Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. Intracoronary Injections of Salbutamol Demonstrate the Presence of Functional ft-Adrenoceptors in the Human Heart Systemic effects of salbutamol and salmeterol in patients with asthma. A comparison of the speeds of action of salmeterol and salbutamol in reversing methacholine-induced bronchoconstriction. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma Tolerance to beta-agonists during acute bronchoconstriction. Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol. The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. Regular inhaled salbutamol and airway responsiveness to allergen Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration.
BACKGROUND In vitro the long acting β2 agonist salmeterol can , in contrast to formoterol , behave as a partial agonist and become a partial antagonist to other β2 agonists . To study this in vivo , the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting β2agonists . METHODS A r and omised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second ( FEV1 ) of 88.4 % predicted and median concentration of methacholine provoking a fall in FEV1 of 20 % or more ( PC20 ) of 0.62 mg/ml at entry . One hour after the last dose of 2 weeks of treatment with formoterol ( 24 μg twice daily by Turbuhaler ) , salmeterol ( 100 μg twice daily by Diskhaler ) , or placebo a methacholine provocation test was performed and continued until there was at least a 30 % decrease in FEV1 . Salbutamol ( 50 μg ) was administered immediately thereafter , followed by ipratropium bromide ( 40 μg ) after a further 30 minutes . Lung function was monitored for 1 hour after provocation . RESULTS There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment . The dose of methacholine needed to provoke a fall in FEV1 of ⩾30 % was higher after pretreatment with formoterol ( 2.48 mg ) than with salmeterol ( 1.58 mg ) or placebo ( 0.74 mg ) . The difference between formoterol and salmeterol was statistically significant : 0.7 doubling dose steps ( 95 % CI 0.1 to 1.2 , p=0.016 ) . The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs ( p<0.0003 for both ) . Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8 % , 7.3 % , and 5.5 % for placebo , formoterol and salmeterol , respectively ( equivalent to increases of 26 % , 14 % , and 12 % , respectively , from the lowest FEV1after methacholine ) . At 30 minutes significant differences remained , but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups . CONCLUSION Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent , indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo . Irrespective of this , prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally , indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol . Patients on regular treatment with long acting β2 agonists  should be made aware that an additional single dose of a short acting β2 agonist may become less effective BACKGROUND The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity . The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects . METHODS A double blind , r and omised , crossover study was carried out in 16 healthy subjects who inhaled formoterol 24 , 48 and 96 μg ( via Turbuhaler ® ) , salmeterol 100 , 200 and 400 μg ( via Diskhaler ® ) , or placebo on separate days . Heart rate , systolic and diastolic blood pressure , and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose . Mean maximum ( or minimum ) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs . Lunch was taken after the four hour readings and , since this caused additional changes to the main outcome measures , data from the first four hours are also presented in a post hoc analysis . RESULTS Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration ; formoterol also caused an early increase in systolic blood pressure . The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol , apart from the glycaemic response . The effects of salmeterol were slightly more prolonged than those of formoterol , although some dose related effects were apparent at eight hours with both drugs . The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values . Relative dose potencies ( 95 % CI ) for maximum heart rate and plasma potassium concentrations were 4.1 ( 3.0 to 5.6 ) and 5.8 ( 4.1 to 8.6 ) over four hours and 2.4 ( 1.2 to 3.8 ) and 3.0 ( 1.2 to 5.7 ) over eight hours . CONCLUSIONS Formoterol and salmeterol cause dose related changes in heart rate , diastolic blood pressure , and plasma glucose and potassium concentrations . Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity . Both drugs have a relatively modest therapeutic window . The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses . Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained BACKGROUND Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear . Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects . A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow ( FBF ) as a measure of peripheral vasodilatation . METHODS Eight men with mild asthma underwent the following treatments : normoxia + placebo ( NP ) , normoxia + salbutamol ( NS ) , hypoxia + placebo ( HP ) , and hypoxia + salbutamol ( HS ) . The period of mask breathing started at t=0 minutes , lasted for 60 minutes , and at 30 minutes 800 μg salbutamol was inhaled . The experiment was completed 30 minutes after the inhalation ( t=60 minutes ) . For the hypoxia treatment the Spo 2 level was 82 % . Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value . RESULTS There were no significant differences in blood pressure and potassium levels between the treatments . After 60 minutes the increase in FBF was 13 % ( 95 % CI –12 to 39 ) more for HP treatment than for NP , 21 % ( 95 % CI –5 to 46 ) more for NS than for NP , and 32 % ( 95 % CI 7 to 58 ) more for HS than for HP ( p=0.016 ) . The inhalation of salbutamol during hypoxia result ed in a significant increase in FBF of 45 % ( 95 % CI 20 to 71 ) compared with NP ( p=0.001 ) . CONCLUSION Patients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death AIMS Inhalers combining long acting beta2-adrenoceptor agonists ( LABA ) and corticosteroids ( ICS ) are indicated at Step 3 of current asthma guidelines . We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function , bronchoprotection , acute salbutamol recovery following methacholine bronchial challenge , and surrogate inflammatory markers in patients with moderate persistent asthma . METHODS Twenty-nine patients with mean FEV1 ( + /- SEM ) of 78 + /- 3 % predicted completed a r and omized , double-blind , double-dummy , cross-over study . Patients received either 4 weeks of budesonide 400 microg + formoterol 12 microg ( BUD + FM ) combination twice daily followed by 1 week of BUD 400 microg alone twice daily , or 4 weeks of fluticasone propionate 250 microg + salmeterol 50 microg ( FP + SM ) combination twice daily followed by 1 week of FP 250 microg alone twice daily . Measurements were made at baseline and following each r and omized treatment . RESULTS FEV1 increase from pretreatment baseline as mean ( + /- SEM ) % predicted was significantly higher ( P < 0.05 ) for BUD + FM ( 8 + /- 1 % ) vs BUD ( 2 + /- 1 % ) , and for FP + SM ( 8 + /- 1 % ) vs FP ( 2 + /- 1 % ) . The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups ; BUD + FM ( 22 + /- 1 % ) , BUD ( 24 + /- 1 % ) , FP + SM ( 23 + /- 1 % ) and FP ( 23 + /- 1 % ) . Salbutamol recovery over 30 min following methacholine challenge as area under curve ( AUC % .min ) was significantly blunted ( P < 0.05 ) with BUD + FM ( 486.7 + /- 35.5 ) vs BUD ( 281.1 + /- 52.8 ) , and with FP + SM ( 553.1 + /- 34.1 ) vs FP ( 368.3 + /- 46.7 ) . There were no significant differences between respective combination inhalers or between respective ICS alone . Decreases in exhaled nitric oxide ( NO ) and serum eosinophilic cationic protein ( ECP ) from baseline were not significantly different between treatments . CONCLUSIONS Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone , but delay acute salbutamol recovery after bronchoconstriction To demonstrate the presence of functional cardiac β2-adrenoceptors in man , we studied the responses to intracoronary injections of salbutamol in three groups of six patients . We injected salbutamol , a selective β2-adrenoceptor agonist , into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly . Salbutamol injections caused a sinus tachycardia . The same doses of salbutamol injected into the aortic root caused no change in heart rate , ruling out a systemic effect . The mean dose required to cause an increase in heart rate of 30 beats/min ( IHR30 ) was 2.6 μg in the first group of six patients . In 12 other patients salbutamol was given after β-blockade to confirm the β2-selectivity of the responses . Doses of practolol ( β1,-selective blockade ) and of propranolol ( β1- and β2-blockade ) that had equal β1-blocking activity were used . In six patients who were given practolol  , the mean IHR30 dose was 2.1 μg . In six patients who were given propranolol , the mean IHR30 dose was significantly greater at 64 μg ( p < 0.001 , practolol vs. propranolol ) . This study demonstrates that direct cardiac β2-adrenoceptor stimulation in man has a positive chronotropic effect 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 We compared the speed of action of the long acting beta-agonist salmeterol with that of salbutamol in order to assess whether reported in vitro differences are likely to have clinical significance . We used methacholine tests to produce a st and ardized level of bronchoconstriction and then observed the rate of recovery of FEV1 towards baseline after the administration by metered dose inhaler of salmeterol 50 micrograms or salbutamol 200 micrograms -- doses which are considered to have similar bronchodilator potency . Twenty asthmatic subjects participated , and a double-blind , r and omized , cross-over study design was followed . Salmeterol showed a significantly slower speed of action with median recovery to 90 % and 95 % of the baseline FEV1 ( pre-methacholine ) occurring after 9.6 and 19.4 min , respectively , compared with 4.8 and 8.3 min , respectively , for salbutamol ( P less than 0.01 ) . These observations are consistent with in vitro findings and suggest that salmeterol is likely to be less satisfactory than salbutamol as a ' rescue medication ' for the treatment of acute episodes of bronchoconstriction The airway response and cardiovascular and hypokalaemic effects of fenoterol , salbutamol , and terbutaline given in multiples of st and ard doses from metered-dose inhalers were studied in ten patients with mild asthma . In a double-blind , crossover , placebo-controlled study the subjects received 2 , 6 , and 18 puffs of each drug with intervals of 90 min , and forced expiratory volume in 1 s , heart rate , QTc interval , plasma potassium concentration , tremor , and bronchial reactivity to histamine were measured . All three drugs produced similar bronchodilatation . However , the rises in heart rate , QTc interval , and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline . The maximum mean ( SD ) increases in heart rate for fenoterol , salbutamol , and terbutaline were 29 ( 24 ) bpm , 8 ( 9 ) bpm , and 8 ( 14 ) bpm , respectively ; falls in plasma potassium were 0.76 ( 0.62 ) mmol/l , 0.46 ( 0.32 ) mmol/l , and 0.52 ( 0.39 ) mmol/l , respectively . Fenoterol afforded no additional protection against histamine compared with salbutamol . These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline . The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists ; fenoterol may in addition be less selective for beta 2 receptors Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects . However , most studies have been conducted in stable asthma . This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction . Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline ( 1 mg q.i.d . ) , budesonide ( 400 microg , b.i.d . ) , both drugs or placebo in a r and omized , double-blind , cross-over study . After each treatment methacholine was administered to induce a 20 % fall in the forced expiratory volume in one second ( FEV1 ) . The response to inhaled salbutamol 100 , 100 , 200 microg at 5 min intervals ) was then measured . Dose-response curves were compared using an analysis of covariance . Pre-methacholine FEV1 , the highest pre-methacholine FEV1 , the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20 % fall in FEV1 ( PD20 ) were used as covariates . There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment : the mean ( 95 % confidence intervals ( CI ) ) area under the dose-response curve was reduced by 36 % ( 24 , 47 ) compared to placebo ( p<0.0001 ) . The reduction in bronchodilator response was not affected by concomitant treatment with budesonide . Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction . Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction . This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist , formoterol . The modifying effect of intravenous corticosteroid was also studied . Ten asthmatic subjects ( using inhaled steroids ) participated in a r and omised , double-blind , placebo-controlled , cross-over study . Formoterol 12 microg b.i.d . or matching placebo was given for 10 - 14 days with > 2 weeks washout . Following each treatment , patients underwent a methacholine challenge to induce a fall in forced expired volume in one second ( FEV1 ) of at least 20 % , then salbutamol 100 microg , 100 microg , and 200 microg was inhaled via a spacer at 5 min intervals , with a further 400 microg at 45 min . After a third single-blind formoterol treatment period , hydrocortisone 200 mg was given intravenously prior to salbutamol . Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry . Regular formoterol result ed in a significantly lower FEV1 after salbutamol at each time point compared to placebo ( p<0.01 ) . The area under the curves ( AUCs ) for 15 ( AUC0 - 15 ) and 45 ( AUC0 - 45 ) min were 28.8 % and 29.5 % lower following formoterol treatment ( p<0.001 ) . Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration . It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol . This bronchodilator tolerance is evident in circumstances of acute bronchconstriction BACKGROUND Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma . However , approximately one-third of patients show little or no initial response to this partial beta(2)-agonist . METHODS We conducted a r and omized , double-blind , proof-of-concept study to investigate whether a full beta(2)-agonist , isoproterenol , offers a therapeutic advantage in adults presenting with acute severe asthma ( FEV(1)<50 % ) who fail to respond to an initial treatment of the partial beta(2)-agonist , albuterol . Study subjects were r and omized to receive a 2-h continuous nebulization of either albuterol ( 7.5mg/h ) ( n=10 , mean FEV(1)=37 % predicted ) or isoproterenol ( 7.5mg/h ) ( n=9 , mean FEV(1)=33 % predicted ) . Respiratory symptoms , vital signs and pulmonary function measures were collected . RESULTS Subjects from both treatment groups had similar baseline characteristics . The percent improvements from baseline FEV(1 ) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol ( 44 vs. 17 % and 63 vs. 24 % , respectively , P<0.05 ) . The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol ( P<0.01 ) . Both treatments were well tolerated , though the mean increase in pulse rate at 60 and 120min ( 21 vs. 1 and 23 vs. 6beats/min , respectively , P<0.05 ) and the mean change in serum potassium at 120min ( -0.52 vs. -0.07meq/L , P<0.05 ) from baseline were significantly greater in the isoproterenol group . CONCLUSIONS Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol , the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms We evaluated the profile of the bronchodilatory effect of three inhaled beta2-agonists , 24 microg formoterol , 50 microg salmeterol and 200 microg salbutamol , in patients with stable , moderately severe asthma . Thirty asthmatics ( mean+/-SD age 54+/-8 yrs ; forced expiratory volume in one second ( FEV1 ) 58+/-12 % predicted ; reversibility of FEV1 21+/-8 % from baseline ) participated in a single-centre , double-blind , r and omized , single-dose , cross-over study . FEV1 was obtained in baseline condition and 10 , 20 , 30 , 60 min , and every hour up to 12 h after inhalation of the trial drug . Specific airway conductance ( sGaw ) was measured at baseline condition and 1 , 3 , 5 , 7 , 10 , 20 , 30 , 60 min , and every hour up to 12 h after inhalation . Formoterol produced a mean increase in sGaw ( as % of baseline ) of 44 % after 1 min , maximal ( 135 % ) after 2 h , and 56 % after 12 h. The mean increase in FEV1 was maximal ( 27 % ) after 2h , and 10 % after 12 h. After salmeterol , mean increase in sGaw amounted to 16 % after 3 min , maximal ( 111 % ) after 2 - 4 h , and 58 % after 12 h. The mean increase in FEV1 was maximally 25 % after 3h , being 11 % after 12 h. After salbutamol , mean increase in sGaw was 44 % after 1 min and maximal ( 100 % ) after 30 min . The peak increase in FEV1 was 25 % . We conclude that formoterol ( 24 microg ) and salmeterol ( 50 microg ) had an equal bronchodilatory capacity , which was similar to that of 200 microg salbutamol and lasted for at least 12 h in patients with asthma . However , formoterol had a more rapid onset of action than salmeterol , equal to that of salbutamol 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 OBJECTIVE --To compare safety of salmeterol and salbutamol in treating asthma . DESIGN --Double blind , r and omised clinical trial in parallel groups over 16 weeks . SETTING --General practice s throughout the United Kingdom . SUBJECTS--25,180 patients with asthma considered to require regular treatment with bronchodilators who were recruited by their general practitioner ( n = 3516 ) . INTERVENTIONS --Salmeterol ( Serevent ) ( 50 micrograms twice daily ) or salbutamol ( 200 micrograms four times a day ) r and omised in the ratio of two patients taking salmeterol to one taking salbutamol . All other drugs including prophylaxis against asthma were continued throughout the study . MAIN OUTCOME MEASURES --All serious events and reasons for withdrawals ( medical and non-medical ) whether or not they were considered to be related to the drugs . RESULTS --Fewer medical withdrawals due to asthma occurred in patients taking salmeterol than in those taking salbutamol ( 2.91 % v 3.79 % ; chi 2 = 13.6 , p = 0.0002 ) . Mortality and admissions to hospital were as expected . There was a small but non-significant excess mortality in the group taking salmeterol and a significant excess of asthma events including deaths in patients with severe asthma on entry . Use of more than two canisters of bronchodilator a month was particularly associated with the occurrence of an adverse asthma event . CONCLUSIONS --Treatment over 16 weeks with either salmeterol or salbutamol was not associated with an incidence of deaths related to asthma in excess of that predicted . Overall control of asthma was better in patients allocated to salmeterol . Serious adverse events occurred in patients most at risk on entry and were probably due to the disease rather than treatment 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 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 Evidence of bronchodilator subsensitivity was sought in studies using the specific beta2 adrenergic agonist , albuterol . After a period of 1 or 2 weeks off all oral sympathomimetic agents , the mean response of the patients to the first dose of albuterol was consistently greater than the response after a period during which the drug had been administered regularly . Maximal decrease in response occurred after 2 weeks ' of treatment , and there was no further decrease after prolonged treatment with the same dose of albuterol for periods as long as 1 year High doses of inhaled salbutamol produce substantial improvements in airway response in patients with asthma , and are associated with dose-dependent systemic beta-adrenoceptor responses . The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol .  Twelve asthmatic patients ( FEV1 , 81 + /- 4 % predicted ) , requiring only occasional inhaled beta-agonists as their sole therapy , were given a 14-day treatment with high dose inhaled salbutamol ( HDS ) , 4,000 micrograms daily , low dose inhaled salbutamol ( LDS ) , 800 micrograms daily , or placebo ( PI ) by metered-dose inhaler in a double-blind , r and omized crossover design . During the 14-day run-in and during washout periods , inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purpose s. At the end of each 14-day treatment , a dose-response curve ( DRC ) was performed , and airway ( FEV1 , FEF25 - 75 ) chronotropic ( HR ) , tremor , and metabolic ( K , Glu ) responses were measured at each step ( from 100 to 4,000 micrograms ) . Treatment had no significant effect on baseline values . There were dose-dependent increases in FEV1 and FEF25 - 75 ( p less than 0.001 ) , and pretreatment with HDS did not displace the DRC to the right . DRC for HR ( p less than 0.001 ) , K ( p less than 0.001 ) , and Glu ( p less than 0.005 ) were attenuated after treatment with HDS compared with PI . There were also differences between HDS and LDS for HR ( p less than 0.001 ) and Glu ( p less than 0.05 ) responses . Frequency and severity of subjective adverse effects were also reduced after HDS : tremor ( p less than 0.001 ) , palpitations ( p less than 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVE To compare the safety of salmeterol xinafoate or placebo added to usual asthma care . DESIGN A 28-week , r and omized , double-blind , placebo-controlled , observational study . SETTING Study subjects were seen once in the study physician 's office for screening and were provided all blinded study medication for the entire study period . Follow-up by telephone was scheduled every 4 weeks . PARTICIPANTS Subjects ( > 12 years old ) with asthma as judged by the study physician were eligible . Individuals with a history of long-acting beta2-agonist use were excluded . INTERVENTIONS Salmeterol , 42 mug bid via metered-dose inhaler ( MDI ) , and placebo bid via MDI . MEASUREMENTS AND RESULTS Following an interim analysis in 26,355 subjects , the study was terminated due to findings in African Americans and difficulties in enrollment . The occurrence of the primary outcome , respiratory-related deaths , or life-threatening experiences was low and not significantly different for salmeterol vs placebo ( 50 vs 36 ; relative risk [ RR ] = 1.40 ; 95 % confidence interval [ CI ] , 0.91 to 2.14 ) . There was a small , significant increase in respiratory-related deaths ( 24 vs 11 ; RR , 2.16 ; 95 % CI , 1.06 to 4.41 ) and asthma-related deaths ( 13 vs 3 ; RR , 4.37 ; 95 % CI , 1.25 to 15.34 ) , and in combined asthma-related deaths or life-threatening experiences ( 37 vs 22 ; RR , 1.71 ; 95 % CI , 1.01 to 2.89 ) in subjects receiving salmeterol vs placebo . The imbalance occurred largely in the African-American sub population : respiratory-related deaths or life-threatening experiences ( 20 vs 5 ; RR , 4.10 ; 95 % CI , 1.54 to 10.90 ) and combined asthma-related deaths or life-threatening experiences ( 19 vs 4 ; RR , 4.92 ; 95 % CI , 1.68 to 14.45 ) in subjects receiving salmeterol vs placebo . CONCLUSIONS For the primary end point in the total population , there were no significant differences between treatments . There were small , but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol . Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects . Whether this risk is due to factors including but not limited to a physiologic treatment effect , genetic factors , or patient behaviors leading to poor outcomes remains unknown BACKGROUND There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting beta(2)-agonists . OBJECTIVES The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol , and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid . MATERIAL S AND METHODS Twelve patients ( mean [ SD ] age , 43 [ 15 ] years ; FEV(1 ) , 57 [ 17 ] % predicted ) with stable , moderate to severe persistent asthma who were all taking inhaled corticosteroids  were evaluated in a r and omized , placebo-controlled , double-blind , double-dummy , crossover study . Patients received treatments each for 2 weeks followed by a bolus ( IV/inhaled ) of corticosteroid or placebo : ( 1 ) placebo inhaler bid + bolus placebo ; ( 2 ) formoterol Turbuhaler 24 microg metered dosage bid ( delivered dosage 18 microg bid ) + placebo ; ( 3 ) formoterol 24 microg bid + bolus IV hydrocortisone , 200 mg ; or ( 4 ) formoterol 24 microg bid + bolus inhaled budesonide , 1,600 microg .  Bronchodilator response to repeated puffs of albuterol ( 200 to 1,600 microg ) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid . The study was powered at the 80 % level to detect a 20 % difference in area under curve between 20 and 80 min ( AUC ) for FEV(1 ) response to albuterol as change from baseline ( primary end point ) . RESULTS There was significant subsensitivity ( p = 0.01 ) of the mean albuterol FEV(1 ) response ( as AUC , L x s ) after formoterol alone ( 737 ) as compared to placebo ( 1,453 ) along with partial reversal by steroid administration : formoterol + hydrocortisone ( 1 , 050 ) , and formoterol + budesonide ( 942 ) . There was a similar pattern of subsensitivity ( p = 0.03 ) for the mean albuterol forced expiratory flow between 25 % and 75 % of vital capacity response ( as AUC , L ) : placebo ( 2,149 ) , formoterol alone ( 1,002 ) , formoterol + hydrocortisone ( 1,402 ) , and formoterol + budesonide ( 1,271 ) . CONCLUSION Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol , which was partially reversed by a bolus dose of systemic or inhaled corticosteroid The peak response and the duration of bronchodilator effect were measured after four inhalations at 20 min intervals of 250 micrograms of aerosolized terbutaline in 13 patients with bronchial asthma . Patients were initially studied after strict avoidance of all adrenergic agents for 2 wk ; they were then studied at 2 wk intervals for 12 wk while receiving 500 micrograms of aerosolized terbutaline q.i.d . The initial testing ( TI ) and the testing at the end of 12 wk ( TII ) were double blind . Both peak response and duration of action decreased significantly between TI and TII . Cumulative dose-response curves showed that further improvement occurred after each inhalation during TI but that there was significant improvement only after the first inhalation during TII
BACKGROUND Epidemiological evidence has suggested a link between beta2-agonists and increased  asthma mortality .
There has been much debate about possible causal links for this association , and whether regular ( daily ) long-acting beta2-agonists are safe .
This is an up date d systematic review .
OBJECTIVES To assess the risk of mortality and non-fatal serious adverse events in trials which r and omised patients with chronic asthma to regular salmeterol and inhaled corticosteroids in comparison to the same dose of inhaled corticosteroids .