delta FEF25 - 75 at six hours 1.29 1/s with placebo v 0.87 1/s with eformoterol ( 95 % CI 0.15 to 0.69 ) . Morning peak expiratory flow rate was significantly improved during treatment with eformoterol ( 451 1/min ) compared with placebo ( 399 1/min ) ( 95 % CI 21 to 82 ) . Systemic beta 2 responses were blunted after eformoterol , together with a reduction in lymphocyte beta 2 receptor binding density . CONCLUSIONS --Regular twice daily eformoterol dry powder may produce bronchodilator subsensitivity in terms of both peak and duration of response to cumulative repeated doses of eformoterol . Systemic beta 2-mediated adverse effects also showed tolerance , which was mirrored by downregulation of lymphocyte beta 2 adrenoceptors The duration and magnitude of the effect of inhaled formoterol ( 12 micrograms ) against exercise-induced bronchoconstriction ( EIB ) was compared with that of inhaled salbutamol ( 200 micrograms ) and that of placebo in 15 children with asthma and EIB in a double-blind , double-dummy , within-patient , placebo-controlled study . The treatments were given by metered dose aerosol on three different days . The exercise test was performed at the 3rd and the 12th hour after dosing . The magnitude of the blocking effect was assessed both by evaluating the lowest FEV1 reading obtained within an hour after each exercise test and by considering the percent decrease below the baseline FEV1 measured before drug administration . Comparison of the lowest values obtained during the hour after each exercise test shows that formoterol was significantly better than both salbutamol ( p = 0.022 ) , and placebo ( p = 0.001 ) in limiting exercise-induced bronchoconstriction after the first exercise test ( 3 h after dosing ) , while no difference was observed between salbutamol and placebo ( p = 0.198 ) . After the second exercise test ( 12 h after dosing ) , formoterol again proved to be more effective than both salbutamol ( p = 0.008 ) and placebo ( p = 0.001 ) , and no significant difference was observed between salbutamol and placebo ( p = 0.391 ) . The evaluation of the mean percentage decrease in FEV1 confirmed the results in favor of formoterol in both the exercise tests . No adverse effects were reported in any treatment group . The protection against EIB is significantly more prolonged after formoterol than after salbutamol , and persists for 12 h after dosing This study aim ed to compare the duration of protection against exercise-induced bronchoconstriction ( EIB ) after inhalation of formoterol ( Oxis ) Turbuhaler with that of terbutaline Turbuhaler and placebo Turbuhaler in asthmatic patients treated regularly with formoterol Turbuhaler 9 microg b.i.d . and inhaled steroids .  The study . performed at three centres ( Göteborg and Lund , Sweden , and Trondheim , Norway ) , consisted of an open-label part with formoterol Turbuhaler 9 microg b.i.d . and a r and omized , double-blind , cross-over part with a single dose ( on top of the regular treatment ) of either formoterol Turbuhaler 9 microg , terbutaline Turbuhaler 0.5 mg or placebo Turbuhaler . The patients attended the clinic six times : twice for screening visits , three times for r and omized treatment and once for a follow-up visit . Patients received regular b.i.d . treatment with formoterol 9 microg for a mean period of 16 days . Formoterol gave a post-exercise fall of 12 , 10 , 15 and 17 % in forced expiratory volume in 1 sec ( FEV1 ) 15 min , 4 , 8 and 12 h after inhalation . The differences compared with placebo ( falls of 26 , 22 , 23 and 22 % ) and terbutaline ( falls of 17 , 18 , 22 and 22 % ) were all statistically significant ( P<0.05 for all comparisons ) . Patients on regular treatment with formoterol Turbuhaler 9 microg b.i.d . have a significant protection against EIB up to 12 h after inhalation of formoterol 9 microg . The protection was also significantly better than that of terbutaline Turbuhaler 0.5 mg The duration of effect of inhaled formoterol ( 24 micrograms ) was compared with that of a placebo and that of inhaled albuterol ( 200 micrograms ) in 12 adult asthmatic subjects who underwent hyperventilation tests with cold dry air ( -20 degrees C ) on 4 study days . On the control day , they were subjected to four hyperventilation tests to ensure functional stability . On the 3 remaining days , after a first hyperventilation test , they inhaled placebo , albuterol , or formoterol in r and omized , double-blind fashion . The hyperventilation test was repeated 1 , 4 , and 8 h and , if the blocking effect was still present , 12 and 24 h after the drug had been administered . The dose of hyperventilation of cold air causing a 20 % fall in FEV1 ( PD20 ) was interpolated on the dose-response curve . The magnitude of the blocking effect at each time interval on each study day was assessed by comparing the changes in PD20 from baseline with the within-day variability of PD20 ( st and ardized change in PD20 ) . The acute bronchodilator effect was not significantly different as assessed 15 min ( 21 + /- 14 % for albuterol and 18 + /- 18 % for formoterol ) and 1 h ( 20 + /- 13 % for albuterol and 18 + /- 17 % for formoterol ) after administering the medication . The duration of the blocking effect , defined as the return to 2 SD from the st and ardized change in PD20 , was significantly more prolonged for formoterol ( 8.0 + /- 3.4 h ) than for albuterol ( 3.0 + /- 1.7 h ) ( t = 4.2 , p less than 0.0001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The aim of the study was to compare the safety and effectiveness of as-needed formoterol with salbutamol in a large international real-life asthma study . Children and adults ( n=18,124 ) were r and omised to 6 months as-needed treatment with open-label formoterol 4.5 µg Turbuhaler ® or salbutamol 200 µg pressurised metered dose inhaler or equivalent . Primary safety variables were asthma-related and nonasthma-related serious adverse events (SAE)s and adverse events (AE)s result ing in discontinuation (DAE)s . The primary efficacy variable was time to first asthma exacerbation . The incidences of AEs , SAEs and DAEs arising from SAEs were not significantly different between treatments . DAEs for nonserious AEs were higher  with formoterol . Asthma-related AEs decreased with formoterol ( 1,098 ( 12.3 % ) versus 1,206 ( 13.5 % ) ) , asthma-related SAEs were similar ( 108 ( 1.2 % ) versus 121 ( 1.4 % ) ) but more asthma-related DAEs occurred in the formoterol group ( 89 ( 1.0 % ) versus 48 ( 0.5 % ) ) . Time to first exacerbation was prolonged ( hazard ratio 0.86 ) and less as-needed and maintenance medication was used with formoterol . Reductions of exacerbations with as-needed  formoterol versus salbutamol increased with increasing age and asthma medication level . This real-life study demonstrates that formoterol as-needed has a similar safety profile  to salbutamol , and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations This study compared the safety of formoterol ( Oxis ® Turbuhaler ® ; 90 µg delivered dose ; 120 µg metered dose ) with terbutaline ( Bricanyl ® Turbuhaler ® ; 10 mg ) , in patients with acute bronchoconstriction . Forty-eight patients ( 31 females ) with a mean age of 45 yrs , were r and omized into two parallel groups ( double-blind design ) . Mean baseline forced expiratory volume in one second ( FEV1 ) was 0.98 L ( 33 % of predicted normal ) . Study drugs were administered on six occasions during 3 h ( formoterol 4.5 µg or terbutaline 0.5 mg·inhalation−1 , 20 inhalations ) . Patients received intravenous prednisolone after 1.5 h and oxygen during the first 3 h. Pulse rate , serum potassium , 12-lead electrocardiogram ( ECG ) , Holter ECG , arterial blood gases and FEV1 were assessed during 12 h after the first dose . Four patients ( one formoterol , three terbutaline ) discontinued . The 12-h mean values of serum potassium decreased from 4.02 to 3.89 mmol·L−1 for formoterol and from 4.22 to 3.76 mmol·L−1 for terbutaline  . Mean 12-h pulse rate was significantly ( p<0.01 ) higher in the terbutaline group ( 101.7 beats per minute ( bpm ) ) than in the formoterol group ( 93.5 bpm ) . No individual patient value was considered clinical ly important or alarming . FEV1 improved in both groups but with no statistically significant difference between treatments . Oxis ® Turbuhaler ® ( 90 µg ) was at least as safe and well tolerated as terbutaline ( 110 mg ) in patients with acute bronchoconstriction OBJECTIVE To quantify the relation between local and systemic magnitudes of effects of inhaled formoterol and salbutamol . METHODS Twenty-eight stable asthmatic patients completed this double-blind , r and omised crossover study . Pre-drug administration FEV1 ( mean 2.08 L ) was 49 - 93 % of predicted and reversibility 16 - 82 % after inhalation of salbutanmol . Patients inhaled three single doses of formoterol fumarate dihydrate ( Oxis ) ( delivered doses of 4.5 , 18 and 54 microg ) via Turbuhaler , two single doses of salbutamol ( 200 and 1800 microg ) via a pressurised metered dose inhaler ( pMDI ) and placebo at intervals of 48 h or more . Individual maximum FEV1 and minimum S-K+ were calculated . A classic sigmoid model of log-dose response was used to discriminate pharmacologically between formoterol and salbutamol . Relative local ( maximum FEV1 ) and systemic ( minimum S-KC ) dose potencies , and their ratio , the relative therapeutic index , were estimated using an on-linear mixed effect model . RESULTS The drug effects were well tolerated and dose dependent The bronchodilating effect was on a part of the dose response curve that could be well approximated by a log-linear function , the serum potassium suppressing effect sometimes was not ( the lowest doses differed only marginally from placebo ) . Thus , a log-linear approximation was used to describe bronchodilation , whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration . A bivariate dose-response model based on these principles was fitted simultaneously to all data . The mean relative therapeutic index was estimated to be 2.5 ( 95%confidence interval : 0.9 - 6.5 ) . CONCLUSIONS The mean relative therapeutic index between formoterol ( Oxis ) 4.5 - 54 microg given via Turbuhaler and salbutamol 200 - 1800 microg given via pMDI was estimated to 2.5 in favour of formoterol ; this trend was not statistically significant Formoterol is a new long-acting beta 2-agonist . We compared the protective effect of 24 micrograms formoterol with 200 micrograms beclomethasone and placebo on inhaled allergen-induced asthmatic responses in mild stable asthmatic subjects . We measured airflow rates , histamine airway responsiveness , cell counts from sputum and peripheral blood , and markers of lymphocyte and eosinophil activation . Adjustments were made for the confounding effect of bronchodilatation produced by formoterol in comparisons using a control inhalation of normal saline . Formoterol caused bronchodilation and inhibition of histamine airway responsiveness for at least 24 h. It completely inhibited the early asthmatic responses when beclomethasone had no effect . Control comparisons of the effect of formoterol and beclomethasone on the allergen-induced late asthmatic response and increase in histamine responsiveness showed each to be equally effective but not to inhibit the responses completely . Formoterol caused bronchodilation in addition to preventing bronchoconstriction . Both drugs inhibited the rise in serum eosinophil cationic protein 24 h after allergen , but neither inhibited the allergen-induced increases in sputum or blood eosinophils or CD25 + lymphocytes . These results suggest that formoterol modifies allergen-induced airway responses through functional antagonism rather than the inhibition of inflammatory cell infiltration OBJECTIVE To review three prospect i ve , r and omized , placebo-controlled , double-blind clinical studies of formoterol ( Foradil Aerolizer ; Novartis Pharmaceuticals ; Basel , Switzerl and ) at dosages of 12 microg and 24 microg bid for the treatment of patients with asthma . DATA SOURCES Clinical studies su bmi tted to the US Food and Drug Administration in support of the approval of Foradil Aerolizer for marketing in the United States . RESULTS More patients treated regularly with formoterol , 24 micro g bid , had a serious asthma exacerbation than did patients who had been treated with placebo .  In the first study , 4 of 135 adult patients ( 3 % ) who had been treated with formoterol  , 24 microg bid , had a serious asthma exacerbation compared to none of 136 placebo-treated patients . In the second study , 5 of 136 patients ( 3.7 % ) treated with formoterol , 24 microg bid , had a serious asthma exacerbation compared to 2 of 141 placebo-treated patients ( 1.4 % ) . In the third study , 11 of 171 pediatric patients ( 6.4 % ) treated with formoterol , 24 microg bid , had a serious asthma exacerbation compared to none of 176 placebo-treated patients . CONCLUSION Regular use of high-dose inhaled formoterol ( 24 microg bid ) may be associated with more frequent serious asthma exacerbations Twelve patients with stable asthma ( mean age , 39 years ; asthma duration , 11 years ; mean forced expiratory volume in 1 s , 65 percent of predicted ; and reversibility , 31 percent ) were studied in a double-blind crossover trial . The patients were studied during three test days . Airway resistance and specific airway conductance ( Raw and SGaw ) were measured using a body plethysmograph and pulse rate , blood pressure , tremor , and subjective effects were recorded before and 1 , 3 , 5 , 10 , 15 , 30 , 60 , and 120 min after the test doses . A baseline Raw variability of + /- 20 percent was allowed between the test days . Formoterol 12 micrograms , 24 micrograms , and terbutaline 500 micrograms were given in a spacer ( Nebulator ) in a r and omized double-blind crossover manner as two puffs with a 30-s interval in between . The effect of formoterol 12 micrograms on Raw was significantly better than terbutaline after 3 , 5 , 10 , 60 , and 120 min . Formoterol 24 micrograms was significantly better than terbutaline as soon as 3 min after inhalation and at every point in time after that . Formoterol 24 micrograms tended to be better than formoterol 12 micrograms but the differences were not significant at any point in time . All three treatments were well-tolerated . No differences were observed for pulse rate , blood pressure , tremor , or palpitations . The overall onset of bronchodilatation after formoterol 12 and 24 micrograms was faster than after terbutaline 500 micrograms . The tolerability of formoterol was good AIMS To determine the role of formoterol in the treatment of children with bronchial asthma who are symptomatic despite regular use of inhaled corticosteroids . METHODS A r and omised , double blind , parallel group , placebo controlled study to investigate the effects of inhaled formoterol ( 12 μg twice a day ) in 32 children with moderate to severe bronchial asthma . The study consisted of two week run in periods and six week treatment periods , during both of which the patients continued their regular anti-inflammatory drugs . The efficacy parameters were symptom scores , bronchodilator use , daily peak expiratory flow rates ( PEFR ) , methacholine hyper-reactivity , forced expiratory volume in one second ( FEV1 ) , lung volumes , and airway conductance . RESULTS Formoterol treatment for six weeks decreased symptom scores , PEFR variability , and the number of rescue salbutamol doses , and increased morning and evening PEFR significantly . No adverse reactions were seen . CONCLUSION These findings suggest that inhaled formoterol is effective in controlling chronic asthma symptoms in children who are symptomatic despite regular use of inhaled corticosteroids BACKGROUND Asthma guidelines recommend that long-acting inhaled beta-agonists should be used as maintenance therapy for patients with asthma inadequately controlled on an inhaled corticosteroid . We studied the safety and efficacy of the long-acting beta-agonist formoterol compared with terbutaline , each taken as needed , in patients with moderate to severe asthma . METHODS Patients were taking an inhaled corticosteroid ( mean dose 870 microg daily ) and had a forced expiratory volume in 1 s ( FEV1 ) of at least 50 % predicted ( mean 74 % ) . Those requiring an inhaled beta-agonist three to eight times a day during the study run-in period ( 362 of 621 who started ) were r and omly assigned formoterol 4.5 microg or terbutaline 0.5 mg as needed by Turbuhaler in daily doses up to 54 microg and 6 mg , respectively , for 12 weeks in a double-blind , parallel-group study . Analyses were by intention to treat . FINDINGS The 362 r and omised patients ( 157 men , 205 women ) had a mean age of 47 years . Patients taking formoterol had a longer time to their first severe asthma exacerbation ( relative-risk ratio 0.55 [ 95 % CI 0.34 - 0.89 ] ) , took fewer inhalations of study drug , and had larger increases in FEV1 ( 5 % ) and morning and evening peak expiratory flow ( mean difference in increase 11 L/min and 8 L/min ) than those taking terbutaline . No safety issues were identified . INTERPRETATION When taken as needed , formoterol 4.5 microg provided better asthma control than terbutaline 0.5 mg in patients requiring moderate doses of relief medication despite inhaled corticosteroid treatment . Safety studies should be extended to a wider population of patients with asthma Clinical benefits have been shown to occur when using the long-acting beta2-agonist formoterol 4.5 microg for as-needed medication rather than terbutaline 500 microg in patients with unstable asthma taking an inhaled corticosteroid . This study compared their effects on health-related quality of life and the relation with conventional clinical indices in the same population . 362 asthmatics were r and omized to use either formoterol 4.5 microg or terbutaline 500 microg as needed , both inhaled via Turbuhaler . The Asthma Quality of Life Question naire ( AQLQ ) was practised at enrolment and completed by 341 patients after r and omization and at 4 , 8 , and 12 weeks . Clinical indices were measured at the same time points . Mean overall AQLQ scores were comparable at baseline , being 4.90 in the formoterol and 4.82 in the terbutaline group and improved during treatment by 0.41 and 0.17 units , respectively ( mean difference 0.24 , 95 % CI 0.08 , 0.39 , P<0.005 ) . Mean improvement in the symptom domain was 0.49 units when using formoterol . Correlations between changes in clinical indices and changes in AQLQ scores during the 12-week period were weak ( maximum r value=0.37 ) . When used for as-needed medication , formoterol 4.5 microg provided an improvement in asthma-specific quality of life and to a somewhat greater extent than the widely used terbutaline 500 microg . The symptom domain in AQLQ showed almost 0.5 units improvement after formoterol , a change that is considered to be clinical ly relevant BACKGROUND Exercise-induced bronchoconstriction occurs in a large proportion of children with asthma , limiting everyday activities important for their physical and social development . OBJECTIVE The purpose of this r and omized , double-blind , placebo-controlled study was to compare the ability of different patterns of antiasthmatic treatment , recommended in childhood asthma , to protect patients from exercise-induced bronchoconstriction . METHODS Children 6 to 18 years of age with atopic asthma were r and omized to a 4-week , placebo-controlled , double-blind trial . Patients were r and omly allocated to receive daily 200 microg budesonide ( twice daily , 100 microg per dose ) + 9 microg formoterol ( twice daily , 4.5 microg per dose ; n = 20 ) ; 200 microg budesonide + 5 or 10 mg montelukast ( once daily at bedtime ; n = 20 ) ; 5 or 10 mg montelukast ( n = 20 ) ; 200 microg budesonide ( n = 20 ) ; or placebo ( n = 20 ) . A st and ardized treadmill exercise challenge was performed before and after treatment . RESULTS Exercise-induced bronchoconstriction , reflected by area under the curve for the FEV1 values from exercise over the 20-minute period and by maximum percent fall in FEV1 after exercise , was significantly diminished after 4 weeks in all active treatment groups , and compared with placebo . Exercise-induced bronchoconstriction protection improved more significantly in the budesonide + montelukast and montelukast groups compared with other therapeutic options . CONCLUSION These data indicate differences in effects on exercise-induced bronchoconstriction between therapeutic options recommended in childhood asthma . Control of childhood asthma with exercise-induced bronchoconstriction can be obtained by using regular controller treatment Lung function is commonly used as the primary endpoint in asthma clinical trials , but it may not reflect changes which are important to patients . The present study compared changes in , and relationships between , traditional and patient-centred end-points during treatment with three classes of asthma medication . Subjects with mild-to-moderate asthma were r and omised to double-blind , double-dummy crossover treatment with eformoterol 12 µg b.i.d . or montelukast 10 mg q.d . , then single-blind treatment with fluticasone 250 µg b.i.d./placebo capsules , with 6-week treatment periods and 1-week washouts .  Individual “ traditional ” end-points ( symptoms , reliever use , forced expiratory volume in one second per cent predicted , morning peak expiratory flow , airway hyperresponsiveness ) and “ patient-centred ” end-points ( asthma control question naire , quality of life , patient global assessment s ) were assessed . Principal component analysis and linear modelling were used to explore overall rank orders for treatment , and relationships between outcomes . A total of 58 subjects were r and omised . The rank order of benefit from eformoterol and fluticasone differed for three factors derived from principal component analysis ( eformoterol > fluticasone for symptom/reliever use factor , fluticasone > eformoterol for lung function factor , eformoterol = fluticasone for patient-centred factor ) . Montelukast was ranked third for all three factors . A significant relationship between patient-based variables and lung function was found only for montelukast treatment . In asthma treatment , traditional end-points do not fully capture patient-centred benefits , and the relationship between end-points differs with medication class The short-term protective effect on exercise-induced asthma ( EIA ) and the duration of action of formoterol , given by metered dose aerosol at a dose of 24 micrograms , were compared with salbutamol ( 200 micrograms ) and placebo in twelve asthmatic EIA-positive patients in a double-blind , placebo-controlled , three period cross-over study . On each treatment day the patients were given one of the drugs or placebo and two exercise tests were performed at the second and at the eighth hour after dosing . Using a st and ard procedure , exercise was performed by treadmill in well-controlled environmental conditions . In the first test at 2 h a significant difference relative to placebo ( p less than 0.001 ) at each incremental time after exercise ( i.e. 5 , 10 , 15 , 20 , 30 min ) was obtained with both formoterol and salbutamol , without any significant difference between formoterol and salbutamol . After the eighth hour test formoterol still protected against EIA in comparison to both salbutamol and placebo . The effect of salbutamol at this time was not different from placebo .  No adverse effects were reported in any treatment group . Formoterol has a long duration of action in protecting against EIA that persisted for eight hours , removing the need to dose with beta 2-agonist before every exercise Many asthma patients remain symptomatic despite maintenance therapy with inhaled corticosteroids ( ICS ) and salbutamol as rescue medication . In the present study the relative efficacy and preference for as-needed formoterol compared with salbutamol was examined . In total , 211 patients with a mean age of 45 yrs ( mean forced expiratory volume in one second ( FEV1 ) 77 % predicted normal ) , using ICS , were r and omised to 3 weeks ' double-blind treatment with as-needed formoterol 4.5 μg Turbuhaler ® and with as-needed salbutamol 100 μg Turbuhaler ® in a cross-over fashion . Overall , lung function and symptom control were better with as-needed formoterol than with as-needed salbutamol . During as-needed formoterol  treatment daytime and night-time symptom scores were lower , peak expiratory flow and FEV1 were higher and patients experienced fewer disturbed nights ( 34 % ) compared with as-needed salbutamol . Patients preferred the formoterol treatment to salbutamol . Of the 162 patients expressing a preference  , formoterol was preferred by 68 % ( 95 % confidence interval : 60–75 ) . Subjective assessment of effectiveness also favoured formoterol , which was perceived as slightly faster acting than salbutamol . In conclusion , as-needed formoterol  improved symptoms and lung function compared with salbutamol and was perceived as more effective and at least as fast acting for symptom relief Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction . This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist , formoterol . The modifying effect of intravenous corticosteroid was also studied . Ten asthmatic subjects ( using inhaled steroids ) participated in a r and omised , double-blind , placebo-controlled , cross-over study . Formoterol 12 microg b.i.d . or matching placebo was given for 10 - 14 days with > 2 weeks washout . Following each treatment , patients underwent a methacholine challenge to induce a fall in forced expired volume in one second ( FEV1 ) of at least 20 % , then salbutamol 100 microg , 100 microg , and 200 microg was inhaled via a spacer at 5 min intervals , with a further 400 microg at 45 min . After a third single-blind formoterol treatment period , hydrocortisone 200 mg was given intravenously prior to salbutamol . Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry . Regular formoterol result ed in a significantly lower FEV1 after salbutamol at each time point compared to placebo ( p<0.01 ) . The area under the curves ( AUCs ) for 15 ( AUC0 - 15 ) and 45 ( AUC0 - 45 ) min were 28.8 % and 29.5 % lower following formoterol treatment ( p<0.001 ) . Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration . It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol . This bronchodilator tolerance is evident in circumstances of acute bronchconstriction To compare the dose-related bronchodilator efficacy and tolerability of formoterol ( Oxis ) Turbuhaler with salmeterol Diskhaler and placebo in children with asthma . A single-dose , r and omized , double-blind , incomplete crossover study of 68 children ( 7 - 17 years ) , with moderate-to-severe asthma , 82 % receiving inhaled corticosteroids .  Patients received four of six treatments [ 4.5 , 9 , 18 , or 36 microg formoterol ( 6 , 12 , 24 or 48 microg metered doses ) , 50 microg salmeterol ( metered dose ) or placebo ] at 12-h visits , separated by > or =3 days . Forced expiratory volume in 1 s ( FEV1 ) , pulse , blood pressure , electrocardiogram , adverse events and urine formoterol  were assessed . The therapeutic ratio of formoterol vs. salmeterol was estimated from the efficacy and systemic effects results . All active treatments significantly improved FEV1 compared with placebo . Formoterol 9 - 36 microg provided dose-related increases over salmeterol in lung function : average 12-h FEV1 ( increases of 4.9 - 8.7 % , p < 0.001 ) and FEV1 at 12 h post-dose ( 7.0 - 12.2 % , p < 0.001 ) . The onset of effect of formoterol was also significantly faster than salmeterol for doses > or = 9 microg . Salmeterol 50 microg was estimated to be equieffective to 3.3 microg formoterol for 12-h average FEV1 and the estimated equieffective dose for a variety of systemic effects was 7.8 - 13.5 microg formoterol . All treatments were well tolerated .  Formoterol ( Oxis ) Turbuhaler 4.5 - 36 microg provided dose-related improvements in bronchodilator efficacy in children with asthma . Formoterol > or = 9 microg provided superior bronchodilator efficacy over 12 h compared with salmeterol Diskhaler 50 microg with no increase in systemic effects Summary The construction of a composite effectiveness measure was explored using clinical data collected routinely in trials of drug therapies for asthma . The measure is the episode-free day ( EFD ) , where an ‘ episode ’ is either an asthma attack , the need for rescue medication , sleep disturbance caused by asthma , or an adverse event . The EFD measure was used in a retrospective cost-effectiveness analysis of a previous Phase III controlled clinical trial of formoterol versus salbutamol , in which 145 patients with bronchial asthma were r and omised to receive maintenance therapy with either inhaled formoterol or inhaled salbutamol over a 12-week period . Average and incremental cost-effectiveness ratios were assessed for the 2 drugs in terms of the total expected cost of drug plus rescue therapy , and EFD rates . The analysis suggests that , with relatively little addition to clinical data collection , economically and clinical ly meaningful composite measures can be constructed to assist in making cost-effectiveness comparisons between alternative asthma therapies The tolerability and the duration of effect of 12 micrograms of formoterol and 25 micrograms of procaterol administered via metered-dose aerosol to 12 stable asthmatic patients were evaluated in a double-blind , placebo controlled trial . FEV1 , pulse rate , and blood pressure were measured at baseline and every two hours after dosing for 12 hours . The bronchodilation peak was observed after two hours for both drugs . Formoterol induced a significant bronchodilating effect for 12 hours compared with both baseline and placebo values . With procaterol , significant bronchodilation occurred for six hours compared with baseline values and four hours compared with placebo . No significant changes were observed in pulse rate and blood pressure with either drug . Four subjects complained of muscle tremor after procaterol administration . We conclude that in subjects with stable asthma , inhaled formoterol at a dose of 12 micrograms maintains significant bronchodilation for 12 hours after dosing and is very well tolerated . Further studies are required to evaluate effectiveness and tolerability of high dose formoterol treatment in acute severe asthma therapy This r and omised , double-blind , double-dummy , crossover , placebo-controlled study assessed the acute tolerability of budesonide/formoterol in a single inhaler ( Symbicort Turbuhaler , AstraZeneca ) administered as a high dose . Fourteen patients with asthma receiving budesonide/formoterol maintenance treatment ( two inhalations of 160/4.5 microg twice daily ) inhaled 10 additional doses of budesonide/formoterol 1600/45 microg ( total daily dose including morning dose of maintenance treatment 1920/54 microg ) or formoterol 45 microg ( Oxis Turbuhaler , AstraZeneca ; total daily dose including morning dose of maintenance treatment 54 microg formoterol ) or placebo in addition to the morning dose of maintenance treatment on 3 separate study days . Serum potassium , pulse rate , blood pressure and ECG were assessed at regular intervals over a 12-h period following dosing . Blood glucose and plasma lactate were assessed over 3 h following dosing . Changes in serum potassium , pulse rate , blood pressure , QTc , blood glucose and plasma lactate occurring with budesonide/formoterol , though statistically significantly different from placebo ( P<0.05 ) , were considered clinical ly unimportant . No clinical ly relevant differences were identified between active treatments . In conclusion , budesonide/formoterol in a single inhaler is well tolerated at high doses such as might be used by patients using budesonide/formoterol  for relief of symptoms of 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 Abstract Objectives : To compare the relative systemic dose potency and tolerability of inhaled formoterol and salbutamol  and to describe elimination of formoterol , particularly any enantioselectivity . Methods : Twelve healthy subjects , aged 18–28 years , completed three open study days , and eleven asthmatic patients , aged 20–56 years , completed four double-blind study days in r and omised , placebo-controlled and crossover fashions . The healthy subjects inhaled 13.5 + 13.5 + 27 μg formoterol ( Oxis ) via Turbuhaler and 300 + 300 + 600 μg salbutamol ( Ventoline ) via a pressurised metered dose inhaler ( pMDI ) . The asthmatics , being on formoterol 9 μg twice daily via Turbuhaler during the study , inhaled the same single doses as the healthy subjects plus 900 + 900 + 1800 μg salbutamol via pMDI . Doses were given cumulatively 30 min apart on separate study days . Placebo was a day of no treatment in the healthy subjects . Double dummies were used for the asthmatics . Cardiovascular and metabolic effects were evaluated . Elimination of formoterol was addressed in the healthy subjects . Results : Formoterol was estimated to be 28–109 times as potent as salbutamol , depending on the systemic effect variable . The duration of systemic action seemed to differ marginally at approximately equieffective doses of formoterol and salbutamol . Systemic effects were well tolerated and tended to be more pronounced in the healthy subjects than in the asthmatic patients . The half-life of the pharmacologically more active (R;R)-formoterol was longer than that of (S;S)-formoterol . Conclusions : Systemically , formoterol was shown to be 28–109 times as potent as salbutamol . Equieffective doses seemed to have a similar duration of effect .  Formoterol and salbutamol  were well tolerated by healthy subjects up to the tested total doses of 54 μg and 1200 μg , respectively , and by asthmatic patients up to the tested total doses of 54 μg and 3600 μg , respectively . Elimination of formoterol was enantioselective 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 Regular use of beta2-agonists might result in increased bronchial hyper-responsiveness ( BHR ) and decreased forced expiratory volume in 1 sec ( FEV1 ) . It has been suggested that these possible detrimental effects are not a real deterioration of the disease , but that it might be only a transient ( rebound ) effect shortly after discontinuing this regular use . Moreover , these effects are thought to occur especially during short-acting and not during long-acting beta2-agonists use . The aim of this study was to invest gate whether a rebound effect ( a pharmacological deterioration effect diminishing after several hours ) in FEV1 and PC20 ( concentration of histamine causing a 20 % fall in FEV1 with regard to baseline ) occurred after cessation of regular use of beta2-agonists , and whether this occurred both after short-acting and long-acting beta2-agonists . Allergic asthmatic patients ( n = 134 ) were r and omly allocated to the use of a short-acting ( salbutamol ) , a long-acting beta2-agonist ( formoterol ) or placebo for 12 weeks ( double-blind , double-dummy ) . No other asthma medication was allowed , including inhaled corticosteroids . At the start and every 4 weeks later FEV and PC20 were measured , each time at least 12 h after the last doses of study medication , which is in the possible rebound period . To investigate whether a ( transient ) rebound effect occurred , parameters were additionally measured at least 72 h later after discontinuation of the study medication . After 12 weeks of short-acting beta2-agonist use , a drop was seen in FEV1 from 85.6 ( + /- 2.21)% predicted to 78.8 ( + /- 2.9)% predicted , measured 15 h ( median ) after the last doses of medication . This was significantly different compared to placebo . When measured 168 h ( median ) later FEV1 recovered to 85.5 ( + /- 2.4)% predicted , comparable to baseline . PC20 decreased with -1.17 ( + /- 0.44 ) doubling dose after 12 weeks of short-acting beta2-agonist use , measured 15 h after the last doses of medication , which was significantly different compared to placebo . However , 168 h later PC20 recovered slightly with + 0.55 ( + /- 0.34 ) doubling dose , but this value was still lower compared to placebo . In contrast , during long-acting beta2-agonist and placebo use no significant changes were seen . In conclusion , the use of short-acting beta2-agonists result ed in a transient ( rebound ) effect in FEV while the effects on PC20 may point to a real deterioration of the disease . Long-acting beta2-agonist and placebo use showed no changes . We conclude that a mono-therapy of short-acting and not of long-acting beta2-agonists might have deleterious effects in asthma PURPOSE The aim of this study was to demonstrate the equivalent efficacy of inhaled formoterol in asthmatic patients , either given as-needed or on a regular twice-daily schedule . METHODS R and omised , open 12-week study in patients with mild to moderate asthma not adequately controlled with inhaled glucocorticosteroids alone . Patients received inhaled formoterol as needed or on a regular schedule ( 2x2 puffs/day with 6 microg formoterol per puff ) . Patients in the twice-daily formoterol group could use salbutamol as a rescue medication . The primary endpoint was the number of patients with asthma exacerbations in each group . RESULTS Thirty-nine centres r and omised 359 patients . The number of patients with asthma exacerbations showed neither a clinical ly relevant nor a statistically significant difference between groups : formoterol as-needed : 3.95 % ( 7 of 177 ) ; twice daily : 3.45 % ( 6 of 174 ) . Patients in the formoterol as-needed group used significantly less formoterol ( -1.5 puffs per day ; P<0.0001 ) . Including the saved rescue medication ( up to one puff per day ) , total beta-2 agonist use in the formoterol as-needed group decreased by approximately 2 - 2.5 puffs per day . Both formoterol treatment schedules were well tolerated . Musculoskeletal pain and tremor were less frequent in the formoterol as-needed group : headaches were slightly more frequent . CONCLUSION Formoterol given as needed and without additional beta-2 agonist , and formoterol given on a regular basis twice daily , supplemented by salbutamol as a rescue medication , appeared equally effective in this clinical study . Drug consumption was markedly lower in the former group OBJECTIVE To study the effectiveness and safety of as-needed treatment of formoterol compared with the short-acting alternative terbutaline . METHODS Two double-blind , 12-month , parallel-group , non-inferiority trials comparing as-needed use of formoterol ( Oxis ) 4.5 microg and terbutaline ( Bricanyl ) 0.5 mg via dry-powder inhaler ( Turbuhaler ) , one in 675 patients with intermittent and one in 455 patients with mild persistent asthma , overall 6 - 87 years of age .  Peak expiratory flow ( PEF ) , symptoms , rescue medication use , exacerbations , airway responsiveness ( metacholine challenge ; subgroup of 127 patients ) , systemic effects ( high single-dose test ; subgroup of 87 patients ) , and safety ( adverse events ) were assessed . RESULTS Formoterol 4.5 microg was as effective as terbutaline 0.5 mg with regard to morning PEF ( non-inferiority ; lower 95 % confidence interval limit above -10 L/min ) . Metacholine sensitivity , exacerbation rates or use of rescue medication did not differ between treatments . Formoterol 54 microg was shown to give less systemic effects than terbutaline 6 mg . Both treatments were safe and well tolerated . CONCLUSIONS Formoterol 4.5 microg used as needed was at least as effective and safe as terbutaline 0.5 mg used as needed in intermittent and mild persistent asthma , and was associated with less systemic effects when administered as high single doses Background : Formoterol ’s effects on the cardiovascular system are well known , but whether these effects are altered by the reformulation of inhalers to replace CFC propellants with HFA propellants is not . Objectives : To evaluate the effect of cumulative doses up to 96 µg of formoterol delivered via an HFA-134a-propelled pMDI , on cardiac safety and the QTc interval , compared the same cumulative doses delivered via a DPI , in adult patients with moderate-to-severe asthma . Methods : This study was a multicenter , double-blind , double-dummy , placebo-controlled , three-period , crossover trial in which 22 patients with moderate-to-severe asthma received cumulative doses up to 96 µg of formoterol ( 12 + 12 + 24 + 48 µg ) delivered via a pMDI or a dry power inhaler ( DPI ) . Vital signs and fourteen 12-lead ECG measurements were taken at each clinic visit and at 5–10 days after the final drug administration . Results : An increase from baseline in QTc interval was observed with all formoterol treatment arms in a dose-dependent manner . The maximum increases were 56.3 , 62.6 and 25.0 ms for the formoterol pMDI , formoterol DPI and placebo treatments , respectively . Heart rate was increased by 10.7 , 14.9 and 6.5 bpm in the pMDI , DPI and placebo groups , respectively . Both formoterol treatments were also associated with a decrease in diastolic blood pressure compared with placebo . Conclusions : With respect to cardiovascular safety parameters , the administration of formoterol via a pMDI device is comparable to its delivery via a DPI PURPOSE The aim of the present study was to evaluate in vivo and in vitro beta 2-adrenoceptor responsiveness after chronic inhaled therapy with the long-acting beta 2-agonist eformoterol or placebo , given twice daily , in patients with mild to moderate asthma . PATIENTS AND METHODS Seven asthmatic patients , age 34 + /- 5 years were evaluated . Mean forced expiratory volume in 1 second ( FEV1 ) ( % predicted ) at entry was 58 + /- 5 % . After at least 2 weeks run-in without beta 2-agonist therapy , patients were r and omized to receive regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily given by metered-dose inhaler for 4 weeks , in a double-blind , crossover design . Dose-response curves ( DRC ) to eformoterol ( cumulative dose 6 micrograms to 126 micrograms ) for airways and systemic beta 2-responses were constructed at the end of each treatment period . Responses were measured at baseline , 30 minutes after each dose , and for 6 hours after the last dose . In addition , in vitro parameters of lymphocyte beta 2-receptor function were evaluated prior to the DRC after each treatment period . RESULTS There was a nonsignificant trend towards higher baseline values after eformoterol compared with placebo for FEV1 : 0.16 L ( 95 % CI -0.04 to 0.36 ) and forced expiratory flow ( FEF25 - 75 ) : 0.27 L/sec ( 95 % CI -0.08 to 0.62 ) . The peak bronchodilator response from the DRC and response 6 hours after the last dose were both significantly ( P < 0.05 ) attenuated after chronic therapy with eformoterol compared with placebo . The mean differences between eformoterol and placebo for delta FEV1 were as follows : peak : 0.26 L ( 95 % CI 0.09 to 0.43 ) , and at 6 hours : 0.39 L ( 95 % CI 0.20 to 0.58 ) . Corresponding values for delta FEF25 - 75 were as follows : peak : 0.41 L/sec ( 95 % CI 0.10 to 0.71 ) , 6 hours 0.52 L/sec ( 95 % CI 0.22 to 0.82 ) . Systemic responses were likewise significantly blunted after eformoterol treatment compared with placebo . There was also subsensitivity of lymphocyte beta 2-adrenoceptor function after treatment with eformoterol compared with placebo . CONCLUSIONS Our results suggest that chronic therapy with eformoterol produces ( 1 ) tachyphylaxis to its bronchodilator response , which was greatest at 6 hours after the last dose , ( 2 ) tachyphylaxis of extrapulmonary beta 2-mediated responses , and ( 3 ) subsensitivity of in vitro beta 2-adrenoceptor function The aim of this study was to evaluate if treatment with inhaled formoterol is appreciated by asthmatics and whether it causes tachyphylaxis .  Twenty stable asthmatics were included in a r and omized , double-blind , crossover study . They were treated for two weeks either with formoterol or salbutamol , with one week washout inbetween . They were given 12 micrograms formoterol or 200 micrograms salbutamol twice daily and instructed to use additional spray doses on dem and . On a diary card they recorded the number of doses , asthma symptoms and peak expiratory flow rate ( PEFR ) before every dose . Forced expiratory volume in one second ( FEV1 ) dose-response curves for salbutamol ( total dose 1.3 mg ) were performed before and after each treatment period to evaluate development of tachyphylaxis . There was a significant difference in favour of formoterol concerning symptoms , PEFR recordings , spray consumption , and preference .  Fifteen patients preferred formoterol and two salbutamol . The dose-response curves before formoterol and before , as well as after salbutamol were almost identical . After formoterol the curve had changed ; both basal and maximum values were higher than before . Thus , no evidence of tachyphylaxis was found , compared to the ordinary beta-stimulant treatment In vitro data suggest that salmeterol , contrary to formoterol , can partly antagonise the effect of short-acting beta(2)-agonist rescue medication . To explore whether this occurs in vivo , we compared the effects of increasing doses ( 200 - 3200 microg ) of fenoterol on the recovery of methacholine induced bronchoconstriction as well as PD(20 ) methacholine in 23 asthmatic patients , during two-week treatment periods with placebo , and st and ard doses of salmeterol or formoterol in a double blind , double-dummy , crossover study . Salmeterol showed a slightly higher propensity for the development of bronchodilator tolerance . The recovery of methacholine induced bronchoconstriction was more complete during regular use of formoterol relative to salmeterol . During regular use of both long-acting beta(2)-agonists the bronchoprotective efficacy of fenoterol was attenuated , but this was more pronounced during salmeterol than during formoterol . The mean maximum increase in PD(20 ) metacholine after the highest dose of fenoterol was 3.97 DD during placebo , 2.47 DD during formoterol ( p<0.001 ) and 1.81 DD during salmeterol treatment ( p<0.001 ) . We conclude that in asthmatic patients the efficacy of short-acting beta(2)-adrenoceptor agonists can be significantly attenuated during regular use of long-acting beta(2)-agonists . In this respect , differences were observed between salmeterol and formoterol that may represent the expression of partial antagonism by salmeterol Aim : To evaluate the efficacy and tolerability of formoterol delivered by Aerolizer in the emergency department . Methods : A single-centre , double-blind , r and omised , placebo-controlled , parallel group study was conducted in patients seeking emergent care for an acute exacerbation of asthma . Patients were r and omly assigned to one of two groups : group 1 ( salbutamol ) , receiving a total dose of 600 μg salbutamol ( 200 + 200 + 200 ) delivered by a meter-dose inhaler into a spacer device as two puffs at 20 min intervals ; and group 2 ( formoterol ) , receiving formoterol 24 μg ( 12 + 12 ) as two dry powder capsules each containing 12 μg of formoterol via Aerolizer at 20 min intervals . The peak expiratory flow rate ( PEFR ) was measured at baseline and 5 min after the second and third doses . Results : 60 subjects receiving salbutamol ( n = 28 ) or formoterol ( n = 32 ) completed the study . Age , gender , baseline PEFR , duration of asthma and previous medication were balanced between the two groups . Mean PEFR increased significantly over baseline values in both the salbutamol and formoterol groups ( 63 % in the salbutamol group , p = 0.001 , and 55 % in the formoterol group , p = 0.001 ) . No significant difference was observed in the increase in PEFR between the groups ( p = 0.99 , 95 % CI −29.62 to 29.59 ) . The proportion of patients reporting adverse events was similar in the two groups . Conclusion : Formoterol was found to be well tolerated and as effective as salbutamol in the management of acute asthma . Further studies are needed to follow the patients after discharge from the emergency room to compare the long-term effect of formoterol on patients ’ stability RATIONALE Formoterol is approved as asthma rescue medication in many countries . The exact duration of the airway vs. systemic effects of formoterol compared with another rescue medication , salbutamol , has not been evaluated . OBJECTIVE To assess the duration of airway bronchodilatory effects vs. systemic effects of inhaled formoterol and salbutamol in asthmatic patients . METHODS Twenty-six patients with stable and reversible asthma were given single doses of formoterol dry-powder inhaler ( OxisTurbuhaler ) 2x9 microg ( lower dose ; LD ) and 6x9 microg ( higher dose ; HD ) , salbutamol ( VentolinDiskhaler ) 3x400 microg ( LD ) and 9x400 microg ( HD ) , and placebo in a r and omized , double-blind , crossover trial . Airway and systemic effects were assessed by forced expiratory volume in 1s ( FEV1 ) , serum potassium , blood pressure , corrected QT-interval ( QTc ) , and palpitation and tremor scores . Time with clinical ly relevant bronchodilation ( FEV1 increase 12 % ) without clinical ly relevant markers of systemic effects ( serum potassium suppression 0.2 mmol/L , QTc-prolongation 20 ms , or heart rate increase 8 beats per minute ) was evaluated . RESULTS Bronchodilation was maintained for 24h with both formoterol doses and for 7 - 11h with salbutamol .  Maximum bronchodilation and systemic effects were similar after formoterol and salbutamol , except for statistically significantly larger maximum heart rate and palpitation and tremor scores after salbutamol .  Systemic responses were similarly brief for formoterol and salbutamol ( 7 h ) . CONCLUSIONS The airway effects of inhaled formoterol are of long duration , whereas the systemic effects are of a similarly short duration as salbutamol . Thus , the time with clinical ly relevant bronchodilation without systemic effects is substantially longer after formoterol than after salbutamol 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 The present study compared the safety of 4.5 µg formoterol with 0.5 mg terbutaline , both by Turbuhaler ® and used as needed , in addition to regular formoterol in moderate asthma . In this double-blind parallel-group study , 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline ( 2–5 inhalations·day−1 during run-in ) were r and omised to either formoterol or terbutaline as needed in addition to formoterol 9 µg b.i.d . over 12 weeks . Adverse events , serum potassium levels , electrocardiogram , vital signs and lung function were assessed monthly ; peak expiratory flow and severe asthma exacerbations were recorded daily . Patients used 2.16 ( range 0.0–6.3 ) formoterol and 2.34 ( range 0.1–7.5 ) terbutaline relief inhalations·day−1 . No clinical ly significant differences in safety variables were found between treatments . Statistically greater increases in cardiac frequency ( 2.6 beats·min−1 , p=0.03 ) were found on terbutaline . There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline , respectively , with no significant difference in time to first exacerbation . There was also no difference between treatments for other efficacy measures ( peak expiratory flow , forced expiratory volume in one second and morning/evening symptom scores ) . Formoterol 4.5 µg as needed was at least as safe , well tolerated and effective as terbutaline 0.5 mg in stable patients ( requiring up to 6 relief inhalations·day−1 ) taking formoterol plus inhaled corticosteroids regularly over 12 weeks Background : For maximum treatment compliance there is a need to provide asthma patients with devices that suit their particular preferences . The Foradil ® Certihaler ™ is a novel multi-dose dry powder inhaler developed to increase the choice of devices available . Objectives : To evaluate the safety and efficacy of formoterol administered via the Foradil Certihaler , or via the single-dose inhaler Foradil ® Aerolizer ® . Methods : This was a r and omized , placebo-controlled , double-dummy , incomplete block crossover , dose-ranging and pharmacokinetic study in patients with persistent asthma . Sixty-seven patients ( mean 48.0 years ) were r and omized  to formoterol 5 , 10 , 15 and 30 µg twice daily via the Certihaler , 12 µg formoterol b.i.d . via the Aerolizer , or placebo in four 1-week double-blind treatment periods separated by 1-week single-blind washouts . Results : All formoterol doses delivered via the Certihaler or the Aerolizer significantly increased FEV1 compared with placebo ( p < 0.0001 ) . Formoterol demonstrated an onset of action of <3 min . All active treatments were well tolerated . Tremor was the most common adverse event and was more pronounced at high doses . At lower doses the incidence of tremor with the Certihaler was similar to that observed with placebo or the Aerolizer . The pharmacokinetic evaluation comprised 41 patients ( mean 45.9 years ) . Urinary excretion of unchanged formoterol and total formoterol increased with dose delivered via the Certihaler . The optimum dose of formoterol via the Certihaler was 10 µg . Conclusion : Delivery of formoterol via the Certihaler or Aerolizer combines rapid relief with enduring control and provides convenient bronchodilation in patients with persistent asthma 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 Short-acting beta(2)-agonists are currently recommended for symptom relief in asthma and the treatment of mild , acute exacerbations in COPD . However , formoterol has as fast an onset of action as salbutamol with the additional benefit of longer-lasting bronchodilation ( approximately 12 h ) . Furthermore , systemic side effects observed with formoterol are of a similar duration but less pronounced than with short-acting beta(2)-agonists . In this double-blind , r and omized , cross-over study , 20 adult patients with reversible chronic airway obstruction ( intrinsic asthma or COPD ) inhaled single doses of formoterol 9 microg or salbutamol 100 microg ( group A ) or formoterol 18 microg or salbutamol 200 microg ( group B ) . FEV(1 ) was measured prior to and 5 , 10 , 15 , 20 , 25 and 30 min following inhalation of study drug . No significant differences in FEV(1 ) values were observed between group A ( P=0.704 ) or group B ( P=0.270 ) at baseline , or at 5 ( Group A : P=0.340 ; Group B : P=0.559 ) and 15 min ( Group A : P=0.526 ; Group B : P=0.818 ) post dose . No adverse events were reported during the study . Formoterol Turbuhaler has as rapid an onset of action as salbutamol pMDI when given at the recommended doses Inhaled formoterol fumarate , a long acting beta 2 agonist , produces bronchodilatation that is sustained for approximately 12 hours . To determine whether such bronchodilator effects are maintained and asthma control sustained during chronic administration , we monitored airflow indices and clinical control in 112 asthmatic patients who self administered formoterol twice daily for periods ranging from 9 to 12 months . Subjects were recruited immediately following completion of a 3-month double-blind comparison of formoterol , 12 micrograms , bid versus salbutamol , 200 micrograms , qid . Assessment s were conducted at baseline , 3 , 6 , and 9 months , where baseline represents the final visit of the 3-month comparative study . Patients were asked to complete diary cards and twice daily PEFR for a 2-week period before each assessment . Throughout the follow-up study , there was no indication of worsening of asthma control or deteriorating lung function . For the patients who continued to receive formoterol , the previous improvement in asthma control and lung function was maintained at the level reached in the 3-month study . There was an improvement in flow rates and asthma symptoms in the group switched from salbutamol to formoterol by the first clinic visit . This improvement in asthma control and lung function was maintained over the subsequent 6 months . Formoterol was well tolerated during the study period . We conclude that prolonged use of formoterol fumarate twice daily results in sustained improvement in symptoms and flow rates in asthma with no evidence of tachyphylaxis 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 Our objective was to compare the efficacy and safety of formoterol ( Foradil ® ) delivered via a novel multidose dry powder inhaler ( Certihaler ™ ) with placebo and albuterol [ pressurized metered-dose inhaler ( pMDI ) ] , in patients with persistent asthma . After a 2-week run-in phase , 265 patients ( 13–81 years ) previously treated with regular/PRN bronchodilators for persistent asthma were r and omized to 12 weeks ' double-blind treatment with formoterol 10 µg BID via Certihaler ( n = 86 ) , albuterol 180 µg QID via pMDI ( n = 88 ) or placebo ( n = 91 ) . The primary efficacy variable was 12-hour AUC of FEV1 after 12 weeks ' treatment . Secondary efficacy variables included peak expiratory flow ( PEF ) , rescue bronchodilator medication use , asthma-related quality of life ( Juniper Mini Asthma Quality of Life Question naire ) , and asthma symptom scores . Formoterol via the Certihaler had an onset of action within 5 minutes and was associated with a clinical ly relevant and statistically significant increase in 12-hour AUC of FEV1 after 12 weeks ' treatment compared with placebo and albuterol ( p < 0.001 and p < 0.05 , respectively ) . Average PEF was significantly superior for formoterol compared with placebo and albuterol ( p < 0.001 and p < 0.05 , respectively ) . Compared with  placebo , rescue albuterol use during the study was significantly lower for formoterol ( p < 0.01 ) and was accompanied by a trend toward an improvement in asthma-related quality of life ( QoL ) . Asthma symptom scores improved to a similar extent for all treatment groups . Treatment with formoterol via Certihaler was well tolerated . Formoterol 10 µg BID , delivered via the novel Certihaler device , is well tolerated and provides rapid , long-lasting , and clinical ly superior bronchodilation to placebo and albuterol via pMDI in patients with persistent asthma 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 Thirteen children , mean age 10·9 yr , with perennial asthma , were studied with respect to the duration of the bronchodilating effect of formoterol , a new long‐acting β2 agonist for inhalation . The duration of action of formoterol metered dose aerosol ( 12 μg ) was compared with salbutamol metered dose aerosol ( 200 μg ) in a double‐blind cross‐over study . Formoterol was found to have significantly better bronchodilating effect 8 hr ( P < 0·01 ) and 12 hr ( P < 0·05 ) after inhalation of the drug . Formoterol ( 24 μg ) was given single‐blindly on the third trial day and showed a tendency towards a better bronchodilating effect ( n.s . ) than formoterol ( 12 μg . ) . There was no difference between the treatments with regard to adverse reactions such as tremor , palpitations , raised heart rate or anxiety . Formoterol proved to be superior to salbutamol as a long‐acting bronchodilator in children with bronchial 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 Virtually all asthma patients use brorichodilators . Formoterol and salbutamol have a rapid onset of bronchodilating effect , whereas salmeterol acts slower . We studied the onset of improvement of dyspnoea sensation after inhalation with these bronchodilators and placebo to reverse a methacholine-induced bronchoconstriction as a model for an acute asthma attack . Seventeen patients with asthma completed this r and omised , double-blind , crossover , double-dummy study . On 4 test days , forced expiratory volume in 1 s ( FEV1 ) and Borg score were recorded and patients were challenged with methacholine until FEV1 fell with > or = 30 % of baseline value . Thereafter , formoterol 12 microg via Turbuhaler , salbutamol 50 microg via Turbuhaler , salmeterol 50 microg via Diskhaler , or placebo was inhaled . FEV1 and Borg scores were assessed during the following 60 min . The first sensed improvement of Borg score was significantly ( P<0.05 ) faster achieved with formoterol ( geometric mean ( Gmean ) ( range ) 1.5 ( 1 - 40 ) min ) and salbutamol 1.8 ( 1 - 10 ) min than with salmeterol 4.5 ( 1 - 30 ) min and placebo 3.4 ( 1 - 40 ) min . The Borg score returned significantly faster to the baseline value with formoterol , salbutamol  , and salmeterol  ( Gmean time 13.8 ( 1 - 75 ) , 13.4 ( 1 - 60 ) , and 18.0 ( 1 - 75 ) min , respectively ) than with placebo ( 33.6 ( 1 - 75 min ) . Formoterol and salbutamol act significantly faster than salmeterol in relieving dyspnoea induced by methacholine-induced bronchoconstriction , in patients with asthma Objective : To assess the cardiovascular and metabolic responses to increasing doses of formoterol administered from a dry powder inhaler . Methods : Twenty patients with mild to moderate asthma were given 12 , 24 , 48 and 96 μg of formoterol or a matched placebo on separate days . The doses were administered using a r and omised , cross-over , double-blind design . The effects on heart rate , blood pressure , electromechanical systole ( QS2I ) , the electrocardiographic QTc interval , plasma potassium ( K ) ; blood glucose and FEV1 were assessed prior to , and for 9 h following each dose . Results : There was no difference between the maximum effects of formoterol 12 μg and placebo ; the 24 μg dose significantly decreased plasma K ( −0.2 mmol · l−1 ) and increased blood glucose ( 1.8 mmol · l−1 ) compared to placebo . The two highest doses affected most of the variables with the 96 μg dose being significantly different from placebo for all indices , heart rate ( 9 beats · min−1 ) , systol BP ( 4 mmHg ) , diastolic BP ( −3 mmHg ) , QS2I ( −11 ms ) , QTc ( 17 ms ) , plasma K ( −0.5 mmol · l−1 ) and blood glucose ( 2.6 mmol · l−1 ) . All doses of  formoterol increased FEV1 . Conclusion : Although there were dose-dependent effects on the extrapulmonary measurements , only the effects at the highest dose may be of clinical significance 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 The Certihaler is a new multi-dose dry powder inhaler for the delivery of formoterol ( Foradil ) , a long-acting beta(2)-agonist . This dose-ranging study compared the efficacy and safety of formoterol 5 , 10 , 15 and 30 microg and placebo administered via the Certihaler or formoterol 12 microg via a single-dose dry powder inhaler ( Aerolizer ) in children with persistent asthma . This was a r and omized , placebo-controlled , double-blind , double-dummy , incomplete block crossover , dose-finding and pharmacokinetic study . Children ( 5 - 12 years , n = 77 ) received four of the active treatments twice weekly ( BID ) for 1 week separated by 1-week single-blind washouts . The primary efficacy variable was 12-h AUC of FEV(1 ) after 1 week 's treatment . Secondary variables included serial 12-h FEV(1 ) .  A subset of patients ( n = 37 ) participated in a pharmacokinetic analysis . All formoterol doses result ed in significant increases in 12-h AUC of FEV(1 ) compared with placebo , and there was no difference between active treatments . The onset of action of formoterol was <3 min for all active treatments . Doses of formoterol > or = 10 microg via the Certihaler increased FEV(1 ) significantly for up to 12 h compared with placebo . The 5 microcg dose via the Certihaler and 12 microg dose via the Aerolizer had a significant effect up to 8 and 7 h post-dose , respectively . Urinary excretion of formoterol via the Certihaler increased in a dose-proportional manner . All formoterol doses were well tolerated , but some patients experienced tremor at the 15 and 30 microg doses . Despite the lack of significant differences between the active doses in the overall bronchodilation , formoterol 10 microg BID via the Certihaler was the dose that provided the best balance between efficacy and tolerability : its duration of action was sustained over 12 h , contrary to that the lower dose ( 5 microg BID ) , whereas its tolerability , especially with regard to tremor , was better than the higher doses ( 15 and 30 microg BID ) . Overall , Certihaler 10 microg BID was not significantly different from formoterol 12 microg BID via Aerolizer Regular beta 2-adrenoceptor agonist therapy may lead to a rebound increase in bronchial responsiveness on discontinuation of therapy and a reduction in bronchoprotective effects .  Formoterol , a long-acting beta 2-agonist , is effective in single doses in the prevention of methacholine-induced bronchoconstriction . In a double-blind , placebo-controlled cross-over study , we examined the effect of an inhaled long-acting beta 2-adrenoceptor agonist , formoterol ( 24 micrograms twice a day ) for 2 wk on airway function and responsiveness in 17 subjects with mild asthma ( mean age , 26.3 + /- 1.4 yr ) who were not taking inhaled glucocorticosteroids .  FEV1 and the provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) were measured at 36 , 60 , and 108 h and at 2 wk after the last dose of regular treatment . In addition , PC20 was measured 12 h after the first and the last dose of formoterol and placebo . PC20 values at 36 , 60 , and 108 h and at 2 wk after formoterol treatment cessation were not significantly different from those after placebo . Mean FEV1 was 3.44 + /- 0.18 L after placebo compared with 3.79 + /- 0.20 L after formoterol ( p < 0.001 ) 12 h after the first dose , and mean PC20 was 0.53 ( GSEM 1.4 ) mg/ml after placebo compared with 2.0 ( GSEM 1.4 ) mg/ml after formoterol ( p < 0.001 ) . After 2 wk of regular treatment , mean FEV1 at 12 h after the final dose of formoterol fell to 3.51 + /- 0.23 L compared with 3.41 + /- 0.18 L after the final dose of placebo ( p = 0.03 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Forty patients with stable asthma and daily need for inhaled beta 2-agonist , were included in a r and omized double-blind study . They were treated for six weeks with inhaled beta 2-agonist , either salbutamol , 4 x 200 micrograms daily , of formoterol , 2 x 12 micrograms and 2 x placebo daily . This was preceded by a run-in period , where all patients received terbutalin-inhalation , 4 x 500 micrograms daily . Twenty patients were given formoterol and 18 salbutamol .  One patient in the  salbutamol-treated group discontinued treatment after three weeks , because of deterioration of asthma . On a diary card , patients recorded peak expiratory flow rate ( PEFR ) morning and evening before medication , score of asthma symptoms ( scale 0 - 3 ; 0 = no symptoms , and 3 = severe symptoms ) and use of additional doses of beta 2-agonist . Forced expiratory volume in 1 sec. ( FEV1 ) , forced vital capacity ( FVC ) and PEFR were obtained after 0 , three and six weeks of treatment . Blinded global assessment of the treatment was performed by both patient and physician at the end of the study . During run-in the two groups of patients were different . The group subsequently treated with salbutamol had a statistical significant ( ss ) higher morning-PEFR , ss fewer asthma-symptom scores than one during night and ss less need for additional puffs of beta 2-agonist . During treatment , the formoterol-treated group showed an ss increase in morning-PEFR , as compared to run-in . Furthermore this group had ss fewer nocturnal symptom scores than one and ss less need for extra beta 2-agonist during night , than the salbutamol-treated group . ( ABSTRACT TRUNCATED AT 250 WORDS Background : Asthma is a chronic inflammatory disease of the airways . Inhaled corticosteroids are very important in anti-inflammatory treatment , but to a great extent they can not control asthma alone . In addition to corticosteroids , long-acting β2 agonists and leukotriene antagonists are used for asthma control . Objective : In this study , the effect of the addition of formoterol and montelukast on asthma control in patients with moderately persistent asthma who were symptomatic while using a low dose of inhaled budesonide  was compared . Methods : At the beginning of the study , 40 symptomatic patients with moderately persistent asthma used  400 µg/day budesonide for a 4-week training period , and were then divided r and omly into two groups , each composed of 20 persons . For the first group ’s treatment regime , inhaled formoterol ( 9 µg ) twice a day was added , and for the second group ’s treatment regime , one-dose oral montelukast ( 10 µg ) was added . These patients were followed up for 8 weeks . The patients ’ peak expiratory flow ( PEF ) values measured in the morning and at night , changes in PEF , forced expiratory volume in 1 s , asthma symptom score and the symptom-relieving therapy used during the 12-week study period were recorded and evaluated in the clinic at the very beginning and at the end of each period . Results : Before the study , the morning PEF value of the group for whom formoterol was added to budesonide ( FB ) was 266.3 ± 59.3 liters/min , and in the group for whom montelukast was added to budesonide ( MB ) , it was 262.8 ± 53.8 liters/min ( p > 0.05 ) . After the 8-week treatment period , the morning PEF values were found to be 320.5 ± 54.4 liters/min in the FB group and 293.3 ± 52.4 liters/min in the MB group ; at the end of the study , it was seen that although there was an increase in morning PEF of 54.2 ± 15.2 liters/min in the FB group , there was an increase of only 30.5 ± 25.3 liters/min in the MB group ( p < 0.0001 ) . Before the study , night PEF values were 287 ± 56.6 liters/min in the FB group and 283 ± 48.5 liters/min in the MB group ( p > 0.05 ) . At the end of the treatment , the night PEF values were found to be 331.5 ± 56.1 liters/min in the FB group and 310 ± 53.1 liters/min in the MB group . At the end of the study , it was observed that although there was an increase in night PEF of 44.5 ± 23.3 liters/min in the FB group , there was an increase of only 27 ± 24.1 liters/min in the MB group ( p < 0.001 ) . Although asthma symptom scores and the use of symptom-relieving drugs showed similarities between the two groups at the beginning of the study , after treatment , the FB group had better results than the MB group with respect to these two parameters ( p < 0.0001 for both ) . It was also seen that the two treatments are tolerated equally well . Conclusion : FB treatment , which causes a considerable improvement in lung function , showed better asthma control than MB treatment in patients with moderately persistent asthma BACKGROUND The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12 - 14 hours . However , the precise role of formoterol in the maintenance treatment of asthma is still under debate . A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma . METHODS In a multicentre double blind , placebo controlled , parallel group study 239 subjects with mild to moderate asthma were r and omly assigned to treatment with either inhaled formoterol 24 micrograms twice daily ( n = 125 ) or placebo ( n = 114 ) during eight months . The study consisted of a four week run in period , a 24 week treatment period , and a four week washout period . All subjects were using regular inhaled corticosteroids ( 100 - 3200 micrograms daily ) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief . The study was performed in 10 outpatient clinics in Canada , and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherl and s. Twice daily self-reported peak expiratory flow ( PEF ) measurements , symptom scores , and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures . Spirometric values were measured at entry , at the start of treatment , after four , 12 and 24 weeks of treatment , and after four weeks washout . RESULTS One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo .  Baseline FEV1 was 67.1 % predicted and mean bronchodilator reversibility was 26 % . The mean total asthma symptom score was 3.6 ( maximum possible 21 ) . A significant decrease in symptoms in favour of formoterol ( difference from placebo -0.64 , 95 % CI -0.04 to -1.23 , p = 0.04 ) was observed . Compared with placebo , morning PEF increased ( difference from placebo 28 l/min , 95 % CI 18.3 to 37.7 , p = 0.0001 ) and the use of short acting beta 1 agonists decreased ( daytime difference from placebo -1.1 inhalation , 95 % CI -1.4 to -0.7 , p = 0.0001 ) in the formoterol group . PEF returned to baseline following discontinuation of formoterol , as did asthma symptom scores . Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study ( 58 and 55 courses , respectively ) . CONCLUSIONS Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF , and decreasing the use of rescue beta 2 agonists . There was no apparent loss of asthma control during 24 weeks of treatment with formoterol In a r and omized , double-blind , between-patient , multicenter study in 301 patients with ROAD , the efficacy and tolerability of the new long-acting selectiveβ2-sympathicomimetic drug formoterol ( 12 µg inhalation b.i.d . ) was compared with salbutamol ( 200 µg inhalation q.i.d . ) . There was no statistically significant ( s.s . ) difference in acute reversibility and long-term efficacy of both drugs , measured by the point in time of expected maximal effect . However , formoterol had a highly s.s . longer duration of action than salbutamol , as shown by peak expiratory flow ( PEF ) measurements : the overall mean morning PEF in the formoterol group was 341 L/min.14 h after the last taken dose and in the salbutamol group this measure was 304 L/min9 h after the last dose . The patients taking formoterol had s.s . less asthma attacks and needed s.s . less rescue medication than those taking salbutamol . In the global assessment of efficacy , formoterol was accepted as being s.s . better ( “ very good ” + “ good ” : 76 % ) than salbutamol ( “ very good ” + “ good ” : 50 % ) . The tolerability of each drug , as reflected by adverse reactions and global assessment , was equally good in both groups . Ninety-one percent of the patients in the formoterol group wanted to receive the same drug again versus 79 % in the salbutamol group 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 This r and omised , double-blind , double-dummy , cumulative dose , multicentre crossover study aim ed to demonstrate non-inferiority in safety of formoterol delivered via Easyhaler versus Aerolizer . The secondary objective was to compare the efficacy of the devices . Thirty-three adult asthmatic subjects entered the study and 32 completed it . The study comprised screening and two study days , with each subject inhaling 96 microg ( 12 , 12 , 24 and 48 microg ) cumulative dose of formoterol via the study inhalers .  Serum potassium ( S-K+ ) , vital signs and spirometry  were performed at baseline , 1h after each dose and additionally 4h after the last dose . The primary safety variable was S-K+ . Secondary safety variables were heart rate , corrected QT interval , blood pressure , serum glucose and adverse events . Spirometry was assessed to evaluate efficacy . The results showed non-inferiority in safety of formoterol inhaled via Easyhaler compared to Aerolizer . The adjusted treatment difference in the S-K+ values after 96 microg cumulative dose of formoterol was 0.14 mmol/L being clearly above the pre-determined lower limit of the non-inferiority criterion of -0.2 mmol/L. There were dose-related changes in secondary efficacy variables after both treatments . The changes were comparable in most of the parameters but heart rate was statistically significantly higher and decrease in diastolic blood pressure greater after formoterol via Aerolizer than that via Easyhaler . The occurrence of adverse events was dose-related , the most common events being tremor , hypokalaemia , headache and palpitation . The spirometry results showed no statistically significant difference in efficacy between the treatments . In conclusion , formoterol delivered via Easyhaler was as safe as via Aerolizer Hedenström H , Wegener T , Boman G , Wåhl and er L , Mel and er B. Effect of inhaled formoterol versus terbutaline on respiratory function in moderate bronchial asthma Long-term treatment with short-acting beta 2-sympathomimetic drugs has recently been suggested to be due to a rise in asthma mortality . This effect has been attributed to an increase in bronchial hyperreactivity , a desensitization of beta 2-adrenoceptors and /or a rebound effect after cessation of the therapy . Formoterol , a new long-acting beta 2-symathomimetic drug , has been reported to possess not only bronchodilatation but also antiinflammatory effects . The aim of the present study was to investigate whether long-term effects of salbutamol and /or formoterol could deteriorate asthma management . Therefore , in a trial lasting 90 days , we evaluated the effects of the two drugs on lung function , on the protection they provided against inhalative provocation with histamine , and on tachyphylaxis as monitored by the beta-adrenergic density on mononuclear leukocytes ( MNL ) .  Two groups of 11 children each with stable asthma were treated with daily doses of either 4 x 200 micrograms salbutamol or 2 x 24 micrograms formoterol in monotherapy . The lung function was measured six times during the trial period , on day 1 , and on day 90 , before and after inhaling the drug and at all investigations both with and without histamine provocation . In both groups , the bronchodilatory effect of either formoterol or salbutamol remained constant . The lung function values before and after drug inhalation ( specific airway resistance sRAW , forced expiration volume FEV1 , vital capacity VC ) did not alter significantly . After histamine provocation , the protection was more pronounced in the formoterol group . No changes in the beta-adrenoceptor density on MNL and no significant side effects were seen throughout the trial period . We therefore conclude that formoterol  protects significantly better against the bronchial challenge with histamine than does salbutamol . Both drugs did not deteriorate the lung function in asthmatic children . In addition , there was no evidence that long-term treatment leads to a desensitization of beta 2-sympathomimetic effects BACKGROUND AND AIM Oxis Turbuhaler is a new dry powder formulation of long-acting beta2-agonist formoterol . This study compared the efficacy and safety of regular use of the long-acting beta2-agonist formoterol and the short-acting terbutaline for 3 months in patients with asthma . METHOD After 1-week run-in , 343 patients received either formoterol 12 microg bid ( F ) ( delivered dose of 9 microg ) , terbutaline 500 microg qid ( T ) or placebo qid , in a parallel-group , double-blind , r and omized manner . They had a mean of 61 % of predicted forced expiratory volume in 1 second ( FEV1 ) and a mean reversibility of 26 % . Eighty-nine percent used inhaled corticosteroids .  RESULTS During run-in mean morning peak expiratory flow ( PEF L/min ) for F was 366 and 348 for T , and 344 for placebo ( P ) . The F group improved morning PEF significantly compared with P ( P = .0022 ) and T ( P = .0001 ) . Changes from run-in were + 18 , -1.5 , and + 5 L/min after F , T , and P , respectively . The F group was statistically significantly better than P and T in increasing evening PEF and in reducing night-time asthma . The F and T statistically significantly reduced the use of rescue medication compared with P. The bronchodilating response to the study drug and to an additional 1.25 mg terbutaline was of the same magnitude before and throughout the study . No statistically significant treatment-by-time interaction was observed ( P > .20 ) . There were no adverse effects of clinical relevance . CONCLUSION Formoterol Turbuhaler , 12 microg bid , was more effective than terbutaline Turbuhaler , 0.5 mg qid , and placebo . Regular use of formoterol or terbutaline did not significantly influence the response to additional inhalation of terbutaline Background : Pressurized metered-dose inhalers ( pMDIs ) have traditionally used CFCs as propellants . However , the worldwide phase-out of CFCs has necessitated the development of new pMDIs that use alternative propellants . One such replacement is the hydrofluoroalkane HFA-134a . Objectives : This study sought to establish the clinical non-inferiority of a new HFA-134a-containing pMDI to a conventional dry powder inhaler ( DPI ) in the administration of formoterol to adult patients with moderate-to-severe , stable persistent asthma . The secondary aim was to collect safety data in a multiple-dose long-term study . Methods : During this multicenter , double-blind , parallel study , 500 patients were r and omized to receive 12 µg of formoterol twice daily for 12 weeks via either an HFA pMDI or a DPI . If necessary , the dose could be increased to 24 µg twice daily . At baseline , all patients ( aged 18–70 years ) had an FEV1 40–80 % of predicted and a documented positive response to the reversibility test . Results : After 12 weeks ’ therapy , the adjusted mean morning PEFR was 343.69 l/min in the formoterol HFA pMDI group and 344.56 l/min in the formoterol DPI group . Because the lower limit of the 95 % CI for the between-group difference ( –11.64 l/min ) was well within the non-inferiority margin ( –20 l/min ) , the HFA device was deemed clinical ly non-inferior to the DPI device . This finding was confirmed when evening PEFR and FEV1 were assessed . Both formulations of formoterol were well tolerated during prolonged multiple dosing . Conclusions : This study provides evidence that the new HFA-formulated formoterol pMDI has a similar efficacy and safety profile to the conventional formoterol DPI in the treatment of patients with moderate-to-severe 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 : Previous studies have indicated the benefits of adding long acting β2 agonists to inhaled corticosteroids in the maintenance treatment of moderate to severe asthma . The effects of adding eformoterol to corticosteroids on asthma control and exacerbations in patients with mild to moderate asthma were studied . Methods : After a run in period of 7–14 days on existing medication , 663 symptomatic patients were r and omised to receive budesonide Turbohaler 400 μg twice daily together with either eformoterol Turbohaler 9 μg ( delivered dose ) or placebo twice daily . After 4 weeks patients whose asthma was well controlled ( n=505 ) were re-r and omised to receive budesonide 400 μg daily and either eformoterol 9 μg or placebo twice daily for a further 6 months . Results : Patients receiving eformoterol  achieved asthma control 10 days sooner than those receiving budesonide alone , and improvements in lung function , symptoms , quality of life , and relief β2 agonist use were significantly greater with eformoterol . During the 6 month follow up the frequency of mild exacerbations was significantly lower in the eformoterol group than in those receiving budesonide alone ( 7.2 versus 10.5 per patient , 95 % confidence interval for ratio 0.49 to 0.96 , p=0.03 ) . The time to first day of poorly controlled asthma was 97 days in the eformoterol group compared with 42 days in the placebo group ( p=0.003 ) . Conclusions : Adding eformoterol to a low or moderate dose of budesonide in mild asthma result ed in faster and more effective control than treatment with budesonide alone . Eformoterol allowed the corticosteroid dose to be reduced while also decreasing the rate of mild exacerbations compared with budesonide alone . These data suggest a therapeutic advantage of adding eformoterol to inhaled corticosteroids in patients with mild to moderate asthma BACKGROUND In response to the phasing out of chlorofluorocarbon ( CFC ) inhalers , a metered dose hydrofluoroalkane ( HFA ) formulation , Modulite ( Chiesi Farmaceutici S.p . A , Parma , Italy ) , to be delivered with a pressurized metered dose inhaler ( pMDI ) , has been developed . Modulite is a HFA formulation technology that has been design ed to provide stable and uniform dose delivery of HFA-based formulations to enable an easy transition from CFC to HFA inhalers . OBJECTIVES The aim of this study was to compare the bronchoprotective and bronchodilator effects of a single dose of 12 microg of formoterol from the HFA Modulite inhaler with the Foradil Aerolizer ( dry powder inhaler , DPI ) and the Foradil CFC inhalers ( Novartis Health Consumer , Basel , Switzerl and ) . METHODS This was a double blind , double dummy , r and omized , placebo-controlled , crossover study conducted in 38 subjects with mild to moderate asthma ( mean forced expiratory volume in 1 s [ FEV1 ] 87.5 % predicted ) . The primary endpoint was methacholine challenge provocative dose required for 20 % fall in the FEV1 ( PD20 ) 90 min post dose . Bronchodilation was assessed with spirometry ( FEV1 , FVC , FEF25 - 75 ) and impulse oscillometry ( resistance at 5 and 20 Hz , reactance at 5 Hz and resonant frequency ) over the 90 min post dose . In a subset of 12 subjects formoterol plasma levels , serum potassium and glucose were determined up to 480 min post dose . RESULTS The three formoterol formulations demonstrated significant ( P < or = 0.05 ) improvements in bronchoprotection compared to placebo and non-inferiority of the HFA preparation compared to the CFC and DPI preparations was demonstrated . Geometric mean PD20 values were 0.51 mg with HFA , 0.62 mg with DPI , 0.62 mg with CFC and 0.2 mg with placebo . The log transformed mean differences in PD20 doubling dose between HFA and ( a ) DPI was -0.28 ( 95 % CI -0.84 - 0.29 , P = 0.57 ) ( b ) CFC was -0.28 ( 95 % CI -0.84 - 0.28 , P = 0.57 ) and ( c ) placebo was 1.38 ( 95 % CI 0.82 - 1.94 , P < 0.001 ) . Serum potassium , glucose and formoterol plasma profiles were comparable for the CFC , HFA and DPI devices . CONCLUSION Our findings of similar efficacy , pharmacokinetics and systemic effects of the HFA formoterol inhaler compared to the CFC and DPI preparations supports the potential use of this novel formulation in the treatment of asthma BACKGROUND Formoterol is a beta2-adrenergic agent which , when inhaled , produces rapid and long-lasting bronchodilatation . OBJECTIVE The aim of this study was to compare the efficacy , safety , and tolerability of formoterol powder for inhalation delivered via the Aerolizer device with placebo and with albuterol delivered via metered-dose inhaler in patients with mild to moderate persistent asthma . METHODS In a multicenter , double-blind , parallel-group study , 541 patients were r and omized at 26 trial sites to receive either formoterol , 12 microg twice daily ; formoterol , 24 microg twice daily ; albuterol , 180 microg four times daily ; or a placebo for 12 weeks . The effects of each treatment on lung function , asthma symptoms , and frequency of rescue albuterol use were evaluated . Adverse effects and clinical laboratory parameters were also evaluated . RESULTS The bronchodilatory effects of formoterol were rapid in onset and persisted for 12 hours . Both formoterol doses were more effective than placebo and albuterol for objective measures of lung function . Morning and evening peak expiratory flow rates were more improved with formoterol , and formoterol provided significantly greater improvements in asthma symptom scores compared with both albuterol and placebo . Overall , patients taking formoterol used significantly less rescue medication than did those taking albuterol or placebo .  Nocturnal awakenings occurred less often with formoterol than with placebo or albuterol . The therapeutic effects of formoterol were maintained over the entire 12 weeks of treatment . Adverse events were similar for all treatment groups , and clinical laboratory data were unremarkable . CONCLUSIONS Rapid-onset , long-acting formoterol , administered via the Aerolizer inhaler , is an effective and safe treatment for patients with mild to moderate persistent asthma This paper deals with a crossover trial on healthy volunteers performed to obtain combined pharmacodynamic , safety and pharmacokinetic data in order to assess the bioequivalence of formoterol fumarate ( CAS 43229 - 80 - 7 ) delivered by mono-dose dry powder inhalers , as test and reference . The trial was carried out on 24 Caucasian healthy male and female volunteers treated with 12 micrograms formoterol fumarate bihydrate capsules for inhalation route . Pharmacodynamics was evaluated through a challenge test with methacholine on the forced expiratory volume in 1 s ( FEV1 ) . Safety was achieved from glucose and potassium serum levels assayed on timed sample s over a 12-h period cost-dosing and from blood pressure , heart rate and ECG recording . Pharmacokinetics was obtained from urinary excretion of formoterol , assessed by a highly sensitive analytical method ( LC-MS-MS ) . Pharmacodynamic , safety and pharmacokinetic results evidence d the bioequivalence of the two formulations investigated . This investigation is an interesting approach how to assess bioequivalence when the classical approach based on the similarity of plasma concentrations can not be applied 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 Inhaled formoterol is a potent selective β2‐agonist with rapid onset and at least 12‐h duration of bronchodilation . The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder ‘ dp ) 12 μg b.i.d . with salbutamol dp 400 μg q.i.d . and placebo in patients with reversible obstructive airway disease ‘ ROAD ) . The study design consisted of a closed 12‐week double‐blind , placebo‐controlled , multicenter trial followed by an open noncomparative , multicenter , 12‐month follow‐up trial , in which the tolerability of formoterol dp was assessed . A total of 304 patients ‘ 146 men , 158 women ) aged 18‐79 years , ill during 0.1‐64 years , were r and omized . No demographic or baseline differences were found among the different treatment groups .  The bronchodilating effect of formoterol  , assessed by morning premedication PEFR , was significantly superior to placebo ‘ P < 0.0001 ) and salbutamol ‘ P < 0.0001 ) . Efficacy was maintained during the open follow‐up study with 12 μg b.i.d . in most of the patients . A few patients , however , needed 24 μg b.i.d . to control their ROAD . Formoterol 12 μg b.i.d . significantly reduced morning and evening asthma symptoms and sleep disturbances , and reduced significantly the need for rescue medication . The tolerability of the three treatment groups was comparable . In conclusion , formoterol 12 μg dp b.i.d . was significantly superior to both salbutamol 400 μg dp q.i.d . and placebo  , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during 1 year of treatment The identification , prevention , and prompt treatment of exacerbations are major objectives of asthma management . We looked at change in PEF , symptoms , and use of rescue beta-agonists  during the 425 severe exacerbations that occurred during a 12-mo parallel group study ( FACET ) in which low and high doses of budesonide with and without formoterol were compared in patients with asthma .  Oral corticosteroids were prescribed for severe exacerbations , the main study end point , defined as the need for a course of oral corticosteroids  ( n = 311 ) or a reduction in morning PEF of > 30 % on two consecutive days . PEF , symptoms , and bronchodilator use over the 14 d before and after the exacerbation were obtained from diary cards . Exacerbations were characterized by a gradual fall in PEF over several days , followed by more rapid changes over 2 to 3 d ; an increase in symptoms and rescue beta-agonist use occurred in parallel , and both the severity and time course of the changes were similar in all treatment groups . Exacerbations identified by the need for oral corticosteroids were associated with more symptoms and smaller changes in PEF than those identified on the basis of PEF criteria . Female sex was the main patient characteristic associated with an increased risk of having a severe exacerbation . Exacerbations may be characterized predominantly by change in symptoms or change in PEF , but the pattern was not affected by the dose of inhaled corticosteroid or by whether the patient was taking formoterol 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 This double-blind , placebo-controlled , r and omized , parallel-group , multicenter study was conducted in 302 children aged 6 - 11 years with asthma not optimally treated with inhaled corticosteroids alone . Patients continued with their existing dose of inhaled corticosteroids and in addition received placebo , formoterol 4.5 microg or formoterol 9 microg b.i.d . , for 12 weeks ( all delivered via Turbuhaler ) . Terbutaline was available as reliever medication . The primary efficacy variable was change from baseline in morning peak expiratory flow ( PEF ) ; secondary efficacy variables included forced expiratory volume in 1 sec ( FEV(1 ) ) , serial PEF measured over 12 hr , evening PEF , asthma symptom score , and quality of life . Compared with placebo , formoterol 4.5 microg and 9 microg improved morning PEF by 8 l/min ( P = 0.035 ) and 11 l/min ( P = 0.0045 ) , respectively . Evening PEF and FEV(1 ) were also significantly increased compared with placebo , with no statistically significant difference between formoterol doses . Lung-function improvements compared with placebo were greater in the middle of the day . Twelve-hour average serial PEF after 3 months increased by 24 l/min ( 95 % CI , 9 , 39 l/min ) in the formoterol 9-microg group , and by 14 l/min ( 95 % CI , 0 , 29 l/min ) in the formoterol 4.5-microg group . The incidence of severe exacerbations in both formoterol groups was numerically lower than in the placebo group , indicating that formoterol may have the potential to improve exacerbation control in children . Both formoterol doses were well-tolerated , and tolerance to the drug 's bronchodilator effect was not observed . Formoterol provided sustained improvements in lung function and was well-tolerated in children with asthma suboptimally treated with inhaled corticosteroids alone UNLABELLED Formoterol solution aerosol has proved to be a fast and long-acting beta 2-sympathicomimetic drug in many clinical trials . The physical stability , however , was such that storage needed to be at 4 degrees C to 8 degrees C before first use ; afterwards , the aerosol could be used for another three months at room temperature . To improve the stability , new ways have been investigated to formulate ann aerosol with improved shelf life and thus more convenient storage conditions , which was reached with a formoterol suspension aerosol . Equivalent single doses between the two formulations revealed no differences in onset or duration of action . In a double-blind , r and omized parallel group multicenter study , organized in the Netherl and s , 186 patients with stable asthma and reversible airway obstruction were treated either with one puff of 12 micrograms twice daily of formoterol metered dose inhaler ( MDI ) supension ( SP ) or a same dose of solution ( SL ) aerosol for 12 weeks to study the efficacy and tolerability of both presentations after a longer period of use . The following criteria of effectiveness were used : the FEV1 values on the mornings of the control days at 0 , + 4 , + 8 , and + 12 weeks , the peak flow values ( PEF ) in the mornings and in the evenings before , and 1/2 to 1 h after treatment , the number of asthma attacks at night and during the day , the number of extra puffs at night and during day , and the subjective impression of patients and investigator . RESULT No statistically significant differences between the two formoterol preparations were found . There was no indication of tachyphylaxis . CONCLUSION The results are consistent with the hypothesis that the biologic effects of formoterol when delivered from MDI containing the two different formulations of the drug are equivalent STUDY OBJECTIVES The primary objective was to determine whether high-dose formoterol , 24 mug bid , was associated with more asthma exacerbations compared with lower formoterol doses in patients with stable persistent asthma .  Serious asthma exacerbations ( life threatening or requiring hospitalization ) were the primary end point . Secondary end points included significant exacerbations requiring systemic corticosteroids , all exacerbations , and changes in FEV1 . DESIGN In a multicenter , placebo-controlled , parallel-group study , patients were r and omized to 16 weeks of treatment with formoterol , 24 microg bid ; formoterol , 12 microg bid , with up to two additional 12-microg doses daily on dem and for worsening symptoms ( 12 microg bid plus on dem and ) ; formoterol , 12 microg bid ; or placebo . The formoterol 12-microg-bid plus on-dem and regimen was administered open label , while the other three regimens were double blind . SETTING Outpatient clinics . PATIENTS A total of 2,085 patients aged > or = 12 years with stable , persistent asthma were enrolled and treated ; 65 % ( n = 1,347 ) received regular concomitant antiinflammatory therapy during the study . MEASUREMENTS AND RESULTS Nine patients had respiratory-related serious adverse events ( SAEs ) requiring hospitalization : two patients ( 0.4 % ) in the 24-microg-bid group ; one patient ( 0.2 % ) in the 12-microg-bid plus on-dem and group ; five patients ( 0.9 % ) in the 12-microg-bid group ; and one patient ( 0.2 % ) in the placebo group . All of these events were asthma related , except for two SAEs in the 12-microg-bid group that were later considered not to be asthma related by independent review ers who were not associated with the conduct of the study . The proportions of patients with significant asthma exacerbations ( requiring systemic corticosteroids ) were similar in the 24-microg-bid group ( 6.3 % , 33 of 527 patients ) , 12-microg-bid group ( 5.9 % , 31 of 527 patients ) and placebo group ( 8.8 % , 45 of 514 patients ) and lower in the 12-microg-bid plus on-dem and group ( 4.4 % , 23 of 517 patients ; p = 0.0057 vs placebo ) . All treatments were well tolerated . All formoterol treatment regimens had a significant effect on FEV1 measured 2 h after dose during the study ( p < 0.0001 vs placebo ) ; and on predose trough FEV1 measured at all visits after baseline ( p < 0.002 vs placebo ) . CONCLUSIONS Treatment with formoterol , 24 microg bid , was not associated with an increase in serious asthma exacerbations compared with the lower formoterol doses or placebo The single-dose effect of formoterol racemate and enantiomers on bronchodilatation up to 24 h was determined . Forty-six reversible asthmatic patients were r and omised to this double blind , crossover study . Formoterol was inhaled by nebulizer ( HaloLite ) ; 4.5 and 36 microg of the racemate ( rac-formoterol ) , 2.25 and 18 microg of (R;R)-formoterol , 18 mirog of (S;S)-formoterol , or placebo .  Airway and systemic effects were assessed by serial measurements of forced expiratory volume during the first second , FEV1 ( 24 h ) , and heart rate ( 4 h ) . Rac- and (R;R)-formoterol significantly and dose-dependently increased FEV1 with similar mean maximal effect . (S;S)-formoterol was without significant effects on FEV1 and heart rate .  (R;R)- and rac-formoterol were still effective 22 - 24 h after single high doses , but this was associated with some systemic side effect ( increased heart rate ) initially . Average 22 - 24 h FEV1 was 8 % ( rac-formoterol 36 microg ) and 11 % ( (R;R)-formoterol 18 microg ) over placebo , respectively . No significant differences in effects were observed between rac- and (R;R)-formoterol . Thus , the single dose bronchodilatating effect of formoterol resides in (R;R)-formoterol . This study does not indicate a clinical ly important advantage of (R;R)-formoterol as acute bronchodilator compared to the racemate 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 BACKGROUND Recent studies have raised concern that regular inhalation of beta2 -agonists may cause a worsening of asthma control compared with on-dem and dosing regimens . OBJECTIVE The objective of this study was to compare the effect of twice daily formoterol ( Foradil ) , 4 times daily albuterol , and on-dem and albuterol on bronchial hyperresponsiveness ( BHR ) , lung function measurements , symptoms , and other indicators of disease control over 6 months in patients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids . We also looked for occurrence of rebound BHR on discontinuation of treatment . METHODS This was a multicenter , parallel-group , double-blind , clinical trial . Methacholine PC20 was the primary outcome variable . Other outcome variables included symptom scores , use of rescue medication , morning peak expiratory flow ( PEF ) , serial FEV1 measurements , and asthma exacerbations . RESULTS Of the 271 r and omized patients , 217 completed the study .  Formoterol was significantly superior to on-dem and albuterol with regard to methacholine PC20 , FEV1 , PEF , symptom scores , and use of rescue medication at each measured time point/interval . Regular albuterol was superior to on-dem and albuterol with regard to PC20 and FEV1 , but not PEF or various clinical scores . After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after r and omization , there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment . The formoterol group had the lowest number of exacerbation days , as defined by high intake of rescue bronchodilator and /or symptom scores , whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups . CONCLUSION In patients with asthma of moderate or greater severity receiving inhaled corticosteroids , formoterol taken twice daily result ed in superior bronchoprotection , bronchodilatation , and clinical control compared with on-dem and albuterol over 6 months . Four times daily albuterol was superior to on-dem and albuterol for only some of the end points . Progressive tolerance and a rebound increase in BHR on discontinuation of beta-agonists were not This article is based on a study first published in Allergy . The bronchodilating effect of the long acting beta 2-agonist formoterol dey powder ( dp ) 12 micrograms twice daily was compared to salbutamol 400 micrograms four times daily and placebo in patients with reversible obstructive airway disease . The study design consisted of a closed 12-week double-blind , placebo-controlled , multicentre trial followed by an open noncomparative , multicentre 12-month follow-up trial , in which tolerability of formoterol dp was assessed . A total of 304 patients aged 18 - 79 years were r and omized . The bronchodilating effect of formoterol , assessed by morning premedication peak flow rate , was significantly superior to placebo ( p < 0.0001 ) and salbutamol ( p < 0.001 ) . Efficacy was maintained during the open follow-up study . Formoterol 12 micrograms twice daily significantly reduced morning and evening asthma symptoms and sleep disturbances , and significantly reduced the need for rescue medication . In conclusion , formoterol 12 micrograms dp twice daily was significantly superior to both salbutamol 400 micrograms dp four times daily and placebo , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during one year of treatment BACKGROUND Patients with exercise-induced bronchospasm ( EIB ) may benefit from a prophylactic beta2-adrenergic agonist that combines rapid onset with long duration of action . OBJECTIVE To compare the protective effect against EIB of a single inhaled dose of formoterol powder delivered via the Aerolizer inhaler ( Novartis Pharmaceuticals , East Hanover , NJ ) with the effect of placebo and albuterol . METHODS Eighteen patients with EIB were r and omized to treatment in a double-blind , placebo-controlled , four-way , crossover study . Seventeen patients completed all four crossover periods . Each patient received in r and om sequence a single dose of formoterol ( 12 or 24 microg ) , albuterol ( 180 microg ) , or placebo at intervals of 5 + /- 2 days . Pulmonary function measurements were taken before and after exercise challenge tests ( ECTs ) at 15 minutes postdosing and at 4 , 8 , and 12 hours postdosing . RESULTS Both doses of formoterol produced significantly greater protection against EIB , compared with placebo , at all timepoints ( P < or = 0.016 ) . The two doses of formoterol were not significantly different from one another at any time . Protection against EIB with albuterol was clinical ly significant only for the 15-minute ECT and was statistically superior to placebo for the 15-minute and 4-hour ECTs . Although formoterol and albuterol exhibited a rapid onset of action , formoterol provided longer-lasting protection over the 12-hour observation period . Rescue medication was used substantially less with either dose of formoterol , compared with albuterol or placebo . All treatments were well tolerated . Two-hour postdosing electrocardiograms and vital signs were unremarkable for all study treatments . CONCLUSION A single dose of formoterol ( 12 or 24 microg ) provides protection against EIB within 15 minutes of dosing and persists for up to 12 hours . Formoterol is safe and well tolerated In this economic evaluation , conducted alongside a r and omized , double-blind clinical trial , economic data were collected from 339 patients with moderate-persistent asthma r and omized to receive twice-daily , double-blind treatment with budesonide/formoterol 160/4.5 microg  in a single inhaler ( n=166 ) or fluticasone propionate 250 microg ( n=173 ) for 12 weeks . The mean number of episode-free days ( EFD ) per patient was significantly greater in the budesonide/formoterol group than the fluticasone group ( 48.71 compared with 42.34 , P=0.0185 ) . Data on medication use , visits to healthcare professionals , and hospitalization were pooled across all six countries and combined with German and Dutch unit cost data to calculate total healthcare costs . Using German unit costs , budesonide/formoterol was associated with significantly lower total healthcare costs per patient over the 12-week period compared with fluticasone ( euro 131 compared with euro 210 , P=0.0043 ) . Using Dutch unit costs , total healthcare costs were slightly numerically lower in the budesonide/formoterol group than the fluticasone group ( euro 102 compared with euro 104 ) , but the difference did not reach statistical significance . Budesonide/formoterol in a single inhaler is more effective than a higher microgram dose of fluticasone alone . It is cost-neutral and may provide cost-savings in some countries This study compared the efficacy of a low dose of formoterol Turbuhaler 6 micrograms b.i.d . ( F ) with that of terbutaline 0.5 mg q.i.d . ( T ) , and placebo ( P ) from Turbuhaler . After a 2-week run-in , 397 adults with mild to moderate asthma were r and omly allocated to one of the treatments for 12 weeks . During run-in , the mean morning peak expiratory flow ( PEF ) was 360 ( F ) , 368 ( T ) and 367 1 min-1 ( P ) . F was better than T ( P = 0.014 ) and P ( P = 0.0001 ) in improving morning PEF [ mean changes from run-in : 20 ( F ) , 9 ( T ) , and 21 min-1 ( P ) ] . F was statistically significantly more effective than either T or P in reducing asthma symptoms . F gave also statistically significantly higher evening PEF and less use of rescue medication than P. Bronchodilator response to study drugs and additional 1.25 mg terbutaline was similar before and after the 12-week treatment period . There were no adverse effects of clinical relevance . In conclusion , formoterol Turbuhaler , 6 micrograms b.i.d . was more effective in improving PEF and offered better asthma control than either terbutaline Turbuhaler , 0.5 mg q.i.d . or placebo . Regular use of formoterol did not reduce the bronchodilator response to additional terbutaline . There were no clinical ly relevant adverse effects BACKGROUND The long-term efficacy and safety of formoterol dry powder capsules for inhalation in pediatric asthma have not previously been evaluated . OBJECTIVE We examined the effectiveness of inhaled formoterol over a period of 12 months in asthmatic children who were still symptomatic despite anti-inflammatory treatment . METHODS After a run-in period , 518 patients ( 5 to 12 years old ) were r and omized in a double-blind manner to receive 12 or 24 microg formoterol dry powder ( Foradil , Novartis Pharma AG , Basel , Switzerl and ) or placebo twice daily for 12 months . The drug was administered by inhaler ( Aerolizer , Novartis Pharma AG ) and was given in addition to their anti-inflammatory treatment . The primary variable was the area under the curve for forced expiratory volume in 1 second measured over 12 hours after the morning dose of study medication . RESULTS The area under the curve for forced expiratory volume in 1 second after the first dose of treatment and after 3 and 12 months of treatment was significantly greater for patients receiving formoterol 12 microg and 24 microg than for patients receiving placebo ( all P < or = 0.0062 ) . Compared with placebo , both doses of formoterol significantly improved morning and evening premedication peak expiratory flow rate ( all P < 0.001 ) . In the group treated with formoterol 24 microg , median symptom score and median dose of rescue medication at night were lower than during the run-in period , whereas the opposite occurred in the placebo group . The incidence of hospitalizations for asthma was higher in the formoterol groups than in the placebo group . CONCLUSION Our results indicate that , in asthmatic children who are still symptomatic despite anti-inflammatory therapy , the addition of formoterol consistently improves airflow obstruction and nocturnal symptoms and reduces the use of rescue medication . However , this treatment requires close disease monitoring to detect early signs of acute exacerbation This study aim ed to investigate the effect of treating patients with moderate asthma with formoterol on quality of life ( QoL ) and to compare several question naires in their ability to detect changes in QoL. In an eight month multicentre , r and omized , placebo-controlled trial , patients with asthma using daily inhaled corticosteroids and beta2-agonists ( > or = 5 inhalations x week(-1 ) ) were r and omized to 6 months treatment with formoterol 24 microg b.i.d . ( by Turbuhaler ) or a matching placebo . Patients recorded symptoms ( maximal score 21 ) and peak expiratory flow ( PEF ) twice daily . QoL was measured with two asthma-specific question naires , the Asthma Quality of Life Question naire ( AQLQ ) and the  Living with Asthma Question naire ( LWAQ ) , and with two generic QoL forms , i.e. the Short Form 36 ( SF36 ) and the Psychological and General Well-Being scale ( PGWB ) at r and omization and after 6 months of treatment . Out of 110 patients studied , 56 received  formoterol and 54 placebo .  Mean baseline forced expiratory volume in one second was 65 % predicted . Mean morning PEF was 369 L x min(-1 ) . Mean total symptom score was 3.6 . Morning PEF increased ( 26.8 L x min(-1 ) , p=0.0001 ) and symptoms decreased ( -1.23 , p=0.012 ) in the formoterol group in contrast to placebo . QoL improvements were measured in the LWAQ total score ( baseline 0.61 , change -0.05 , p=0.048 ) and the physical construct of the LWAQ ( baseline 0.71 , change 0.07 , p=0.044 ) . The AQLQ and the generic QoL instruments showed no significant changes . In conclusion , the improvement in quality of life reported after 6 months was very small and only reflected by the Living with Asthma Question naire 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 The present study was design ed to observe the effects of 8 wk of treatment with formoterol ( Foradil ) 24 microgram , budesonide 400 microgram , and matched placebo inhaled twice a day on inflammatory indices in the bronchial mucosa of 64 patients with mild atopic asthma . Biopsies were obtained at the start and 1 wk before stopping a 9-wk period of treatment , and inflammatory cell numbers were assessed in the submucosa and epithelium by immunohistochemistry . Regular formoterol significantly reduced the number of submucosal mast cells , with a similar trend for eosinophils but not activated T cells . A subgroup analysis conducted in biopsies with > = 10 eosinophils per mm2 revealed a significant reduction in eosinophil numbers when compared with both pretreatment baseline ( p < 0.01 ) and changes after placebo ( p < 0.01 ) . Parallel , but less pronounced , effects were observed on mast cell but not on CD25(+ ) T cell numbers . There was no effect of any of the three treatments on BAL levels of mast cell or eosinophil mediators . We conclude that regular treatment with inhaled formoterol reduces rather than increases inflammatory cells in the mucosa of asthmatic patients . It is possible that these cellular effects of formoterol may contribute to the therapeutic efficacy of this drug when used regularly in the 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 This r and omized , double-blind , crossover study in two parts compared tolerability to high doses of formoterol ( Oxis Turbuhaler ) with that of high doses of terbutaline ( Bricanyl Turbuhaler ) . After Holter monitoring at home , 12 patients were treated with 4 + 4 + 4 doses of formoterol Turbuhaler , 6 microg x dose(-1 ) , ( total daily metered dose 72 microg ) or 4 + 4 + 4 doses of terbutaline Turbuhaler , 0.5 mg x dose(-1 ) ( daily dose 6 mg ) given in the morning , after lunch and in the evening , for 3 consecutive days . After a one week washout period at home , patients received the alternative treatment . Thereafter , 15 other patients received 8 + 6 + 6 doses of formoterol Turbuhaler ( total daily metered dose 120 microg ) or 8 + 6 + 6 doses of terbutaline Turbuhaler ( daily dose 10 mg ) . Pulse , cardiac frequency , blood pressure , serum potassium , electrocardiogram and forced expiratory volume in one second ( FEV1 ) were registered at regular intervals and Holter monitoring was applied during all 4 treatment days . Terbutaline 6 mg showed significantly greater systemic effects than formoterol 72 microg on pulse , blood pressure , cardiac frequency and QTc ( QT interval corrected for heart rate ) .  Terbutaline 10 mg had significantly greater effects than formoterol 120 microg on serum potassium levels , pulse , cardiac frequency and QTc . No differences in FEV1 levels were found . Both drugs were safe and generally well tolerated on both dose levels . In conclusion , high doses of formoterol Turbuhaler over 3 days were generally safe and well tolerated . Daily doses of 6 mg and 10 mg terbutaline Turbuhaler were systemically more potent than 72 microg and 120 microg formoterol , respectively . The safety margin thus appears to be wide if patients happen to use extra doses of formoterol in addition to those prescribed for regular use This double-blind , double-dummy , crossover study evaluated the tolerability of high-dose formoterol and salbutamol .  Sixteen adults with mild/moderate persistent asthma ( FEV1 > or = 70 % predicted ) were r and omized to receive either formoterol 36 microg three times daily ( TID ) at 5-h intervals via Aerolizer ( total daily dose 108 microg ) , or salbutamol 600 microg TID via pressurized metered-dose inhaler ( total daily dose 1800 microg ) for 3 consecutive days . After a 3 - 7-day washout period patients received the other treatment . FEV1 was measured 15 min pre-dose and 2 h post-dose . Both formoterol and salbutamol were associated with decreased plasma potassium ( mean of minimum values : 3.4 and 3.6 mmol/L , respectively ; P<0.001 ) , increased serum glucose ( mean of maximum values : 8.3 and 7.9 mmol/L , respectively ; P=0.021 ) , and small increases in mean QTc interval ( mean of maximum values : 428.8 and 417.4 ms , respectively ; P<0.001 ) . However , none of these effects was clinical ly significant . Both treatments increased FEV1 to a mean maximum of 4.6 L ( P=0.613 ) , but the mean FEV1 AUC(0 - 72)h for formoterol was significantly greater than for salbutamol ( 302.2 L h , vs. 277.4 L h ; P<0.001 ) . No patients discontinued due to treatment-related adverse events . High-dose formoterol via Aerolizer did not produce any clinical ly significant systemic effects in patients with mild/moderate asthma Administration of different doses of formoterol from a recently developed multiple dose dry powder device was tested in a placebo-controlled , single-centre , double-blind , within-patient trial . Eighteen patients of both sexes , aged 18 - 65 years , with a FEV1 of 50 - 80 % and a reversibility of at least 15 % were r and omized . During four treatment periods of 8 days each , divided by approximately 6 days , patients received placebo or 6 , 12 or 24 micrograms ( PL , F6 , F12 and F24 , respectively ) of formoterol from the powder device . Efficacy parameters ( FEV1 ) and safety parameters ( primarily pulse rate , electrocardiogram [ ECG ] and subjective experiences ) were evaluated during 24 hours on the last day of each treatment period . Peak flow and the number of puffs of used rescue medication ( 100 micrograms of salbutamol ) were registered during treatment periods . For efficacy analysis , 17 patients remained . For FEV1 0.5 hour before the last dose and 12 and 24 hours after the last dose all formoterol doses were statistically significant superior to placebo . Clinical ly relevant differences from placebo were found up to 8 hours ( F6 ) and 12 hours ( F12 and F24 ) . The difference between doses was clinical ly relevant for the area under the FEV1 curve between F6 and F24 . PEF on the treatment days corresponded to these findings . In three cases of 13 reported adverse effects , the relation to trial medication was probable ( tremor ) or possible ( insomnia and hyperaesthesia ) . All other safety measurements showed no significant differences . We conclude that formoterol dry powder in the newly developed multiple dose inhalation device is an effective and safe beta 2-stimulant with a long duration of action in doses of 6 , 12 and 24 micrograms . The 24 micrograms dose is superior to the 6 micrograms dose . Efficacy decreased considerably between the 12th and 24th hour after dosing BACKGROUND & OBJECTIVE Because of environmental concerns CFC-containing pressurised metered dose inhalers ( pMDI ) had to be replaced by dry powder inhalers ( DPI ) . The Novolizer , a novel DPI has previously been shown to be as effective as the Turbuhaler in delivering budesonide . The objective of this study was to show non-inferiority of inhaled formoterol therapy delivered through the Novolizer compared to formoterol delivered through the Aerolizer in patients suffering from moderate to severe asthma . METHODS In this double-blind , double-dummy , multicentre study 392 patients were r and omised and received a dose of 12 microg formoterol twice daily for 4 weeks either through the Aerolizer or the Novolizer .  FEV1 after 4 weeks of treatment was the primary variable . Secondary variables were FVC , PEF , consumption of short-acting ; 2 adrenoceptor agonists , asthma symptoms , tolerability and safety . RESULTS After 4 weeks of treatment , the mean trough FEV1 ( 95 % CI ) was 2.34 L ( 2.24 - 2.45 ) for the Novolizer and 2.31 L ( 2.21 - 2.41 ) for the Aerolizer . Non-inferiority was proven ( p<0.0001 , pre-defined ; of 0.25 L ) . All secondary variables ( incl . PEF ) confirmed these findings . Treatment with both devices was safe and well tolerated . CONCLUSION Inhalation of 12 microg formoterol twice daily via Novolizer was shown to be equally therapeutically effective compared to the inhalation via Aerolizer in the treatment of moderate to severe persistent asthma . Treatment via both inhalers was safe and well tolerated The duration of action of inhaled formoterol , a new long-acting beta-2-agonist , was compared to inhaled salbutamol and placebo in a double-blind , r and omized , cross-over study in 16 children ( 8 - 12 years old ) with stable moderate to serve asthma . Mean baseline FEV1 was 68 + /- 8 % predicted . On the 4 study days , baseline FEV1 was within 15 % of the FEV1 on visit 1 . Two-three days apart , each patient inhaled either placebo , salbutamol ( 200 micrograms ) formoterol ( 12 or 24 micrograms ) . FEV1 and PEF were measured repeatedly during 8 and 12 hours respectively . After formoterol , improvement over placebo remained significant at 8 hours for FEV1 ( p = 0.006 ) and 12 hours for PEF ( p = 0.01 ) . When compared to salbutamol , it was significant at 8 hours for PEF ( p = 0.03 ) . There were no significant differences in lung function when comparing the 12 micrograms and 24 micrograms doses of formoterol . Side-effects were minimal OBJECTIVES To study whether Formoterol treatment affect the bronchodilator response to salbutamol after methacholine-provocation test ( MPT ) in asthmatic children . STUDY DESIGN A prospect i ve , double-blind , r and omized , placebo-controlled study . Children aged 7 - 16 years with mild-persistent to moderate asthma treated with inhaled corticosteroids , were enrolled . After 2-weeks of run-in period , subjects were r and omized to inhaled Formoterol 9 microg bid ( n=19 ) or placebo ( n=19 ) for 2 weeks . MPT with salbutamol-recovery curve was performed at the beginning and at the end of the trial period . Measurements of peak expiratory flow rate ( PEFR ) , symptoms score , rescue bronchodilator usage and side effects were recorded daily . The primary end-points were the change in FEV1 0 - 10 min after salbutamol inhalation and the recovery time from 80 to 100 % of pretest FEV1 . Statistical analyses were performed by ANOVA with repeated measures . RESULTS There was a decrease in the bronchodilator response to salbutamol and an improved PEFR in the Formoterol group . There was no difference in all other parameters . CONCLUSION Formoterol decreases the bronchodilator response to salbutamol following MPT . Whether this phenomenon has clinical implication during acute asthma needs further studies Current therapy in Russia for long-term management of asthma is mainly non-steroidal . This provided the opportunity to compare the efficacy and safety of formoterol ( Oxis ) Turbuhaler plus budesonide ( Pulmicort ) Turbuhaler with budesonide Turbuhaler alone in adults ( n=338 ) with mild to moderate asthma who had little previous exposure to inhaled corticosteroids . The 12-week study followed a r and omised , double-blind , parallel group design and included an open control group of patients who were treated with conventional non-corticosteroid therapy . Patients treated with formoterol plus budesonide benefited from a significantly greater improvement in their pulmonary function and asthma symptoms compared with budesonide alone ( 95 % Cl of difference in mean morning peak expiratory flow [ PEF ] 8.7 - 36.3 l/min , p=0.0015 ) .  Non-corticosteroid  treatment was significantly less effective than formoterol plus budesonide and budesonide alone ( 95 % CIs of differences in mean morning PEF were 36.4 - 63.6 l/min and 14.1 - 41.1 l/min , respectively , both p=0.0001 ) . Although the incidence and frequency of adverse events was not significantly different between the groups , formoterol plus budesonide and budesonide alone were better tolerated than non-corticosteroid treatment , and there were fewer incidences of asthma deterioration . Overall , formoterol Turbuhaler plus budesonide Turbuhaler was the safest and most effective treatment BACKGROUND Aerosol delivery and deposition to the oropharynx and the lungs have been found to be different for solution-type and suspension-type metered-dose aerosols used for treatment of asthma . We investigated possible differences in clinical effects between solution and suspension metered-dose formoterol aerosols . METHODS A total of 24 patients with asthma ( forced expiratory volume in 1 second , < or = 70 % predicted ) inhaled single doses ( 12 micrograms or 24 micrograms ) of formoterol solution and suspension so that we could investigate the immediate tremor , airway , and cardiovascular responses in a r and omized , double-blind , crossover trial . Fenoterol suspension aerosol ( 400 micrograms ) was used for comparison ( single-blind , post study , nonr and omized administration ) . Fenoterol ( 400 micrograms ) as a rescue medication was inhaled after 120 minutes on each of the 5 study days . RESULTS The order of mean ( + /- SEM ) maximum tremor acceleration was as follows : 12 micrograms formoterol solution ( 67.92 + /- 4.54 cm x sec-2 ) < 24 micrograms solution ( 73.46 + /- 4.51 cm x sec-2 ) < 12 micrograms suspension ( 80.87 + /- 5.08 cm x sec-2 ) < fenoterol ( 84.13 + /- 4.21 cm x sec-2 ) < 24 micrograms formoterol suspension 88.54 + /- 6.26 cm x sec-2 ) . Maximum increase in specific airway conductance ranged from 0.48 + / 0.03 to 0.55 + /- 0.04 sec-1 x kPa-1 for all drugs ( p > 0.05 ) . No change in cardiovascular parameters occurred ( p > 0.05 ) . CONCLUSION No difference in the bronchial response to either formulation of formoterol was found . Tremor response to suspension aerosol ( 24 micrograms > 12 micrograms ) was higher than that to solution aerosol ( 24 micrograms > 12 micrograms ) , indicating possible differences in systemic absorption because of a different deposition pattern . Rescue medication demonstrated systemic effects on tremor that were additive to those of formoterol Long-acting beta(2)-adrenoceptor agonists attenuate the  allergen-induced late asthmatic reaction .  We evaluated whether other mechanisms in addition to airway smooth muscle relaxation may be implicated in this protective effect . The effects of formoterol ( Foradil Aerolizer(TM ) , 24 microg dry powder ) on the late asthmatic reaction were assessed by a r and omised crossover factorial study in 24 patients with asthma . Four challenge/treatment combinations were tested : ( A ) saline/placebo , ( B ) saline/formoterol , ( C ) allergen/placebo , ( D ) allergen/formoterol . Formoterol and placebo were administered double blind after the last inhalation of the allergen or saline .  FEV(1 ) was measured up to 32 h. The bronchodilator effect of formoterol was estimated as ( B-A ) and the overall protective effect as ( D-C ) . The effect not due to bronchodilation was estimated as [(D-C)-(B-A)]/2 . The bronchodilator effect of formoterol was statistically significant up to 5h ( all P < or = 0.015 ) . Formoterol significantly attenuated the late asthmatic reaction between 3 and 32 h after allergen inhalation ( all P < or = 0.0012 ) . The difference between this protective effect and the bronchodilator effect was statistically significant at 5 h and between 7 and 28 h after allergen inhalation ( all P < or = 0.035 ) . Our results suggest that functional antagonism may not be the sole mechanism by which formoterol attenuates the allergen-induced late asthmatic reaction The peak response and the duration of bronchodilator effect were measured after four inhalations at 20 min intervals of 250 micrograms of aerosolized terbutaline in 13 patients with bronchial asthma . Patients were initially studied after strict avoidance of all adrenergic agents for 2 wk ; they were then studied at 2 wk intervals for 12 wk while receiving 500 micrograms of aerosolized terbutaline q.i.d . The initial testing ( TI ) and the testing at the end of 12 wk ( TII ) were double blind . Both peak response and duration of action decreased significantly between TI and TII . Cumulative dose-response curves showed that further improvement occurred after each inhalation during TI but that there was significant improvement only after the first inhalation during TII 89 subjects with stable asthma took part in a double-blind , placebo-controlled , r and omized , crossover study of the effects of regular versus on-dem and inhaled bronchodilator therapy . The subjects inhaled fenoterol or placebo by a dry powder delivery system for 24 weeks . Control of asthma was judged by daily morning and evening peak expiratory flow rates , symptom diaries , use of additional inhaled bronchodilator , and requirement for short courses of prednisone . Of 64 subjects who completed the trial , 57 showed a clear difference in degree of control of asthma between the fenoterol and placebo periods : in 17 ( 30 % [ 95 % confidence interval 18.4 - 43.4 % ] ) asthma was better controlled during regular inhaled bronchodilator treatment , whereas in 40 ( 70 % [ 56.6 - 81.6 % ] ) control was better during placebo treatment with bronchodilator for symptom relief only . Mean airway responsiveness to methacholine increased slightly during the fenoterol period . The adverse effect of regular bronchodilator inhalation occurred not only among subjects who used a bronchodilator as sole treatment ( 2 were better and 10 were worse during regular bronchodilator treatment ) but also among those who took inhaled corticosteroids ( 14 were better and 29 were worse ) . Thus , regular inhalation of a beta-sympathomimetic agent was associated with deterioration of asthma control in the majority of subjects . The trends to use of regular , higher doses or longer-acting inhaled beta-sympathomimetic treatment may be an important causal factor in the worldwide increase in morbidity from asthma
BACKGROUND Epidemiological evidence has suggested a link between beta(2)-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 formoterol versus placebo or regular short-acting beta(2)-agonists .