Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease. Efficacy of salmeterol xinafoate in the treatment of COPD. Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study. Symptoms are an important outcome in chronic obstructive pulmonary disease clinical trials: results of a 3-month comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long-term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline. The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD) Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomised, double blind, placebo controlled, crossover study.
The aim of this study was to evaluate the effects of single and chronic dosing with salmeterol on exercise capacity and lung function in patients with chronic obstructive pulmonary disease.
                Twenty nine patients of mean (SE) age 64 (1.5) years, forced expiratory volume in one second (FEV1) 42(3)% of predicted, and 5-15% reversibility to salbutamol 200 micrograms were randomised to receive four weeks treatment with salmeterol 50 micrograms twice daily or placebo in a double blind crossover fashion with a one week washout period in between. Measurements of spirometric parameters, static lung volumes, and exercise capacity were made one and six hours after a single dose, and six hours after the final dose of salmeterol or placebo.
                Salmeterol produced a small increase in FEV1 at one and six hours after a single dose, and this was maintained after chronic dosing (mean difference and 95% CI versus placebo): single dosing at one hour 0.07 (95% CI 0.02 to 0.11) 1, single dosing at six hours 0.16 (95% CI 0.09 to 0.22) 1, chronic dosing at six hours 0.11 (95% CI 0.03 to 0.19) 1. The increase in forced vital capacity (FVC) was greater with salmeterol than with placebo six hours after single but not chronic dosing: single dosing at six hours 0.17 (95% CI 0.04 to 0.29) 1, chronic dosing at six hours 0.02 (95% CI -0.18 to 0.22) 1. Slow vital capacity was increased after treatment with salmeterol compared with placebo one and six hours after single but not after chronic dosing. There were no significant differences in static lung volumes or exercise capacity after single or chronic dosing with salmeterol compared with placebo. Patients reported a significantly lower Borg score for perceived exertion following the six minute walk after chronic treatment with salmeterol compared with placebo.
                Salmeterol produced a small improvement in spirometric values compared with placebo consistent with the degree of reversibility originally shown by the subjects to salbutamol 200 micrograms. This was not associated with improvements in static lung volumes or exercise capacity, but there was some symptomatic benefit in that patients were able to walk the same distance in six minutes with less perceived exertion. To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD.
                A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial.
                Multiple sites at clinics and university medical centers throughout the United States.
                Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. Interventions: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks.
                Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments.
                These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD. The aim of this study was to compare the effects of formoterol, ipratropium bromide and a placebo on walking distance, lung function, symptoms and quality of life (QoL) in chronic obstructive pulmonary disease (COPD) patients. A total of 183 patients (mean age 64 yrs, 86 female) with moderate-to-severe nonreversible COPD participated in this randomised, double-blind, parallel-group study. After a 2-week placebo run-in, patients were randomised to formoterol Turbuhaler 18 microg b.i.d. (delivered dose), ipratropium bromide 80 microg t.i.d. via a pressurised metered dose inhaler, or placebo for 12 weeks. Inhaled short-acting beta2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose. The primary variable was walking distance in the shuttle walking test (SWT). Baseline mean SWT distance was 325 m, mean forced expiratory volume in one second (FEV1) was 40% predicted. Clinically significant improvements in SWT (>30 m) were seen in 41, 38 and 30% of formoterol, ipratropium and placebo patients, respectively (not significant). Mean increases from run-in were 19, 17 and 5 m in the formoterol, ipratropium and placebo groups, respectively. Both active treatments significantly improved FEV1, forced vital capacity, peak expiratory flow and daytime dyspnoea score compared with placebo. Formoterol reduced relief medication use compared with placebo. Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms, without significant improvements in the shuttle walking test. The need to manage the key symptoms of chronic obstructive pulmonary disease (COPD) (breathlessness, cough and sputum) is an important treatment objective. Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism. The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies; the results of a 3-month, placebo-controlled multi-centre study are reported. Effect on patient symptoms was determined using a novel patient-reported assessment instrument, the Breathlessness, Cough and Sputum Scale (BCSS). Patients with smoking-related COPD were required to complete a 2-week baseline period before being randomized to one of three treatment groups; sibenadet (500 microg three times daily) plus placebo (twice daily); salmeterol (50 microg twice daily) plus placebo (three times daily); placebo (twice daily) plus a second placebo (three times daily). All treatments were delivered via pressurized metered dose inhaler (pMDI) for 12 weeks. From enrolment, patients were required to complete daily diary cards to record symptoms of breathlessness, cough and sputum, medication use and adverse events. The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period. Secondary measures included assessment of lung function, rescue medication use, exacerbations, health-related quality of life, opinion of efficacy and safety. Although an initial reduction in BCSS total score (indicating symptom improvement) was seen with sibenadet therapy, this effect was not maintained for the study duration. Salmeterol therapy, however, resulted in a sustained reduction in BCSS total score. No notable benefit over placebo was seen in lung function, exacerbations or health-related quality of life with either active treatment. While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy, they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD. The efficacy and safety of salmeterol alone was compared with the combination of salmeterol plus ipratropium and with placebo during long-term treatment in patients with stable chronic obstructive pulmonary disease. In addition, the single-dose effect in response to the first dose of treatment was studied over 12 h. The patients (n=144; age 64+/-7 yrs, forced expiratory volume in one second (FEV1) 44+/-11% pred) participated in a three-centre double-blind double-placebo parallel group study and were randomized after a run-in period of 2 weeks to receive either salmeterol 50 microg b.i.d., salmeterol 5 microg b.i.d. plus ipratropium 40 microg q.i.d. or placebo for a period of 12 weeks. The single-dose study demonstrated that salmeterol produced a significant increase in FEV1 (peak of 7% pred) and specific airway conductance (sGaw) (maximum of 60% baseline) for > or =12 h. The combination of salmeterol plus ipratropium elicited a greater bronchodilator response (11% and 94% increases respectively) than salmeterol alone during the first 6 h after inhalation. During treatment there were significant improvements in daytime symptom scores and morning peak expiratory flow in both the salmeterol and the salmeterol plus ipratropium groups (p<0.001), with an associated decrease in the use of rescue salbutamol. Improvements in FEV1 and sGaw were greater in the salmeterol plus ipratropium group than in the patients receiving only salmeterol. Thirty-five patients had an exacerbation; 11 (23%) in the salmeterol group (versus placebo NS), six (13%) in the salmeterol plus ipratropium group (versus placebo p<0.01) and 18 (36%) in the placebo group. In conclusion, in patients with severe stable chronic obstructive pulmonary disease, long-term treatment with either salmeterol alone or salmeterol plus ipratropium is safe and effective. There was added benefit from the combination therapy in terms of improvement in airways obstruction, but not for improvement in symptom control or need for rescue salbutamol. Chronic obstructive pulmonary disease (COPD) is a condition in which continuous bronchodilation may have clinical advantages. This study evaluated salmeterol, a beta-agonist bronchodilator with a duration of action substantially longer than that of short-acting beta-agonists, compared with ipratropium, an anticholinergic bronchodilator, and placebo in patients with COPD. Four hundred and five patients with COPD received either salmeterol 42 microg twice daily, ipratropium bromide 36 microg four times daily, or placebo for 12 wk in this randomized, double-blind, parallel-group study. Patients were stratified on the basis of bronchodilator response to albuterol (> 12% and > 200-ml improvement) and were randomized within each stratum. Bronchodilator response was measured over 12 h four times during the treatment period. Salmeterol provided similar maximal bronchodilatation to ipratropium but had a longer duration of action and a more constant bronchodilatory effect with no evidence of bronchodilator tolerance. Both active treatments were well tolerated. Salmeterol was an effective bronchodilator with a consistent effect over this 12-wk study in patients with COPD, including those "unresponsive" to albuterol. The long duration of action of salmeterol offers the advantage of twice daily dosing compared with the required four times a day dosing with ipratropium. To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD.
                A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations.
                Eighty-one centers worldwide.
                Eight hundred fifty-four patients with symptomatic COPD.
                Comparison of twice-daily inhaled formoterol dry powder (12 or 24 microg), PL, and THEO (individualized doses) over 12 months.
                Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV(1) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p < 0.001 for all comparisons). Therapy with formoterol, 12 microg, was significantly more effective than that with THEO (p < or = 0.026). Formoterol significantly reduced the percentage of "bad days" (i.e., days with at least two individual symptom scores > or = 2 and/or a reduction in peak expiratory flow from a baseline of > 20%; p < or = 0.035 vs. PL and THEO), and the use of salbutamol rescue medication (p < or = 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months (p < or = 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol.
                Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD. Bronchodilator agents are central to the symptomatic management of Chronic Obstructive Pulmonary Disease (COPD), and long-acting inhaled bronchodilators are regarded as more convenient. The role of inhaled corticosteroids still remains controversial, but there is increasing evidence that they may improve FEV(1) and symptoms in the long-term.
                of the present small pilot study was to compare Salmeterol & Fluticasone (SM&FP) 50/250 microg bid via a single Diskus inhaler with SM 50 microg bid alone, and with placebo (P) in the treatment of moderate COPD.
                Eighteen moderate COPD patients (53-77 yr, mean basal FEV(1)=49.1% pred.+/-5.0 s.d.; mean FEV(1) reversibility=3.6% bsln+/-3.8 s.d.) treated with theophylline 400 mg/day and beta(2) short acting prn, were divided into three matched groups of six subjects according to a double-blind design, and treated with SM&FP 50/250 microcg, or SM 50 microcg alone, or P via Diskus inhaler bid for 52 weeks. In bsln, after 4, 12, 24, 36 and 52 weeks, FEV(1) (% pred), morning PEF (l/s), the daily symptom score, and the number of exacerbations (compared with the previous year) were considered. Statistics. t-test, anova in each treatment group, and anova among basal values and among the 52 week values were used, being p<0.05 accepted. Also changes (DeltaFEV(1)) from baseline were compared at different control times.
                The mean number of exacerbations/yr decreased from 3.5+/-0.8 to 1.16+/-0.75 s.d. exacerbation/yr in the SM&FP group (t-test p<0.001); from 3.0+/-0.89 to 2.3+/-0.81 s.d. in the SM group (t-test p=ns); and from 3.16+/-1.16 to 4.16+/-0.75 s.d. in the P group (t-test p=ns). Patients receiving SM&FP showed the highest mean improvement in FEV(1) (+7.3%+/-3.3 s.d.) over the baseline pre-treatment value after 36 weeks of treatment (anova p<0.001), being FEV(1) unchanged after 52 weeks of treatment in SM group (+0.33%+/-2.4 s.d.) and with a substantial decrease following P (-2.6%+/-1.2 s.d.) (anova p<0.001). Morning PEF (l/min) increased in subjects treated with SM&FP (anova p<0.001), while it remained unchanged in SM and P group (in both, anova p=ns). After 52 weeks of treatment, only subjects treated with SM&FP showed a reduction of the daily symptoms score from 3.6+/-0.7 to 2.0+/-0.2 s.d. (anova p=0.008). Daily beta(2) short acting prn consumption was reduced only in SM&FP group from 4.2+/-0.81 to 2.2+/-1.2 s.d. after 52 weeks (anova p<0.001).
                SM&FP 50/250 microcg regularly assumed in combination via a single Diskus inhaler for a 52 week period improves respiratory function (such as FEV(1), morning PEF), and and symptom score significantly in moderate COPD previously treated with theophylline, and at an higher extent than SM alone or P. The use of beta(2) short acting prn is also reduced, together with the number of exacerbations. In the past, the role of long-acting beta(2-) agonists in chronic obstructive pulmonary disease (COPD) relative to other agents has been unclear.
                To compare the effect of adding salmeterol (50 microg bid) or placebo to concurrent anticholinergic therapy on symptom scores, quality of life, prebronchodilator lung function and exacerbations in patients with moderately severe COPD.
                This was a double-blind, randomized, parallel-group study in patients aged 40 years or older receiving anticholinergic medication. Patients were randomly assigned to treatment with placebo (n=207) or salmeterol (n=201) via a Diskus/Accuhaler inhaler for 24 weeks.
                The morning trough (prestudy drug) forced expiratory volume in 1 s (FEV(1)) increased significantly above baseline levels among the salmeterol-treated patients. Improvement in FEV(1) was greater in the salmeterol group than in the placebo group at four weeks (difference 0.06 L, P<0.005), eight weeks (0.06 L, P<0.005) and 16 weeks (0.05 L, P<0.05) after the start of treatment. There was a nonsignificant trend in favour of salmeterol after 24 weeks of treatment (P=0.198). Improvements in morning peak flow were significantly greater in the salmeterol group over 24 weeks (P<0.01). Although symptom scores were numerically higher in the salmeterol group than in the placebo group and there was less requirement for rescue bronchodilator use, these differences were not statistically significant. In the salmeterol group, fewer patients had exacerbations of COPD, and there was a trend toward an improved quality of life. The safety profile of the two groups was similar.
                Salmeterol has a beneficial effect when added to existing anticholinergic therapy in patients with COPD. The regular use of salmeterol for six months was not associated with worsening of the underlying airflow obstruction; rather, there was a tendency for the trough FEV1 to improve above the baseline levels over the treatment period. To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting beta(2)-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD.
                Randomized, double-blind, multicenter, placebo-controlled study.
                Seventy-six investigative sites in the United States.
                Seven hundred twenty-three patients > or =40 years of age with COPD and a mean baseline FEV(1) of 42% predicted.
                FP (250 microg), SM (50 microg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks.
                Primary efficacy measures were morning predose (ie, trough FEV(1)) for FSC compared with SM and 2-h postdose FEV(1) for FSC compared with FP. Other efficacy measures were as follows: morning peak expiratory flow rate (PEF); transition dyspnea index; chronic respiratory disease questionnaire; chronic bronchitis symptom questionnaire; exacerbations; and other symptomatic measures.
                At Endpoint (ie, the last on-treatment, post-baseline assessment), treatment with FSC significantly (p < or = 0.012) increased the morning predose FEV(1) (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p < or = 0.001) increased the 2-h postdose FEV(1) (281 mL) compared with FP (147 mL) and placebo (58 mL). Improvements in lung function with FSC compared with FP and SM, and with FP and SM compared with placebo, as measured by the average daily morning PEF, was observed within approximately 24 h after the initiation of treatment, indicating an early onset of effect (p < or = 0.034). Compared with placebo, FSC significantly improved dyspnea, quality of life, and symptoms of chronic bronchitis. The incidence of adverse effects (except for an increase in oral candidiasis with FSC and FP) were similar among the treatment groups.
                Treatment with FSC (FP, 250 microg, and SM, 50 microg) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD, with no additional safety concerns for the combination treatment vs that with the individual components. The objectives of this study were to compare the efficacy and safety of salmeterol xinafoate (50 and 100 microg b.i.d.) with that of placebo, when added to existing therapy, in the treatment of patients with chronic obstructive pulmonary disease (COPD). Six hundred and seventy four patients were randomized to receive either salmeterol 50 microg b.i.d., salmeterol 100 microg b.i.d., or placebo treatment for a period of 16 weeks. The results showed a significant improvement in daily symptom scores noted for patients taking either 50 microg (p=0.043) or 100 microg b.i.d. salmeterol (p=0.01) compared with placebo, with a corresponding decrease in additional daytime salbutamol requirements for both salmeterol groups. The same pattern was reflected for night-time symptoms and additional salbutamol use. During treatment, forced expiratory volume in one second (FEV1) measurements improved significantly in each salmeterol group, with up to a 7% improvement observed at the end of the study. Although no difference was observed between treatment groups for the distance walked in 6 min, patients treated with salmeterol 50 microg b.i.d. were significantly less breathless than those treated with placebo after their 6 min walk, after 8 weeks (p=0.024) and 16 weeks (p=0.004) of therapy. Adverse events were similar in all three groups except for tremor, which was significantly higher in the 100 microg b.i.d. salmeterol group (p=0.005) compared both with 50 microg b.i.d. salmeterol and placebo. Salmeterol offered further positive improvement to the effect of therapy in patients with chronic obstructive pulmonary disease when added to their existing regimens. This clinical improvement was similar both with 50 and 100 microg b.i.d. dosage, although the group receiving 50 microg b.i.d. tolerated the drug better than those receiving 100 microg b.i.d. salmeterol. This randomized controlled trial examined the benefits of combining an inhaled corticosteroid, fluticasone propionate (F), with an inhaled long-acting beta(2)-agonist, salmeterol (S), to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease (COPD). A total of 691 patients with COPD received the combination of F and S (FSC), S (50 mcg), F (500 mcg), or placebo twice daily via the Diskus device for 24 weeks. A significantly greater increase in predose FEV(1) at the endpoint was observed after FSC (156 ml) compared with S (107 ml, p = 0.012) and placebo (-4 ml, p < 0.0001). A significantly greater increase in 2-hour postdose FEV(1) at the endpoint was observed after treatment with FSC (261 ml) compared with F (138 ml, p < 0.001) and placebo (28 ml, p < 0.001). There were greater improvements in the Transition Dyspnea Index with FSC (2.1) compared with F (1.3, p = 0.033), S (0.9, p < 0.001), and placebo (0.4, p < 0.0001). The incidence of adverse effects (except for an increase in oral candidiasis with FSC and F) was similar among the treatment groups. We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo. The acute response to bronchodilators in patients with chronic obstructive pulmonary disease (COPD) is modest; it has, however, been suggested that these patients may benefit from long term treatment.
                To investigate the efficacy of salmeterol in smokers with moderate to severe COPD a double blind, randomised, crossover comparison was performed between salmeterol (50 micrograms twice daily) and placebo in 63 patients with stable COPD (mean age 65 years). Prior to inclusion, all patients had a forced expiratory volume in one second (FEV1) of < 60% of predicted and an improvement in FEV1 of < 15% following 400 micrograms inhaled salbutamol. Patients received four weeks of therapy with each of the treatment regimens. Assessment of efficacy was made with recording of morning and evening peak expiratory flow rates (PEF), respiratory symptoms, and use of rescue salbutamol. FEV1 was measured before and after nebulised salbutamol prior to randomisation and at the end of each treatment period.
                Morning PEF values were higher during the salmeterol than during the placebo period, although the mean treatment difference was small (12 l/min (95% confidence limits 6 to 17)). No difference in mean evening PEF values was found. Diurnal variation in PEF, assessed as the difference between the morning PEF and that of the previous evening, was more pronounced during the placebo than during the salmeterol period. The mean spirometric values (including reversibility in FEV1) obtained at the end of the two treatment periods were similar. Compared with placebo, treatment with salmeterol was associated with lower daytime and night time symptom scores and less use of rescue salbutamol both during the day and the night. The patients rated the treatment with salmeterol better than treatment with placebo.
                This study shows that, compared with placebo, treatment with salmeterol produces an improvement in respiratory symptoms and morning PEF values in patients with moderate to severe COPD. Treatment with long acting beta agonists may therefore result in an improvement in functional status, even in patients suffering from apparently nonreversible obstructive pulmonary disease.
This review shows that the treatment of patients with COPD with salmeterol 50 mcg produces modest increases in lung function. There were varying effects for other important outcomes such as health related quality of life or reduction in symptoms. However, there was a consistent reduction in exacerbations which may help people with COPD who suffer frequent deterioration of symptoms prompting healthcare utilisation. The strength of evidence for the use of salmeterol 100 mcg, formoterol 12 mcg, 18 mcg, 24 mcg was insufficient to provide clear indications for practice.