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Introduction: Several long-term studies designed to assess pharmacological treatments for Chronic Obstructive Pulmonary Disease (COPD) have been published recently. Only such long-term studies allow an accurate analysis of the effect of treatments on criteria of effectiveness such as survival or decline in pulmonary function. A review of these studies is opportune., Background: The high drop out rate, which is not a random event, leads to serious methodological problems that are of importance in the interpretation of these studies. Post hoc analysis of both the TORCH and UPLIFT trials suggest a positive effect of long-acting bronchodilators on survival. Up to now, no treatment has convincingly demonstrated an effect on the rate of decline of FEV(1). The treatments evaluated lead to a decrease in exacerbation rates and an improvement in quality of life although the effects of inhaled corticosteroids are subject to methodological concerns. The treatments are all well tolerated., Viewpoint: The design of future studies should avoid the withdrawal of treatments at enrolment into a study in order to limit the number of drop outs., Conclusion: Long-term studies have made important progress in the knowledge, not only of the effects of the treatments assessed but also of the methodological issues which need to be addressed., (Copyright 2009 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The TORCH study (Towards a Revolution in COPD Health) was a double-blind, randomised, placebo-controlled clinical trial, investigating the combination of salmeterol/fluticasone propionate for 3 years in COPD. The primary end point was on all-cause mortality. Secondary end points included COPD exacerbation rate, lung function and health status. More than 6000 patients were randomised. In this article, we briefly report the most significant results of the study. The efficacy on mortality (reduction of the risk of death of 17.5%) was near the predetermined level of statistical significance (p = 0.052); the combination had a significant effect on the three pillars of COPD management, that is: improvement of quality of life and respiratory function, and reduction of the rate of exacerbations. In addition to being effective, the combination salmeterol/fluticasone (50/500 microg 2x/day) is well tolerated in COPD and had a favourable benefit/risk ratio.

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.

Context: The basics of asthma treatment are well defined in the guidelines, however the criteria for the choice between fixed and free combinations of inhaled corticosteroids and long acting beta 2-agonist have not been clearly established., Method: A modified Juniper questionnaire (using peak expiratory flow rather than maximal expiratory volume per second) was used by 421 general practitioners to assess asthma control in 861 adult patients (aged 47 +/- 17 years) having received inhaled corticosteroids and long-acting beta 2-agonist in a fixed (n = 413) or free (n = 448) combination for at least 6 weeks., Results: Treatment groups were comparable for demographics, asthma history and severity as assessed by the physician. Despite better compliance to treatment in the fixed combination group and a mean daily dose of corticosteroids around two-fold greater compared with free combination group (913 +/- 450 micrograms/d vs 401 +/- 178 micrograms/d), the mean Juniper score was lower in the free combination group (1.60 +/- 0.94 vs 1.73 +/- 0.96) with a greater percentage of patients controlled (Juniper score < 2): 67.6% vs 60.8%. Other treatments for asthma were significantly less frequent with the free combination (14.2% vs 22.3%), as were local side effects and notably voice changes (3.3% vs 9.5%., Comments: The apparently greater efficacy/safety ratio of the free combination was probably due to the greater severity of asthma in the patients treated with a fixed combination. This highlights the interest of free combinations as first-line therapy for patient with mild to moderate asthma.

International guidelines on asthma recommend to add inhaled long-acting b2-agonists in patients insufficiently controlled with an inhaled corticosteroid alone. A multicentre prospective study was carried out in 250 children (age 8.4 +/- 2.7 years) whose asthma remained symptomatic with impaired lung function despite a treatment with 400-1000 micrograms/day of beclomethasone or equivalent. Salmeterol 100 micrograms/day was added to the previous dose of inhaled corticosteroid for 2 months. PEFR was improved as soon as the first month of treatment (67.2 +/- 44.4 L/min, p < 0.001) and at month 2 (75.0 +/- 44.1 L/min, p < 0.001). The percentage of symptomatic patients, the number of days and nights with symptoms, the number of days with prn bronchodilator use were significantly reduced (p < 0.001). The decrease in the distress and severity scores of the Childhood Asthma Questionnaire indicated an improvement in quality of life due to better asthma control. This study showed that lung function and symptoms were significantly improved as soon as the first month of treatment, improvement maintained thereafter, with a better quality of life and a good tolerability.

Salmeterol is an original molecule with a selective-beta-2-sympathomimetic effect which is intended to a prolonged treatment of asthma. This inhaled preparation has a long duration of action which points to its use on a BID regimen. Results of the phase III development has been assessed in 2,277 subjects. Salmeterol administered at a dose of 50 micrograms morning and evening results in a marked increase in FEV1, which remains superior to 15% by comparison with baseline 12 hours after the last dose in the majority of subjects. In the specific case of more severe asthma (FEV1 less than 50% of predicted), the use of 100 micrograms morning and evening allows for an extra-improvement in FEV1. In the majority of studies, salmeterol has resulted in an almost complete remission of the clinical symptomatology: disappearance or major diminution in the use of inhaled salbutamol administered as a rescue medication on a PRN basis (during the day and at night) and of nocturnal awakenings, global improvement of clinical scores. Daily peak expiratory flow rates (morning and night values) are considerably improved (greater than or equal to 50 l/min) with a significant reduction of daily swings. Lung function tests are also very significantly improved. Salmeterol has proved to be largely superior to the comparison medications, salbutamol taken at a dose of 200 micrograms four times a day, and optimal therapy with theophylline. Clinical acceptability of salmeterol is good and is not different from salbutamol.

The author suggests various means to improve the management of asthma through: 1) a multidisciplinary approach; 2) prevention which should include reduction of allergenic and offending exposure; 3) a better information and education of asthmatic patients; 4) a more objective therapeutic follow-up; 5) a "physical medicine". A therapeutic improvement is also needed through a better comprehension of asthma by the patient and the physician. Salmeterol is a promising medication because of its long bronchodilator and protective effect. A better knowledge to define its strategic use of this new drug is needed.

Asthma is now considered as an inflammatory condition and the purpose of the treatment is directed towards the control of inflammation. Recent therapeutic guidelines have been proposed and suggested the early use of antiinflammatory preparations. Salmeterol has a prolonged bronchodilator and protective effect against physical stimuli such as exercise and exposure to cold air. Clinical studies have all shown a superiority of salmeterol by comparison with salbutamol in the treatment of asthma. Recent in vitro and in vivo studies also suggest that salmeterol may have an extra non-bronchodilator effect. Salmeterol appears to be a safe preparation if administered at a dose of 50 to 100 micrograms on a BID regimen. It has been argued that the regular use of salmeterol can mask the worsening of bronchial inflammation although clinical studies have not substantiated this potential risk. Other studies are required to answer this question. A scheme incorporating salmeterol in the guidelines for the treatment of asthma is proposed.

Ninety-six patients with nocturnal asthma (FEV1 = 60-90% pred, reversibility greater than or equal to 15%, at least 2 awakenings in the week preceding the trial) were included in a double-blind, randomized, crossover, multicenter study which compared the efficacy and side effects of inhaled salmeterol (50 micrograms morning and evening) to the association theophylline-ketotifen (300 mg and 1 mg morning and evening, respectively). The trial included a run-in period of 14 days and 2 periods of successive treatment of 28 days each. The efficacy was expressed in terms of therapeutic success, defined by the total disappearance of nocturnal symptoms during the treatment week. A statistically significant difference (p less than 0.01) was found between salmeterol and the association for this criteria: during the first period, 46% of subjects treated by salmeterol did not present nocturnal awakenings during the last treatment week by comparison with 15% of subjects taking the association; during the second period, corresponding figures were 39% for salmeterol by comparison with 26% for the association. Differences were also significant, favoring salmeterol, for other criteria (lung function tests, extra-need for salbutamol). Side effects were 5 times more frequent for the association (p less than 0.004). Salmeterol is clearly superior to the association theophylline-ketotifen in the treatment of nocturnal asthma.

Nineteen subjects with isolated exercise-induced asthma (FEV1, FEF25-75%, PEFR, FVC greater than 95% predicted values, fall in FEV1 of at least 15% after exercise, typical recent symptoms of exercise-induced asthma, no other treatment) were entered in a multicenter trial carried out in a double blind, double placebo, cross-over manner. After a one-month baseline period, subjects underwent an exercise after inhaling 100 micrograms of salmeterol (n = 12) or 40 mg of sodium cromoglycate (n = 7). Treatments were alternated before the second exercise which took place at least 2 days after the first. Efficacy was assessed by examining changes in FEV1, FEF25-75% after exercise carried out 30 minutes and 7 hours after administering the treatment by comparison with baseline values (assessments done 1, 10 and 30 minutes after exercise, lowest of three values kept for the analysis of each parameter). FEV1 and FEF25-75% were significantly higher 30 minutes after taking salmeterol. Salmeterol was found to be superior to sodium cromoglycate for all parameters 7 hours after administering the drug. Both treatments were well tolerated. This study confirms that the longer duration of effect of salmeterol and its superiority by comparison with the standard treatments of exercise-induced asthma.

The duration of the blocking effect of salmeterol (50 micrograms), albuterol (200 micrograms) and placebo was compared in a double-blind study carried out in 12 adult asthmatic subjects who underwent hyperventilation tests with cold dry air on 4 study days. On the first day, the hyperventilation test was carried out at various time intervals with spontaneous functional recovery between each test. The response was assessed by interpolating the dose of cold dry air causing a 20% fall in FEV1 (PD20). On the three other days, the active or placebo medications were administered. Spirometry was assessed 15 minutes and 1 hour later. The hyperventilation test was then performed and repeated at various time intervals after administering the drug. The mean duration of the blocking effect was 0.25 hour for placebo, 3.5 hours for albuterol, and of 15.9 hours for salmeterol. Eight of the 12 subjects still showed some blocking effect eight hours after salmeterol by comparison with only one subject after albuterol. The authors conclude that salmeterol has a significantly longer effect than albuterol on bronchoconstriction induced by hyperventilation.

Salmeterol is a new long acting bronchodilator which is specific for beta-2 adrenergic receptors. Its bronchodilator effects can persist for at least 12 hours after inhalation. This drug can inhibit the bronchoconstrictor effects of methacholine up to 12 hours after inhalation and this effect is proportional to the administered dose. Salmeterol improves daily expiratory flow rates and blocks exercise-induced bronchoconstriction. A 50 micrograms dose, inhaled before an antigenic bronchoprovocation, can markedly reduce for up to 24 hours the immediate and late bronchospastic responses to antigen. Moreover, salmeterol inhibits the increase in bronchial responsiveness induced by antigenic exposure. This latter effect does not seem to be related to a persisting bronchodilatation. The responsible mechanisms for this inhibition of allergic response or if its effects are only due to a functional antagonism remain to be explored. A particularly relevant point would be to determine of salmeterol diminishes or blocks the inflammatory bronchial asthmatic reaction.

Salmeterol is an original molecule characterized by its long duration of action (greater than 12 hrs in humans). Salmeterol is a highly selective beta-2 agonist that is from 2 to 15 times more potent than salbutamol on beta-2 receptors of bronchial smooth muscle and 10,000 times more potent than isoprenaline on beta-1 receptors. The duration of action of salmeterol on bronchial smooth muscle has been shown to be much superior than all other beta-2 sympathomimetics that have been studied, including formoterol. Salmeterol has two side chains that are linked by a long hydroxycarbon chain. Its long duration of action could be explained by the link to the cell membrane through an exo-site which is distinct from the beta-2 receptor. In vitro and in the animal model, salmeterol has a triple effect: inhibition of the liberation of inflammatory mediators (histamine, prostaglandins, leukotrienes), inhibition of cell influx and of protein extravasation. The relevance of this effect remains to be establish in humans.