Cost-effectiveness of eformoterol Turbohaler versus salmeterol Accuhaler in children with symptomatic asthma

We conducted an economic evaluation in a UK setting based on a 12-week prospective randomized open-label parallel-group comparison of eformoterol Turbohaler 12 microg b. i.d. with salmeterol Accuhaler 50 microg b. i.d. in children aged 6-17 with symptomatic asthma receiving inhaled corticosteroids and short-acting beta2-agonists. The principal effectiveness measure was percentage of symptom-free days with no short-acting beta2-agonist use during the study period. Asthma-related medication, unscheduled physician contacts and hospitalizations were collected prospectively and cost to the UK NHS calculated using year 2,000 prices.The economic evaluation included 73 patients in the eformoterol group and 72 patients in the salmeterol group. The mean age of patients was 11.6 years (eformoterol) and 11.8 years (salmeterol). The mean percentage of symptom-free days with no short-acting beta2-agonist use was 39% in the eformoterol group and 30% in the salmeterol group. Mean per patient daily cost was 1.15 pounds in the eformoterol group and 1.39 pounds in the salmeterol group. Both cost and effectiveness differences favoured eformoterol (P < 0.05; one-sided). Sensitivity analysis confirmed the results to be robust to changes in effectiveness, price and resource utilisation parameters. Eformoterol delivered by Turbohaler was found to be significantly more effective and less expensive than salmeterol Accuhaler in this study.     

Adverse effects of beta-agonists: are they clinically relevant?

Inhaled beta(2)-adrenoceptor agonists (beta(2)-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective beta-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia. The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized beta(2)-agonists. Nebulized and oral beta(2)-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a beta-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting beta(2)-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial beta(2)-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular beta(2)-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting beta(2)-agonists, in contradistinction, a number of studies have shown that long-acting beta(2)-agonists have positive anti-inflammatory effects. An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting beta-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting beta-agonists had significant advantages over regular use of short-acting beta-agonists. More studies and data are needed on the regular use of beta(2)-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the beta-receptor, who might be more prone to adverse effects.     

The long and short of beta2-agonists

For patients whose asthma is not adequately controlled with inhaled corticosteroid (ICS) therapy alone, increasing the dose of ICS or the addition of a long-acting beta(2)-agonist is recommended. Greater improvements in lung function are achieved with the addition of a long-acting beta(2)-agonist to ICS therapy, rather than doubling the dose of ICS. Formoterol and salmeterol have a similarly long duration of effect (up to 12 h). However, as a result of their different chemical structures, there are marked pharmacological differences in the mechanism of action which affect their speeds of onset. These differences amount to a more rapid onset of effect for formoterol compared with salmeterol. Long-acting beta(2)-agonists appear to be well tolerated at elevated doses. These two features (tolerability at high doses and rapid onset of effect) support the use of formoterol as a reliever medication in addition to use in maintenance therapy. The long-acting beta(2)-agonists can be considered as beneficial additions to ICS therapy for the management of moderate-to-severe asthma.     

A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge

OBJECTIVES: To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids (ICS) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction. METHODS: A double-blind, placebo-controlled study was performed at 16 centers in the United States. Patients with asthma (n = 122, ages 15-58) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were randomized to receive either montelukast (10 mg once daily), salmeterol (50microg twice daily), or placebo for 4 weeks. Standardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline, week 1 and 4. RESULTS: Maximum achievable forced expiratory volume in 1 s (FEV1) percent predicted after rescue beta2-agonist improved in the montelukast (+1.5%) and placebo (+1.2%) groups at 4 weeks, but diminished in the salmeterol (-3.9%) group (P < 0.001). Although pre-exercise FEV1 was greatest with salmeterol (P = 0.10), patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol (P < 0.001). Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol (P < 0.001). Five minutes after rescue beta2-agonist, 92% of patients taking montelukast and 68% of those taking placebo had recovered to pre-exercise levels, whereas only 50% of those taking salmeterol had recovered to pre-exercise levels. CONCLUSION: In patients whose asthma symptoms remain uncontrolled using ICS, addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinically meaningful protection against exercise-induced bronchoconstriction.     

Acute protection against exercise-induced bronchoconstriction by formoterol, salmeterol and terbutaline.

The onset of bronchoprotection as obtained by various beta2-agonists has not been examined in a comparitive study. In this study, the onset of bronchodilation and protection against exercise-induced bronchoconstriction in asthmatics after inhalation of the long-acting beta2-agonists formoterol and salmeterol and the short-acting beta2-agonist terbutaline were measured. Twenty-five subjects with asthma and a history of exercise-induced bronchoconstriction (mean baseline forced expiratory volume in one second (FEV1): 90% predicted; mean fall in FEV1 after exercise: 31% from baseline) were enrolled in this double-blind, double-dummy, placebo-controlled, randomized, four-period crossover study. Exercise challenges were performed on 12 days at either 5, 30, or 60 min after inhalation of a single dose of formoterol (12 microg Turbuhaler), salmeterol (50 microg Diskus), terbutaline (500 microg Turbuhaler) or placebo. Exercise-induced bronchoconstriction (maximum fall in FEV1 or area under the curve) did not differ significantly between terbutaline, formorerol and salmeterol either 5, 30, or 60 min after inhalation of the study medication. In contrast, the onset of bronchodilation was slower after salmeterol compared to terbutaline and formoterol (p<0.05, each), which both showed a similar time course. At all time points between 5 and 60 min, formoterol provided significantly greater bronchodilation than salmeterol (p<0.05). These data indicate that equipotent doses of the bronchodilators salmeterol, formoterol and terbutaline were similarly effective with respect to their short-term protective potency against exercise-induced bronchoconstriction, despite the fact that the time course of bronchodilation was significantly different between the three beta2-agonists.     

The effect of salmeterol on markers of airway inflammation following segmental allergen challenge

Inflammation is a critical component of asthma. Drugs that control asthma generally reduce the degree of airway inflammation. There is theoretical controversy surrounding the effects of beta(2)-agonists on airway inflammation, with some studies suggesting an anti-inflammatory effect, and others predicting a proinflammatory influence. We conducted a double-blind, placebo-controlled, crossover study of the effect of the long-acting beta(2)-agonist salmeterol on airway inflammation induced by segmental allergen challenge (SAC). We studied 13 allergic asthmatics controlled with as needed inhaled short-acting beta(2)-agonists alone, and used bronchoalveolar lavage 5 min and 48 h after SAC to assess airway inflammation, and the effects of salmeterol on this process. Salmeterol therapy improved FEV(1), but had no significant effect on the immediate or late cellular response to SAC. One measure of superoxide production was reduced, and interleukin-4 (IL-4) was reduced in baseline samples, but other indices of airway inflammation were unchanged by salmeterol therapy. We conclude that salmeterol therapy alone does not meaningfully reduce airway inflammation induced by SAC, but equally importantly, does not result in amplified inflammation.     

The perception of dyspnoea in patients with asthma, before and following treatment with inhaled glucocorticosteroids

This study was designed in order to establish the perception of breathlessness during rest and while breathing against resistance, in patients with asthma, before and after 8 weeks of inhaled glucocorticoids (IGC) treatment and to compare these parameters in patients with and without improvement in FEV1. Sixty-seven asthmatic patients, with moderate asthma, attending the asthma clinic, and 20 normal subjects were studied. After a 2-week run-in period, in which the subjects were asked to use exclusively beta2-agonists as needed, the asthmatic patients were randomized to receive either treatment with IGC, 250 microg of fluticasone propionate (FP) twice a day, via a diskhaler (47 patients), or to receive placebo (20 patients) and to serve as a control group, for 8 weeks. Spirometry and measurements for the sensation of dyspnoea were performed before and at the end of the treatment period. The mean dyspnoea score during breathing against resistance was significantly lower (P<0.05) in the patients with asthma than in normal subjects, before entering the study. Following 8 weeks of inhaled FP, there was a significant improvement in the mean dyspnoea score during breathing against resistance in the asthmatics receiving IGCs but not in the control group (P<005). In the study group 32 patients had an improved FEV1 > 15% and 15 patients did not. There was a statistically significant difference in perception of dyspnoea (P<0.01), between the group of patients with a improved FEV1 and the group of patients that were under IGC treatment without improvement in their FEV1. There was also a difference in the mean beta2-agonists consumption between the two groups (P<0.01). Asthmatic patients have a significantly lower perception of dyspnoea compared to normal subjects. IGC treatment was associated with increased perception of dyspnoea. However, this improvement was noted only in patients with improved FEV1, while the patients without improvement remained with an equal degree of dyspnoea perception and beta2-agonists consumption.     

A fixed combination of fluticasone and salmeterol permits better control of asthma than a beclomethasone dipropionate and montelukast combination

It is now recommended to add an inhaled long-acting beta 2-agonist, or as an alternative, to add a leukotriene-antagonist, in patients whose asthma is insufficiently controlled with an inhaled corticosteroid alone. A randomised, multicentre, open-label, parallel-group study was carried out in 246 patients of at least 15 years, whose asthma was not adequately controlled with a medium dose of an inhaled corticosteroid. They received either fluticasone/salmeterol combination 250/50 micrograms one inhalation twice daily or CFC beclomethasone dipropionate 250 micrograms two puffs twice daily plus montelukast 10 mg in the evening for 12 weeks. The mean morning PEFR (main criterion) was significantly (p = 0.017) more improved with fluticasone/salmeterol (+44.2 L/min) than with beclomethasone dipropionate plus montelukast (+31.0 L/min). Other outcomes showed significantly better improvements (p 0.022 Pound) with fluticasone/salmeterol than with beclomethasone plus montelukast. The two treatments were well tolerated. Fluticasone/salmeterol provided a better asthma control than beclomethasone dipropionate plus montelukast in patients insufficiently controlled with an inhaled corticosteroid alone.     

A One-Week Dose-Ranging Study of Inhaled Salmeterol in Children with Asthma

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 μg and 42 μg administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral β-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vita signs, electrocardiogram (ECC), and 24-hr ECG (Holter) monitoring. Both the 21 -μg and 42-μg doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV₁) (p ≤ 0.02) and PEFR (p ≤ 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-μg dosage producing consistently higher serial FEV₁and PEFR than did the 21 -μg dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p ≤ 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECCs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 μg or 42 μg twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 μg twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 μg.     

Adverse Effects of β-Agonists

Inhaled β₂-adrenoceptor agonists (β₂-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective β-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of β₂-agonists. However, in subsequent studies, the long-acting β₂-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia.The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized β₂-agonists. Nebulized and oral β₂-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a β-agonist for patients with cardiovascular disease.A potential mechanism for adverse effects with regular use of β₂-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting β₂-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial β₂-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular β₂-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting β₂-agonists, in contradistinction, a number of studies have shown that long-acting β₂-agonists have positive anti-inflammatory effects.An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting β-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting β-agonists had significant advantages over regular use of short-acting β-agonists. More studies and data are needed on the regular use of β₂-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the β-receptor, who might be more prone to adverse effects.     

Unaltered perception of dyspnoea during treatment with long-acting beta2-agonists.

There is the possibility that during treatment with inhaled long-acting beta2-agonists that a loss of perception of dyspnoea might occur and that the forced expiratory volume in one second (FEV1) might fall precipitously during bronchial provocation. This study investigated these possibilities during methacholine provocation, continued until there was > or =30% fall in FEV1, mimicking a moderate asthma attack. Nineteen asthmatic patients were asked to score their dyspnoea as a Borg score during provocation with methacholine. One hour prior to this provocation, the patients used the last morning dose of 14 days treatment with either formoterol (twice daily 24 microg by Turbuhaler), salmeterol (twice daily 100 microg by Diskhaler) and placebo in a double-blind, randomized, double-dummy, cross-over design. The perception of dyspnoea, expressed as the Borg score divided by the change in FEV1 at > or =30% fall in FEV1, was similar on the three test days at 0.067, 0.076 and 0.074%(-1) after formoterol, salmeterol and placebo treatment, respectively (p=0.16). The slope of the methacholine dose response curve did not differ (p=0.52). In conclusion, no suggestion was found for an abnormal perception of dyspnoea or an exaggerated fall in forced expiratory volume in one second during provocation with methacholine under long-acting beta2-agonist treatment.     

A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists

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 standard 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.     

Long-acting beta 2-adrenoceptor agonists: a new perspective in the treatment of asthma.

New long-acting beta 2-adrenoceptor agonists, formoterol and salmeterol, may soon appear in several European countries for treatment of asthma. This review examines currently available information and compares the basic pharmacology and describes the clinical effects of these new drugs. The long duration of bronchodilation seen in clinical studies seems to be similar, whereas in isolated tissues there might be a difference in the binding characteristics to the beta 2-adrenoceptor. Long-acting beta 2-agonists could have an inhibitory effect on inflammatory events related to asthma, but the clinical relevance of these effects is not clear at present. Long-term studies up to one year with both new drugs have not shown any unexpected side-effects, and no tachyphylaxis to beta-adrenoceptor stimulation has been reported. Patients appear to strongly prefer the new drugs compared to the short-acting beta 2-agonists. The potential place for these drugs in the treatment of asthma is discussed and some pitfalls pointed out. It is likely that the long-acting beta 2-agonists will be beneficial to many asthmatic patients.     

Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma

Lung mucociliary clearance is impaired in stable asthma. The long-acting beta2-agonist salmeterol has been shown in vitro to cause a significant increase in ciliary beat frequency. It seemed possible therefore that salmeterol may also have a favourable effect on lung mucociliary transport in asthmatic patients. Fourteen patients with asthma participated in a double-blind, placebo-controlled, crossover study to assess the effect of 2 weeks of treatment with salmeterol MDI (50 microg b.d.) on lung mucociliary clearance. The 11 patients who completed the study (seven males, four females) had a mean +/- SE age of 50 +/- 4 years, % predicted FEV1 of 74 +/- 8% and a tobacco consumption history of 13 +/- 7 pack-years (seven non-smokers, four exsmokers). Lung mucociliary transport was measured by a radioaerosol technique. Pulmonary function indices (FEV1, FVC, and PEF) were significantly improved on salmeterol relative to placebo. The main radioaerosol finding was a significant increase in the penetration of radioaerosol into the lung with 24-h radioaerosol rising from 40 +/- 5% on placebo to 49 +/- 4% (P < 0.01) on salmeterol. Despite this increased penetration, a slight favourable change occurred in tracheobronchial aerosol clearance. This study demonstrates that 2 weeks salmeterol treatment influences deposition of particles within the lung by increasing airway patency and indicates a beneficial effect of MDI salmeterol on lung mucociliary clearance.     

Effect of formoterol and salmeterol on IL-6 and IL-8 release in airway epithelial cells

Beta(2)-adrenoceptors are widely distributed and occur on airway epithelial cells. The aim of this study was to find out whether the two long-acting beta(2)-agonists formoterol and salmeterol influence interleukin-6 (IL-6) and -8 (IL-8) release from airway epithelial cells in vitro. A549 cells and primary bronchial epithelial cells (PBEC) were stimulated with organic dust from pig barns. Non-stimulated and dust-stimulated cells were incubated for 24h with formoterol or salmeterol (10(-13)-10(-6)M) and the release of IL-6 and IL-8 into the medium was assessed by ELISA technique. Propranolol (10(-5)M) or sotalol (10(-3)M) were used to block the beta(2)-agonist mediated effects. Formoterol and salmeterol both induced enhancement of IL-6 and IL-8 release and added to the effect of organic dust. This enhanced release was blocked by a beta-blocker in PBEC but not in A549 cells. To our knowledge, this is the first time beta(2)-agonists have been shown to stimulate IL-6 release from airway epithelial cells. The results indicate different mechanisms of beta(2)-agonist action in bronchial and alveolar epithelial cells. Furthermore, our results indicate that A549 cells do not possess functional beta(2)-adrenoceptors.     

Beta2-agonist eutomers: a rational option for the treatment of asthma?

Beta2-adrenoceptor agonists (beta2-agonists) such as albuterol (salbutamol) and terbutaline and their long-acting analogs salmeterol and formoterol are widely used as bronchodilators in the treatment of asthma. They are chiral drugs historically marketed as racemic mixtures of an active (eutomer) and essentially inactive (distomer) stereoisomer. Despite their obvious therapeutic value and widespread use, beta2-agonists have been implicated, somewhat controversially, in causing an increase in asthma mortality and a deterioration of asthma control by a mechanism that remains elusive. Inherent toxicity of the distomers has been widely touted as an explanation and has given rise to pressure for the replacement of the racemates with pure eutomer formulations (the so-called chiral or racemic switch). This has culminated in the recent introduction into clinical practice of the single active stereoisomer of albuterol (levalbuterol) and the promise of other pure beta2-agonist eutomer formulations to follow. This article examines the evidence on which these chiral switches are based. Clinical studies designed to reveal negative effects of beta2-agonists have searched for reductions in lung function, increases in airway responsiveness to bronchoconstrictor mediators and worsening of asthma control. Crossover studies administering the pure stereoisomers and racemate of albuterol have not shown a clear superiority of the pure eutomer formulation over the racemate in terms of either bronchial hyperresponsiveness, tachyphylaxis to bronchoprotective effects or improvements in lung function. Clinical toxicity of beta2-agonist distomers on any aspect of asthmatic lung function has also not been demonstrated in the relatively short-term inhalational studies (single dose or repeated dose studies <1 week) that have been carried out. In animal studies, the administration of beta2-agonist racemates and distomers has been shown to enhance bronchial hyperresponsiveness but only in ovalbumin-sensitized animals where the relevance to humans is questionable. The pharmacokinetics and metabolism of beta(2)-agonist stereoisomers appear to be essentially similar whether administered as single stereoisomers or as racemates. Levalbuterol may be slightly more potent than an equivalent dose given as racemate, but there is some evidence that it forms a small amount of the distomer in vivo which detracts somewhat from its purported benefits over use of the racemate. Whilst there remains a clear need for studies of longer duration with sensitive clinical endpoints to evaluate the benefits of beta2-agonist eutomers and to investigate distomer toxicity, the chiral switch for beta2-agonists in general, and for albuterol in particular, does not appear to be justified on the basis of the evidence available to date.     

Long-acting beta(2)-agonists in management of childhood asthma: A critical review of the literature

This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled salmeterol or formoterol cause prolonged bronchodilatation (>12 h) and extended bronchoprotection against exercise-induced bronchoconstriction in children, some children achieving full protection for more than 12 h. Heterogeneity in bronchoprotection has been observed, and individual dose-titration may be attempted. The onset of action of formoterol is comparable to salbutamol, while salmeterol has a slower onset of action. Partial tolerance develops when long-acting beta(2)-agonists are used as regular treatment, including cross-tolerance to short-acting beta(2)-agonists. Regular treatment with salmeterol in children with or without corticosteroids provides statistically significant bronchodilatation, but the degree of improvement in lung function or bronchoprotection against exercise and nonspecific irritants is small with regular use. There is no evidence of anti-inflammatory effects from inhaled long-acting beta(2)-agonists, which is reflected by unchanged or increased bronchial hyperreactivity and no reduction of exacerbation rates. The evidence does not support a recommendation for long-acting beta(2)-agonists as monotherapy, nor does it support their general use as regular add-on therapy. In conclusion, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue medication instead of short-acting beta(2)-agonists for pediatric asthma management.