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The differential risk of pneumonia among inhaled corticosteroid (ICS) use in patients with COPD requires more investigation, especially regarding beclomethasone-containing inhalers. The goal of this study was to compare the risk and benefit profile of different ICS/long-acting βThis retrospective cohort study was conducted by using national health insurance claims data from the years 2009 to 2015 in Taiwan and included patients with COPD with new ICS/LABA use. Propensity score matching and Cox regression models were used to estimate the hazard ratios of severe pneumonia and acute exacerbation for different ICS/LABA users.Both budesonide/formoterol (BUD/FOR) dry-powder inhalers and beclomethasone/formoterol (BEC/FOR) metered-dose inhalers, compared with fluticasone propionate/salmeterol (FLU/SAL) delivered via the same device type, were associated with a lower risk of severe pneumonia (BUD/FOR hazard ratio [HR], 0.83 [95% CI, 0.70-0.98]; BEC/FOR HR, 0.69 [95% CI, 0.58-0.81]) and severe acute exacerbation (BUD/FOR HR, 0.88 [95% CI, 0.78-0.99]; BEC/FOR HR, 0.82 [95% CI, 0.72-0.93]). After additionally adjusting for the average daily ICS dose, BUD/FOR dry-powder inhaler users continued to have a significantly decreased risk of severe pneumonia (18%), although BEC/FOR metered-dose inhaler users did not. The results were consistent in most of the prespecified subgroups and across all the sensitivity analyses.This study augments the existing evidence concerning the different safety and effectiveness outcomes of ICS/LABA combinations in patients with COPD, which may be considered when making clinical treatment decisions.

Background The airway contains airway smooth muscle and airway vascular smooth muscle. The acute effects of inhaled long-acting β 2 -adrenergic agonists (LABAs) alone, or in combination with an inhaled glucocorticoid (ICS), on airway smooth muscle tone in asthma are known; however, to the best of our knowledge, their effect on airway vascular smooth muscle tone has not been investigated previously. The objective of this study was to investigate the immediate effects of a LABA and an ICS alone and in combination on airway blood flow (Qaw) as an index of airway vascular smooth muscle tone in patients with stable asthma. Methods Fourteen subjects with moderate asthma inhaled single doses of salmeterol (50 μg), fluticasone propionate (250 μg), salmeterol/fluticasone propionate (50/250 μg), or placebo; Qaw was measured before and serially for 240 min after drug administration. Results Mean Qaw increased after salmeterol and salmeterol/fluticasone propionate, with peaks at 60 min of 34% and 40%, respectively, and returned to baseline by 240 min after inhalation. Fluticasone propionate alone caused a transient decrease in mean Qaw. The maximal changes in Qaw, which occurred at different times, were 60% for salmeterol, 67% for salmeterol/fluticasone propionate, and −19% for fluticasone propionate ( P Conclusions The LABA salmeterol has an acute vasodilator action on the airway of subjects with stable asthma. The addition of fluticasone propionate, which by itself causes vasoconstriction, does not attenuate the salmeterol-induced vasodilation, suggesting that fluticasone propionate potentiates the vasodilator effect of salmeterol. The vasodilation could be of clinical benefit by promoting the vascular clearance of inflammatory mediators including spasmogens from the airway. Trial registry ClinicalTrials.gov ; No.: NCT01231230 ; URL: www.clinicaltrials.gov

Background Patients with mild persistent asthma constitute about 70% of the asthma population; thus, it is important to know which first-line treatment is best for the management of mild asthma. We compared benefits of first-line treatment with ciclesonide and a combination of fluticasone and salmeterol in patients with mild asthma. Methods Patients aged 12 to 75 years with mild persistent asthma were enrolled in a randomized, double-blind, placebo-controlled study. After run-in, patients were randomized to ciclesonide 160 μg once daily (CIC160), fluticasone propionate/salmeterol 100/50 μg bid (FP200/S100), or placebo for 52 weeks. The primary variable was time to first severe asthma exacerbation; the coprimary variable was the percentage of poorly controlled asthma days. Patients recorded asthma symptoms and salbutamol use in electronic diaries and completed a standardized version of the Asthma Quality of Life Questionnaire. Results Compared with placebo, the time to first severe asthma exacerbation was prolonged, and lung function was improved with FP200/S100 treatment ( P = .0002) but not with CIC160. Both CIC160 and FP200/S100 provided significantly fewer poorly controlled asthma days than placebo ( P ≤ .0016 for both active treatments). Moreover, both active treatments provided significantly more asthma symptom-free days ( P ≤ .0001), rescue medication-free days ( P = .0005, one-sided), and days with asthma control ( P ≤ .0033). Overall Asthma Quality of Life Questionnaire scores were significantly higher in both active treatment groups than placebo ( P ≤ .0017). Conclusions In mild asthma, FP200/S100 prolonged time to first severe asthma exacerbation, and CIC160 and FP200/S100 were clinically equieffective for most measures of asthma control. Trial registry ClinicalTrials.gov; No.: NCT00163358; URL: www.clinicaltrials.gov

Background The effect of the long acting β 2 -agonist/corticosteroid combination salmeterol-fluticasone propionate (SFC) on respiratory muscles and ventilation in severe COPD is unknown. As COPD hyperinflation worsens, diaphragm efficiency decreases, and a compensatory increase in chest wall inspiratory muscle activity occurs. If a bronchodilator successfully alleviates hyperinflation and improves diaphragm efficiency in severe COPD, then the extraordinary activation of the chest wall may be relieved. We examined directly the effect on the parasternal intercostal respiratory chest wall muscle and ventilation of four puffs of salmeterol 25 μg and fluticasone propionate 125 μg via the metered dose combination inhaler in 12 patients with severe Global Initiative on Obstructive Lung Disease stage III-IV COPD, mean FEV 1 = 0.91 L (32% predicted). Methods We measured parasternal intercostal electromyogram (EMG) recorded from implanted fine-wire electrodes, ventilation, and breathing pattern, during resting and CO 2 -stimulated breathing. Full pulmonary function tests were recorded at the beginning and end of the study. Results In this patient group, severe airflow obstruction and hyperinflation were poorly reversible after SFC: FEV 1 increased 4.2%, functional residual capacity decreased 1.4%, and inspiratory capacity increased 5.9%. However, with SFC there was a significant increase in minute ventilation, tidal volume, and mean inspiratory flow. There was a very large decrease in directly recorded parasternal EMG, with parasternal EMG disappearing completely in some patients after SFC. Conclusions In severe COPD, with minimal change in hyperinflation or pulmonary mechanics, salmeterol-fluticasone induced a significant decrease in activity of the chest wall parasternal inspiratory muscle. This may be of practical benefit to reverse the extensive use of the chest wall muscles and alleviate dyspnea in severe COPD.

Few studies of the efficacy and safety of therapy with combinations of salmeterol/fluticasone propionate (SFCs) have been conducted in Chinese patients with COPD, and the benefits of combination therapy in nonsmoking patients with COPD are, to our knowledge, not known.The aims were to establish the efficacy and tolerability of the therapy with SFC (salmeterol, 50 microg/fluticasone, 500 microg, twice daily) in the management of Chinese COPD patients and to investigate the effectiveness of SFC in nonsmokers with COPD.This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Changes in prebronchodilator and postbronchodilator FEV(1), quality of life determined by the St. George Respiratory Questionnaire (SGRQ) scores, relief bronchodilator use, nighttime awakenings, and frequency of exacerbations of COPD were measured in patients randomized to receive SFC (n = 297) or placebo (n = 148). Never-smokers, former smokers, and current smokers accounted for 11.7%, 66.7%, and 21.6%, respectively, of the study population.After 24 weeks, the mean changes in prebronchodilator and postbronchodilator FEV(1) were 180 mL (95% confidence interval [CI], approximately 91 to 268; p0.001) and 65 mL (95% CI, approximately 14 to 115; p = 0.012), respectively, greater for the SFC group than that for the placebo group. The differences in response to treatment were significant (all p0.0001) in former or current smokers but not in never-smokers (p0.05). The mean improvement in the total SGRQ score for the SFC group was 5.74 (p0.01) greater than that for the placebo group. SFC significantly reduced the frequency of nighttime awakenings and the use of relief bronchodilator. The adjusted ratio of exacerbations of COPD for the SFC group relative to the placebo group was 0.61 (95% CI, approximately 0.45 to 0.84; p0.01). There were no significant differences between the SFC and placebo groups in safety measures.SFC therapy achieved sustained improvement in lung function, quality of life, and control of symptoms, and was well tolerated in Chinese patients. Greater improvements in lung function were found only for COPD patients with a history of smoking.http://ctr.gsk.co.uk/Summary/fluticasone_salmeterol/studylist.asp Identifier: No. SCO100540.

Salmeterol (S) and montelukast (M) individually inhibit the obstructive consequences of thermal stimuli such as exercise and hyperventilation (HV), but there is no information on whether these drugs can interact positively.Randomized trial.University teaching hospital.Atopic asthmatic patients with sensitivity to thermal provocations.Eleven asthmatic patients generated stimulus-response curves to isocapnic HV while breathing frigid air without any interventions and then after pretreatment with 42 mug of S, 10 mg of M, and the combination. The order of testing was randomly determined.Minute ventilation (Ve) was increased in 20-L increments until FEV(1) fellor= 15%. Measurements were obtained before and 1 h after drug administration, and then again 5 min after each bout of HV. In the nonintervention trial, the provocation commenced after the patients presented to the laboratory. In the control challenge, the mean (+/- SEM) FEV(1) decreased 24.6 +/- 1.7% from baseline. S and M both increased the mean prechallenge FEV(1) significantly (S, 10.4 +/- 1.7% [p0.01]; M, 4.1 +/- 1.3% [p = 0.02]; S + M, p = 0.01). The combination of S + M produced greater bronchodilatation (mean improvement, 12.4 +/- 2.3%) than M alone (p = 0.004), but not greater than S alone (p = 0.80). Both drugs blunted the obstructive response similarly (protection: M, 34.6 +/- 15.1%; S, 60 +/- 8.7%; p = 0.13). The benefits added arithmetically with the combined regimen (protection with S + M, 84.9 +/- 5.5%; p = 0.01 vs S alone; p = 0.003 vs M alone).These data indicate that the concurrent administration of single standard doses of S and M appears to provide greater protection against thermal stimuli than does either drug alone. Further experimentation will be required to ascertain whether the combination will provide additional clinical benefits to patients over those of the single agents.

Bronchodilators form the foundation of symptomatic treatment of COPD. Several long-acting bronchodilators are now available for use in COPD, but publications of large-scale studies of their efficacy have, for the most part, postdated the publication of major clinical guidelines. This article provides a critical review of large (or =50 patients), double-blind, clinical trials of three long-acting bronchodilators in COPD (the once-daily anticholinergic tiotropium, and the twice-daily beta(2)-agonists formoterol and salmeterol) within the context of the objectives of treatment defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Fourteen published studies were identified, of which 12 studies were published since the release of the GOLD guidelines. All three long-acting bronchodilators were found to effectively improve lung function; however, they differed in their effects on outcomes other than bronchodilation, with salmeterol demonstrating inconsistent efficacy compared with placebo in preventing exacerbations and improving health status, and only tiotropium demonstrating consistent superiority to the short-acting bronchodilator ipratropium. Based on this review, a treatment algorithm for the introduction of long-acting bronchodilators to patients with COPD is proposed, which includes the use of long-acting bronchodilators early in the treatment algorithm.

Study objectives: To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting β 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. Design: Randomized, double-blind, multicenter, placebo-controlled study. Setting: Seventy-six investigative sites in the United States. Patients Seven hundred twenty-three patients ≥ 40 years of age with COPD and a mean baseline FEV 1 of 42% predicted. Interventions: FP (250 μg), SM (50 μg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks. Measurements: 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. Results: At Endpoint ( ie , the last on-treatment, post-baseline assessment), treatment with FSC significantly (p ≤ 0.012) increased the morning predose FEV 1 (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p ≤ 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 ≤ 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. Conclusions: Treatment with FSC (FP, 250 μg, and SM, 50 μg) 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.

Background Patients with COPD have an increased risk of cardiovascular disease. Despite the clinical benefits of long-acting β-agonist agents in the treatment of COPD, patients may be at an increased risk of cardiovascular toxicity, including tachyarrhythmia due to β-adrenergic stimulation. Objective To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data. Design Randomized, double-blind, parallel group, multiple-dose studies, which included salmeterol, 50 μg bid, and placebo arms. Study selection Seven of a total of 17 studies met the predefined inclusion requirements and were pooled. A total of 1,443 patients received placebo, while 1,410 patients received salmeterol, 50 μg bid. The median duration of treatment was 24 weeks (range, 12 to 52 weeks). Results Treatment with salmeterol, 50 μg bid, showed no increased risk of cardiovascular adverse events (AEs) compared with placebo (relative risk, 1.03; 95% confidence interval, 0.8 to 1.3; p = 0.838). Both groups had a similar incidence of cardiovascular events (8%), including cardiovascular deaths. The incidence of cardiovascular AEs increased with age, concurrent cardiovascular conditions, and treatment with antiarrhythmic/bradycardic agents, although increases were comparable in both treatment groups. There were no episodes of sustained ventricular tachycardia, and no clinically significant differences were observed in 24-h heart rate, ventricular and supraventricular ectopic events, qualitative ECGs, QT intervals, or vital signs between the salmeterol, 50 μg bid, group and the placebo group. Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease. Conclusions Treatment with salmeterol, 50 μg bid, does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo.

Objective Using a model of natural allergen exposure, we examined the effect of regular treatment with salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO). Design Double-blind, randomized, parallel-group study. Setting Specialist allergy unit in a university hospital. Patients Asthmatic patients sensitized to pollen allergens were randomly allocated to monotherapy with salmeterol (n = 14) or placebo (n = 13). Interventions Salmeterol, 25 μg, and placebo inhalers, two puffs bid, for 6 weeks. Measurements Spirometry, the level of a provocative concentration of a substance (methacholine) causing a 20% fall in FEV 1 (PC 20 ), the PC 20 level for adenosine 5′-monophosphate (AMP), and ENO were measured before the pollen season and were repeated at the height of the pollen season after 6 weeks of treatment with salmeterol or placebo. Results The decrease in FEV 1 during the pollen season was significantly larger in the placebo group than in the salmeterol group, the mean difference in the change between the groups being 0.20 L (95% confidence interval, 0.03 to 0.35; p = 0.047). Changes in PC 20 for methacholine, PC 20 for AMP, and ENO levels were not significantly different between treatment groups. However, a mean (± SEM) decrease in the PC 20 for methacholine of −1.0 ± 0.4 doubling concentrations was observed within the placebo group (p = 0.03), whereas no significant changes were observed within the salmeterol group. A significant decrease in PC 20 for AMP (doubling concentrations) was observed within the placebo group (−2.1 ± 0.6; p = 0.003) and the salmeterol group (−1.5 ± 0.4; p = 0.003). ENO concentrations increased significantly among the placebo and the salmeterol groups during natural pollen exposure. Conclusion These observations indicate that natural allergen exposure and the regular use of salmeterol are not associated with a greater increase in ENO and airway responsiveness than allergen exposure alone.

Background: Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. Methods: A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 g once daily via dry-powder inhaler, compared with salmeterol, 50 g bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George’s Respiratory Questionnaire (SGRQ). Results: A total of 623 patients participated (tiotropium, n 209; salmeterol, n 213; and placebo, n 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV1 (mean, 1.08 0.37 L; percent predicted, 40 12% [ SD]). Compared with placebo treatment, the mean predose morning FEV1 following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV1 (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, 5.14 U (p < 0.05 vs placebo); salmeterol, 3.54 U (p 0.4 vs placebo); and placebo, 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). Conclusions: Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD. (CHEST 2002; 122:47–55)

The role of tiotropium for the treatment of asthma has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium in patients with asthma.Randomized placebo-controlled trials were included. Primary outcomes were peak and trough FEV1 and morning and evening peak expiratory flow (PEF).Thirteen studies (4,966 patients) were included. Three different therapeutic protocols were identified. Tiotropium as an add-on to inhaled corticosteroids (ICSs) showed statistically and clinically significant increases in PEF (22-24 L/min) and FEV1 (140-150 mL). Additionally, tiotropium decreased the rate of exacerbations (number needed to treat for benefit [NNTB], 36) and improved asthma control. The use of tiotropium in patients poorly controlled despite the use of medium to high doses of ICS was not inferior to salmeterol. Finally, the use of tiotropium as an add-on to ICS/salmeterol combination increased pulmonary function to a clinically significant magnitude, reduced asthma exacerbations (relative risk, 0.70; 95% CI, 0.53-0.94; P.02; I2 = 0%; NNTB, 17), and improved asthma control compared with ICS/salmeterol. Tiotropium was well tolerated, and no potential safety signals were observed.Tiotropium resulted noninferiorly to salmeterol and superiorly to placebo in patients with moderate to severe asthma who were not adequately controlled by ICS or ICS/salmeterol. Major benefits were concentrated in the increase in lung function and in the case of patients with severe asthma, in the reduction of exacerbations.

Background Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied. Objectives To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD. Methods Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20μ g/mL), patients were randomly assigned to receive salmeterol (42μ g bid) plus theophylline, salmeterol (42 μg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires. Results All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p ≤ 0.045) greater improvements in pulmonary function; significantly (p ≤ 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p ≤ 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar. Conclusion Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.

To assess whether the withdrawal of salmeterol treatment for 3 days (72 h) can restore its bronchoprotective ability on specific bronchial provocative test (sBPT) with allergen, which was completely lost after 1 week of regular treatment with salmeterol.Single-blind design.We investigated 10 nonsmoking subjects (8 men and 2 women; mean +/- SD age, 24 +/- 8 years) with mild intermittent allergic asthma in the stable phase of the disease, who were never previously treated with regular beta(2)-agonists. Subjects with a previous positive early airway response (EAR) to a screening allergen challenge were considered. They underwent sBPT with allergen after a single dose of inhaled salmeterol, 50 microg (T(1)), and then underwent sBPT after 1 week of regular treatment with inhaled salmeterol, 50 microg bid (T(2)); after that, they continued inhaled salmeterol treatment for 4 days, and then changed to inhaled salmeterol with placebo (two puffs bid) for 3 days (72 h) and underwent sBPT with allergen after a single dose of salmeterol, 50 microg (T(3)).EAR to allergen (DeltaFEV(1)or = 20% with respect to postdiluent value) was completely abolished by a single dose of salmeterol (T(1); protection index [PI]or = 50% in all subjects), but it was still present after 1 week of regular treatment with salmeterol (T(2); PI50% in all subjects). The maximum FEV(1) percentage fall during sBPT with allergen was significantly lower after withdrawal of regular inhaled salmeterol (T(3)) than after regular treatment with salmeterol (T(2)) (mean, 23% vs 29.5%; range, 4 to 41% vs 18 to 49%, respectively; p0.05); a similar result was obtained considering the PI of salmeterol on sBPT with allergen (mean, 44% vs 20%; range, 2 to 86% vs - 11 to 49%, respectively; p0.05). However, the maximum FEV(1) percentage fall and PI were significantly different in T(3) than after T(1), and only 4 of 10 patients showed in T(3) a PIor = 50%.The bronchoprotective effect of salmeterol on allergen-induced EAR, completely lost after 1 week of regular treatment with salmeterol, may be partially restored by the withdrawal of salmeterol therapy for 3 days (72 h). However, this withdrawal time period is not sufficient to recover the baseline bronchoprotective efficacy of the first dose of salmeterol.

Dyspnea is a common complaint during daily activities in patients with advanced COPD. The mechanisms underlying dyspnea and the appropriate treatment strategies to relieve it are still not totally understood. We hypothesized that the perception of dyspnea (POD) may be modified by the accumulative effect of bronchodilator therapy, exercise, and inspiratory muscle training (IMT).Spirometry, submaximal exercise performance, inspiratory muscle strength and endurance, and the POD were assessed before and following three consecutive 6-week periods of therapy with a long-acting bronchodilator (LABD), the LABD plus exercise, and the LABD plus exercise plus IMT in 30 patients with moderate-to-severe COPD.There was a small, statistically insignificant, increase in FEV(1) in the study group (mean [+/- SEM] increase, 1.42+/-0.3 to 1.49+/-0.4 L) following the LABD therapy period, and no additional increase following the two other periods of therapy. There was a significant increase (p0.05) in the 6-min walk distance following the therapy period with the LABD plus exercise (mean increase, 252+/-41 to 294+/-47 m) and an additional small increase following the therapy period with the LABD plus exercise plus IMT period (mean increase, 252+/-41 to 302+/-49 m). The decrease in the POD was small and statistically not significant following the therapy periods with the LABD and the LABD plus exercise. The major and statistically significant decrease in the POD was noted following the therapy period with the LABD plus exercise plus IMT.In patients with moderate-to-severe COPD, following sequential periods of therapy with the LABD, the LABD plus exercise, and the LABD plus exercise plus IMT, there is a cumulative benefit in the POD. The most significant improvement was associated with IMT and not with the LABD and exercise training. The FEV(1) was moderately increased following the therapy period with the LABD, and the addition of exercise has most affected the 6-min walk distance.

Study objectives: To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma. Design: A prospective, double-blind, randomized placebo-controlled trial. Setting: Medical wards of a large university-based hospital. Patients: Forty-three patients admitted for an acute exacerbation of asthma. Interventions: Salmeterol (42 mg) or two puffs of placebo every 12 h in addition to standard therapy (short-acting b-agonists, corticosteroids, and anticholinergic agents). Results: No clinically adverse effects were seen with the addition of salmeterol to conventional therapy. After salmeterol, there was no difference in pulse, respiratory rate, oxygen saturation by pulse oximetry, severity of symptoms, or dyspnea score. Patients receiving salmeterol had greater FEV1 percent improvements than the placebo group at 12, 24, 36, and 48 h. These findings were not statistically significant. By paired Student’s t tests, there were significant improvements in FEV1 (p 5 0.03) and FVC (p 5 0.03) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group. In a subgroup analysis of patients with an initial FEV1 < 1.5 L, the absolute FEV1 percent improvement for salmeterol vs placebo was 51% vs 16% at 24 h and 54% vs 40% at 48 h. The relative FEV1 percent improvement for salmeterol vs placebo was 17% vs 8% at 24 h and 18% vs 14% at 48 h. Conclusion: The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma. Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma. (CHEST 2000; 118:313‐320)

We wished to evaluate whether the combination of a leukotriene receptor antagonist and long-acting beta(2)-agonist might confer additive beneficial effects in terms of bronchoprotection and bronchodilatation, in mild to moderate asthmatic patients who were suboptimally controlled on inhaled corticosteroids alone.Twelve asthmatic patients were enrolled into a single-blind, placebo-controlled, crossover study, receiving additive therapy as either of the following: (1) montelukast alone, 10 mg (ML(10)); (2) inhaled salmeterol alone, 50 microg (SM(50)); (3) ML(10) and SM(50); (4) ML(10) and inhaled salmeterol, 100 microg (SM(100)); or (5) placebo inhaler and tablet. Trough measurements were made of adenosine monophosphate (AMP) bronchial challenge (the provocative concentration of a drug [AMP] causing a fall of/= 20% in FEV(1) [PC(20)]) as the primary end point, and spirometry, following single doses of either placebo or active treatments (12 h after salmeterol, and 24 h after monteleukast, respectively).Compared to placebo, all active treatments led to significant improvements (p0.05) in geometric mean AMP-PC(20): placebo, 42 mg/mL; ML(10), 106 mg/mL; SM(50), 115 mg/mL; ML(10) and SM(50), 183 mg/mL; and ML(10) and SM(100), 247 mg/mL. The effects of montelukast and salmeterol were numerically additive, with ML(10) and SM(100) being significantly different (p0.05) from ML(10) alone. For mean FEV(1) and forced expiratory flow rate between 25% and 75% of vital capacity, there were significant differences (p0.05) between both combination therapies vs ML(10) alone.Our results suggest additive benefits of a single dose of a long-acting beta(2)-agonist and leukotriene antagonist, in terms of bronchoprotection and bronchodilation. Further studies in more severe asthmatics are required to evaluate long-term clinical effects.

Study objective Isolated case reports of asthmatic fatalities accompanied by the use of salmeterol have raised the question whether a paradoxical effect of salmeterol or its vehicle on the airways might contribute to these fatalities. We questioned whether salmeterol′s solvent, xinafoic acid, has detrimental effects on the tone of airways or on β-adrenoceptor binding. Materials and methods Basenji-greyhound dogs were anesthetized and their peripheral airways challenged with xinafoic acid via a wedged bronchoscope technique. Radioligand binding assays were performed in lung membranes prepared from these dogs. Results In contrast to a methacholine control, xinafoic acid (0.001 to 1.0 mg/mL) aerosolized into the peripheral airways of anesthetized dogs did not increase airway resistance. Xinafoate alone had no significant effect on the specific binding of 125 I-cyanopindolol to lung membranes and did not affect the affinity of salmeterol for theβ -adrenoceptor in the absence or presence of xinafoate, respectively (−log concentration that inhibits 50% [IC 50 ] of the high-affinity site, 7.7 ± 0.15 and 7.9 ± 0.27; −log IC 50 of the low-affinity site = 5.6 ± 0.44 and 5.3 ± 0.28 [n = 4]). Conclusion These findings suggest that xinafoic acid, the solvent for salmeterol, does not have direct airway irritant effects, does not bind to β-adrenoceptors, and does not impair the binding of salmeterol to β-adrenoceptors. Thus, xinafoate is unlikely to contribute to the worsening of airway symptoms in asthmatics using salmeterol xinafoate.

Background Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations. However, the influence of asthma medication on the ability to perceive symptoms is still to be documented. This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction (MIB) in subjects with mild asthma, using inhaled salbutamol on an “as required” basis (n= 15), and in subjects with moderate asthma, using daily inhaled beclomethasone (mean daily dose, 640 μg; n=15) in addition to salbutamol to control their asthma. Methods Methacholine challenges (MC) were performed at entry into the study, and then before, 1, and 12 h following inhalation of 50 μg of salmeterol or a placebo, after a 15-day baseline period; and after 4 weeks of twice daily use of those treatments. The measurements were then repeated with the alternate treatment after a 15-day washout period. Finally, a last MC was performed after another 15-day washout period. For each MC, the perception score of bronchoconstriction-associated breathlessness at 20% fall in FEV 1 (PS 20 ) was evaluated on a modified Borg scale from 0 to 10. Results Subjects using regular beclomethasone had a higher baseline PS 20 than those using only salbutamol (means: 3.06±0.06 and 2.01 ±0.07, p=0.0001). Short- and long-term use of salmeterol did not change significantly the PS 20 compared with placebo (p>0.05) in either group (with or without corticosteroid). Although there were some intraindividual variations, mean PS 20 did not vary significantly throughout the study. Conclusion These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol. Patients using inhaled corticosteroids show a greater perception of MIB.

There are several reports of documented adverse cardiac effects during treatment with beta-agonists. Since one should be aware that this may be a problem in patients with preexisting cardiac disorders, we have conducted a randomized, single-blind, balanced, crossover, placebo-controlled study to assess the cardiac effects of two single doses of formoterol (12 microg and 24 microg) and one single dose of salmeterol (50 microg) in 12 patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia (PaO260 mm Hg).Each patient was evaluated at a screening visit that included spirometry, blood gas analysis, plasma potassium measurement, and 12-lead ECG. In following nonconsecutive days, all patients underwent Holter monitoring 24 h during each of the four treatments. Holter monitoring was started soon before drug administration in the morning. Plasma potassium level was measured before drug inhalation, at 2-h intervals for 6 h, and at 9, 12, and 24 h following administration. None of our patients took rescue medication during the 24-h period.Holter monitoring showed a heart rate higher after formoterol, 24 microg, than after formoterol, 12 microg, and salmeterol, 50 microg, and supraventricular or ventricular premature beats more often after formoterol, 24 microg. Formoterol, 24 microg, significantly reduced plasma potassium level for 9 h when compared with placebo, whereas formoterol, 12 microg, was different after 2 h and salmeterol, 50 microg, from 4 to 6 h.The results of this study suggest that if a COPD patient is suffering from preexisting cardiac arrhythmias and hypoxemia, long-acting beta-agonists may have adverse effects on the myocardium, although the recommended single dose of salmeterol and formoterol, 12 microg, allows a higher safety margin than formoterol, 24 microg.

Objective To review the pharmacology of the long-acting inhaled β 2 -agonists, salmeterol and formoterol, summarize results of their clinical trials, evaluate their safety records, and discuss their roles in the treatment of asthma. Data sources Preclinical and clinical studies involving salmeterol or formoterol were identified by a MEDLINE search, weekly computerized literature updates, and manual searches. Studies of satisfactory quality were chosen for review. Data synthesis Salmeterol and formoterol are potent and selective β 2 -adrenoceptor agonists with durations of action > 12 h. Their major differences are that formoterol has a rapid onset of action and is a partial agonist of high intrinsic efficacy, whereas salmeterol has a delayed onset and is a partial agonist of low intrinsic efficacy. Twice daily use of either drug results in improved lung function, reduced symptoms, and a better quality of life. These agents protect against exercise-induced asthma for 12 h and eliminate nighttime awakening in most patients. Limited tolerance develops, especially to their bronchoprotective effects, but their improvement of lung function is sustained. Conclusions Regular use of salmeterol or formoterol provides subjective and objective amelioration of asthma in patients experiencing excessive symptoms or physiologic impairment despite the regular administration of low doses of inhaled corticosteroids (equivalent to approximately 500 μg/d of beclomethasone). Intermittent use of either long-acting β 2 -agonist can provide prolonged protection against exercise-induced asthma or nighttime symptoms. Patients should be instructed to continue taking inhaled steroids when long-acting β 2 -agonists are administered on a regular schedule and to not take long-acting β 2 -agonists between regularly scheduled doses. Used properly, they are effective and safe adjunctive agents in the treatment of asthma.

Study objective To determine the efficacy of salmeterol alone in a group of patients with moderate asthma with nocturnal worsening of symptoms. Design Double-blind, randomized, placebo-controlled crossover study. Setting Tertiary care hospital specializing in respiratory diseases. Participants Ten patients with nocturnal asthma. Interventions Subjects were randomized to salmeterol, 100 µg twice daily, or placebo for 6 weeks with a 1-week washout between treatment periods. Symptoms, nocturnal awakenings, and β 2 -agonist use were recorded daily. Spirometry was performed at weeks 1 and 6 of each period at bedtime and at 4 AM, and methacholine challenge was performed at 4 AM followed by bronchoscopy with BAL. BAL fluid analysis included cell count and differential count, eosinophil cationic protein, Charcot-Leyden crystal protein, leukotriene B 4 , and thromboxane B 2 . Results The percentage of nights with awakenings decreased significantly with salmeterol (69.8±8.7% vs 30.6±10.8% for placebo and salmeterol, respectively; p=0.02). The percentage of 24-h days with supplemental inhaled β 2 -agonist use significantly decreased with salmeterol (85.9±9.4% vs 70.4±10.1% for placebo and salmeterol, respectively; p=0.04). There were no significant differences in bronchial reactivity, 4 AM FEV 1 , overnight percentage change in FEV 1 , or indexes of airway inflammation. Conclusions Salmeterol alone improves the number of nocturnal awakenings and supplemental 24-h β 2 -agonist use in nocturnal asthma without significantly altering lung function and airway inflammation.

This study tested the capability of a single 42-microgram dose of inhaled salmeterol xinafoate, a long-acting beta 2-agonist, to protect against bronchoconstrictive effects of exposure to 0.75 ppm sulfur dioxide (SO2) during exercise, for up to 24 h. Ten SO2-responsive adult volunteers with stable asthma were studied under 4 conditions of drug pretreatment/exposure, administered in random order, double-blind: salmeterol/SO2, placebo/SO2, salmeterol/clean air, and placebo/clean air. Each subject underwent 10-min exposure/exercise challenges in a chamber 1, 12, 18, and 24 h after pretreatment. Exercise ventilation rates averaged 29 L/min. Response was measured as the decrement in FEV1 between preexposure and postexposure (lowest value within 30 min). After salmeterol, mean decrement post-SO2 was 7% at 1 h and 12% at 12 h. At 18 and 24 h after salmeterol, and at all times after placebo, mean decrements were 25 to 30%. After 18 and 24 h, salmeterol still improved base-line FEV1 relative to placebo, although improvement was not statistically significant at 24 h. Acute symptom increases accompanied FEV1 decrements.In our asthmatic subjects, pretreatment with salmeterol imparted clinically and statistically significant (p0.01) protection against bronchoconstriction induced by SO2/exercise for at least 12 h, and maintained an improvement in lung function for as much as 18 h.

A dose-ranging study was conducted to evaluate the efficacy and safety of a new long-acting, selective beta 2-adrenoceptor agonist, salmeterol.Adolescents and adults (N = 160) with mild-to-moderate asthma received salmeterol (10.5, 21, 42, or 84 micrograms) or placebo by metered-dose inhaler twice daily for 1 week. Twelve-hour serial spirometry measurements were performed on the first and last days of treatment, and patients recorded their peak expiratory flow (PEF) twice daily on diary cards.On day 1, salmeterol produced greater bronchodilation than placebo (p = 0.001), and both the 42-micrograms and 84-micrograms doses of salmeterol were significantly more effective in improving FEV1 responses than the two lower doses of salmeterol (p0.05). After 1 week of treatment, all but the 21-micrograms dose of salmeterol remained statistically superior to placebo (p0.01), but significant differences between salmeterol doses were no longer evident, despite an apparent dose-response effect. Only the 42-micrograms and 84-micrograms doses of salmeterol sustained bronchodilation for 12 h in the majority of patients at both treatment days. The degree of improvement in morning and evening PEF was also found to be dose related. There was no significant difference among treatment groups in the overall incidence of adverse events; however, pharmacologically predictable events (eg, tremor) occurred significantly more often with salmeterol, 84 micrograms.Salmeterol, 42 micrograms, was similar in efficacy to 84 micrograms but was associated with a lower incidence of adverse events. Salmeterol, 42 micrograms twice daily, is a safe and effective dosage for patients with mild-to-moderate asthma who are persistently symptomatic and require maintenance bronchodilator therapy.

Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids (ICSs). Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD. We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study.This was a 2-year, double-blind, double-dummy parallel study of 1,323 patients randomized to salmeterol/fluticasone propionate 50/500 μg bid (SFC) or tiotropium 18 μg once daily (Tio). Baseline demographics, including serum C-reactive protein (CRP) levels, were measured, and daily record cards (DRCs) were completed.We identified 87 pneumonia reports from adverse event records (SFC=62; Tio=25) in 74 patients (SFC=50; Tio=24), compared with 2,255 exacerbations (SFC=1,185; Tio=1,070). Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level10 mg/L. Numbers of de novo pneumonias (events that were not preceded by symptoms of an exacerbation) were similar between treatment groups, but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs (SFC=32; Tio=7). Similar results were seen when analysis was confined to radiologically confirmed events.Pneumonia is much less frequent than exacerbation in COPD. The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations. Earlier identification and treatment of these events to prevent pneumonia merits further investigation.ClinicalTrials.gov; No.: NCT00361959; Study No.: SC040036; URL: clinicaltrials.gov.

Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study.A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 microg), FP (500 microg), or SFC (SAL 50 microg/FP 500 microg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded.At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was -3.1% for placebo, -1.7% for SAL, -2.9% for FP, and -3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, -0.3%, and -0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%).Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo.ClinicalTrials.gov Identifier: NTC00268216.

Despite 20 years of debate, several US Food and Drug Administration (FDA) hearings, black-box warnings, and many descriptive articles and metaanalyses, controversy regarding the safety of long-acting beta-agonist (LABA) treatment in asthma patients continues. This has resulted in a recent call for another large and definitive safety study. This commentary focuses first on data provided in the metaanalysis recently undertaken by the FDA of safety outcomes among 60,954 individuals in 110 LABA trials, and second on the sample size that would be required for a new definitive study of LABA safety in the presence of mandatory treatment with an inhaled corticosteroid (ICS). A critical stratified analysis in the FDA report involving 15,192 individuals indicates that a LABA used with mandatory ICS therapy was not associated with an increased risk of asthma-related mortality, intubations, or exacerbations (risk difference [RD], 0.25 per 1,000 individuals; 95% confidence interval [CI], -1.69 to 2.18). Using the same stratified data to calculate the sample size required to prove or disprove an association between the use of LABA with mandatory ICS therapy and adverse outcomes, assuming the RD is exactly 0.25, and ignoring the 95% CI, which includes 0.0 or even a negative risk, such a study is both logistically and scientifically impossible. A new study is not practicable, nor is one needed in the light of current analyses of existing data. It is time to learn from the past, to rigorously avoid LABA monotherapy in asthma, and to use a LABA (when indicated) always in mandatory combination with appropriate doses of an ICS.

A 6-week, multicenter, randomized, double-blind, parallel-group study was conducted in patients with COPD to compare lung function improvements of tiotropium, 18 microg qd, plus formoterol, 12 microg bid, to salmeterol, 50 microg bid, plus fluticasone, 500 microg bid.Following a screening visit, subjects entered a run-in period in which they received regular ipratropium. At randomization, patients were assigned to either tiotropium plus formoterol or salmeterol plus fluticasone. After 6 weeks of treatment, a 12-h lung function profile was obtained. The coprimary end points were FEV(1) area under the curve for the time period 0 to 12 h (AUC(0-12)) and peak FEV(1).A total of 729 patients were screened, and 605 patients were randomized and treated. A total of 592 patients (baseline FEV(1), 1.32 +/- 0.43 L/min [+/-SD]) were included in the analysis. After 6 weeks, the 12-h lung function profiles in the group receiving tiotropium plus formoterol were superior to those in the group receiving salmeterol plus fluticasone (mean difference in FEV(1) AUC(0-12), 78 mL [p = 0.0006]; mean difference in FVC AUC(0-12), 173 mL, p0.0001). Also, peak responses were in favor of tiotropium plus formoterol (difference in peak FEV(1), 103 mL [p0.0001]; difference in peak FVC, 214 mL [p0.0001]), as were FEV(1) and FVC at each individual time point after dose (p0.05). Predose FVC was significantly higher with the bronchodilator combination, while predose FEV(1) and rescue medication use did not differ significantly between groups. Both treatments were well tolerated.Tiotropium plus formoterol was superior in lung function over the day compared to salmeterol plus fluticasone in patients with moderate COPD. Long-term studies in patients with severe COPD are warranted to assess the relative efficacy of different treatment combinations.Clinicaltrials.gov Identifier: NCT00239421.

ackground and objective: It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls. Methods: A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV1 following exercise (ΔFEV1). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 μg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum ΔFEV1 at 2 h postdose. Secondary end points included maximum ΔFEV1 at the two later time points, and other measures (including recovery time and need for β-agonist rescue) at all time points. Results: The maximum ΔFEV1 magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [± SE], 13.2 ± 1.2%, 11.7 ± 1.2%, and 10.0 ± 1.1% vs 21.8 ± 1.2%, 16.8 ± 1.3%, and 14.0 ± 1.1%, respectively; p ≤ 0.001, < 0.01, and < 0.05). All secondary end point results supported the primary end point. Montelukast and salmeterol had similar efficacy at 2 and 8.5 h, but only montelukast was effective at 24 h. Conclusion: Montelukast provided significant protection against EIB having an onset within 2 h following a single oral dose and lasting for at least 24 h.

Study objective To compare the safety of salmeterol xinafoate or placebo added to usual asthma care. Design A 28-week, randomized, 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 β 2 -agonist use were excluded. Interventions Salmeterol, 42 μg 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 subpopulation: 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.

To examine the effect of fluticasone propionate, 250 microg/salmeterol, 50 microg combination (FSC 250/50) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD.This was a randomized, double-blind, parallel-group study.Eligible patients wereor = 40 years old with a diagnosis of COPD, prealbuterol FEV(1)70% of predicted, FEV1/FVC ratioor = 0.70, and functional residual capacity (FRC)or = 120% of predicted normal.Patients were randomized to FSC 250/50; salmeterol, 50 microg; or placebo twice daily for 8 weeks. Predose and postdose spirometry, plethysmography, and constant-load cycle cardiopulmonary exercise test evaluations were compared. The primary comparison was FSC 250/50 with placebo. The salmeterol group was included for exploratory comparisons with FSC 250/50.A total of 185 patients (mean baseline FEV1 of 41% predicted) were enrolled. At rest, FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity (IC) compared with placebo (differences of - 0.35 +/- 0.12 L and 0.33 +/- 0.06 L [mean +/- SE], respectively, at week 8; por = 0.003) and increased exercise endurance time (difference, 132 +/- 45 s; p = 0.004). At a standardized time during exercise (isotime), FSC 250/50 increased postdose IC by 0.20 +/- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation (p0.05 vs placebo at week 8). Improvement in exercise time was significantly correlated with the increase in IC (r = 0.45, p0.001) but not FEV1 (r = 0.23, p = 0.08). Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50.We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo.

Cigarette smoking has been associated with impaired endothelium-dependent relaxation responses in the brachial and coronary arteries (endothelial dysfunction). The aim of the present study was to determine whether the airway circulation is also affected and whether pharmacologic treatment has an effect on endothelial function in patients with COPD.Airway blood flow (Qaw) responses to therapy with inhaled albuterol, which causes endothelium-dependent vasodilation, were measured with a noninvasive soluble-gas-uptake technique in age-matched healthy current smokers (n = 10), healthy ex-smokers (n = 10), ex-smokers with COPD (n = 10), and healthy lifetime nonsmokers. In the ex-smokers with COPD, the albuterol responsiveness measurement was repeated after 4 weeks of treatment with fluticasone/salmeterol and after a drug washout period of 4 or 8 weeks.The mean (+/- SE) baseline Qaw values ranged between 40.7 +/- 3.9 and 50.9 +/- 2.8 microL/min/mL anatomic dead space in the four groups (differences were not significant). The mean FEV(1) was 53.4 +/- 2.3% predicted in the ex-smokers with COPD. Albuterol inhalation increased mean Qaw significantly in lifetime nonsmokers (50.1 +/- 8.3% predicted; p0.05) and healthy ex-smokers (37.2 +/- 3.4% predicted; p0.05), but not in healthy current smokers (13.9 +/- 3.2% predicted; difference was not significant) and ex-smokers with COPD (9.7 +/- 4.5% predicted; difference was not significant). While fluticasone/salmeterol did not change Qaw significantly, it restored albuterol responsiveness (67.6 +/- 11.1% predicted; p0.05) in the ex-smokers with COPD; this effect was no longer seen after the drug washout period.Cigarette smoking is associated with a blunted vasodilator response to inhaled albuterol in the airway as an expression of endothelial dysfunction, with a partial recovery of albuterol responsiveness after smoking cessation in healthy ex-smokers but not in ex-smokers with COPD. In the latter group, combined glucocorticoid/long-acting beta(2)-adrenergic agonist treatment restores albuterol responsiveness. The role of endothelial dysfunction in the physiopathology of COPD remains to be examined.

To compare the safety of salmeterol xinafoate or placebo added to usual asthma care.A 28-week, randomized, double-blind, placebo-controlled, observational study.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.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.Salmeterol, 42 mug bid via metered-dose inhaler (MDI), and placebo bid via MDI.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 subpopulation: 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.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.

We measured tracheal mucus velocity (TMV), a marker of mucociliary clearance (MCC), in sheep before and for 12 h after treatment with salmeterol, albuterol, ipratropium, or vehicle to determine the effects on normal MCC. We also determined if these agents could reverse the depression in TMV caused by inhaled human neutrophil elastase (HNE), a model of abnormal MCC.Study 1: TMV was measured initially and then for 6 h after metered-dose inhaler treatment with salmeterol (42 microg), albuterol (180 microg), ipratropium bromide (36 microg), or vehicle. After 6 h, the sheep in the albuterol and ipratropium treatment arms were administered a second dose of drug, whereas the salmeterol and vehicle treatment arms received vehicle. TMV was measured for another 6 h. Study 2: Six sheep inhaled HNE aerosol, which significantly reduced TMV by 2 h. At this point, the sheep were treated with either salmeterol, albuterol, ipratropium, or vehicle, and the effects on TMV were measured for another 6 h. This experiment was repeated in four sheep using only salmeterol and albuterol, but the posttreatment measurements were extended to 12 h.Study 1: Only salmeterol and albuterol increased TMV (p0.05) during the initial 6-h period. From 6 to 12 h only, the salmeterol-treated sheep had TMV that remained at or above the initial TMV for the entire time, although both albuterol and ipratropium showed enhancement of TMV compared to vehicle. Study 2: Salmeterol and albuterol reversed the HNE-induced depression in TMV to a similar degree over the 6-h time course. However, the protection afforded by salmeterol was more prolonged than that seen with albuterol if the posttreatment interval was extended to 12 h. Ipratropium and vehicle had no effect.We conclude that salmeterol and albuterol can stimulate normal MCC and reverse HNE-induced mucociliary dysfunction and that salmeterol has a longer duration of action in these models of normal and abnormal MCC.

Background Exposure in a swine house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects. Study objectives The aim was to investigate whether a long-acting β 2 -agonist, salmeterol, alters the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust in a swine barn. Design and subjects The study includes three separate parts. In the first part (part 1), healthy subjects inhaled salmeterol (50 μg bid, n = 8) or placebo (n = 8) over 2 weeks. In part 2, healthy subjects inhaled one single dose of salmeterol (100 μg, n = 6) or placebo (n = 6) 1 h prior to exposure in a swine barn, which was followed by a bronchial methacholine challenge. In part 3, eight healthy individuals inhaled placebo or salmeterol (100 μg), 2 h or 8 h prior to a bronchial methacholine provocation, without being exposed in the swine barn. Results Exposure caused an increase of bronchial responsiveness to methacholine by 3.2 doubling concentration steps (25 to 75th percentiles, 2.8 to 4.1) and 2.6 doubling concentration steps (25 to 75th percentiles, 1.4 to 3.7) in the placebo and salmeterol groups (2 weeks), respectively, with no significant differences between the groups (p = 0.3; part 1). Similar results were obtained when salmeterol was administered as a single dose (part 2) prior to exposure. However, salmeterol significantly attenuated the bronchial responsiveness to methacholine by 1.2 doubling concentration steps (0.8 to 1.7) 8 h after inhalation (part 3). Conclusions Salmeterol inhalation did not protect against the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust when administered for 2 weeks or as a single dose prior to exposure. This lack of protection cannot be explained by homologous β 2 -adrenoceptor desensitization. We hypothesize that exposure to organic material may alter the airway response to β 2 -agonists.

Study objectives We investigated the effects of β 2 -adrenergic agonists salmeterol and formoterol on heart rate variability (HRV) in adult asthmatic patients using time-domain measures of HRV. Patients Thirty-nine adult patients with asthma were studied. All patients showed a mild-to-moderate decrease in baseline FEV 1 . Any diseases that might have influenced the autonomic function were excluded. All patients underwent a complete physical examination and medical history that revealed no cardiovascular disease or medication. Methods The β 2 -adrenergic inhaled agonists salmeterol, 50 μg, and formoterol, 12 μg, were used in the study. HRV analysis was performed for each 5-min segment: 5 min and 10 min before inhalation of the study drug, and 5, 10, 15, 20, 25, and 30 min after inhalation. Time-domain parameters of HRV were calculated: (1) the SD all normal-to-normal intervals; (2) the SD of the mean of all normal-to-normal intervals in all 5-min segments of the entire recording; (3) the root mean square of differences between adjacent normal-to-normal intervals; (4) the mean of the SD of all normal-to-normal intervals in all the 5-min intervals; and (5) the SD of the SD of all normal-to-normal intervals in all the 5-min intervals. Results Baseline HRV parameters were not significantly different between formoterol and salmeterol groups. There were no significant differences in HRV parameters after formoterol and salmeterol inhalation. The HRV parameters in each 5-min segment in the formoterol group were not statistically significant different when compared to the same segment in the salmeterol group. Conclusion Salmeterol and formoterol have no short-term adverse effects on HRV.

Study objectives: To compare the effect of montelukast and the long-acting 2-agonist salmeterol on cardiopulmonary exercise economy and physical performance in adult patients with asthma during exercise. Design and patients: Asthmatic patients (n 18), aged 18 to 35 years with exercise-induced bronchoconstriction (EIB), using a double-blind, double-dummy cross-over design. Montelukast, 10 mg/d, was compared to inhaled salmeterol, 50 g bid. The study medication was administered for at least 5 days prior to testing, with a washout period of at least 5 days. Treadmill exercise tests (5.3% inclination, 15°C ambient temperature) were performed at work loads of 80% of maximal oxygen uptake (V u O2max) [6 min], rest (4 min), 60% of V u O2max (6 min), and finally step increments until exhaustion. Measurements and results: We investigated parameters of gas exchange, physical performance, and lung function. After montelukast, the oxygen pulse was higher than after salmeterol, at 80% of V u O2max (p 0.035), and 6 min at 60% of V u O2max (p 0.011). Lung function during exercise, running time to exhaustion, Borg score, lactate levels, V u O2max, carbon dioxide elimination, minute ventilation, ventilatory equivalents, respiratory exchange ratio, and heart rate were not significantly different between the two treatments. The maximal postexercise fall in FEV1 from baseline occurred 2 min after run to exhaustion, and was greater after salmeterol than after montelukast: mean, 16.2% (SD, 11.0) vs 10.0% (SD, 12.2) [p < 0.001]. Conclusions: In adult asthmatics with EIB, montelukast may have a more favorable effect on the oxygen pulse, thus suggesting improved gas exchange during exercise. (CHEST 2004; 126:1154 –1160)

To evaluate the effect of treatment with beclomethasone dipropionate (500 microg bid) and salmeterol (50 microg bid) on lung function and respiratory symptoms in 20 subjects with occupational asthma (OA) still exposed to the work environment cause of their disease.At enrollment and every 6 months for 3 years, respiratory symptom score (from 0 [no symptoms] to 2 [moderate-to-severe symptoms]), spirometry, methacholine challenge, peak expiratory flow (PEF) variability, and the use of rescue salbutamol were evaluated. During the 3 years of follow-up, 10 subjects were excluded from the study because they retired or changed jobs.Symptoms of work-related asthma started 12.6 +/- 13.1 years (mean +/- SD) before diagnosis. At baseline, mean FEV(1) was 80.2% of predicted values and provocative dose of methacholine causing a 20% fall in FEV(1) (PD(20)) was 1,001 +/- 1,275 microg; the workers received 2.1 +/- 2.4 puffs of salbutamol per day. After 3 years, no significant differences in any of the morbidity outcomes (FEV(1), PD(20), PEF variability, use of rescue salbutamol, respiratory symptom score) were found as compared with baseline or run-in values.Regular treatment with inhaled corticosteroids and long-acting bronchodilators seems to prevent respiratory deterioration over a 3-year period in workers with mild-to-moderate persistent OA who were still exposed at work to the environmental cause of their disease.

To determine if persistent airway tissue mast cells are associated with treatment failure when patients discontinue inhaled corticosteroids (ICS).Double-blind, randomized, placebo-controlled trial.Multicenter, tertiary referral centers.Forty-five subjects with asthma recruited from six medical centers in the United States.The Asthma Clinical Research Network undertook a 28-week, randomized, multicenter, double-blind, placebo-controlled trial of 164 subjects with clinically stable, persistent asthma. A subset of subjects (n = 45) underwent bronchoscopy with endobronchial biopsy and BAL at the end of a 6-week run-in period, during which all subjects received triamcinolone acetonide (TAA), 400 microg bid. Airway tissue mast cells, eosinophils, neutrophils, macrophages, and T cells were quantified morphometrically along with determination of BAL tryptase. At the end of the run-in period, subjects were then randomized to receive salmeterol (42 micro g bid), placebo, or continue TAA for 16 weeks followed by a second bronchoscopy.Outcome variables included airway tissue mast cells, eosinophils, neutrophils, macrophages, and T cells that were quantified morphometrically and BAL tryptase. Thirty-five subjects completed the treatment phase; an additional 10 subjects, who were randomized to either salmeterol or placebo after the run-in, had treatment failure. When the bronchoscopy results performed at the end of the run-in, prior to randomization, were analyzed, the treatment failure group demonstrated significantly more tissue mast cells as compared to the nontreatment failure group despite 6 weeks of therapy with TAA (p = 0.04). BAL tryptase was also significantly higher in the treatment failure group (p0.0001). Of those subjects who completed the study, tissue mast cells and BAL tryptase did not change significantly within any of the treatment groups during the treatment phase (p0.05).Persistent elevations in airway tissue mast cells and BAL tryptase after treatment with TAA predict treatment failure in patients for whom discontinuation of ICS is being considered.

Study objective: Several studies have demonstrated the superiority of salmeterol and formoterol to either regular treatment with albuterol or placebo. However, to date there have been no trials comparing the efficacy of salmeterol and formoterol in patients with severe asthma. Design: We undertook a randomized, placebo-controlled, crossover study to compare 4 weeks of treatment with inhaled formoterol (12 g twice daily) or salmeterol (50 g twice daily) in patients with severe asthma whose conditions were not being adequately controlled by therapy with high doses of inhaled corticosteroids (ie, > 1,500 g daily) or with regular oral corticosteroid treatment. Morning pretreatment peak expiratory flow (PEF) during the last 14 days of the treatment period was the primary outcome variable. Patients recorded morning and evening pretreatment PEF, daytime and nighttime symptom scores, and any use of rescue medication. Spirometry and bronchial reversibility were performed after each treatment. Results: Forty-two nonsmoking patients (29 women; mean age, 45 2 years; mean [ SEM] FEV1, 61.8 3.4% of predicted) took part in the trial, and 27 patients completed the trial. The mean morning PEF was greater in patients receiving formoterol (mean increase, 14.4 L/min; 95% confidence interval [CI]. 0.2 to 28.6) or salmeterol (mean increase, 14.8 L/min; 95% CI, 0.5 to 29.1) compared with those receiving placebo, but there was no difference between these treatments. There were no significant treatment effects for any of the secondary outcome variables (ie, FEV1, FVC, mean evening PEF, mean daytime symptom score, or nighttime symptom score). Conclusion: We conclude that the long-acting 2-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma, but that there is no difference in efficacy between the two drugs. (CHEST 2002; 121:1401–1406)

Objective To compare asthma-related health-care utilization and expenditures for patients prescribed one of three dual-controller therapies: fluticasone plus salmeterol, inhaled corticosteroids (ICS) [excluding fluticasone] plus salmeterol, and ICS plus a leukotriene modifier (LTM). Materials and methods: Asthma-related medical claims from two major health plans were obtained for the 12 months before and after the initiation of dual therapy. A total of 1,325 patients ≥ 12 years old with no claims for COPD or respiratory tract cancer were selected from the approximately 3.5 million lives covered. Multivariable regression was used to assess differences in asthma-related expenditures. To compensate for positive skew, all cost variables were log-transformed. Results: Risk-adjusted total asthma-related costs for the fluticasone-plus-salmeterol cohort (n = 121), the ICS-plus-salmeterol cohort (n = 844), and the ICS-plus-LTM cohort (n = 30) were $975, $1,089, and $1,268, respectively. Risk-adjusted pharmacy costs were $813, $841, and $996, respectively. Generalized linear modeling, controlling for baseline covariates, indicated that compared to ICS-plus-LTM therapy, fluticasone-plus-salmeterol therapy was associated with a significant reduction in asthma-related total (p = 0.0014) and pharmacy (p = 0.001) costs. Similar results were found when the ICS-plus-salmeterol group and the ICS-plus-LTM group were compared (p = 0.0001). The number of inpatient, outpatient, and emergency department visits and their corresponding costs were lower for the fluticasone-plus-salmeterol cohort, but were not statistically significant (p > 0.05). Conclusion Results from managed-care practice suggest that treatment with fluticasone plus salmeterol, and more broadly ICS plus salmeterol, yield important cost savings when compared to treatment with ICS plus LTM.

beta(2)-Adrenergic agonists are commonly used as bronchodilators to treat patients with COPD. In addition to prolonged bronchodilation, long-acting beta(2)-agonists (LABAs) exert other effects that may be of clinical relevance. These include inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as nonsmooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa, and attenuation of neutrophil recruitment and activation. This review details the possible alternative mechanisms of action of the LABAs, salmeterol and formoterol, in COPD.

Objective To assess the addition of a leukotriene receptor antagonist and a long-acting ββ 2 -agonist as second-line therapy in asthma. Design Placebo-controlled, double-dummy, crossover study. Setting Outpatient clinic. Patients Twenty patients with persistent asthma not controlled with inhaled corticosteroid therapy. Interventions Montelukast, 10 mg once daily, or salmeterol, 50 μμg bid, each for 2 weeks with 1-week run-in and washout placebo periods. Measurements and results Adenosine monophosphate (AMP) bronchial challenge, blood eosinophil count (EOS), exhaled nitric oxide, and lung function after both placebo periods and after the first and last doses of each active treatment. Patients recorded their domiciliary peak expiratory flow (PEF), asthma symptoms, and rescue bronchodilator requirement (RES) twice daily throughout the study. For the primary end point of the provocative concentration of AMP causing a 20% fall in FEV 1 , compared to placebo (47.5 ± 13.0 mg/mL), there were significant differences with the first (114.1 ± 36.9 mg/mL) and last (94.2 ± 30.4 mg/mL) doses of montelukast as well as the first (160.1 ± 64.5 mg/mL) but not the last (70.1 ± 23.7 mg/mL) dose of salmeterol. Only montelukast produced significant suppression of the EOS. Neither drug affected exhaled nitric oxide levels. There were significant improvements with the first doses of salmeterol for all parameters of lung function. After 2 weeks of treatment, there were significant improvements with both drugs for RES and morning PEF. There were no significant differences between drugs for any end points except EOS. Conclusions Montelukast and salmeterol exhibited significant improvements in asthma control when given as second-line therapy. Montelukast also produced significant effects on AMP challenge and EOS suggesting anti-inflammatory activity.

Study objectives: To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice settings. Design: A randomized, double-blind, 6-month, parallel-group study involving 253 centers. Setting: Primarily nonspecialist practices (n 5 232). Patients: A total of 911 subjects (417 men; 494 women) who met American Thoracic Society asthma criteria were enrolled and randomized to treatment with either twice-daily salmeterol aerosol (50 mg; n 5 455) or matching placebo twice daily (n 5 456). Both groups were allowed to take salbutamol as needed. All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study. Measurements and results: The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization, emergency department visit, or use of prednisone during the treatment period. A total of 712 subjects competed the study. There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%, respectively; p 5 0.935; power > 88%). Peak expiratory flow was significantly higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p < 0.01). Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo (p < 0.001). The proportion of subjects sleeping through the night was significantly higher in the salmeterol group (74%) as compared to placebo (68%; p 5 0.028). Conclusions: Salmeterol treatment is effective in subjects typically cared for in the primary-care setting and does not increase the frequency of severe exacerbations. (CHEST 2001; 119:714‐719)

Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors, with formoterol being a full agonist. The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40% of patients and is known to predispose to agonist-induced downregulation and desensitization.To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction (the primary end point) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism.Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were randomized to completion (mean [SEM] age, 35.8 [3.2] years; mean FEV(1), 76.9 [2. 5]% predicted). Patients received three different treatments for 1 week in randomized, double-blind, crossover fashion, with a 1-week washout period between treatments: formoterol, 12 microg bid; salmeterol, 50 microg bid; and placebo. For each of the randomized treatment periods, there were three separate methacholine challenges: baseline after washout, 12 h after the first dose, and 12 h after the last dose.Both salmeterol and formoterol exhibited significantly (p0.05) greater bronchoprotection than placebo for their effects after single or repeated dosing, although there was no significant difference between the two drugs. The geometric mean fold protection vs placebo (95% confidence interval [CI]) for the first dose was 1.6-fold (95% CI, 1.1 to 2.2) for salmeterol and 1.9-fold (95% CI, 1.1 to 3.2) for formoterol, and for last dose was 1.6-fold (95% CI, 1.2 to 2.3) for salmeterol and 1. 9-fold (95% CI, 1.2 to 2.8) for formoterol. Salmeterol and formoterol produced significant (p0.05) increases in FEV(1) and forced expiratory flow after 25 to 75% of vital capacity has been expelled, after the first but not the last dose compared to placebo, while there were significant (p0.05) improvements in domiciliary peak flows during treatment with both drugs.Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype. There was a significant residual degree of bronchoprotection after 1 week of treatment, which was not significantly different compared to the first-dose effect.

Study objective To determine whether a spacer device designed as a valved holding chamber with a flow signal increases the efficacy of the long-acting β 2 -agonist, salmeterol, in patients who use incorrect technique with metered-dose inhaler (MDI) alone. Design Double-blind, randomized, placebo-controlled study. Setting University hospital outpatient rooms. Patients Twenty adult outpatients with stable persistent asthma, receiving a daily anti-inflammatory drug. Interventions Patients were randomized to either salmeterol MDI (incorrect use: 1 s after actuating MDI, inhale rapidly) and placebo plus spacer (correct use: inhale slowly as MDI is actuated, continue to inhale slowly and deeply) or placebo MDI (incorrect use) and salmeterol plus spacer (correct use). The following week, patients received the opposite treatment. The dose was two puffs from each device on each treatment day; each puff was separated by 1 min. Measurements and results After baseline peak expiratory flow (PEF), salmeterol was administered and serial PEF determined (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h). Administration of salmeterol MDI plus spacer resulted in significantly greater increases in PEF from baseline vs MDI at 4 h (44 L/min vs 10 L/min; p Conclusion We conclude that patients who have poor timing and rapid inhalation with salmeterol MDI alone will have greater increases in PEF at 4 h and 6 h and no additional side effects if the dose is administered with a valved holding chamber that is used correctly. Further study is needed regarding other errors in MDI technique with salmeterol.

To compare the efficacy, safety, and effects on sleep quality of salmeterol and extended-release theophylline in patients with nocturnal asthma.Randomized, double-blind, double-dummy, three-period crossover.Outpatients at a single center. Patients spent 1 night during screening and 2 nights during each study period in a sleep laboratory for completion of sleep studies.Male and female patients who were at least 18 years old with nocturnal asthma (baseline FEV1, 50 to 90% of predicted) and who required regular bronchodilator therapy. Patients on inhaled corticosteroids, cromolyn, and nedocromil were allowed into the study if their dosing remained constant throughout the study.Inhaled salmeterol (42 microg per actuation), extended-release oral theophylline (titrated to serum levels of 10 to 20 microg/mL), and placebo taken twice daily.Efficacy measurements included nocturnal spirometry, nocturnal polysomnography, sleep questionnaires, and daily measurements of lung function and symptoms. Salmeterol was superior to theophylline (por = 0.05) in maintaining nocturnal FEV1 levels and was superior to placebo (por = 0.05) in improving morning and evening peak expiratory flow (PEF) and in decreasing nighttime albuterol use. The use of salmeterol significantly increased the percentage of days and nights with no albuterol use and decreased daytime albuterol use compared with theophylline and placebo (por = 0.05). Sleep quality global scores significantly improved with salmeterol and placebo (p0.001) but not with theophylline. The effects on sleep architecture were similar across treatment groups.Salmeterol (but not theophylline) was associated with sustained improvements in morning PEF, protection from nighttime lung function deterioration, reductions in albuterol use, and improvements in patient perceptions of sleep. No differences were seen in polysomnographic measures of sleep quality.

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 FEV1or = 65% predicted and no clinically significant concurrent disease.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 (p0.0001) 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 (p0.05). 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.

To evaluate the effect of salmeterol on asthma-specific quality of life in patients experiencing significant nocturnal symptoms.Randomized, double-blind, placebo-controlled, multicenter clinical trial.Allergy/respiratory care clinics.Nonsmokersor = 12 years of age with nocturnal asthma symptoms on at least 6 of 14 days during screening andor = 15% decrease in peak expiratory flow (PEF) from baseline on nocturnal awakening at least once during screening.Salmeterol, 42 microg, or placebo twice daily. Patients were allowed to continue theophylline, inhaled corticosteroids, and "as-needed" albuterol.Outcome measures included Asthma Quality of Life Questionnaire (AQLQ) global and individual domain scores, FEV1, PEF, nighttime awakenings, asthma symptoms, and supplemental albuterol use. Mean change from baseline for the global and domain AQLQ scores was significantly greater (por = 0.005) with salmeterol compared with placebo. At week 12, salmeterol significantly (p0.001 compared with placebo) increased mean change from baseline in FEV1, morning and evening PEF, percentage of symptom-free days, percentage of nights with no awakenings due to asthma, and the percentage of days and nights with no supplemental albuterol use. Significant improvements in PEF were observed after treatment with salmeterol regardless of concomitant treatment with theophylline (p0.05).These results provide evidence that validates the role of salmeterol in improving quality of life in patients with moderate persistent asthma who exhibited nocturnal asthma symptoms and supports the efficacy of salmeterol compared with that of placebo (ie, "as-needed" albuterol).

This study investigates the long-term cardiovascular safety of salmeterol powder vs placebo in adolescent and adult patients with mild persistent asthma.Multicenter, randomized, double-blind, placebo-controlled, parallel-group study.Eighteen US clinical centers.Three hundred fifty-two patients (or = 12 years) with mild persistent asthma (durationor = 6 months) requiring pharmacotherapy; with FEV1 of 70 to 90% of predicted and without abnormal ECG/continuous ambulatory ECG (Holter).Randomized to twice-daily salmeterol powder (50 microg) or placebo via breath-actuated device for 52 weeks. Backup albuterol was available to control asthma symptoms.Cardiovascular safety was regularly assessed by 12-lead ECG with a 15-s lead II rhythm strip, 24-h continuous ambulatory ECG (Holter) monitoring, serial vital sign measurements, and review of adverse cardiovascular events. No deaths occurred during the study. No clinically significant between-group differences were observed in pulse rate, ECG QTc interval, median number of ventricular or supraventricular ectopic events, incidence of ventricular ectopic couplets and runs, or incidence of100 ventricular or supraventricular ectopic events in 24 h. No clinically significant between-group differences were observed in arterial BP or incidence of adverse cardiovascular events. Salmeterol was well tolerated throughout the 52-week study period, with a cardiovascular safety profile similar to that of placebo.Long-term, twice-daily pharmacotherapy with salmeterol powder is safe and is not associated with unfavorable clinically significant changes in cardiac function or increases in cardiovascular adverse effects.