fluticasone and Pulmonary-Disease--Chronic-Obstructive

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines

A literature search was performed using public databases. The time course characteristics of the probability of a moderate or severe exacerbation in stable COPD patients treated with LABA/LAMA and LABA/ICS FDCs were described by the parametric survival function. A random-effects model in a single-arm meta-analysis was used to analyze the incidence of serious adverse events (SAEs) and pneumonia.. This study showed that not all LABA/LAMA FDCs were superior to LABA/ICS FDCs in safety and in preventing moderate or severe exacerbations in patients with stable COPD, providing important quantitative information for COPD-related guidelines.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Combinations; Fluticasone; Formoterol Fumarate; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive

Fluticasone propionate/formoterol fumarate (FP/FORM) is one of the newer combinations among inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA) combination formulations currently available. To evaluate the efficacy and safety of this FP/FORM combination, it is important to review all the available evidence and take a comprehensive look at the current and relevant data in the patient population suffering from asthma and chronic obstructive pulmonary disease (COPD).. In this focused review, we summarize the available literature published until January 2021 using the PubMed/Medline and Cochrane Controlled Trials Register databases on the efficacy and safety of FP/FORM with its mono-components; concurrent administration of FP+FORM; and with other ICS/LABA combinations in asthma and COPD patients.. FP/FORM combination therapy is a strong alternative in the treatment of persistent asthma and moderate-severe COPD. Extensive study of several trials has established the superior efficacy of FP/FORM combination therapy over FP or FORM monotherapy, comparable efficacy with FP+FORM and non-inferiority to other ICS/LABA fixed-dose combinations. The safety profile of FP/FORM has also been found to be comparable with respect to its mono-components and their concurrent use, and also other ICS/LABA combinations such as formoterol/budesonide and fluticasone/salmeterol.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Drug Combinations; Fluticasone; Formoterol Fumarate; Humans; Propionates; Pulmonary Disease, Chronic Obstructive

There has been debate on whether inhaled corticosteroids (ICS) reduce the incidence of lung cancer amongst patients with Chronic Obstructive Lung Disease (COPD). We aimed to perform a systematic review and dose-response meta-analysis on available observational data.. We performed both a dose response and high versus low random effects meta-analysis on observational studies measuring whether lung cancer incidence was lower in patients using ICS with COPD. We report relative risk (RR) with 95% confidence intervals (CI), as well as risk difference. We use the GRADE framework to report our results.. Our dose-response suggested a reduction in the incidence of lung cancer for every 500 ug/day of fluticasone equivalent ICS (RR 0.82 [95% 0.68-0.95]). Using a baseline risk of 7.2%, we calculated risk difference of 14 fewer cases per 1000 ([95% CI 24.7-3.8 fewer]). Similarly, our results suggested that for every 1000 ug/day of fluticasone equivalent ICS, there was a larger reduction in incidence of lung cancer (RR 0.68 [0.44-0.93]), with a risk difference of 24.7 fewer cases per 1000 ([95% CI 43.2-5.4 fewer]). The certainty of the evidence was low to very low, due to risk of bias and inconsistency.. There may be a reduction in the incidence for lung cancer in COPD patients who use ICS. However, the quality of the evidence is low to very low, therefore, we are limited in making strong claims about the true effect of ICS on lung cancer incidence.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Fluticasone; Humans; Incidence; Lung Neoplasms; Pulmonary Disease, Chronic Obstructive

Inhaled corticosteroids (ICSs) have been widely used in chronic airway diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. However, whether ICS use causes mycobacterial infection is uncertain. Some conclusions of published studies were inconsistent.. We aimed to investigate the association between the use of ICSs and mycobacterial infections in patients with chronic airway diseases.. This review was registered on PROSPERO (CRD42021284607). We focused on examining the association between ICS use and mycobacterial infection (nontuberculous mycobacterial [NTM] infection as well as tuberculosis [TB]). We searched PubMed (MEDLINE), Sciencenet, Cochrane, and EMBASE databases for studies up to 2021 to retrieve articles. The enrollment conditions included gender, enrollment diagnosis and ICS use in chronic airway disease patients, and so on. Preclinical studies, review articles, editorials, reviews, conference abstracts, and book chapters were excluded. Methodologically, the study was assessed using the Newcastle Ottawa Scale, and Rev-man5 was used for statistical analysis.. Ten studies (including 4 NTM and 6 TB articles) with 517,556 patients met the inclusion criteria and were included in this meta-analysis. From the NTM pooled analyses, ICS use was associated with increased odds of NTM infection in patients with chronic airway diseases (odds ratio [OR] = 3.93, 95% confidence interval [CI] 2.12-7.27), subgroup analysis showed that high-dose ICS use (OR = 2.27, 95% CI 2.08-2.48) and fluticasone use (OR = 2.42, 95% CI 2.23-2.63) were associated with increased odds of NTM infection risk in patients with chronic respiratory diseases. The TB pooled analyses showed a significant association between ICS use and risk of TB infection in patients with chronic respiratory diseases (OR = 2.01, 95% CI 1.23-3.29). Subgroup analysis showed that in chronic respiratory diseases, ICS use increased odds of TB infection in high-dose ICS use (OR = 1.70, 95% CI 1.56-1.86) and in COPD patients (OR = 1.45, 95% CI 1.29-1.63).. Our meta-analysis indicated that ICS use may increase the odds of mycobacterial infection in chronic respiratory disease patients, and this conclusion is more applicable to patients with high dose of ICS or fluticasone in NTM infection subgroups. In addition, high-dose ICS use may have higher risk of TB infection in patients with chronic respiratory diseases, especially COPD. Therefore, we should be vigilant about the application of ICS use in chronic respiratory diseases to avoid infection.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Asthma; Fluticasone; Humans; Mycobacterium Infections, Nontuberculous; Pulmonary Disease, Chronic Obstructive; Tuberculosis

The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile. In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon. Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as "maintenance plus reliever therapy" (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles. We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as "anti-inflammatory reliever".

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Fluticasone; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive

Glucocorticoids are anti-inflammatory drugs used in combination with inhaled bronchodilators, such as β2-agonists and antimuscarinics, for the treatment of stable chronic obstructive pulmonary disease (COPD), to improve respiratory symptoms, such as exertional dyspnoea, and to decrease the risk of future COPD exacerbations. However, it remains controversial whether their regular long-term use increases the risk of developing diabetes mellitus. The objective of this narrative review is therefore to analyse all the randomized controlled trials performed in patients with stable COPD to identify the risk of new onset diabetes mellitus during a long-term (at least 52 weeks) regular treatment with inhaled glucocorticoids alone compared to placebo. From a literature search on PubMed, 19 studies fulfilling these criteria have been identified. The inhaled glucocorticoids administered were: fluticasone propionate (7 studies), budesonide (6 studies), mometasone furoate (3 studies), beclomethasone dipropionate (1 study), triamcinolone acetonide (1 study), and fluticasone furoate (1 study) respectively. Only 3 out of the 19 trials identified in our narrative review reported data on diabetes mellitus, and in these the incidence of diabetes mellitus was not significantly different in both treatment arms (inhaled glucocorticoids and placebo), regardless of the type of glucocorticoid used.

Topics: Bronchodilator Agents; Diabetes Mellitus; Fluticasone; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive

Candidiasis is a rare entity reported as an isolated and primary laryngeal disease. In this condition, inhaled steroids were the single most common predisposing factor. Also mycotic infections of larynx are frequently seen in patients with immune insufficiency, although they have also been reported in individual with normal immune status. We report a case of isolated laryngeal Candidiasis in an immunocompetent individual, with an unusual presentation with exophytic lesion, edema, ulceration, white plaque, and pseudomembranous formation mimicking supraglottic carcinoma, to highlight the clinical of this condition and provide a review of the literature.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Anti-Asthmatic Agents; Antifungal Agents; Asthma; Candidiasis; Diagnosis, Differential; Fluticasone; Humans; Laryngeal Diseases; Laryngeal Neoplasms; Laryngoscopy; Male; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate

We aimed to assess the association between inhaled corticosteroids (ICSs) and the risk of upper respiratory tract infection (URTI) in patients with chronic obstructive pulmonary disease (COPD).. PubMed, Embase, Cochrane Library and Clinical Trials.gov were searched from inception to October 2019. Randomized controlled trials (RCTs) of any ICSs vs control for COPD with reporting of URTI as an adverse event were included. The study was registered with PROSPERO prospectively (#CRD42020153134).. Seventeen RCTs (20,478 patients) were included. ICSs significantly increased the risk of URTI in COPD patients (RR, 1.13; 95% CI 1.03-1.24; P = 0.01; heterogeneity: I. Long-term use of ICSs does not increase the risk of URTI in patients with COPD. Short-term use of high-dose fluticasone increases the risk of URTI in patients with COPD, but not mometasone or budesonide.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Budesonide; Fluticasone; Humans; Mometasone Furoate; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Tract Infections

Inhaled corticosteroids (ICS) are widely used and recommended to treat chronic obstructive pulmonary disease (COPD). While generally considered safe, several studies demonstrated an increased risk of pneumonia with the use of ICS in COPD patients. Although all ICS indicated for COPD carry the class labeling warning of increased pneumonia risk, evidence suggests an intraclass difference in the risk of pneumonia between inhaled budesonide and fluticasone. To date, systematic reviews of direct-comparison studies have not been performed to assess if an intraclass difference exists.. This review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most commonly used ICS in COPD.. A search of the medical literature was conducted in PubMed and Embase for the time period of 01/01/69-05/31/19. The search strategy combined terms that defined the patient/disease type, exposures, outcome, and the study/publication type. Descriptive and comparative statistics reported for fluticasone- and budesonide-containing products in each study, including data for pneumonia event subgroups, were extracted and reported by dose, seriousness, or practice setting. Controlled clinical trials and observational studies meeting the inclusion criteria were assessed for methodologic quality by using the appropriate tool from the list of study quality assessment tools developed by the National Institutes of Health.. The summary relative risk (RR) ratio across 5 included studies (57,199 patients) was 1.13 (95% CI: 1.09-1.19), representing a 13.5% increased risk of pneumonia among fluticasone users compared to budesonide users. Similarly, summary RR ratio for serious pneumonia implied a 14.4% increased risk of serious pneumonia among fluticasone users compared to budesonide users (pooled RR: 1.14; 95% CI: 1.09-1.20).. There is likely a clinically important intraclass difference in the risk of pneumonia between fluticasone- and budesonide-containing inhaled medications in COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Budesonide; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Inhaled corticosteroids (ICS) are generally used to treat patients with chronic obstructive pulmonary disease (COPD) who suffer from repeated exacerbations. Recently, it was reported that ICS treatment increased the risk of pneumonia in COPD patients. But it is controversial.The objective of this paper is to clarify the associations between ICS treatment and the risk of pneumonia in COPD patients.. PubMed, Cochrane Library, Clinical Trials.gov, and Embase were searched from February 2019 to June 2019. Randomized clinical trials (RCTs) were incorporatedthat compared ICS with non-ICS treatment on the risk of pneumonia in COPD patients. Meta-analyses were conducted by the Peto and Mantel-Haenszel approaches with corresponding 95% CIs.. Twenty-five trials (N = 49,982 subjects) were included. Pooled results demonstrated a significantly increased risk of pneumonia with ICS use in COPD patients (RR, 1.59, 95% CI, 1.33-1.90; I. Use of ICS increases the risk of pneumonia in patients with COPD. The above is prominent for fluticasone-containing ICSs but not for budesonide-containing ICSs.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Budesonide; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk

Population-based studies have shown a significant heterogeneity in patients with chronic obstructive pulmonary disease (COPD), regarding both the attainment of maximal lung function and the subsequent decline over time. This review will highlight recent advances in the understanding of lung function trajectory in COPD, focusing on factors that influence peak adult lung function, markers of accelerated lung function decline and pharmacologic interventions in early phases of the disease.. Recent data have shown that individuals with lower lung function early in life will go on to develop lower forced expiratory volume in 1 s (FEV1) in adulthood. Smoking can amplify the effect of specific childhood exposures on maximal adult lung function. Clinical symptoms such as chronic mucous hypersecretion and the biomarker club cell secretory protein have been associated with lung function decline over time. New computed tomography imaging markers also show promise as a way to detect early small airway disease, but need to be examined more longitudinally. In addition to these advances, a slower decline in FEV1 has been demonstrated in two randomized clinical trials studying tiotropium and inhaled fluticasone.. A better understanding of lung function development and eventual decline in those at risk for progression to COPD will aide in a precision medicine approach, in which markers for those at risk of low maximal lung function and accelerated decline are identified. Targeted therapy can then be used early to modify disease activity and outcomes.

Topics: Biomarkers; Bronchitis, Chronic; Bronchodilator Agents; Disease Progression; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Smoking; Tiotropium Bromide; Tomography, X-Ray Computed; Uteroglobin

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Animals; Budesonide; Fluticasone; Humans; Immunocompromised Host; Lung; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterised by largely irreversible changes in air flow due to irritants such as tobacco smoke. Patients with COPD experience acute exacerbations. Severe disease may progress to chronic respiratory failure. We reviewed the literature on basic medications available for COPD, using the standard Prescrire methodology. There are few clinical data on treatment of mild COPD. Regular medication is not necessary for patients who do not have recurrent symptoms. Eliminating exposure to cigarette smoke and other irritants such as workplace irritants, is the only measure known to improve the outcome of COPD. Evaluation of inhaled short-acting beta-2 agonists is based mainly on short-term trials. These drugs have been shown to improve dyspnoea. Salmeterol and formoterol, two long-acting beta-2 agonists, have been extensively evaluated in symptomatic patients. Compared with no treatment, these drugs reduce breathlessness and acute exacerbations, preventing about two hospital admissions per 100 patients with moderate to severe COPD treated for 7 months. Indacaterol and olodateroldo not have a better harm-benefit balance. Inhaled beta-2 agonists occasionally provoke cardiovascular disorders. No excess mortality has been reported among the thousands of COPD patients included in clinical trials. There Is little evidence that ipratropium, an inhaled short-acting anti-muscarinic bronchodilator, improves COPD symptoms. A risk of Increased mortality among COPD patients treated with ipratroplum cannot be ruled out. Tiotroplum, an inhaled long-acting antimuscarinic bronchodilator, has been extensively evaluated In COPD. Tiotroplum has symptomatic efficacy in COPD, reducing dyspnoea and acute exacerbations. Tiotroplum had no tangible advantages over long-acting beta-2 agonists in seven randomised trials including more than 12 000 patients. Glycopyrronium and aclidinium, two other Inhaled long-acting antimuscarinics, do not appear to be more effective. Tiotroplum, like other inhaled anti-muscarinics, has antimuscarinic adverse effects including cardiac, visual and buccal disorders. Glycopyronium may carry a higher risk of serious cardiovascular effects. Combination of an antimuscarinic with an inhaled beta-2 agonist improves symptoms in 7% to 10% of patients. In patients with one or two COPD exacerbations per year, adding an Inhaled corticosterold (beclometa- sone, budesonide or fluticasone) to a long-acting

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aminopyridines; Benzamides; Bronchodilator Agents; Budesonide; Cyclopropanes; Fluticasone; Formoterol Fumarate; Humans; Ipratropium; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Recurrence; Salmeterol Xinafoate; Theophylline; Tiotropium Bromide

Among Chinese populations worldwide, Chinese herbal medicines (CHMs) are often used as an adjunct to pharmacotherapy in managing chronic obstructive pulmonary disease (COPD). However, the relative performance among different CHM is unknown.The aim of this study was to evaluate comparative effectiveness of different CHM when used with salmeterol and fluticasone propionate (SFP), compared with SFP alone.This study is a systematic review of randomized controlled trials (RCTs) with network meta-analyses (NMAs).Eight electronic databases were searched. Data from RCTs were extracted for random effect pairwise meta-analyses. Pooled relative risk (RR) with 95% confidence interval (CI) was used to quantify the impact of CHM and SFP on forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) scoring, and 6-Minute Walk Test (6MWT). NMA was used to explore the most effective CHM when used with SFP.Eleven RCTs (n = 925) assessing 11 different CHM were included. Result from pairwise meta-analyses indicated favorable, clinically relevant benefit of CHM and SFP on FEV1 [7 studies, pooled weighted mean difference (WMD) = 0.20 L, 95% CI: 0.06-0.34 L], SGRQ scoring (5 studies, pooled WMD = -4.99, 95% CI: -7.73 to -2.24), and 6MWT (3 studies, pooled WMD = 32.84 m, 95% CI: 18.26-47.42). Results from NMA showed no differences on the comparative effectiveness among CHM formulations for improving FEV1. For SGRQ, NMA suggested that Runfeijianpibushen decoction and Renshenbufei pills performed best. Use of CHM on top of SFP can provide clinically relevant benefit for COPD patients on FEV1 and SGRQ. Additional use of Runfeijianpibushen decoction and Renshenbufei pills showed better effect on improving SGRQ.Use of CHM and SFP may provide clinically relevant benefit for COPD patients on FEV1, SGRQ, and 6MWT. Use of different CHM formulae included in this NMA showed similar effect for increasing FEV1, while the additional use of Runfeijianpibushen formula and Renshenbufei Pills showed better effect on improving SGRQ. Well conducted, adequately powered trials are needed to confirm their effectiveness in the future.

Topics: Bronchodilator Agents; Drug Therapy, Combination; Drugs, Chinese Herbal; Fluticasone; Forced Expiratory Volume; Humans; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Walk Test

In the treatment of chronic obstructive pulmonary disease (COPD), bronchodilators such as long acting muscarinic antagonist (LAMA) and long acting β agonist(LABA) play key roles for improving respiratory function and symptoms, and reducing risk of exacerbation. However, inhaled corticosteroid (ICS), a key medicine for bronchial asthma, is limitedly used in COPD treatment. Japanese Respiratory Society recommends to use ICS for severe COPD patients who have been frequently exacerbated, because previous clinical studies indicated that ICS reduces exacerbation in moderate to severe COPD patients. Asthma sometimes overlaps with COPD, and symptoms of those patients are not well controlled by the bronchodilation therapy alone. Therefore, ICS/LABA or ICS/LAMA should be prescribed to those overlapped patients. Concentration of exhaled nitrogen oxide and percentage of peripheral eosinophil may be good biomarkers for discriminating the COPD patients who have good response to ICS treatment.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asthma; Biomarkers; Breath Tests; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Delayed-Action Preparations; Disease Progression; Drug Combinations; Drug Therapy, Combination; Eosinophils; Fluticasone; Glucocorticoids; Humans; Leukocyte Count; Muscarinic Antagonists; Nitrogen Oxides; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Severity of Illness Index; Tiotropium Bromide

This article presents a brief review and summarizes current therapies for the treatment of chronic obstructive pulmonary disease, major depression, and rheumatoid arthritis. One new pharmaceutical agent is highlighted for each of the topics.

Topics: Anti-Anxiety Agents; Arthritis, Rheumatoid; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Depressive Disorder; Fluticasone; Humans; Nursing Process; Piperazines; Piperidines; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Pyrroles; Sulfides; United States; Vortioxetine

Inhaled corticosteroids (ICS) are anti-inflammatory drugs that have proven benefits for people with worsening symptoms of chronic obstructive pulmonary disease (COPD) and repeated exacerbations. They are commonly used as combination inhalers with long-acting beta2-agonists (LABA) to reduce exacerbation rates and all-cause mortality, and to improve lung function and quality of life. The most common combinations of ICS and LABA used in combination inhalers are fluticasone and salmeterol, budesonide and formoterol and a new formulation of fluticasone in combination with vilanterol, which is now available. ICS have been associated with increased risk of pneumonia, but the magnitude of risk and how this compares with different ICS remain unclear. Recent reviews conducted to address their safety have not compared the relative safety of these two drugs when used alone or in combination with LABA.. To assess the risk of pneumonia associated with the use of fluticasone and budesonide for COPD.. We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), clinicaltrials.gov, reference lists of existing systematic reviews and manufacturer websites. The most recent searches were conducted in September 2013.. We included parallel-group randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies were included if they compared the ICS budesonide or fluticasone versus placebo, or either ICS in combination with a LABA versus the same LABA as monotherapy for people with COPD.. Two review authors independently extracted study characteristics, numerical data and risk of bias information for each included study.We looked at direct comparisons of ICS versus placebo separately from comparisons of ICS/LABA versus LABA for all outcomes, and we combined these with subgroups when no important heterogeneity was noted. After assessing for transitivity, we conducted an indirect comparison to compare budesonide versus fluticasone monotherapy, but we could not do the same for the combination therapies because of systematic differences between the budesonide and fluticasone combination data sets.When appropriate, we explored the effects of ICS dose, duration of ICS therapy and baseline severity on the primary outcome. Findings of all outcomes are presented in 'Summary of findings' tables using GRADEPro.. We found 43 studies that met the inclusion criteria, and more evidence was provided for fluticasone (26 studies; n = 21,247) than for budesonide (17 studies; n = 10,150). Evidence from the budesonide studies was more inconsistent and less precise, and the studies were shorter. The populations within studies were more often male with a mean age of around 63, mean pack-years smoked over 40 and mean predicted forced expiratory volume of one second (FEV1) less than 50%.High or uneven dropout was considered a high risk of bias in almost 40% of the trials, but conclusions for the primary outcome did not change when the trials at high risk of bias were removed in a sensitivity analysis.Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality), and no evidence suggested that this outcome was reduced by delivering it in combination with salmeterol or vilanterol (subgroup differences: I(2) = 0%, P value 0.51), or that different doses, trial duration or baseline severity significantly affected the estimate. Budesonide also increased non-fatal serious adverse pneumonia events compared with placebo, but the effect was less precise and was based on shorter trials (OR 1.62, 95% CI 1.00 to 2.62; six more per 1000 treated over nine months; moderate quality). Some of the variation in the budesonide data could be explained by a significant difference between the two commonly used doses: 640 mcg was associated with a larger effect than 320 mcg relative to placebo (subgroup differences: I(2) = 74%, P value 0.05).An indirect comparison of budesonide versus fluticasone monotherapy revealed no significant differences with respect to serious adverse events (pneumonia-related or all-cause) or mortality. The risk of any pneumonia event (i.e. less serious cases treated in the community) was higher with fluticasone than with budesonide (OR 1.86, 95% CI 1.04 to 3.34); this was the only significant difference reported between the two drugs. However, this finding should be interpreted with caution because of possible differences in the assignment of pneumonia diagnosis, and because no trials directly compared the two drugs.No significant difference in overall mortality rates was observed between either of the inhaled steroids and the control interventions (both high-quality evidence), and pneumonia-related deaths were too rare to. Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort data and established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significant difference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potential confounding factor in their comparison.Primary research should accurately measure pneumonia outcomes and should clarify both the definition and the method of diagnosis used, especially for new formulations such as fluticasone furoate, for which little evidence of the associated pneumonia risk is currently available. Similarly, systematic reviews and cohorts should address the reliability of assigning 'pneumonia' as an adverse event or cause of death and should determine how this affects the applicability of findings.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Combination therapy (inhaled corticosteroids and long-acting beta2-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments.. To compare the relative effects of inhaled combination therapy and tiotropium on markers of exacerbations, symptoms, quality of life, lung function, pneumonia and serious adverse events in patients with chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials (November 2012) and reference lists of articles. We also contacted authors of the studies.. We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta2-agonist against inhaled tiotropium bromide.. Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We resolved discrepancies through discussion.. One large, two-year trial (INSPIRE) and two smaller, shorter trials on a total of 1528 participants were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data were not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto odds ratio (OR) 0.55; 95% confidence interval (CI) 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was 11 times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all-cause hospital admissions in patients on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium when compared as either an odds ratio or a rate ratio (mean number of exacerbations per patient per year). Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (rate ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (rate ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than in those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew.. Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled long-acting beta2-agonist/steroid combination therapies with tiotropium are also required.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Patient Dropouts; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Inhaled corticosteroids (ICSs) are the mainstay of anti-inflammatory treatment in subjects with asthma and COPD. This review evaluates the role of nebulizers as an alternative to inhalers for delivering ICSs in asthma and COPD. I selected 16 randomized, placebo-controlled, blinded, long-term studies, mostly carried out in asthma (n = 14) and COPD. Nebulized budesonide has been demonstrated to be effective and safe in children ages 1-8 years, and, with less evidence, in infants and adults with asthma. Other investigations, with the addition of in vitro and in vivo comparison studies, have shown that nebulized beclomethasone, fluticasone, and flunisolide are effective alternatives to nebulized budesonide in asthma and COPD. Efficient delivery of nebulized ICSs requires that the nebulizer system, the nebulized drug formulation, and the inhaling subject interact properly. The practices of mixing nebulized ICSs with bronchodilators and using nebulized ICSs in acute settings are promising, but require further confirmations, and at present cannot be recommended. I conclude that nebulizers may be considered as an effective alternative to inhalers for delivering ICSs and can be recommended to asthmatic and COPD subjects who are unwilling or unable to use inhalers. Newer formulations could possibly offer a relevant advance for a more efficient nebulization of ICSs.

Topics: Administration, Inhalation; Androstadienes; Asthma; Beclomethasone; Dose-Response Relationship, Drug; Equipment Design; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

A recent case-controlled study reported an increased risk of diabetes mellitus in patients treated with inhaled corticosteroids for asthma or COPD, versus age-matched controls.. The purpose of the current study was to evaluate whether there was an increased risk of new onset diabetes mellitus or hyperglycaemia among patients with asthma or COPD treated with inhaled corticosteroids.. A retrospective analysis evaluated all double-blind, placebo-controlled, trials in patients ≥4 years of age involving budesonide or budesonide/formoterol in asthma (26 trials; budesonide: n = 9067; placebo: n = 5926), and in COPD (8 trials; budesonide: n = 4616; non-ICS: n = 3643). A secondary dataset evaluated all double-blind, controlled trials in asthma involving the use of inhaled corticosteroids (60 trials; budesonide: n = 33,496; fluticasone: n = 2773).. In the primary asthma dataset, the occurrence of diabetes mellitus/hyperglycaemia adverse events (AEs) was 0.13% for budesonide and 0.13% for placebo (HR 0.98 [95% CI: 0.38-2.50], p = 0.96) and serious adverse events (SAEs) was 0% for budesonide and 0.05% for placebo. In the secondary dataset, the occurrence of diabetes/hyperglycaemia as AE and SAE was 0.19% and 0.03%, respectively. In the COPD dataset, the occurrence of diabetes mellitus/hyperglycaemia AEs was 1.3% for budesonide and 1.2% for non-ICS (HR 0.99 [95% CI: 0.67-1.46], p = 0.96) and SAEs was 0.1% for budesonide and 0.03% for non-ICS.. Treatment with inhaled corticosteroids in patients with asthma or COPD was not associated with increased risk of new onset diabetes mellitus or hyperglycaemia.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Budesonide; Diabetes Mellitus; Double-Blind Method; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Hyperglycemia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors

Both inhaled steroids (ICS) and long-acting beta(2)-agonists (LABA) are used in the management of chronic obstructive pulmonary disease (COPD). This updated review compared compound LABA plus ICS therapy (LABA/ICS) with the LABA component drug given alone.. To assess the efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD.. We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search was November 2011.. We included randomised, double-blind controlled trials. We included trials comparing compound ICS and LABA preparations with their component LABA preparations in people with COPD.. Two authors independently assessed study risk of bias and extracted data. The primary outcomes were exacerbations, mortality and pneumonia, while secondary outcomes were health-related quality of life (measured by validated scales), lung function, withdrawals due to lack of efficacy, withdrawals due to adverse events and side-effects. Dichotomous data were analysed as random-effects model odds ratios or rate ratios with 95% confidence intervals (CIs), and continuous data as mean differences and 95% CIs. We rated the quality of evidence for exacerbations, mortality and pneumonia according to recommendations made by the GRADE working group.. Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality.Primary outcomes There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were lower in comparison to those with LABA alone, from nine studies which randomised 9921 participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our confidence in this effect was limited by statistical heterogeneity between the results of the studies (I(2) = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed as the number of people experiencing one or more exacerbations over the course of the study, FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6 studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation. Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this effect from high to moderate.There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to 1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency). There was no significant difference in mortality between people on combined inhalers and those on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95% CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were no significant differences between the results for either exacerbations or pneumonia from trials adding different doses o. Concerns over the analysis and availability of data from the studies bring into question the superiority of ICS/LABA over LABA alone in preventing exacerbations. The effects on hospitalisations were inconsistent and require further exploration. There was moderate quality evidence of an increased risk of pneumonia with ICS/LABA. There was moderate quality evidence that treatments had similar effects on mortality. Quality of life, symptoms score, rescue medication use and FEV(1) improved more on ICS/LABA than on LABA, but the average differences were probably not clinically significant for these outcomes. To an individual patient the increased risk of pneumonia needs to be balanced against the possible reduction in exacerbations.More information would be useful on the relative benefits and adverse event rates with combination inhalers using different doses of inhaled corticosteroids. Evidence from head-to-head comparisons is needed to assess the comparative risks and benefits of the different combination inhalers.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pneumonia; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

Primary care specialists provide first-line care of chronic obstructive pulmonary disease (COPD), characterized by progressive, partially reversible airflow limitation induced mainly by smoking. Spirometry and questionnaires are important for COPD diagnosis, staging and prognosis. Smoking cessation, immunizations, pulmonary rehabilitation and self-management action plans comprise nonpharmacologic COPD management. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) and Towards a Revolution in COPD Health (TORCH) megatrials provide evidence for maintenance pharmacotherapy to reduce exacerbations and improve patient symptoms and health-related quality of life. Although the primary outcomes--lung function decline (UPLIFT®) and mortality (TORCH)--were negative, long-acting bronchodilators in both trials reduced exacerbation rates and improved health status. Tiotropium added to usual care (in UPLIFT®) and salmeterol/fluticasone therapy (in TORCH) improved key patient-centered outcomes with no significant mortality risk or excess in serious cardiac adverse events associated with the study drugs. These results provide strong evidence of efficacy and acceptable safety profiles of maintenance pharmacotherapies in patient-centered outcomes and support combination drug regimens in patients with moderate to very severe COPD.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Prognosis; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD.. MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (≥24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose-response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I(2) statistic.. Sixteen RCTs (14 fluticasone, 2 budesonide) with 17,513 participants, and seven observational studies (n=69,000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I(2)=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I(2)=37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001).. Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.

Topics: Administration, Inhalation; Aged; Androstadienes; Budesonide; Dose-Response Relationship, Drug; Female; Fluticasone; Fractures, Bone; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment

This analysis was designed to provide a comparison between budesonide/formoterol and salmeterol/fluticasone for the relative incidence of pneumonia adverse events, pneumonia serious adverse events and pneumonia-related mortality in patients being treated for chronic obstructive pulmonary disease.. An initial literature search revealed no suitable head-to-head trials between budesonide/formoterol and salmeterol/fluticasone and therefore a systematic review was conducted to find randomised controlled trials providing data for input into an adjusted indirect comparison of the two combination treatments using placebo as a common comparator. The Bucher adjusted indirect comparison method was used to calculate odds ratios and 95% confidence intervals.. Eight salmeterol/fluticasone trials and four budesonide/formoterol trials were identified as being relevant for the analyses. The proportion of patients experiencing a pneumonia adverse event was significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.47; 95% confidence interval, 0.28-0.80). The proportion of patients experiencing a pneumonia serious adverse event was also significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.41; 95% confidence interval, 0.19-0.86). However, there were too few events to draw any firm conclusions on pneumonia-related mortality.. The results of the indirect comparison support the hypothesis that budesonide/formoterol is associated with fewer pneumonia events than salmeterol/fluticasone in chronic obstructive pulmonary disease. The limitations of the analysis are that the results from a single study, TORCH, have a large bearing on the overall findings of the analysis, and that there is heterogeneity in the length and the dosing of the included studies, although it does not appear that heterogeneity affected the reported results. Another important limitation is the lack of predefined diagnostic standards for pneumonia in these studies.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Ethanolamines; Fluticasone; Formoterol Fumarate; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Sample Size

Long-acting beta(2)-agonists and inhaled corticosteroids can be used as maintenance therapy by patients with moderate to severe chronic obstructive pulmonary disease. These interventions are often taken together in a combination inhaler. However, the relative added value of the two individual components is unclear.. To determine the relative effects of inhaled corticosteroids (ICS) compared to long-acting beta(2)-agonists (LABA) on clinical outcomes in patients with stable chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials (latest search August 2011) and reference lists of articles.. We included randomised controlled trials comparing inhaled corticosteroids and long-acting beta(2)-agonists in the treatment of patients with stable chronic obstructive pulmonary disease.. Three authors independently assessed trials for inclusion and then extracted data on trial quality, study outcomes and adverse events. We also contacted study authors for additional information.. We identified seven randomised trials (5997 participants) of good quality with a duration of six months to three years. All of the trials compared ICS/LABA combination inhalers with LABA and ICS as individual components. Four of these trials included fluticasone and salmeterol monocomponents and the remaining three included budesonide and formoterol monocomponents. There was no statistically significant difference in our primary outcome, the number of patients experiencing exacerbations (odds ratio (OR) 1.22; 95% CI 0.89 to 1.67), or the rate of exacerbations per patient year (rate ratio (RR) 0.96; 95% CI 0.89 to 1.02) between inhaled corticosteroids and long-acting beta(2)-agonists. The incidence of pneumonia, our co-primary outcome, was significantly higher among patients on inhaled corticosteroids than on long-acting beta(2)-agonists whether classified as an adverse event (OR 1.38; 95% CI 1.10 to 1.73) or serious adverse event (Peto OR 1.48; 95% CI 1.13 to 1.93). Results of the secondary outcomes analysis were as follows. Mortality was higher in patients on inhaled corticosteroids compared to patients on long-acting beta(2)-agonists (Peto OR 1.17; 95% CI 0.97 to 1.42), although the difference was not statistically significant. Patients treated with beta(2)-agonists showed greater improvements in pre-bronchodilator FEV(1) compared to those treated with inhaled corticosteroids (mean difference (MD) 18.99 mL; 95% CI 0.52 to 37.46), whilst greater improvements in health-related quality of life were observed in patients receiving inhaled corticosteroids compared to those receiving long-acting beta(2)-agonists (St George's Respiratory Questionnaire (SGRQ) MD -0.74; 95% CI -1.42 to -0.06). In both cases the differences were statistically significant but rather small in magnitude. There were no statistically significant differences between ICS and LABA in the number of hospitalisations due to exacerbations, number of mild exacerbations, peak expiratory flow, dyspnoea, symptoms scores, use of rescue medication, adverse events, all cause hospitalisations, or withdrawals from studies.. Placebo-controlled trials have established the benefits of both long-acting beta-agonist and inhaled corticosteroid therapy for COPD patients as individual therapies. This review, which included trials allowing comparisons between LABA and ICS, has shown that the two therapies confer similar benefits across the majority of outcomes, including the frequency of exacerbations and mortality. Use of long-acting beta-agonists appears to confer a small additional benefit in terms of improvements in lung function compared to inhaled corticosteroids. On the other hand, inhaled corticosteroid therapy shows a small advantage over long-acting beta-agonist therapy in terms of health-related quality of life, but inhaled corticosteroids also increase the risk of pneumonia. This review supports current guidelines advocating long-acting beta-agonists as frontline therapy for COPD, with regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent exacerbations.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

The primary aim of pharmachotherapy in COPD is improvement of exertional dyspnea and quality of life through its bronchodilator effects. However, there is emerging evidence that pharmacotherapy may reduce exacerbations, alleviate annual decline of pulmonary function, and even favorably affect mortality, thus changing natural history of COPD. The large-scaled randomized clinical trials, such as TORCH, UPLIFT, have revealed that combination of long acting beta2 agonist (LABA) and inhaled corticosteroids (ICS), LABA/ICS, and/or tiotropium alone may have such effects. In addition, carbocisteine, which is a mucolytic and anti-oxidant agent, has been shown to reduce exacerbations in COPD. Future directions on pharmacotherapy are personalized medicine based on phenotyping of the disease and development of new agents which may cure airway inflammation in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Long-acting beta(2)-agonists and inhaled corticosteroids can be used as maintenance therapy by patients with moderate to severe chronic obstructive pulmonary disease. These interventions are often taken together in a combination inhaler. However, the relative added value of the two individual components is unclear.. To determine the relative effects of inhaled corticosteroids (ICS) compared to long-acting beta(2)-agonists (LABA) on clinical outcomes in patients with stable chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials (latest search August 2011) and reference lists of articles.. We included randomised controlled trials comparing inhaled corticosteroids and long-acting beta(2)-agonists in the treatment of patients with stable chronic obstructive pulmonary disease.. Three authors independently assessed trials for inclusion and then extracted data on trial quality, study outcomes and adverse events. We also contacted study authors for additional information.. We identified seven randomised trials (5997 participants) of good quality with a duration of six months to three years. All of the trials compared ICS/LABA combination inhalers with LABA and ICS as individual components. Four of these trials included fluticasone and salmeterol monocomponents and the remaining three included budesonide and formoterol monocomponents. There was no statistically significant difference in our primary outcome, the number of patients experiencing exacerbations (odds ratio (OR) 1.22; 95% CI 0.89 to 1.67), or the rate of exacerbations per patient year (rate ratio (RR) 0.96; 95% CI 0.89 to 1.02) between inhaled corticosteroids and long-acting beta(2)-agonists. The incidence of pneumonia, our co-primary outcome, was significantly higher among patients on inhaled corticosteroids than on long-acting beta(2)-agonists whether classified as an adverse event (OR 1.38; 95% CI 1.10 to 1.73) or serious adverse event (Peto OR 1.48; 95% CI 1.13 to 1.93). Results of the secondary outcomes analysis were as follows. Mortality was higher in patients on inhaled corticosteroids compared to patients on long-acting beta(2)-agonists (Peto OR 1.17; 95% CI 0.97 to 1.42), although the difference was not statistically significant. Patients treated with beta(2)-agonists showed greater improvements in pre-bronchodilator FEV(1) compared to those treated with inhaled corticosteroids (mean difference (MD) 18.99 mL; 95% CI 0.52 to 37.46), whilst greater improvements in health-related quality of life were observed in patients receiving inhaled corticosteroids compared to those receiving long-acting beta(2)-agonists (St George's Respiratory Questionnaire (SGRQ) MD -0.74; 95% CI -1.42 to -0.06). In both cases the differences were statistically significant but rather small in magnitude. There were no statistically significant differences between ICS and LABA in the number of hospitalisations due to exacerbations, number of mild exacerbations, peak expiratory flow, dyspnoea, symptoms scores, use of rescue medication, adverse events, all cause hospitalisations, or withdrawals from studies.. Placebo-controlled trials have established the benefits of both long-acting beta-agonist and inhaled corticosteroid therapy for COPD patients as individual therapies. This review, which included trials allowing comparisons between LABA and ICS, has shown that the two therapies confer similar benefits across the majority of outcomes, including the frequency of exacerbations and mortality. Use of long-acting beta-agonists appears to confer a small additional benefit in terms of improvements in lung function compared to inhaled corticosteroids. On the other hand, inhaled corticosteroid therapy shows a small advantage over long-acting beta-agonist therapy in terms of health-related quality of life, but inhaled corticosteroids also increase the risk of pneumonia. This review supports current guidelines advocating long-acting beta-agonists as frontline therapy for COPD, with regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent exacerbations.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

The prevention and relief of symptoms by regular use of bronchodilators is central to the pharmacological management of chronic obstructive pulmonary disease (COPD).. The aim of this article is to review the effects of inhaled muscarinic antagonists in the treatment of stable COPD.. An update of the clinical studies performed with the long-acting inhaled muscarinic antagonist (LAMA) tiotropium bromide in patients with COPD is given. In recent years, combinations of a LAMA and a long-acting inhaled beta2-agonist (LABA), and 'triple therapy' consisting of a LAMA, a LABA, and an inhaled steroid are being developed. Issues of safety of inhaled anticholinergics in COPD are discussed and a short overview of new LAMAs being developed for COPD is given.. The importance of anticholinergic drug treatment in COPD was largely advanced by the development of the first LAMA, tiotropium bromide. The vast experience obtained with tiotropium bromide has paved the way for new LAMAs such as aclidinium bromide and glycopyrrolate (NVA-237).

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Androstadienes; Bronchodilator Agents; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation, Preclinical; Drug Therapy, Combination; Drugs, Investigational; Fluticasone; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

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

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Combined Modality Therapy; Drug Therapy, Combination; Female; Fluticasone; Humans; Ipratropium; Long-Term Care; Male; Middle Aged; Prednisone; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Triamcinolone

Combination therapy (inhaled corticosteroids and long-acting beta(2)-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments.. To assess the relative effects of inhaled combination therapy and tiotropium on patients with COPD.. We searched the Cochrane Airways Group Specialised Register of trials (March 2010) and reference lists of articles. We also contacted authors of the studies.. We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta(2)-agonist against inhaled tiotropium bromide.. Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. Discrepancies were resolved through discussion.. One large two year trial (INSPIRE) and two smaller, shorter trials (Dawber 2005; SCO40034) were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data was not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto OR 0.55; 95% CI 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was eleven times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all cause hospital admissions in patents on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium. Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (Rate Ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (Rate Ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew.. Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled LABA/steroid combination therapies with tiotropium are also required.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Patient Dropouts; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

While several studies have examined adherence to controller medications for the treatment of COPD, few systematic reviews have taken the translational step to identifying important and necessary areas for further research. The objective of this study was to review data on the outcomes of adherence to various controller therapies in patients with COPD in an effort to help prescribers understand adherence properties for each therapy.. This is a systematic review of studies investigating adherence to an array of controller pharmaceutical regimens. The studies were obtained from PubMed during 2008 and 2009 using the following key words: chronic obstructive pulmonary disease, COPD, adherence, controller medication, and persistence. Only articles encompassing adherence or persistence data to controller medications and published after 1990 were utilized.. After the search results were filtered for only the articles that pertained to adherence or persistence measurements in COPD, 35 articles remained; and finally, discounting those articles not published in English, articles which did not compare treatments for COPD, as well as those which were review articles, ten applicable articles remained. Each of these found low levels of medication adherence and/or persistence among patients receiving medications for COPD. Patients receiving fluticasone/salmeterol (FSC) and tiotropium (TIO) for treatment showed the highest adherence among all controller medications. Patients who were married, older, and white were more likely to adhere to their medications.. Characteristics of the medication used (i.e. dosing schedule, formulation, etc.) as well as patient characteristics affect the adherence/persistence to medications for the treatment of COPD. Further patient education is necessary in order to effectively improve disease management and patient outcomes in COPD. There is a need for future research and educational efforts to improve adherence in COPD and more clearly identify specific behavioral and treatment characteristics associated with specific COPD medications that can facilitate adherence.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Fluticasone; Humans; Medication Adherence; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Self Administration; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is one of the most important respiratory diseases, characterized by its multicomponent complexity, with chronic inflammation, increased airway resistance and exacerbations. Several drugs are currently available for its treatment, which act on distinct targets. Bronchodilators, especially prolonged-action bronchodilators, are the most potent and there are two groups: beta-2 mimetics and anticholinergics. Inhaled corticosteroids are the main anti-inflammatory drugs but have modest efficacy and their use is reserved for patients with severe disease and frequent exacerbations and/or asthma traits. Associating these three drugs can improve symptom control, improve quality of life and reduce the number of exacerbations. The present article reviews the evidence supporting this triple combination, as well as published studies.

Topics: Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Clinical Trials as Topic; Delayed-Action Preparations; Drug Therapy, Combination; Ethanolamines; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Humans; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

For many years, chronic obstructive pulmonary disease (COPD) was considered a disease of fixed airflow obstruction for which there was no good treatment. Out of desperation and frustration, health care providers extrapolated from asthma to COPD, and standard asthma therapy was adopted without evidence for efficacy. In recent years, we have gained a better understanding of the pathophysiologic differences between asthma and COPD, and prospective controlled trials have provided a rationale for therapy. Smoking cessation is critically important, both as primary prevention and as an effective way to slow the decrease in lung function in patients with established disease. beta(2)-Adrenergic and anticholinergic agonists improve lung function and relieve symptoms in most patients. Tiotropium improves exercise tolerance and quality of life and reduces exacerbations and hospitalizations. The increase in lung function seen with tiotropium is sustained with continued use over at least 3 to 4 years. Inhaled corticosteroids decrease exacerbations and improve quality of life, and their effect seems greatest in patients with lower lung function and in exacerbation-prone patients. There is no evidence that inhaled corticosteroids alone affect mortality, despite the reduction in exacerbations and increased risk of pneumonia. In some patient populations, inhaled fluticasone, salmeterol, or the combination might slow the rate of loss of lung function. Rather than reflexively using effective asthma therapy in the patient with COPD, current and future therapy for COPD is increasingly evidence based and targeted to specific inflammatory pathways that are important in patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Albuterol; Androstadienes; Antioxidants; Asthma; Bacterial Vaccines; Bronchodilator Agents; Clinical Trials as Topic; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Viral Vaccines

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Diagnostic Imaging; Fluticasone; Humans; Immunity, Innate; Muscle, Skeletal; Oxygen Inhalation Therapy; Pulmonary Disease, Chronic Obstructive; Respiratory Muscles; Salmeterol Xinafoate; Smoking Cessation

Patients with asthma and COPD commonly use inhaled drugs. The 3 types of currently available devices for inhaled therapy (Metered-dose inhaler, dry powder inhaler, and nebulizer) are clinically equivalent. However, since many different inhalers are available for inhaled therapy, the choice of the delivery device is important for optimizing the results of aerosol therapy. Traditional press-and-breathe Metered Dose Inhalers (pMDIs) have recently improved their ecological appeal, can be used in every clinical and environmental situation, their dosing is convenient and highly reproducible, but their efficient delivery remains highly technique dependent. Poor inhalation technique can be minimised by the use of add-on valved holding chambers, which are seldom used in the clinical practice possibly because they are cumbersome. Breath Actuated devices (BAIs), such as Dry Powder Inhalers (DPIs), which are environmental-friendly, safe, effective, reliable, portable and self-contained, overcome problems of handbreath co-ordination associated with pMDIs usage, but their use is also undermined by common errors of inhalation technique in real life. Nebulizers are cumbersome and time-comsuming for use and maintenance, but their use needs less cooperation than inhalers. Although nebulizer practice is not always evidence-based, some patients, mainly elderly prefer nebulizers for regular long-term usage. Despite the introduction of newer devices, clear advantages of a particular delivery system over other inhalers in terms of compliance, preference, and cost-effectiveness are not currently available. The objective of an ideal and easy-to use inhaler is far from reality. Patient education is the critical factor in the use and misuse of delivery devices and effectiveness of aerosol therapy. The choice of the device has to be tailored according to the patient's needs, situation, and preference. Whatever the chosen inhaler, education from health caregivers has a key-role for improving inhaler technique and compliance. Differences among delivery devices represent another challenge to patient use and caregiver instruction.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aerosols; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Caregivers; Child; Fluticasone; Follow-Up Studies; Humans; Metered Dose Inhalers; Nebulizers and Vaporizers; Patient Compliance; Patient Education as Topic; Patient Satisfaction; Physicians; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Respiratory Therapy; Salmeterol Xinafoate; Time Factors

In chronic obstructive pulmonary disease (COPD), the rate of decline in forced expiratory volume in 1 second (FEV1) and progression to disability and death are accelerated. COPD management goals include preventing or slowing the progressive loss of lung function, relieving symptoms, improving exercise tolerance and the patient's health status, preventing and treating exacerbations and complications, minimizing side effects of treatment, and reducing mortality. Although lung function is important for diagnosis of COPD and classification of its severity, clinicians and patients are also very interested in symptoms, ability to function, and general well-being (health status). Consequently, increasing attention is being given to these patient-centered outcomes. It is possible to modify patient-centered outcomes; however, it remains to be seen whether doing so can also alter the natural course of the disease and reduce mortality. Two long-term clinical trials--Towards a Revolution in COPD Health (TORCH) and Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT)--will help to answer the question of whether pharmacologic interventions are effective in changing the clinical course of COPD. The TORCH study examines the long-term effects of combination therapy with an inhaled long-acting beta-agonist (salmeterol) and a corticosteroid (fluticasone) on reduction of all-cause mortality over 3 years. The 4-year UPLIFT study examines the effects of maintenance treatment with the once-daily anticholinergic bronchodilator tiotropium on the yearly rate of decline in trough FEV1 and the yearly rate of decline in FEV1 90 minutes after maximal or near-maximal bronchodilator administration. This article examines the rationale for each of these studies and provides an overview of study methodology as well as preliminary demographic data.

Topics: Acute Disease; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Patient Admission; Patient-Centered Care; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Clinical trials of a combination therapy of an inhaled corticosteroid, fluticasone propionate (FP), with a long-acting beta2-agonist, salmeterol (Sal), have demonstrated a greater improvement in lung function and in quality of life measures after the combination compared with either component of alone. In a subanalysis of the data of the TRISTAN study, Sal/FP reduced exacerbation rates in COPD patients with a baseline FEV1 < 50% of predicted. A combination therapy of budesonide and formoterol improved quality of life and FEV1, and reduced exacerbations better than either component alone. In studies of FP or of Sal/FP in COPD, there was a reduction in all-cause mortality by 25% relative to placebo. Sal/FP has anti-inflammatory effects in COPD airways. FP inhibits markers of systemic inflammation, and it is not known whether Sal/FP has an advantage over FP alone. While long-acting beta2-agonists such as Sal can be recommended for treatment of moderate COPD, addition of inhaled steroid therapy such as FP should be considered in more severe disease.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; United Kingdom

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Evidence-Based Medicine; Fluticasone; Formoterol Fumarate; Humans; Meta-Analysis as Topic; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Treatment Outcome

Patients with chronic obstructive pulmonary disease (COPD) are predisposed to atherosclerosis and coronary artery disease, but the underlying mechanisms are unclear. Although there is wide acceptance that atherosclerosis is related to systemic inflammation, the cause(s) and mechanism(s) of pulmonary inflammation in stable COPD remain unknown. Infectious (bacterial and viral) as well as noninfectious agents can cause acute exacerbations in COPD, and they intensify local and systemic inflammation. Although it is not known how systemic inflammation develops in stable COPD, there is good evidence to suggest that it occurs and that the intensity of systemic inflammation is linked to the severity of airflow obstruction. We postulate that systemic inflammation provides the linkage between COPD and atherosclerosis. Inhaled corticosteroids have been shown to improve health outcomes in COPD, but the mechanism by which this occurs is a pivotal and challenging question that has yet to be answered. To prove the concept that inhaled corticosteroids could suppress systemic inflammation (as exemplified by serum C-reactive protein [CRP] levels), a double-blind, placebo-controlled clinical trial was conducted in a group of patients with mild to moderate COPD. We found that withdrawal of inhaled corticosteroids increased serum CRP levels, and that reintroduction of inhaled fluticasone could suppress CRP levels.

Topics: Androstadienes; Anti-Inflammatory Agents; Arteriosclerosis; C-Reactive Protein; Fluticasone; Humans; Inflammation; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Medication for the treatment of asthma and chronic obstructive pulmonary disease should be given locally by inhalation. There is, however, no such thing as an ideal inhaler, or 'Idealhaler', which has all desired properties with no drawbacks. In this short review, we have compared the relative merits of the two most commonly used dry powder inhalers -- Turbuhaler and Diskus. Clinical effect is related to the amount of inhaled drug that reaches the lungs, and this in turn depends on the amount of fine particles generated at inhalation. Turbuhaler is more than twice as effective as Diskus at generating fine particles, and the higher lung deposition with Turbuhaler is accompanied by a lower variability in lung deposition. Compared with Diskus, the lung deposition with Turbuhaler is affected less by factors such as humidity.

Topics: Administration, Inhalation; Androstadienes; Asthma; Bronchodilator Agents; Budesonide; Fluticasone; Humans; Nebulizers and Vaporizers; Particle Size; Pulmonary Disease, Chronic Obstructive

The impact of long-term inhaled corticosteroid (ICS) therapy on bone mineral density (BMD) is poorly understood.. To evaluate the impact of long-term ICS use on BMD.. Random-effects meta-analysis. Published and unpublished literature were identified by searches of MEDLINE and EMBASE databases and consultation with experts. Studies reporting BMD among adult asthma and chronic obstructive pulmonary disease (COPD) patients using ICS and non-ICS controls were identified. Studies selected for review included at least 1 year of follow-up. Two independent reviewers evaluated studies; data from those meeting specified inclusion criteria were abstracted for inclusion in the meta-analysis.. Fourteen (5.3%) of 266 reviewed studies met specified inclusion criteria. Sufficient data were available to perform meta-analysis on 3 measures for ICS-using patients (lumbar, femoral neck, and major trochanter BMD) and 1 measure (lumbar BMD) for non-ICS-using controls. Using current National Asthma Education and Prevention Program definitions, the majority of studies (12 of 14) included patients receiving moderate to high doses of ICSs. Among ICS users, annual changes from baseline in lumbar, femoral neck, and major trochanter BMD (-0.23%, -0.17%, and +1.46%, respectively) were not statistically significant. Mean changes in lumbar BMD were also not significantly different from controls (-0.02%). Further, annual changes in lumbar BMD were not statistically significant for subgroups of patients with asthma or COPD.. Long-term use of ICSs in patients with asthma or COPD was not associated with significant changes in BMD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bone Density; Budesonide; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Triamcinolone Acetonide

Deleterious effect of oral corticosteroids on bone has been well documented, whereas this remains debated for inhaled ones (ICS). Our objectives were to analyze the effects of ICS on bone mineral density, fracture risk and bone markers. We performed an exhaustive systematic research of all controlled trials potentially containing pertinent data, peer-reviewed by a dedicated WHO expert group, and comprehensive meta-analyses of the data. Inclusion criteria were ICS, and BMD/markers/fractures in asthma/chronic obstructive pulmonary diseases (COPD) and healthy patients. Analyses were performed in a conservative fashion using professional dedicated softwares and stratified by outcome, study design and ICS type. Results were expressed as standardized mean difference/effect size (ES), relative risk (RR) or odds ratio (OR), depending on study design and outcome units. Publication bias was investigated. Twenty-three trials were reviewed; 11 papers fit the inclusion criteria and were assessed for the main analysis. Quality scores for the randomized controlled trials (RCTs) were 80%, 71% for the prospective cohort studies, and 78% for the retrospective cohort and cross-sectional studies. We globally assessed ICS effects on BMD and found deleterious effects: ES=0.61 ( p=0.001) for healthy subjects, and ES=0.27 ( p<0.001) for asthma/COPD patients. For these patients, this effect was 0.21 ( p<0.01) at the lumbar spine, and 0.26 ( p<0.001) at the hip or femoral neck. A single study evaluated the impact of ICS on hip fracture and reported an increased OR of 1.6 (1.24; 2.03). Lumbar fracture rate differences did not reach the level of statistical significance: 1.87 (0.5; 6.94). Osteocalcin and PICP were decreased and ICTP, pyridinoline and deoxypyridinoline levels were not significantly affected. Budesonide (BUD) appeared to be the ICS inducing the less deleterious effects on bone, followed by beclomethasone dipropionate (BDP) and triamcinolone (TRI). Publication bias investigation provided non-significant results. In our meta-analyses, BUD at a mean daily dose (SD) of 686 microg (158 microg), BDP at 703 microg (123 microg) and TRI at 1,000 microg (282 microg) were found to affect bone mineral density and markers in patients suffering from the two major respiratory diseases. These findings could have practical implication in the long-term management of asthmatic and COPD patients.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bone and Bones; Bone Density; Budesonide; Fluticasone; Fractures, Bone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Triamcinolone Acetonide

Long-acting beta-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. However, they have only been available until recently via separate administration. They have been developed in order to facilitate adherence to medication regimens, and to improve efficacy.. To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations in the treatment of adults with chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group chronic obstructive pulmonary disease (COPD) trials register (March 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), LILACS (all years to March 2003) and reference lists of articles. We also contacted manufacturers and researchers in the field.. Studies were included if they were randomised, with adequate blinding procedures in place. Studies could compare a combined inhaled corticosteroids and long-acting beta-agonist preparation with either component preparation or placebo. Studies comparing different members of each class of combined therapies were included. Two reviewers independently assessed trial quality and extracted data.. Four randomised trials with 2986 participants were included. Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were studied in the trials. No meta-analysis on clinical outcomes was possible due to different outcome assessment across studies. All studies demonstrated a reduction in exacerbation rates versus placebo. Budesonide/formoterol was more effective than formoterol in reducing exacerbations in one study from 1.84 to 1.42 exacerbations per year. Fluticasone/salmeterol did not significantly reduce exacerbations compared with either of its component treatments. Fluticasone/salmeterol led to better quality of life compared with placebo (two studies), although there were conflicting results when compared with inhaled corticosteroid alone (two studies). There was no significant difference between fluticasone/salmeterol and long-acting beta-agonist (two studies). Budesonide/formoterol led to statistically significant differences in quality of life compared with placebo, but not when compared with component inhaled corticosteroid or beta-agonist (one study).. For the primary outcome of exacerbations, budesonide/formoterol had a modest advantage over a component medication, formoterol, in a single trial, but fluticasone/salmeterol did not result in a significant reduction in exacerbations compared to either of its components. The combination of steroids and long-acting beta-agonist in one inhaler was effective in improving symptoms compared with placebo and on certain clinical outcomes compared with one of the individual components alone. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, including the assessment of the comparative effects with separate administration of the two drugs in double-dummy trials.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

The use of inhaled steroids in the management of chronic obstructive pulmonary disease (COPD) is controversially discussed. Neither the optimistic view of the 90s nor the current pessimistic view on these substances seems to be justified. It becomes apparent that a more differentiated approach, depending on the clinical situation and the cellular composition in the airways, is necessary. Patients with severe inflammation, poor lung function, and frequent exacerbations seem to benefit more from inhaled steroids. Patients in early stages of the disease with occasional symptoms only, and patients predominantly suffering from emphysema than from bronchitis seem to have no benefit from this treatment option. Special attention should be turned to mixed types with asthma-like symptoms. The combination of inhaled long-acting beta 2-mimetics and steroids seems to be of advantage; for a final judgment, however, the results of ongoing clinical trials have to be awaited.

Topics: Administration, Inhalation; Administration, Topical; Adrenergic beta-Agonists; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Double-Blind Method; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Ipratropium; Multicenter Studies as Topic; Placebos; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk; Smoking; Theophylline; Time Factors; Triamcinolone

Salmeterol/fluticasone propionate is a fixed-dose combination of the long-acting beta2-adrenoceptor agonist salmeterol and the corticosteroid fluticasone propionate and is inhaled via the Diskus powder inhaler. In three randomized, double-blind, 24-week or 52-week studies in >2850 patients with chronic obstructive pulmonary disease (COPD), administration of salmeterol/fluticasone propionate 50/250 microg twice daily (in one study) and salmeterol/fluticasone propionate 50/500 microg twice daily (in the other studies) provided greater improvement in lung function than placebo or either component alone at the same nominal dosage. Both strengths of the combination product administered twice daily resulted in clinically meaningful increases in scores in health-related quality-of-life questionnaires that were specific for respiratory disease. Improvements in this and almost all other secondary measures of efficacy, including symptomatic outcomes, were significantly greater with the combination product than with placebo. Administration of salmeterol/fluticasone propionate as a combination product did not result in any untoward interactions that affected the pharmacodynamic, pharmacokinetic or tolerability profiles of the individual components. Candidiasis, hoarseness/dysphonia, throat irritation and headache occurred more frequently with salmeterol/fluticasone propionate than with placebo in patients with COPD.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Salmeterol Xinafoate

Seretide (Advair [North America], GlaxoSmithKline) is an inhaler combination formulation intended for the maintenance therapy of obstructive airways disease. Seretide was developed and made available initially as three multi-dose, dry powder inhaler formulations delivering 50 microg/puff of the long acting beta(2) agonist salmeterol and either 100, 250 or 500 microg/puff of the inhaled corticosteroid fluticasone propionate. In addition to the initial multi-dose dry powder inhaler system (Diskus or Accuhaler), a chlorofluorocarbon (CFC)-free pressurised aerosol formulation has become available. Studied mostly extensively as a maintenance therapy for patients with persistent asthma, the combination inhaler is at least equivalent to its components administered separately and is superior to monotherapy with salmeterol or inhaled corticosteroid in both paediatric and adult populations. The combination has a logical role in the treatment of moderate-to-severe asthma, offering the advantage of increased convenience and possibly improved compliance. In addition to improvements in lung function, symptom scores and quality of life, the combination therapy reduces exacerbation rates, an outcome that contributes to favourable cost-effectiveness. A role as initial maintenance therapy in all forms of persistent asthma is also plausible but there are fewer data concerning the impact of Seretide in milder forms of persistent asthma. Clinical trials are underway to examine the potential role of Seretide in patients with chronic obstructive pulmonary disease (COPD). Salmeterol has been shown to be an effective first-line bronchodilator in COPD and fluticasone has been shown to reduce the frequency and or severity of exacerbations in COPD patients in two key trials. At a time when the prevalence of both asthma and COPD is increasing, Seretide is a valuable step in the management of these common obstructive lung diseases.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Anti-Inflammatory Agents; Clinical Trials as Topic; Drug Combinations; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

In 2019, the U.S. Food and Drug Administration (FDA) approved the first generic maintenance inhaler for asthma and chronic obstructive pulmonary disease (COPD). The inhaler, Wixela Inhub (fluticasone-salmeterol; Viatris), is a substitutable version of the dry powder inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline). When approving complex generic products like inhalers, the FDA applies a special "weight-of-evidence" approach. In this case, manufacturers were required to perform a randomized controlled trial in patients with asthma but not COPD, although the product received approval for both indications.. To compare the effectiveness and safety of generic (Wixela Inhub) and brand-name (Advair Diskus) fluticasone-salmeterol among patients with COPD treated in routine care.. A 1:1 propensity score-matched cohort study.. A large, longitudinal health care database.. Adults older than 40 years with a diagnosis of COPD.. Incidence of first moderate or severe COPD exacerbation (effectiveness outcome) and incidence of first pneumonia hospitalization (safety outcome) in the 365 days after cohort entry.. Among 45 369 patients (27 305 Advair Diskus users and 18 064 Wixela Inhub users), 10 012 matched pairs were identified for the primary analysis. Compared with Advair Diskus use, Wixela Inhub use was associated with a nearly identical incidence of first moderate or severe COPD exacerbation (hazard ratio [HR], 0.97 [95% CI, 0.90 to 1.04]) and first pneumonia hospitalization (HR, 0.99 [CI, 0.86 to 1.15]).. Follow-up times were short, reflecting real-world clinical practice. The possibility of residual confounding cannot be completely excluded.. Use of generic and brand-name fluticasone-salmeterol was associated with similar outcomes among patients with COPD treated in routine practice.. National Heart, Lung, and Blood Institute.

Topics: Administration, Inhalation; Adult; Androstadienes; Asthma; Bronchodilator Agents; Cohort Studies; Drug Combinations; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Chronic mucus hypersecretion (CMH) is a clinical phenotype of COPD. This exploratory post hoc analysis assessed relationship between CMH status and treatment response in IMPACT.. Patients were randomized to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg, FF/VI 100/25 μg or UMEC/VI 62.5/25 μg and designated CMH+ if they scored 1/2 in St George's Respiratory Questionnaire (SGRQ) questions 1 and 2. Endpoints assessed by baseline CMH status included on-treatment exacerbation rates, change from baseline in trough forced expiratory volume in 1 second, SGRQ total score, COPD Assessment Test (CAT) score, proportion of SGRQ and CAT responders at Week 52 and safety.. Of 10,355 patients in the intent-to-treat population, 10,250 reported baseline SGRQ data (CMH+: 62% [n = 6383]). FF/UMEC/VI significantly (p < 0.001) reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in CMH+ (rate ratio: 0.87 and 0.72) and CMH- patients (0.82 and 0.80). FF/UMEC/VI significantly (p < 0.05) reduced on-treatment severe exacerbation rates versus UMEC/VI in CMH+ (0.62) and CMH- (0.74) subgroups. Similar improvements in health status and lung function with FF/UMEC/VI were observed, regardless of CMH status. In CMH+ patients, FF/VI significantly (p < 0.001) reduced on-treatment moderate/severe and severe exacerbation rates versus UMEC/VI (0.83 and 0.70).. FF/UMEC/VI had a favourable benefit: risk profile versus dual therapies irrespective of CMH status. The presence of CMH did not influence treatment response or exacerbations, lung function and/or health status. However, CMH did generate differences when dual therapies were compared and the impact of CMH should be considered in future trial design.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Fluticasone; Forced Expiratory Volume; Humans; Mucus; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status.. IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed.. Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers.. FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers.. GSK (CTT116855/NCT02164513).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Given between-country differences in healthcare systems, treatment costs, and disease management guidelines, country-specific cost-effectiveness analyses are important. This study evaluated the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI among patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations from a Spanish healthcare system perspective.. Baseline data and treatment effects from the IMPACT trial were populated into the validated GALAXY COPD progression model. Utilities were estimated using Spanish observational data. Direct healthcare costs (2019 €) were informed by Spanish public sources. A 3% discount rate for costs and benefits was applied. The time horizon and treatment duration were 3 years (base case). One-way sensitivity, scenario, and probabilistic sensitivity analyses were performed.. FF/UMEC/VI treatment resulted in fewer exacerbations over 3 years (4.130 vs 3.648) versus FF/VI, with a mean (95% confidence interval [CI]) incremental cost of €444 (€149, €713) per patient and benefit of 0.064 (0.053, 0.076) quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of €6887 per QALY gained. FF/UMEC/VI was a dominant treatment strategy versus UMEC/VI, resulting in fewer exacerbations (4.130 vs 3.360), with a mean (95% CI) incremental cost of -€450 (-€844, -€149) and benefit of 0.054 (0.043, 0.064) QALYs. FF/UMEC/VI was cost-effective versus FF/VI and UMEC/VI across all analyses.. FF/UMEC/VI was predicted to be a cost-effective treatment option versus FF/VI or UMEC/VI in symptomatic COPD patients at risk of exacerbations in Spain, across all scenarios and sensitivity analyses.

Topics: Administration, Inhalation; Benzyl Alcohols; Chlorobenzenes; Cost-Benefit Analysis; Drug Combinations; Fluticasone; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Spain

There is an emerging role for blood eosinophil count (EOS) as a biomarker to guide inhaled corticosteroid (ICS) therapy in COPD. Since ICS administration could influence EOS, we hypothesised that change in EOS following treatment with ICS may predict outcomes of long-term therapy.In a

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Leukocyte Count; Male; Middle Aged; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Retrospective Studies

Exacerbations account for the greatest proportion of costs associated with chronic obstructive pulmonary disease (COPD). Here we aimed to evaluate, from the US payer perspective, the costs associated with moderate and severe COPD exacerbation events for patients treated with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) compared with FF/VI or UMEC/VI.. This post hoc, within-trial economic analysis used data derived from the InforMing the PAthway of COPD Treatment (IMPACT) study (NCT02164513).. Treatment groups within the IMPACT trial received either triple therapy with FF/UMEC/VI (100/62.5/25 mcg) or dual therapy (FF/VI [100/25 mcg] or UMEC/VI [62.5/25 mcg]). The primary end point for this IMPACT post hoc analysis was cost differences between the treatment arms related to 1-year on-treatment combined moderate and severe COPD exacerbation events.. The final study sample for this within-trial analysis consisted of 10,355 patients, 49% of whom experienced an on-treatment moderate or severe exacerbation during the study. The mean 1-year on-treatment cost estimate associated with combined moderate and severe exacerbations was highest with UMEC/VI and lowest with FF/UMEC/VI ($6205 vs $4913, respectively). Mean cost differences were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI (-$549 [95% CI, -$565 to -$533] and -$1292 [95% CI, -$1313 to -$1272], respectively; both P <.0001).. Treatment with FF/UMEC/VI compared with FF/VI or UMEC/VI in the US healthcare system resulted in lower exacerbation-related costs for combined moderate/severe exacerbation events, as well as moderate and severe exacerbations separately.

Topics: Administration, Inhalation; Adult; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Respiratory Function Tests; Severity of Illness Index

Chronic obstructive pulmonary disease exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n = 457) from the FLAME (Effect of Indacaterol Glycopyrronium vs. Fluticasone Salmeterol on COPD Exacerbations) study used the Exacerbations of COPD Tool (EXACT) to capture symptom-defined exacerbations.. To evaluate the effect of indacaterol/glycopyrronium versus salmeterol/fluticasone on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU).. All patients in FLAME used an electronic diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery, and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time to first symptom-defined (EXACT) exacerbation and assessed differences between symptom-defined and HCRU events in terms of number, severity, and concordance.. A nonsignificant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio, 0.83; 95% confidence interval [CI], 0.60-1.14; P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with indacaterol/glycopyrronium versus salmeterol/fluticasone (hazard ratio, 0.76; 95% CI, 0.56-1.03; P = 0.075). These results were consistent with data from the overall FLAME population. Of the symptom-defined (EXACT) events, 23.5% corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (κ index, 0.24; 95% CI, 0.15-0.33).

Topics: Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Risk Factors; Salmeterol Xinafoate; Surveys and Questionnaires

COPD patients have challenges for effective use of inhalers due to advanced age, fixed airflow obstruction and comorbid medical conditions. Published clinical trials investigate drug efficacy but rarely consider the inhaler device. This trial investigates device efficacy, comparing clinical outcomes for the same medication via two different devices. Our intention was to communicate the results and to critically appraise the study protocol to inform planning of future device comparison research. Subjects with spirometry confirming at least moderate COPD were randomly assigned to inhaler sequence; starting with Accuhaler or metered dose inhaler and spacer (MDI/s). After baseline testing, subjects were assigned to fluticasone propionate/salmeterol xinafoate (SFC) 500/50 mcg twice daily via the first device for 6 weeks' duration, then changed to the alternate device for the following 6 weeks. Subjects were reassessed in terms of health-related quality of life (HRQL), exercise endurance and lung function after each exposure period.. The recruitment target was not achieved due to unanticipated developments within the pharmaceutical industry, potentially compromising the study's power. Study outcomes did not differ significantly according to the allocated inhaler device even after adjusting for baseline lung function or inhaler technique. Recommendations for future device comparison protocols are offered. Trial registration Australia and New Zealand Clinical Trials Registry, Current Controlled Trials ACTRN12618000075280, date of registration: 18.01.2018. Retrospectively registered.

Topics: Aged; Bronchodilator Agents; Cross-Over Studies; Female; Fluticasone; Humans; Male; Metered Dose Inhalers; Middle Aged; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Single-Blind Method

Directly recorded patient experience of symptoms and health-related quality of life (HRQoL) can complement lung function and exacerbation rate data in chronic obstructive pulmonary disease (COPD) clinical studies. The FULFIL study recorded daily symptoms and activity limitation together with additional patient-reported outcomes of dyspnea and HRQoL, as part of the prespecified analyses. FULFIL co-primary endpoint data have been previously reported.. FF/UMEC/VI showed greater reductions from baseline in 4-weekly mean E-RS: COPD total and all subscale scores compared with BUD/FOR; differences were statistically significant (P < 0.05) at each time period. FF/UMEC/VI also demonstrated greater improvements from baseline at weeks 4 and 24 in SGRQ domain scores and TDI focal score compared with BUD/FOR. At weeks 4 and 24, improvements greater than the minimal clinically important difference from baseline were observed in CAT score with FF/UMEC/VI, but not BUD/FOR; differences were statistically significant (P ≤ 0.003).. These findings demonstrate sustained daily symptom and HRQoL benefits of FF/UMEC/VI versus BUD/FOR. The inclusion of the CAT may provide data that are readily generalizable to everyday clinical practice.. ClinicalTrials.gov number: NCT02345161.. GSK.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Chlorobenzenes; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Dyspnea; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Surveys and Questionnaires

Topics: Adult; Aged; Benzyl Alcohols; Chlorobenzenes; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Switzerland

Use of inhaled corticosteroids (ICS) increases the risk of pneumonia in chronic obstructive pulmonary disease (COPD), but the magnitude of risk with different ICS remains unclear.. A post hoc analysis of the 4-year UPLIFT® trial to assess whether pneumonia risk differed by type of ICS (fluticasone propionate [FP], other ICS, or no ICS) in permanent users (defined by use until end of study) or in users at baseline (sensitivity analysis).. For the permanent-users analysis, 825 patients receiving FP throughout the trial, 825 patients receiving other ICS and 825 patients not receiving ICS were matched on relevant baseline features 1:1:1. A significantly greater risk of pneumonia was observed for FP versus no ICS: the hazard ratio (HR) for risk of pneumonia was 1.33 (95% confidence interval [CI] 1.00, 1.75; p = 0.046) and the rate ratio (RR) was 1.58 (95% CI 1.05, 2.37; p = 0.028). A greater risk was also found for FP versus other ICS: HR 1.28 (95% CI 0.97, 1.68; p = 0.078) and RR 1.48 (95% CI 1.00, 2.19; p = 0.049). A higher proportion of patients on FP were hospitalized with pneumonia (7.9%) versus other ICS (6.7%) or no ICS (5.9%). Whilst other ICS use was associated with the highest number of fatal pneumonia events, the total number of fatal pneumonia incidents was low. A similar pattern was observed in the sensitivity analyses, which included 4002 patients on different treatments at baseline (FP, other ICS, and no ICS) and considered potential switches during the study.. The results support existing evidence of an increased pneumonia risk with FP use compared with other ICS and no ICS use in patients with COPD. Healthcare professionals should evaluate the risk-benefit ratio of using ICS when making treatment decisions with their patients.. Post hoc analysis of UPLIFT®. ClinicalTrials.gov number: NCT00144339 . Retrospectively registered September 2, 2005.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Research Design; Risk Factors; Tiotropium Bromide

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1 s (FEV. Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV. Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8 weeks after the event.. WISDOM (ClinicalTrials.gov number, NCT00975195 ).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Spirometry; Tiotropium Bromide

Inhaled corticosteroid-containing medications reduce the frequency of COPD exacerbations (mainly infectious in origin) while paradoxically increasing the risk of other respiratory infections

Topics: Administration, Inhalation; Bacterial Load; Bronchodilator Agents; Drug Monitoring; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Long Term Adverse Effects; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Respiratory Tract Infections; Salmeterol Xinafoate; Sputum; Treatment Outcome; Viral Load

These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed.. At week 24, differences in change from baseline in the morning predose trough FEV. We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD.. ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Antagonists; Prednisone; Pulmonary Disease, Chronic Obstructive; Suspensions; Vital Capacity

Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD.In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 µg twice daily), 30-month treatment with fluticasone/salmeterol (500/50 µg twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models.In patients using ICS during GL1 and using ICS 0-50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchi; Bronchodilator Agents; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Inflammation; Linear Models; Male; Middle Aged; Netherlands; Neutrophils; Pulmonary Disease, Chronic Obstructive; Sputum; Withholding Treatment

Bronchodilator therapy is the backbone of the management of chronic obstructive pulmonary disease. In some patients, inhaled corticosteroids can be prescribed in combination with bronchodilators. Through a subgroup analysis of pooled data from two large phase III clinical trials of bronchodilator therapy according to concomitant inhaled corticosteroid use (user vs. non-user), we sought to evaluate the clinical benefit of adding inhaled corticosteroids to dual bronchodilator therapy in chronic obstructive pulmonary disease. The primary focus of this analysis of pooled data from the phase III ACLIFORM and AUGMENT studies was to evaluate the efficacy of aclidinium/formoterol on lung function stratified by inhaled corticosteroid use. We found that lung-function end points were significantly improved regardless of concomitant inhaled corticosteroid use among patients treated with the dual bronchodilator aclidinium/formoterol 400/12 µg twice daily compared with placebo and both monotherapies. Together with the previously reported observations that aclidinium/formoterol 400/12 µg reduces exacerbations vs. placebo in inhaled corticosteroid users and improves dyspnoea compared to monotherapy in inhaled corticosteroid non-users, these data suggest that both groups achieve lung function improvements, which translates to different clinical benefits depending on whether or not a patient is receiving concomitant inhaled corticosteroids.CHRONIC LUNG DISEASE: 'TRIPLE' THERAPY COULD PROVE BENEFICIAL: A dual bronchodilator therapy taken together with corticosteroid inhalers may benefit patients with severe chronic lung disease. Bronchodilator drugs relax the lungs and widen airways in patients with chronic obstructive pulmonary disease (COPD). While recent studies have shown that a dual bronchodilator therapy containing aclidinium and formoterol significantly improves lung function in COPD, little is known about combining the dual therapy with inhaled corticosteroids (ICSs). Anthony D'Urzo at the University of Toronto, Canada, and co-workers analysed data from 3394 patients with COPD undergoing dual therapy trials. Of these, 1180 were already taking ICSs. The team compared symptoms in the ICS group with those not taking ICSs. The dual therapy improved lung function across both groups regardless of ICS use, though patients gained different clinical benefits depending on ICS use and disease severity.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Beclomethasone; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Dyspnea; Female; Fluticasone; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tropanes

The place of combinations of bronchodilators (longacting beta-agonist / muscarinic agonist or LABA / LAMA) in the prevention of the exacerbations of the chronic obstructive pulmonary disease (COPD) is not still clearly established, and need a comparison with combination of LABA/ inhaled steroids. FLAME was a randomized non-inferiority phase 3 study comparing indacaterol/glycopyrronium 110/50 μg (IND/GLY) once daily with salmeterol/proprionate of fluticasone 50/500 μg (SAL/FC) twice daily. The primary objective of the study was to demonstrate that IND/GLY was non-inferior to SAL/FC in terms of reduction of all COPD exacerbations (mild/moderate/severe) during 52 weeks of treatment in patients having had at least 1 exacerbation in previous 12 months. The combination IND/GLY showed not only non inferiority, but also superiority, to SAL/FC in reducing the annual rate of all COPD exacerbations (mild, moderate, or severe) by 11 % by comparison with SAL/FC (p = 0.003), and by 17 % for the annual rate of moderate or severe exacerbations (p inferior to 0.001). IND/GLY prolonged the time to the first COPD exacerbation by 16 % for mild, 22 % for moderate and 19 % for severe by comparison with SAL/FC (all with p inferior to 0.05). FLAME study showed that IND/GLY, a steroid-free option, is more effective than SAL/FC in preventing COPD exacerbations in patients with one or more exacerbations in the past year.. Résumé : La place des associations de bronchodilatateurs (bêta-2 mimétiques /anticholinergiques à longue durée d’action ou LABA/LAMA) dans la prévention des exacerbations de la broncho-pneumopathie chronique obstructive (BPCO) n’est pas encore clairement établie, et nécessite une comparaison avec les associations de LABA/corticostéroïdes inhalés (CSI). FLAME est une étude randomisée de non-infériorité, de phase 3, comparant l’association indacatérol/glycopyrronium 110/50 μg (IND/GLY) 1/jour au salmétérol/propionate de fluticasone 50/500 μg (SAL/FC) 2/jour, d’une durée de 52 semaines. Le critère d’investigation principal est de démontrer que l’IND/GLY n’est pas inférieur au SAL/FC dans la réduction du taux d’exacerbations (légères/modérées/sévères) de patients BPCO ayant eu au moins une exacerbation dans les 12 mois qui précèdent. L’IND/GLY s’est révélée non seulement non inférieure, mais est aussi supérieure, à l’association SAL/FC dans la réduction du taux des exacerbations (légères, modérées et sévères) avec une réduction de 11 % par rapport à l’association SAL/FC (p 0,003) et de 17 % pour les exacerbations modérées ou sévères (p inférieur à 0,001). L’association IND/ GLY augmente le temps avant la première exacerbation de 16 % pour les légères, de 22 % pour les modérées et de 19 % pour les sévères par rapport au SAL/FC (toutes différences avec un p inférieur à 0,05). L’étude FLAME a montré qu’IND/GLY, une option sans CSI, est plus efficace que l’association SAL/FC pour la prévention des exacerbations de BPCO chez des patients ayant eu au moins une exacerbation l’année qui précède.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Female; Fluticasone; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate; Treatment Outcome

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Severity of Illness Index; Tiotropium Bromide; Withholding Treatment

Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.. The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.. This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat(®) and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler(®) for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.. Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).. Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Female; Fluticasone; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Identification of a biomarker that predicts response to inhaled corticosteroids (ICS) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease (COPD) and guide treatment.The ISOLDE study randomised 751 patients (mean post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.4 L: 50% predicted normal) to fluticasone propionate 500 μg twice daily or placebo for 3 years, finding no difference in FEV1 rate of decline between treatments (p=0.16) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo (p=0.026). We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit.Patients with eosinophils <2% (n=456) had a similar rate of post-bronchodilator FEV1 decline with fluticasone propionate as placebo (-2.9 mL·year(-1); p=0.688). With eosinophils ≥2% (n=214), the rate of decline decreased by 33.9 mL·year(-1) with fluticasone propionate versus placebo (p=0.003). Exacerbation rate reduction on ICS for fluticasone propionate versus placebo was higher in the eosinophil <2% group compared with the ≥2% group; time-to-first moderate/severe exacerbation was not different between treatments in either group.A baseline blood eosinophil count of ≥2% identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS: prospective testing of this hypothesis is now warranted.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Bronchodilator Agents; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Retrospective Studies; Smoking

Blood eosinophil counts might predict response to inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn.. WISDOM was a 12-month, randomised, parallel-group trial in which patients received 18 μg tiotropium, 100 μg salmeterol, and 1000 μg fluticasone propionate daily for 6 weeks and were then randomly assigned (1:1) electronically to receive either continued or reduced ICS over 12 weeks. We did a post-hoc analysis after complete ICS withdrawal (months 3-12) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels. The WISDOM trial is registered at ClinicalTrials.gov, number NCT00975195.. In the 2296 patients receiving treatment after ICS withdrawal, moderate or severe exacerbation rate was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts (out of total white blood cell count) of 2% or greater (rate ratio 1·22 [95% CI 1·02-1·48]), 4% or greater (1·63 [1·19-2·24]), and 5% or greater (1·82 [1·20-2·76]). The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose, with significant treatment-by-subgroup interaction reached for 4% and 5% only. Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL, and mutually exclusive subgroups.. Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations. Our data suggest that counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal, an effect not seen in most patients with eosinophil counts below these thresholds.. Boehringer Ingelheim.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Female; Fluticasone; Humans; Leukocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome; Withholding Treatment

Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk.. In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40-80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or the combination of fluticasone furoate (100 μg) and vilanterol (25 μg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676.. Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74-1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77-1·08]; p=0·284; vilanterol, 0·96 [0·81-1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1-15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1-14]), but not vilanterol (difference -2 mL per year [95% CI -8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75-1·14]) with similar findings for fluticasone furoate (0·90 [0·72-1·11]) and vilanterol (0·99 [0·80-1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups.. In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline.. GlaxoSmithKline.

Topics: Adult; Aged; Aged, 80 and over; Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Treatment Outcome

Topics: Adrenergic beta-2 Receptor Agonists; Double-Blind Method; Drug Combinations; Fluticasone; Glycopyrrolate; Guideline Adherence; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate

The WISDOM study (NCT00975195) reported a change in lung function following withdrawal of fluticasone propionate in patients with severe to very severe COPD treated with tiotropium and salmeterol. However, little is known about the validity of home-based spirometry measurements of lung function in COPD. Therefore, as part of this study, following suitable training, patients recorded daily home-based spirometry measurements in addition to undergoing periodic in-clinic spirometric testing throughout the study duration. We subsequently determined the validity of home-based spirometry for detecting changes in lung function by comparing in-clinic and home-based forced expiratory volume in 1 second in patients who underwent stepwise fluticasone propionate withdrawal over 12 weeks versus patients remaining on fluticasone propionate for 52 weeks. Bland-Altman analysis of these data confirmed good agreement between in-clinic and home-based measurements, both across all visits and at the individual visits at study weeks 6, 12, 18, and 52. There was a measurable difference between the forced expiratory volume in 1 second values recorded at home and in the clinic (mean difference of -0.05 L), which may be due to suboptimal patient effort in performing unsupervised recordings. However, this difference remained consistent over time. Overall, these data demonstrate that home-based and in-clinic spirometric measurements were equally valid and reliable for assessing lung function in patients with COPD, and suggest that home-based spirometry may be a useful tool to facilitate analysis of changes in lung function on a day-to-day basis.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Drug Administration Schedule; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Observer Variation; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Self Care; Severity of Illness Index; Spirometry; Time Factors; Treatment Outcome; Vital Capacity

This study assessed the effects of inhaled corticosteroid (ICS) on airway vascular remodeling in chronic obstructive pulmonary disease (COPD).. Thirty-four subjects with mild-to-moderate COPD were randomly allocated 2:1 to ICS or placebo treatment in a double-blinded clinical trial over 6 months. Available tissue was compared before and after treatment for vessel density, and expression of VEGF, TGF-β1, and TGF-β1-related phosphorylated transcription factors p-SMAD 2/3. This clinical trial has been registered and allocated with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 17/10/2012 with reference number ACTRN12612001111864.. There were no significant baseline differences between treatment groups. With ICS, vessels and angiogenic factors did not change in hypervascular reticular basement membrane, but in the hypovascular lamina propria (LP), vessels increased and this had a proportionate effect on lung air trapping. There was modest evidence for a reduction in LP vessels staining for VEGF with ICS treatment, but a marked and significant reduction in p-SMAD 2/3 expression.. Six-month high-dose ICS treatment had little effect on hypervascularity or angiogenic growth factors in the reticular basement membrane in COPD, but normalized hypovascularity in the LP, and this was physiologically relevant, though accompanied by a paradoxical reduction in growth factor expression.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents; Australia; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Humans; Lung; Male; Middle Aged; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Smad2 Protein; Smad3 Protein; Time Factors; Transforming Growth Factor beta1; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Remodeling

We previously observed that 30 months of inhaled corticosteroid (ICS) treatment can attenuate FEV1 decline in COPD, but it is unclear whether withdrawal induces a relapse. We hypothesized that FEV1 decline, airway hyperresponsiveness (AHR), and quality of life (QOL) deteriorate after ICS cessation even after prolonged use.. One hundred fourteen patients with moderate to severe COPD finished randomized 6-month or 30-month treatment with fluticasone (500 μg bid), 30-month treatment with fluticasone and salmeterol (500/50 μg bid), or placebo (first part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease [GLUCOLD] study [GL1]). The subsequent 5 years, patients were prospectively followed annually, treated by their physician (GLUCOLD follow-up study [GL2]). Postbronchodilator FEV1, AHR, and QOL were initially recorded at baseline, at 30 months (GL1), and annually during GL2. Analysis was performed by linear mixed-effects models.. Among 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICSs during GL1, but only using ICSs 0% to 50% of the time during GL2 (n = 56 of 79), had significantly accelerated annual FEV1 decline compared with GL1 (difference GL2-GL1 [95% CI]: 30-month treatment with fluticasone and salmeterol, -68 mL/y [-112 to -25], P = .002; 30-month treatment with fluticasone, -73 mL/y [-119 to -26], P = .002), accompanied by deterioration in AHR and QOL.. ICS discontinuation after 30 months in COPD can worsen lung function decline, AHR, and QOL during 5-year follow-up. This suggests that ICS treatment lacks sustained disease-modifying effect after treatment cessation.. ClinicalTrials.gov; No.: NCT00158847; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cohort Studies; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recurrence; Withholding Treatment

The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA).. This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone.. 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively.. GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP.. NCT01513460.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Australia; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glycopyrrolate; Health Status; Humans; Male; Middle Aged; New Zealand; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Glycopyrrolate; Indans; Lung Volume Measurements; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate

Inhaled corticosteroid/long-acting β2-agonist combination therapy is recommended in chronic obstructive pulmonary disease (COPD) patients at high risk of exacerbations. The EFFECT (Efficacy of Fluticasone propionate/FormotErol in COPD Treatment) trial is a Phase III, 52-week, randomized, double-blind study to evaluate the efficacy and safety of two doses of fluticasone propionate/formoterol compared to formoterol monotherapy in COPD patients with FEV1 ≥50% predicted and a history of exacerbations. The primary endpoint is the annualized rate of moderate and severe exacerbations. Secondary endpoints include pre-dose FEV1, EXACT-PRO (EXAcerbations of Chronic pulmonary disease Tool - Patient-Reported Outcome)-defined exacerbations, St George's Respiratory Questionnaire for COPD, COPD Assessment Test, and EXACT-Respiratory Symptoms total score. Lung-specific biomarkers (surfactant protein D and CC chemokine ligand-18) will be measured in a subset of patients to explore their relationship to other clinical indices in COPD and their predictive utility. Pneumonia will be diagnosed per criteria defined by the British Thoracic Society community acquired pneumonia guideline, primarily by radiological confirmation and, additionally, using clinical criteria when a chest radiograph cannot be obtained. Serial measurements of serum potassium, vital signs and electrocardiograms, 24-hour Holter monitoring, and 24-hour urinary cortisol measurement will be performed in a subset of patients in addition to conventional safety assessments.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Androstadienes; Biomarkers; Bronchodilator Agents; Chemokines, CC; Clinical Protocols; Disease Progression; Double-Blind Method; Drug Combinations; Ethanolamines; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Recovery of Function; Research Design; Spirometry; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vital Capacity

The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD.. Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30-80% of predicted, compatible with GOLD stages II-III), age 45-75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study.. Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04).. Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD.. ClinicalTrials.gov NCT00158847.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Drug Administration Schedule; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Phenotype; Placebo Effect; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry; Sputum; Treatment Outcome

Regular treatment with inhaled corticosteroids (ICS) is known to reduce airway hyperresponsiveness (AHR) to adenosine 5'-monophosphate (AMP) in asthma even after a single dose of fluticasone propionate (FP).. To determine whether this rapid protective effect of a single dose of FP is also present in COPD.. 23 mild asthmatic and 24 COPD subjects with documented AHR to both AMP and methacholine took part in a randomized, double-blind, placebo-controlled, crossover study to measure AHR to inhaled AMP and methacholine 2 h after either 1000 μg FP or matched placebo.. In subjects with asthma, 1000 μg FP in a single dose significantly attenuated the constrictor response to AMP, geometric mean (range) PC20AMP values increasing from a 19.2 (1.3-116.3) to 81.5 (9.6-1600.0) (p < 0.001; post-placebo vs post-FP) mg/ml. Change in the airways response to inhaled AMP after FP was well within test variability in patients with COPD, with PC20AMP values 59.6 (11.3-183.9) and 76.3 (21.0-445.3) (p = 0.022; post-placebo vs post-FP) mg/ml. Additionally, FP failed to significantly attenuate the bronchial response to methacholine in both asthma and COPD subjects. A change in doubling dilution, between placebo and following a single dose of FP, in AMP had a better sensitivity and specificity of 95.8% and 65.2%, compared to methacholine of 79.2% and 43.5% respectively in delineating between COPD and asthma.. A single dose of 1000 μg FP rapidly improves AHR to AMP in asthmatics but not in COPD subjects. This may provide a convenient way by which provocation challenge with inhaled AMP may help in discriminating asthma from COPD.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adult; Aged; Androstadienes; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Humans; Male; Methacholine Chloride; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sensitivity and Specificity

A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV1). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone±salmeterol by reducing the rate of FEV1 decline, yet the underlying mechanisms are unknown.. Whole-genome gene expression profiling using the Affymetrix Gene ST array (V.1.0) was performed on 221 bronchial biopsies available from 89 COPD patients at baseline and after 6 and 30 months of fluticasone±salmeterol and placebo treatment in GLUCOLD.. Linear mixed effects modelling revealed that the expression of 138 genes decreased, whereas the expression of 140 genes significantly upregulated after both 6 and 30 months of treatment with fluticasone±salmeterol versus placebo. A more pronounced treatment-induced change in the expression of 50 and 55 of these 278 genes was associated with a lower rate of decline in FEV1 and Saint George Respiratory Questionnaire, respectively. Genes decreasing with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signalling, p53 signalling and T cell signalling. Genes increasing with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Finally, the fluticasone-induced gene expression changes were enriched among genes that change in the airway epithelium in smokers with versus without COPD in an independent data set.. The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and molecular phenotype-driven therapy of COPD.

Topics: Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Gene Expression Profiling; Humans; Male; Middle Aged; Phenotype; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Time Factors; Up-Regulation

We recently reported that epithelial-mesenchymal transition (EMT) is active in the airways in chronic obstructive pulmonary disease (COPD), suggesting presence of an active profibrotic and promalignant stroma. With no data available on potential treatment effects, we undertook a blinded analysis of inhaled corticosteroids (ICS) effects versus placebo on EMT markers in previously obtained endobronchial biopsies in COPD patients, as a "proof of concept" study.. Assessment of the effects of inhaled fluticasone propionate (FP; 500 μg twice daily for 6 months) versus placebo in 34 COPD patients (23 on fluticasone propionate and eleven on placebo). The end points were epidermal growth factor receptor (EGFR; marker of epithelial activation) and the biomarkers of EMT: reticular basement membrane (Rbm) fragmentation ("hallmark" structural marker), matrix metalloproteinase-9 (MMP-9) cell expression, and S100A4 expression in basal epithelial and Rbm cells (mesenchymal transition markers).. Epithelial activation, "clefts/fragmentation" in the Rbm, and changes in the other biomarkers all regressed on ICS, at or close to conventional levels of statistical significance. From these data, we have been able to nominate primary and secondary end points and develop power calculations that would be applicable to a definitive prospective study.. Although only a pilot "proof of concept" study, this trial provided strong suggestive support for an anti-EMT effect of ICS in COPD airways. A larger and fully powered prospective study is now indicated as this issue is likely to be extremely important. Such studies may clarify the links between ICS use and better clinical outcomes and protection against lung cancer in COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Airway Remodeling; Androstadienes; Australia; Biomarkers; Double-Blind Method; Drug Administration Schedule; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Fluticasone; Humans; Lung; Male; Matrix Metalloproteinase 9; Middle Aged; Pilot Projects; Prospective Studies; Pulmonary Disease, Chronic Obstructive; S100 Calcium-Binding Protein A4; S100 Proteins; Treatment Outcome

We recently published that platelet-activating factor receptor (PAFr) is upregulated on the epithelium of the proximal airways of current smokers and also in bronchial epithelial cells exposed to cigarette smoke extract. These treated cells also showed upregulation of Streptococcus pneumoniae adhesion. Bacterial wall phosphorylcholine specifically binds to PAFr expressed on airway epithelium, thus facilitating adherence and tissue invasion, which may be relevant to chronic obstructive pulmonary disease (COPD). Moreover, the use of inhaled corticosteroids (ICS) in COPD patients is associated with an increased risk of invasive respiratory pneumococcal infections.. In this study, we have investigated whether PAFr expression is especially upregulated in airway epithelium in COPD patients and whether this expression may be modulated by ICS therapy.. We cross-sectionally evaluated PAFr expression in bronchial biopsies from 15 COPD patients who were current smokers (COPD-smokers) and 12 COPD-ex-smokers, and we compared these to biopsies from 16 smokers with normal lung function. We assessed immunostaining with anti-PAFr monoclonal antibody. We also used material from a previous double-blinded randomized placebo-controlled 6-month ICS intervention study in COPD patients to explore the effect of ICS on PAFr expression. We employed computer-aided image analysis to quantify the percentage of epithelium stained for PAFr.. Markedly enhanced expression of PAFr was found in both COPD-smokers (P<0.005) and COPD-ex-smokers (P<0.002) compared to smokers with normal lung function. There was little evidence that PAFr expression was affected by ICS therapy over 6 months.. Epithelial PAFr expression is upregulated in smokers, especially in those with COPD, and is not obviously affected by ICS therapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Androstadienes; Biopsy; Bronchi; Cross-Sectional Studies; Epithelial Cells; Female; Fluticasone; Humans; Image Interpretation, Computer-Assisted; Immunohistochemistry; Male; Middle Aged; Platelet Membrane Glycoproteins; Pulmonary Disease, Chronic Obstructive; Receptors, G-Protein-Coupled; Smoking; Smoking Cessation; Smoking Prevention; Time Factors; Treatment Outcome; Up-Regulation; Young Adult

This study focused on repeatability data and minimal important difference (MID) estimates of the endurance shuttle walking test (ESWT). 255 chronic obstructive pulmonary disease patients (forced expiratory volume in 1 s 54.7±13.2% predicted) completed four ESWTs at different times during the 8-week study: two under baseline conditions with tiotropium (1 week apart), one after a single dose and one after 4 weeks of either fluticasone propionate/salmeterol combination or placebo in addition to tiotropium. 97 patients performed all the tests with a portable metabolic system. Reproducibility of test performance and cardiorespiratory response was investigated with the data obtained on the first two ESWTs. The mean differences between the first two ESWT performances (-6.7±72.2 s and -7.3±113.1 m for endurance time and walking distance, respectively) were not statistically significant. The between-test end-exercise and isotime values for each cardiorespiratory parameter were not significantly different from each other. With the exception of arterial oxygen saturation by pulse oximetry, the repeatability of cardiorespiratory adaptations to ESWT was also confirmed with strong Pearson and intraclass correlation coefficients. Finally, changes of 56-61 s and 70-82 m in endurance time and distance walked, respectively, were perceived by patients. This study provides methodological information supporting the reliability of the ESWT and suggests MID estimates for this test.

Topics: Aged; Androstadienes; Anthropometry; Bronchodilator Agents; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Scopolamine Derivatives; Tiotropium Bromide; Walking

Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored.. In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored.. As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P<0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group.. In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.).

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Withholding Treatment

Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed-dose combination of indacaterol (IND), a long-acting β2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults.. To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium (IND + GLY), and with the fixed-dose combination of salmeterol/fluticasone (SFC), in a moderate-to-severe COPD population with low-exacerbation risk. The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality-adjusted life year.. Assuming equal efficacy, a cost-minimisation analysis compared IND/GLY vs IND + GLY using model inputs from the double-blind, randomised SHINE trial. The double-blind, randomised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC. To consider ICS-related pneumonia events, published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used. Direct and indirect drug costs as well as drug acquisition costs (in Swedish Krona [SEK]) were derived from published Swedish sources. Cost and effects were discounted with 3%. Uncertainty was assessed by one-way and probabilistic sensitivity analyses (PSA).. IND/GLY was cost-saving vs IND + GLY with incremental savings of SEK (EUR) 768 (85), and 3309 (368) per patient over one and five years. IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK (EUR) 2744 (303), 8854 (976), 13,938 (1536), 27,495 (3031) and 43,033 (4744) over one, three, five, ten years and lifetime. The PSA indicated that all iterations produced dominant results for IND/GLY.. IND/GLY is cost-minimising vs IND + GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden. Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Double-Blind Method; Drug Combinations; Drug Costs; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Monte Carlo Method; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate; Sweden

To compare the difference in clinical efficacy on chronic obstructive pulmonary disease (COPD) at stable stage in the patients among the combined therapy of cutting method and western medication (combined therapy), simple cutting method and simple western medication.. One hundred and twenty cases of COPD were randomized into three groups, 40 cases in each one. In the cutting method group, for excessive phlegm pattern/syndrome, Feishu (BL 13), Danzhong (CV 17), Dingchuan (EX-B 1) and Yuji (LU 10) were selected as the main acupoints, and Lieque (LU 7) and Pianli (LI 6) were as the supplementary acupoints. For the pattern/syndrome of failure to consolidate kidney primary, Shenshu (BL 23), Pishu (BL 20), Guanyuan (CV 4) and Yuji (LU 10) were selected as main acupoints, and Jueyinshu (BL 14) and Zusanli (ST 36) were as the supplementary acupoint. Three acupoints were selected alternatively in each treatment and the cutting method was applied once every 10 days. Three treatments made one session. Two sessions of treatment were required. In the western medication group, salbutamol sulfate aerosol, one press (200 μg/press) was used each night, as well as salmeterol xinafoate and fluticasone propionate powder for inhalation, one inhalation each night. The treatment of 1 month made one session. Two sessions were required. In the combined therapy group, the cutting method and western medication were applied in combination. The results of clinical symptom score, lung function test, arterial blood gas analysis, degree of inflation as well as clinical efficacy were observed before and after treatment in each group.. Except the degree of lung inflation, the clinical symptom score, indices of lung function test, partial pressure of arterial blood gas (PaO2) and partial pressure of carbon dioxide (PaCO2) were all obviously improved after treatment as compared with those before treatment in each group (all P<0.05). They were apparently improved after treatment in the combined therapy group and the cutting method group as compared with those in the western medication group (all P<0.05). The total effective rate was 77.5% (31/40) in the combined therapy group and was 75.0% (30/40) in the cutting method group, both better than 60.0% (24/40) in the western medication group (both P<0.05).. The simple cutting method based on syndrome differentiation and the combined therapy with western medication achieve the superior efficacy on COPD at stable stage as compared with the simple western medication. The effect mechanism is possibly related to the improvement of bronchial airway function through constant acupoint stimulation.

Topics: Acupuncture Points; Acupuncture Therapy; Aged; Albuterol; Androstadienes; Combined Modality Therapy; Female; Fluticasone; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD), which involves changes in extracellular matrix. This is thought to contribute to airway remodeling and airflow obstruction. We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation, but can also attenuate lung function decline in moderate-severe COPD. We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD.. To compare major extracellular matrix components (elastic fibers; proteoglycans [versican, decorin]; collagens type I and III) in bronchial biopsies 1) after 30-months inhaled steroids treatment or placebo; and 2) between current and ex-smokers with COPD.. We included 64 moderate-severe, steroid-naive COPD patients (24/40 (ex)-smokers, 62±7 years, 46 (31-54) packyears, post-bronchodilator forced expiratory volume in one second (FEV1) 62±9% predicted) at baseline in this randomized, controlled trial. 19 and 13 patients received 30-months treatment with fluticasone or placebo, respectively. Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content. Percentage and density of stained area were calculated by digital image analysis.. 30-Months inhaled steroids increased the percentage stained area of versican (9.6% [CI 0.9 to 18.3%]; p = 0.03) and collagen III (20.6% [CI 3.8 to 37.4%]; p = 0.02) compared to placebo. Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment (Rs = 0.45, p = 0.04). There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins.. These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD. This is associated with increased lung function, suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD. Smoking status is not associated with bronchial extracellular matrix proteins.. ClinicalTrials.gov NCT00158847.

Topics: Administration, Inhalation; Adult; Androstadienes; Biopsy; Bronchi; Collagen Type I; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fluticasone; Forced Expiratory Volume; Humans; Immunohistochemistry; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Smoking; Steroids

To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist.. Observational retrospective pairwise cohort study matched (1:1) for propensity score.. Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009.. Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol.. Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality.. 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each. In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19,170 patient years of follow up. Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol: rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively. The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6). The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003). All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59).. There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD.. Clinical Trials.gov NCT01146392.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Budesonide; Cohort Studies; Ethanolamines; Fluticasone; Formoterol Fumarate; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Triple inhalation therapy with tiotropium (Tio) and salmeterol/fluticasone propionate combination (SFC) is widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the effects of triple therapy on airway structural changes remain unknown.. The aim of the study was to assess the effects of Tio, salmeterol (SM), SFC and Tio plus SFC on airway dimensions in COPD.. A randomized, open-label, 4-way study (n = 60) was conducted comparing 16-week treatment periods of Tio (18 μg once daily), SM (50 μg twice daily), SFC (50/250 μg twice daily) and Tio (18 μg once daily) plus SFC (50/250 μg twice daily). Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/√BSA and luminal area (Ai)/BSA at the right apical segmental bronchus were measured. Pulmonary function and the St. George's Respiratory Questionnaire (SGRQ) were evaluated.. Tio plus SFC resulted in a significant decrease in WA corrected for BSA and WA% compared with Tio, SM and SFC (p < 0.05 for all). The changes in WA% and Ai/BSA were significantly correlated with changes in forced expiratory volume in 1 s (r = -0.86, p < 0.001, and r = 0.48, p < 0.05, respectively). There were more significant improvements in SGRQ scores after treatment with triple therapy than after the 3 other treatments.. Tio plus SFC therapy is more effective than Tio, SM and SFC for reducing airway wall thickness in COPD.

Topics: Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal repair in the lung resulting in airway obstruction associated with emphysema and peripheral airway fibrosis. Because the presence and degree of airways disease and emphysema varies between COPD patients, this may explain the heterogeneity in the response to treatment. It is currently unknown whether and to what extent inhaled steroids can affect the abnormal repair process in the airways and lung parenchyma in COPD. We investigated the effects of fluticasone on transforming growth factor (TGF)-β- and cigarette smoke-induced changes in mothers against decapentaplegic homolog (Smad) signaling and extracellular matrix (ECM) production in airway and parenchymal lung fibroblasts from patients with severe COPD. We showed that TGF-β-induced ECM production by pulmonary fibroblasts, but not activation of the Smad pathway, was sensitive to the effects of fluticasone. Fluticasone induced decorin production by airway fibroblasts and partly reversed the negative effects of TGF-β treatment. Fluticasone inhibited biglycan production in both airway and parenchymal fibroblasts and procollagen 1 production only in parenchymal fibroblasts, thereby restoring the basal difference in procollagen 1 production between airway and parenchymal fibroblasts. Our findings suggest that the effects of steroids on the airway compartment may be beneficial for patients with severe COPD, i.e., restoration of decorin loss around the airways, whereas the effects of steroids on the parenchyma may be detrimental, since the tissue repair response, i.e., biglycan and procollagen production, is inhibited. More research is needed to further disentangle these differential effects of steroid treatment on the different lung compartments and its impact on tissue repair and remodeling in COPD.

Topics: Androstadienes; Anti-Inflammatory Agents; Biglycan; Cells, Cultured; Decorin; Female; Fibroblasts; Fluticasone; Gene Expression Regulation; Humans; Lung; Procollagen; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Smoking; Transforming Growth Factor beta

Patients with severe or very severe chronic obstructive pulmonary disease (COPD) frequently suffer repeated exacerbations generating high health care utilization costs. Combined corticosteroid and bronchodilator treatment using a single inhaler might - via improved compliance - reduce exacerbation rates.. Our aim was to obtain descriptive data on exacerbation rates in patients with severe or very severe COPD (GOLD Stages III and IV as per GOLD 2009 classification) receiving salmeterol xinafoate/fluticasone propionate via a single inhaler (SFC) or via separate inhalers (Sal/FP) in addition to individual existing therapy in order to investigate the potential benefit of a fixed combination device as compared with two separate devices due to potentially improved patients' compliance.. This prospective, randomized, open-label, parallel-group, multi-center, exploratory study was conducted in Germany in 2007-2009. Patients were required to have suffered ≥ 2 moderate/severe exacerbations in the preceding year.. 213 patients (SFC: 108 patients, Sal/FP: 105 patients) from 23 centers were evaluated. Approximately 25% of patients showed COPD Stage IV. On average patients had suffered 2.3 ± 0.6 moderate/severe exacerbations in the preceding year. The annual rate of moderate/severe exacerbations observed in the study was similar in both treatment groups (SFC: 0.86 ± 0.13; Sal/FP: 0.86 ± 0.14; exacerbation rate ratio SFC/Sal/FP: 1.00; p = 0.73; negative binomial model). Compliance was high and comparable in both groups. Besides COPD exacerbations, pneumonia (5.6%) and nasopharyngitis (5.2%) were the most common adverse events.. Observed exacerbation rates were lower than those reported at baseline. No substantial difference was observed between administration of salmeterol xinafoate/fluticasone propionate via a single inhaler and separate inhalers. Treatment was safe and well tolerated. ClinicalTrials.gov Identifier: NCT00527826.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Delivery of Health Care; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Health Care Costs; Humans; Male; Medication Adherence; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Severity of Illness Index; Treatment Outcome; Vital Capacity

Frequent exacerbations induce a high burden to Chronic Obstructive Pulmonary Disease (COPD). We investigated the course of exacerbations in the published COSMIC study that investigated the effects of 1-year withdrawal of fluticasone after a 3-month run-in treatment period with salmeterol/fluticasone in patients with COPD.. In 373 patients, we evaluated diary cards for symptoms, Peak Expiratory Flow (PEF), and salbutamol use and assessed their course during exacerbations.. There were 492 exacerbations in 224 patients. The level of symptoms of cough, sputum, dyspnea and nocturnal awakening steadily increased from 2 weeks prior to exacerbation, with a sharp rise during the last week. Symptoms of cough, sputum, and dyspnea reverted to baseline values at different rates (after 4, 4, and 7 weeks respectively), whereas symptoms of nocturnal awakening were still increased after eight weeks. The course of symptoms was similar around a first and second exacerbation. Increases in symptoms and salbutamol use and decreases in PEF were associated with a higher risk to develop an exacerbation, but with moderate predictive values, the areas under the receiver operating curves ranging from 0.63 to 0.70.. Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation. COPD exacerbations are preceded by increased symptoms and salbutamol use and lower PEF, yet predictive values are too low to warrant daily use in clinical practice.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Time Factors; Withholding Treatment

Data comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid (ICS) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) are scarce, though these therapeutic strategies are widely used in clinical practice.. We performed a randomized, crossover clinical trial of two × 8 weeks comparing tiotropium (18 μg once daily) + salmeterol (50 μg twice daily) (T + S) to salmeterol + fluticasone (50/500 μg twice daily) (S + F) in COPD (forced expiratory volume in 1 s (FEV(1)) ≤65% predicted, and thoracic gas volume (TGV) ≥120% predicted). Coprimary endpoints were postbronchodilator TGV and exercise endurance time (EET).. In 309 patients, at baseline, prebronchodilator FEV(1) was 1.36 L (46% predicted), TGV was 5.42 L (165% predicted), and EET = 458 s. Relative to S + F, T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks (p < 0.0001) and 87 ± 44 ml after 8 weeks (p < 0.05). EET was nonsignificantly increased following T + S treatment (20 ± 15 s at 4 weeks, 15 ± 13 s at 8 weeks) vs. S + F. BORG dyspnea score at exercise isotime was reduced in favor of T + S.. The two bronchodilators decreased hyperinflation significantly more than one bronchodilator and ICS. This difference was not reflected in EET. (ClinicalTrials.gov number, NCT00530842).

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Exercise Test; Exercise Tolerance; Female; Fluticasone; Humans; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV(1)) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV(1) level and inflammatory markers in COPD patients.We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV(1) decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting β2-agonists. Additionally we investigate the association of MRP1 variants with FEV(1) decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV(1) decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV(1) decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV(1) decline than in those with a weak staining. None of the variants was associated with FEV(1) decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV(1) decline occurring selectively in COPD patients with long-term (30-month) ICS therapy.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Fluticasone; Forced Expiratory Volume; Humans; Middle Aged; Multidrug Resistance-Associated Proteins; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

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 level>10 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.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Albuterol; Androstadienes; Bronchodilator Agents; C-Reactive Protein; Double-Blind Method; Female; Fluticasone; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

There is limited knowledge regarding sex differences and outcomes in patients with chronic obstructive pulmonary disease (COPD).. Determine sex differences in survival, causes of death, and patient-centered outcomes in the 3-year Toward a Revolution in COPD Health (TORCH) study.. A total of 1,481 women and 4,631 men with COPD were enrolled in TORCH, a trial comparing salmeterol, 50 μg, plus fluticasone propionate, 500 μg, twice a day and each component individually. Causes of death were determined by an endpoint committee. Sex differences in survival were explored using a Cox proportional hazards model adjusted for other baseline factors. Exacerbation rate was compared using a negative binomial model. Dyspnea was evaluated using the Medical Research Council scale and health status using the St. George's Respiratory Questionnaire.. At baseline, women were younger (63 vs. 66 yr), had higher FEV(1) (47% vs. 44% predicted), and worse St. George's Respiratory Questionnaire (51.3 vs. 48.7) and Medical Research Council score. During the study, 707 (15.3%) men and 168 (11.3%) women died. After adjusting for differences in baseline factors, the risk of dying was 16% higher in men than in women; however, this was not statistically significant (hazard ratio 1.16 [95% CI, 0.98-1.39]). Causes of death were similar in women and men. Exacerbation rate was 25% higher in women than in men.. Women enrolled in TORCH had a lower mortality rate than men but similar causes of death. The risk of dying was similar in women and men after adjusting for important baseline variables. Women reported more exacerbations, and worse dyspnea and health status scores than men. Clinical trial registered with www.clinicaltrials.gov (NCT00268216).

Topics: Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Cause of Death; Chi-Square Distribution; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Sex Factors; Surveys and Questionnaires

Topics: Administration, Inhalation; Aged; Androstadienes; Biomarkers; Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Spirometry; Treatment Outcome

Little is known about factors that determine health status decline in clinical trials of COPD.. To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo.. St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months.. Data from 4951 patients in 28 countries were available. SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains. SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001). There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women. Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1. The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change.. In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors. Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation.. ClinicalTrials.gov: NCT00268216.

Topics: Adrenergic beta-2 Receptor Agonists; Age Factors; Aged; Albuterol; Androstadienes; Asia; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Combinations; Europe; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Health Status; Health Status Indicators; Humans; Lung; Male; Middle Aged; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk Assessment; Risk Factors; Salmeterol Xinafoate; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome; United States

Combination therapy with corticosteroid and long-acting β(2)-agonists (LABA) in a single inhaler is associated with superior effects on airway function and exercise performance in COPD compared with LABA monotherapy. The physiological effects of adding inhaled corticosteroid monotherapy to maintenance bronchodilator therapy (long-acting anticholinergics and LABA singly or in combination) in COPD are unknown.. This was a randomized, double-blind, placebo-controlled, crossover study (NCT00387036) to compare the effects of inhaled fluticasone propionate 500 μg (FP500) twice-daily and placebo (PLA) on airway function during rest and exercise, measured during constant work rate cycle exercise at 75% of maximum incremental cycle work rate, in 17 patients with COPD (FEV(1) ≤ 70% predicted).. After treatment with FP500 compared to PLA, there were significant increases in post-dose measurements of FEV(1) (+115 mL, P = 0.006) and the FEV(1)/FVC ratio (+2.5%, P = 0.017), along with decreases in plethysmographic residual volume (-0.32L; P = 0.031), functional residual capacity (-0.30L, P = 0.033), and total lung capacity (-0.30L, P = 0.027) but no changes in vital capacity or inspiratory capacity (IC). Post-treatment comparisons demonstrated a significant improvement in endurance time by 188 ± 362 s with FP500 (P = 0.047) with no concomitant increase in dyspnea intensity. End-inspiratory and end-expiratory lung volumes were reduced at rest and throughout exercise with FP500 compared with PLA (P < 0.05).. Inhaled FP500 monotherapy was associated with consistent and clinically important improvements in FEV(1), static lung volumes, dynamic operating lung volumes, and exercise endurance when added to established maintenance long-acting bronchodilator therapy in patients with moderate to severe COPD.

Topics: Aged; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Dyspnea; Exercise; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Rest; Treatment Outcome

Salmeterol and fluticasone combination (SFC) has anti-inflammatory effects and improves clinical symptoms in patients with chronic obstructive pulmonary disease (COPD). However, the anti-inflammatory mechanism of SFC remains unclear. In this study, we investigated the inflammatory responses of COPD, as well as the relationship of the inflammatory factors with the levels of CD4+CD25+Foxp3+ regulatory T cells (Foxp3+Tregs) after SFC therapy.. Twenty-one patients with moderate or severe COPD received treatment with 50/500 μg of SFC twice a day for 12 weeks. Before and after treatment, the patients were evaluated using the Modified Medical Research Council (MMRC) dyspnea scale and by conducting a 6-min walk test. The number of neutrophils, monocytes and lymphocytes in induced sputum were counted. Levels of cytokines, including pre-inflammatory IL-8, TNF-α, IL-17A and cytokine IL-10, in the sputum supernatant and peripheral blood were measured by ELISA. The proportion of Foxp3+Tregs in the total CD4+ T cell of the peripheral blood was determined by flow cytometry. The relationship between IL-17A levels and the percentage of Foxp3+Tregs was analyzed by statistical analysis.. After treatment with SFC, the forced expiratory volume in 1 s as a percentage of predicted values (FEV1%) and the 6-min walk distance in the COPD patients significantly increased, while dyspnea scores decreased. The total number of cells, neutrophils, and the percentage of neutrophils in induced sputum reduced notably, while the proportion of monocytes was significantly increased. Levels of the inflammatory cytokines IL-8, TNF-α, and IL-17A in the sputum supernatant and in the blood were markedly lowered, while IL-10 levels were unchanged. The proportion of Foxp3+Tregs in the total CD4+T cell population in the peripheral blood was drastically higher than that before treatment. The level of IL-17A was negatively correlated with the proportion of Foxp3+Tregs in CD4+T cells.. SFC can reduce the levels of inflammatory factors and improve symptoms of COPD. The levels of inflammatory factors are associated with the variation of Foxp3+Tregs in COPD.. This study was registered with http://www.chictr.org (Chinese Clinical Trial Register) as follows: ChiCTR-TNC-10001270.

Topics: Adult; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; CD4 Antigens; Cytokines; Female; Fluticasone; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Interleukin-2 Receptor alpha Subunit; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; T-Lymphocytes, Regulatory; Treatment Outcome

The primary aim of pharmachotherapy in COPD is improvement of exertional dyspnea and quality of life through its bronchodilator effects. However, there is emerging evidence that pharmacotherapy may reduce exacerbations, alleviate annual decline of pulmonary function, and even favorably affect mortality, thus changing natural history of COPD. The large-scaled randomized clinical trials, such as TORCH, UPLIFT, have revealed that combination of long acting beta2 agonist (LABA) and inhaled corticosteroids (ICS), LABA/ICS, and/or tiotropium alone may have such effects. In addition, carbocisteine, which is a mucolytic and anti-oxidant agent, has been shown to reduce exacerbations in COPD. Future directions on pharmacotherapy are personalized medicine based on phenotyping of the disease and development of new agents which may cure airway inflammation in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400-123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200-241,700) USD compared to 24,200 (15,200-56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Drug Combinations; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate

The synergistic interactions between pharmacotherapy and pulmonary rehabilitation has been provided, but it remains to be established whether this may also apply to more severe patients.. We have examined whether tiotropium enhances the effects of exercise training in patients with advanced COPD (FEV(1)

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Combined Modality Therapy; Drug Administration Schedule; Drug Synergism; Dyspnea; Exercise Tolerance; Female; Fluticasone; Humans; Male; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD.. To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L).. In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD.. Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD.. clinicaltrials.gov; Identifier NCT00241631.

Topics: Administration, Inhalation; Administration, Oral; Aged; Androstadienes; Bronchodilator Agents; Capsules; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Histone Deacetylase 2; Humans; Linear Models; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Theophylline; Treatment Outcome

The Towards a Revolution in COPD Health (TORCH) trial was an international clinical trial of chronic obstructive pulmonary disease (COPD) patients where cause of death was assigned by an independent committee. Comparison of death certificate data and adjudicated cause of death allows a unique opportunity to determine death certificate accuracy and frequency of COPD listing on death certificates of COPD patients. In this analysis, the authors determine the concordance between adjudicated cause of death and primary and secondary cause of death from death certificates. In 317 (80%) of informative deaths, the primary or secondary cause of death from certificates agreed with adjudicated cause of death. Only 229 (58%) of death certificates in these COPD patients listed COPD on the certificate. COPD was not listed on the death certificate in 21% of deaths adjudicated to be caused by COPD exacerbation. Compared with pulmonary causes, the listing of COPD on certificates occurred with less frequency than cardiovascular, cancer and other categories of death. The combined primary and secondary listing on death certificates has good concordance with actual cause of death. COPD is under-reported on death certificates, and this under-reporting is more frequent when the primary cause of death is not pulmonary.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cause of Death; Data Interpretation, Statistical; Death Certificates; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Previous studies have suggested that long-term use of beta agonists to treat chronic obstructive pulmonary disease (COPD) may increase the risk of cardiovascular adverse events. In this post hoc analysis, data from the TOwards a Revolution in COPD Health (TORCH) study were used to investigate whether use of the long-acting beta(2) agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD.. TORCH was a randomised, double-blind, placebo controlled study conducted at 444 centres in 42 countries. Patients (n=6184; safety population) received twice daily combined salmeterol 50 microg plus fluticasone propionate 500 microg (SFC), either component alone, or placebo. Adverse events were recorded every 12 weeks for 3 years.. The probability of having a cardiovascular adverse event by 3 years was 24.2% for placebo, 22.7% for salmeterol, 24.3% for fluticasone propionate and 20.8% for SFC. Although a history of myocardial infarction doubled the probability of cardiovascular adverse events, the event rates remained similar across treatment groups.. Post hoc analysis of the 3-year TORCH dataset showed that salmeterol alone or in combination (SFC) did not increase the risk of cardiovascular events in patients with moderate to severe COPD.

Topics: Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Evidence suggests that systemic inflammation may play an important role in the progression and morbidity of chronic obstructive pulmonary disease. It remains controversial whether inhaled corticosteroid in combination with a long-acting beta(2)-adrenoceptor agonist can attenuate systemic inflammation. We evaluated the effect of salmeterol/fluticasone propionate on circulating C-reactive protein level in stable chronic obstructive pulmonary disease patients.. An open-label clinical trial was conducted to recruit 122 outpatients with stable moderate-to-severe chronic obstructive pulmonary disease from department of respiratory medicine in two teaching hospitals between June 2007 and March 2008. Patients were randomized into two groups (1:1) to receive either the combination of 50 microg salmeterol and 500 microg fluticasone twice daily (n = 61), or the combination of 206 microg albuterol and 36 microg ipratropium q.i.d (n = 61) over 6 months. Circulating C-reactive protein concentrations were measured before randomization and during the follow-up. The efficacy of treatment was also assessed by spirometry, as well as health status and dyspnea score at baseline and after 6-month treatment.. Baseline characteristics of two groups were similar. Compared with ipratropium/albuterol, the combination of salmeterol/fluticasone significantly reduced circulating level of C-reactive protein (-1.73 vs. 0.08 mg/L, respectively, P < 0.05) after 6-month treatment. Forced expiratory volume in one second (FEV(1)) and health status also improved significantly in salmeterol/fluticasone group compared with ipratropium/albuterol. Salmeterol/fluticasone treatment subjects who had a decrease of circulating C-reactive protein level had a significant improvement in FEV(1) and St George's Respiratory Questionnaire total scores compared with those who did not (185 vs. 83 ml and -5.71 vs. -1.79 units, respectively, both P < 0.01).. Salmeterol/fluticasone treatment reduced circulating C-reactive protein concentration in clinically stable moderate-to-severe chronic obstructive pulmonary disease patients after 6-month treatment.

Topics: Albuterol; Androstadienes; C-Reactive Protein; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

indacaterol is a novel, inhaled once-daily ultra-long-acting β(2)-agonist for the treatment of chronic obstructive pulmonary disease (COPD).. this study compared the onset of action of single doses of indacaterol 150 and 300 μg with salbutamol 200 μg, salmeterol-fluticasone 50/500 μg, and placebo in moderate-to-severe COPD patients.. this was a multicenter, randomized, double-blind, placebo-controlled crossover study. The primary variable was forced expiratory volume in one second (FEV(1)) at five minutes postdose.. out of 89 patients randomized (mean age 62 years), 86 completed the study. At five minutes postdose, both indacaterol doses were statistically and clinically superior to placebo (P < 0.001), with treatment-placebo differences in FEV(1) of 100 (95% confidence interval [CI] 70-130) mL and 120 (95% CI 90-150) mL for indacaterol 150 and 300 μg, respectively. FEV(1) at five minutes postdose with both indacaterol doses was numerically higher than for salbutamol (10 and 30 mL for indacaterol 150 and 300 μg, respectively) and significantly higher than for salmeterol-fluticasone (50 mL, P = 0.003; 70 mL, P < 0.001, respectively). Moreover, both indacaterol doses showed significantly higher FEV(1) than placebo (P < 0.001) at all postdose time points. The numbers of patients with an FEV(1) increase of at least 12% and 200 mL at five minutes postdose were 16 (18.8%), 24 (27.6%), 20 (23.3%), 8 (9.1%), and 3 (3.4%) for indacaterol 150 and 300 μg, salbutamol 200 μg, salmeterol-fluticasone 50/500 μg, and placebo, respectively.. single doses of indacaterol 150 and 300 μg demonstrated a fast onset of action similar to that for salbutamol and faster than that for salmeterol-fluticasone.

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Female; Fluticasone; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate

The anti-inflammatory effects of salmeterol/fluticasone (SFP), tiotropium/fluticasone (Tio+FP) and tiotropium (Tio) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients. Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study. Subjects (n = 99) were randomised (not double blinded) and received either SFP (100/1,000 microg daily), Tio+FP (18/1,000 microg daily) or Tio (18 microg daily) for 12 weeks. Induced sputum and serum C-reactive protein (CRP) were analysed prior to and at the end of treatment. The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum, compared with treatment with Tio alone. There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels. The reduction in IL-8 showed significant association with the reduction in MMP-9. All treatment groups failed to significantly reduce the numbers of total cells, neutrophils, macrophages and eosinophils in induced sputum; in addition, there were no treatment differences in terms of improvement of forced expiratory volume in one second, forced vital capacity, CRP or quality of life between the three groups. The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fluticasone; Humans; Inflammation; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Sputum; Tiotropium Bromide

Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD.. To investigate whether treatment with the inhaled corticosteroid fluticasone propionate (FP) or the anti-oxidative agent N-acetylcysteine (NAC) are effective in primary care patients.. The study was a 3-year placebo-controlled randomised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment. Patients were (ex-)smokers with chronic bronchitis or COPD. Interventions were inhaled FP 500microg b.i.d., oral NAC 600mg o.d., or placebo. Exacerbation rate and quality of life measured with the Chronic Respiratory Questionnaire (CRQ) were the primary outcomes, FEV(1) decline and respiratory symptoms secondary outcomes.. 286 patients recruited from 44 general practices were randomised. Exacerbation rate was 1.35 times higher for NAC (p=0.054) and 1.30 times higher for FP (p=0.095) compared with placebo. CRQ total scores did not differ between NAC (p=0.306) or FP (p=0.581) treatment compared to placebo. Annual postbronchodilator FEV(1) decline was 64mL [SD 5.4] for NAC [p=0.569 versus placebo], 59mL [SD 5.7] for FP [p=0.935], and 60mL [SD 5.4] for placebo.. No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis.

Topics: Acetylcysteine; Adult; Aged; Androstadienes; Bronchitis, Chronic; Bronchodilator Agents; Expectorants; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Netherlands; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Quality of Life; Smoking; Treatment Outcome

The effects of tiotropium, a long-acting anticholinergic drug, were compared with those of the combination of salmeterol, a long-acting beta(2)-agonist, and fluticasone, an inhaled corticosteroid, in patients with COPD.. A 4-month, randomized, open cross-over study of tiotropium, 18 microg once daily, versus salmeterol, 50 microg, plus fluticasone, 200 microg, twice daily, was conducted in patients with COPD. Efficacy was assessed by spirometry and responses to the St George's Respiratory Questionnaire (SGRQ). After 4 months, patients were asked to select their subsequent therapy and indicate the reasons for their selection.. A total of 78 patients completed the study. There were no significant differences in the improvements in FEV(1) or SGRQ scores between the therapies. Similar numbers of patients selected tiotropium (42.3%) and salmeterol plus fluticasone (57.7%). However, those who preferred one of the therapies demonstrated greater improvements in SGRQ scores with that therapy. One subgroup of patients (30.8%) showed greater improvements in dyspnoea and FEV(1) in response to tiotropium, and the other subgroup of patients (35.9%) showed greater improvements in dyspnoea and FEV(1) in response to salmeterol plus fluticasone. Some patients (14.1%) selected salmeterol plus fluticasone because of positive effects on sputum expectoration.. The study was unblinded and the results need to be interpreted with caution. However, tiotropium and salmeterol plus fluticasone had similar overall effects on pulmonary function and SGRQ scores in patients with COPD. Responses to the two therapies were heterogeneous, and the patients who showed greater improvements in FEV(1) or SGRQ scores with one of the therapies preferred it for their subsequent treatment.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Lung; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD).. A prospective randomized, double-blind, double-dummy placebo-controlled, crossover investigation of inhaled steroids and oral leukotriene blockers.. A United States Department of Veterans Affairs Health Care System outpatient setting.. Adults with type 2 diabetes and asthma or COPD.. Subjects (n=12) were randomized to receive either inhaled fluticasone propionate (440 microg twice daily) and oral placebo, or inhaled placebo and oral montelukast (10 mg/day). After 6 weeks, subjects were switched to the opposite therapy for 6 weeks. The primary outcome measure was the change in the percentage of glycosylated hemoglobin (%HbA1c) at 6 weeks relative to the baseline value.. Ten patients completed the study. The difference between the mean within-subject changes in %HbA1c associated with 6-week periods of fluticasone and the mean changes associated with montelukast therapy was small but statistically significant (mean difference=0.25; P<0.025). Neither fluticasone nor oral montelukast therapy for 6 weeks led to a significantly different mean % HbA1c compared with the relevant baseline (mean differences=0.11 and -0.14, respectively).. The absence of a clinically significant within-subject difference in the changes in %HbA1c associated with fluticasone versus oral montelukast therapy, or between either therapy or baseline does not warrant recommending changes in therapy for asthma or diabetes in patients with these co-morbid conditions. However, we suggest that clinicians carefully monitor blood glucose control when diabetic patients initiate ICS, especially with higher dosages.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Anti-Asthmatic Agents; Bronchodilator Agents; Cross-Over Studies; Cyclopropanes; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Fluticasone; Glucose; Glycated Hemoglobin; Humans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quinolines; Sulfides; Treatment Outcome

This study investigated the value of adding Ismigen, a polyvalent mechanical bacterial lysate, to therapy of COPD patients (FEV(1) <60% predicted) under regular treatment with salmeterol/fluticasone (SFC).. 63 patients enrolled from September to December 2007 were randomly divided into two groups (A and B). All patients were treated with salmeterol/fluticasone (SFC) 50/500 microg BID. Thirty-three subjects also received Ismigen one capsule daily the first 10 days of three consecutive months (group B). This treatment was reaped three months after the end of the first course. We assessed at inclusion and at scheduled (every 2 months) or intercurrent visit: symptoms (amount and colour of sputum, severity of dyspnoea, frequency of cough, fever), diagnosis of exacerbation, concomitant medications (antibiotics and oral corticosteroids) and hospitalization.. During the course of the study two patients died. At the end of the observation period (12 months), another six patients could not be visited because they had withdrawn. Compared with SFC, adding on Ismigen reduced the total number of exacerbations (23 out of 30 patients in group A and 21 out of 33 patients in group B), the number (rate) of exacerbations per patient per year (18 out of 27 patients [0.67] in group A and 15 out of 28 patients [0.54] in group B), the number of exacerbations that needed treatment with oral corticosteroids (12 out of 23 [52%] in group A and 9 out of 21 [43%] in group B) and the total number (rate) of hospitalizations (4/30 [0.13] in group A and 3/33 [0.09] in group B). There were no significant differences between treatments with respect to their effect on the symptoms of exacerbations. A decrease in the need for antibiotics was also observed in group B.. Our data suggest that COPD patients benefit from the addition of Ismigen on top of the routine maintenance treatment with SFC.

Topics: Adjuvants, Immunologic; Aged; Albuterol; Androstadienes; Bacteria; Bronchodilator Agents; Cell Extracts; Disease Progression; Drug Combinations; Female; Fluticasone; Hospitalization; Humans; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate

The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease.. TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: >or= 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).. Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.. In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages. Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease. The effects were similar to those reported for the study as a whole. Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.. Clinicaltrial.gov registration NCT00268216; Study number: SCO30003.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Combinations; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Smoking

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.

Topics: Aged; Albuterol; Androstadienes; Bone Density; Bone Diseases, Metabolic; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Fractures, Bone; Humans; Male; Middle Aged; Osteoporosis; Prevalence; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Treatment Outcome; United States

Salmeterol/fluticasone combination (SFC) therapy is used to control inflammation in the distal airway of patients with well-controlled asthma, but the efficacy of this approach is unclear.. The goal of the study was to evaluate the effect of pranlukast, a leukotriene receptor antagonist (LTRA), on distal airway inflammation and pulmonary resistance in patients with asthma that was well-controlled using SFC therapy alone.. The subjects were 32 patients with well-controlled asthma (age 61.1+/-17.8 years old, Step 3 in the GINA guidelines, Asthma Control Test score 23.2+/-1.8 points) based on use of SFC therapy alone for more than 3 months. These subjects were randomly assigned to groups receiving SFC alone or SFC+LTRA (pranlukast 450 mg daily) and then switched to the opposite group after 4 weeks in a crossover manner. Eosinophilic inflammation in induced sputum samples was assessed after each treatment period. Sputum was induced by inhalation of 10% hypertonic saline for 15 min. Impulse oscillometry parameters (R5, R20, X5 and AX) and spirometry were examined during each period. The Asthma-related Quality of Life Questionnaire (AQLQ) was also administered in each period.. The ECP levels in late-phase sputum were significantly higher than those in early-phase sputum with SFC therapy alone (178.3+/-166.0 vs. 65.5+/-68.9 microg/l, p<0.001), whereas these values did not differ significantly with SFC+LTRA treatment (70.9+/-95.1 vs. 54.6+/-65.7, p=0.554). ECP levels in late-phase sputum with SFC therapy were also significantly higher than those with SFC+LTRA (p=0.045). The values of R5, R20, R5-R20 (kPa/(L/s)), and AX (kPa/L) all significantly improved during with SFC+LTRA treatment compared with SFC alone (median (25-75 percentile)): 0.350 (0.283-0.440) vs. 0.340 (0.280-0.378), p=0.036; 0.280 (0.233-0.365) vs. 0.270 (0.240-0.318), p=0.019; 0.050 (0.030-0.110) vs. 0.500 (0.030-0.073), p=0.032; and 0.570 (0.308-1.045) vs. 0.410 (0.263-0.820), p=0.014; respectively. Pulmonary function indexes did not differ significantly between the two treatments, but the symptom and activity limitation domains of the AQLQ were significantly improved by SFC+LTRA treatment.. This study suggests that the combination of SFC and LTRA may give better control of residual eosinophilic inflammation in the distal airway compared with SFC therapy alone.

Topics: Aged; Albuterol; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Bronchodilator Agents; Chromones; Cross-Over Studies; Drug Combinations; Drug Therapy, Combination; Emotions; Environment; Eosinophils; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Sputum

Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity.. Data on drug adherence from a randomised double-blind trial comparing inhaled salmeterol 50 microg + fluticasone propionate 500 microg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study.. Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence.. Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Epidemiologic Methods; Female; Fluticasone; Hospitalization; Humans; Male; Medication Adherence; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD).. To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.. Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847). 2 university medical centers in The Netherlands.. 114 steroid-naive current or former smokers with moderate to severe COPD.. Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.. Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).. 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level.. The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.. ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. .

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchi; Bronchodilator Agents; Cell Count; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Smoking; Sputum; Treatment Outcome

Prevention and treatment of COPD exacerbations are recognized as key goals in disease management. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg (FSC 250/50) and salmeterol 50 mcg (SAL) twice-daily on moderate/severe exacerbations. Subjects received treatment with FSC 250/50 during a one month run-in, followed by randomization to FSC 250/50 or SAL for 52 weeks. Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics, oral corticosteroids and/or hospitalization. In 797 subjects with COPD (mean FEV(1) = 0.98L, 34% predicted normal), treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4% compared with SAL (1.10 and 1.59 per subject per year, respectively, p < 0.001), the annual rate of exacerbations requiring oral corticosteroids by 34% (p < 0.001) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36% (p = 0.043). Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL. Statistically significant reductions in albuterol use, dyspnea scores, and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL. The incidence of adverse events was similar across groups. Pneumonia was reported more frequently with FSC 250/50 compared with SAL (7% vs. 2%). FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations. These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Recurrence; Salmeterol Xinafoate; Time Factors; Treatment Outcome

The TORCH (Towards a Revolution in COPD Health) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease. These include collection of off-treatment exacerbation data, analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids (ICS) prior to randomisation. When effective medications are available to patients who withdraw, inclusion of off-treatment data can mask important treatment effects on exacerbation rates. Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments. The negative binomial model is currently the best approach to statistical analysis of exacerbation rates, while analysis of time to exacerbation can supplement this approach. In the TORCH trial, exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments. Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo, regardless of prior use of ICS before entry to the study. Factorial analysis provides an alternative analysis for trials with combinations of treatments, but assumes no interaction between treatments, an assumption which cannot be verified by a significance test. No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Research Design; Salmeterol Xinafoate; Time Factors; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline.. In a post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg, either component alone or placebo, on the rate of post-bronchodilator FEV(1) decline in patients with moderate or severe COPD.. A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis.. Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV(1) was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV(1) decline by 16 ml/year compared with placebo (95% confidence interval [CI], 7-25; P < 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5-22; P = 0.003). Rates of decline were similar among the active treatment arms. FEV(1) declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV(1) decline.. Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV(1) in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www.clinicaltrials.gov (NCT00268216).

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Body Mass Index; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Smoking; Spirometry; Survival Analysis

COPD exacerbations are associated with significant morbidity and mortality. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations.. Patients received standardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in, followed by randomization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months. Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids, antibiotics, or hospitalization.. In 782 patients with COPD (mean FEV(1)=0.94+/-0.36 L, 33% predicted normal), treatment with fluticasone propionate/salmeterol 250/50 significantly reduced (1) the annual rate of moderate to severe exacerbations by 30.5% compared with salmeterol (1.06 and 1.53 per subject per year, respectively, p<0.001), (2) the risk of time to first exacerbation by 25% (hazard ratio=0.750, p=0.003) and (3) the annual rate of exacerbations requiring oral corticosteroids by 40% (p<0.001). Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol. Adverse events were reported for a similar percentage of subjects across groups. A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol (7% vs. 4%).. We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year. The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered. This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD.

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Smoking

Little is known about the combination of different medications in chronic obstructive pulmonary disease (COPD). This study determined the cost effectiveness of adding salmeterol (S) or fluticasone/salmeterol (FS) to tiotropium (T) for COPD.. This concurrent, prospective, economic analysis was based on costs and health outcomes from a 52 week randomised study comparing: (1) T 18 microg once daily + placebo twice daily (TP group); (2) T 18 microg once daily + S 25 microg/puff, 2 puffs twice daily (TS group); and (3) T 18 microg once daily + FS 250/25 microg/puff, 2 puffs twice daily (TFS group). The incremental cost effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality adjusted life year (QALY) between treatments. A combination of imputation and bootstrapping was used to quantify uncertainty, and extensive sensitivity analyses were performed.. The average patient in the TP group generated CAN$2678 in direct medical costs compared with $2801 (TS group) and $4042 (TFS group). The TS strategy was dominated by TP and TFS. Compared with TP, the TFS strategy resulted in ICERs of $6510 per exacerbation avoided, and $243,180 per QALY gained. In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP.. TFS had significantly better quality of life and fewer hospitalisations than patients treated with TP but these improvements in health outcomes were associated with increased costs. Neither TFS nor TS are economically attractive alternatives compared with monotherapy with T.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Delayed-Action Preparations; Drug Combinations; Fluticasone; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Theophylline; Tiotropium Bromide

The Federal Drug Administration (FDA) approved the use of Fluticasone 250 microg/Salmeterol 50 microg 1 puff bid for maintenance therapy in patients with COPD associated with chronic bronchitis. Short-acting beta agonists (SABA) have been the recommended rescue medication; however, previous studies have shown that combination short-acting Albuterol (alb) /Ipratropium bromide (IB) has superior bronchodilator properties to albuterol alone in patients with COPD. The safety and efficacy of Albuterol compared to Albuterol/Ipratropium bromide as rescue medications for COPD patients on maintenance combination therapy of ICS/LABA has not been evaluated. Double-blind randomized crossover trial with COPD subjects receiving Fluticasone/ Salmeterol 500 microg/50 microg (Flu/Sal) 1 puff twice daily and 2 puffs of Albuterol Sulfate (90 microg micrograms per inhalation) or 2 puffs of Albuterol (90 microg/puff and Ipratropium Bromide 18 microg/puff. Either Albuterol Sulfate (90 micrograms/puff) or Alb (90 micrograms/puff)/IB used prn for 3 weeks before crossing over to the other rescue formulation. This is a non-inferiority study where safety and efficacy outcomes were serially assessed, including adverse events, Baseline (BDI)/Transition Dyspnea Index (TDI), St. George Respiratory Questionnaire (SGRQ), SF36, diary cards, 24-hour cardiac monitoring, potassium and glucose levels and other adverse events. Twenty subjects completed the study. The mean age was 62.5 (+/- 14.5); 12 were males. The mean baseline FEV(1) (range) was 1.12 L (0.56-1.67) or 40.6 (21-65)% predicted. There were no statistically significant differences between either rescue inhaler formulation with regard to measures neither of lung function or dyspnea nor in terms of safety parameters of cardiac monitoring, glucose and potassium levels and other adverse events. SABA and combination SABA/Ipratropium bromide are equally safe and efficacious as rescue inhalers for patients on combination Fluticasone 500 microg/Salmeterol 50 microg.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Humans; Ipratropium; Male; Maximum Tolerated Dose; Middle Aged; Probability; Pulmonary Disease, Chronic Obstructive; Reference Values; Respiratory Function Tests; Risk Assessment; Salmeterol Xinafoate; Severity of Illness Index; Treatment Outcome

Bronchodilator reversibility (BDR) is common in smoking-related COPD, but the airway pathology underlying this has not been described. In particular, it is not known whether BDR is associated with underlying airway eosinophilia and whether BDR is predictive of a better response to inhaled corticosteroid (ICS) treatment.. A double-blind, placebo-controlled, randomized 2:1 study of fluticasone propionate (FP), 500 microg twice daily versus placebo over 6 months was performed in subjects with mild to moderate COPD. Subjects with a clinical history of asthma were excluded, but not on BDR criteria alone. Induced sputum, BAL and endobronchial biopsies (EBB) were performed in 36 subjects at baseline, and 30 of these provided a second full set of samples (FP, n = 19; placebo, n = 11).. Baseline BDR was not related to airway eosinophilia and did not predict response to ICS. Post-bronchodilator FEV(1) increased in the FP group compared with the placebo group (P = 0.05), and there were within-treatment group reductions in total symptom scores with FP (P < 0.05). Compared with placebo, FP reduced macrophage numbers but increased neutrophil numbers in EBB (P = 0.01 and P = 0.003, respectively). BAL neutrophil and epithelial cell numbers were also reduced with FP (P = 0.03 for both). There were within-treatment group reductions in the numbers of EBB mast cells and CD8+ve lymphocytes with FP (P = 0.007).. BDR was not related to any particular inflammatory phenotype or any clinical or anti-inflammatory response to ICS in these subjects with mild to moderate COPD.

Topics: Administration, Inhalation; Aged; Androstadienes; Anti-Inflammatory Agents; Cell Count; Cross-Sectional Studies; Double-Blind Method; Eosinophilia; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Respiratory Mucosa; Sputum; Treatment Outcome

To observe the efficacy of combination therapy with inhaled salmeterol/fluticasone and tiotropium in reducing the frequency of acute episodes of symptom exacerbation and improving lung function and health status in chronic obstructive pulmonary disease (COPD).. One hundred and twenty-six patients (M/F: 92/34) with COPD were treated in a randomised, parallel-group, controlled study with salmeterol/fluticasone (50/250 microg) twice daily and tiotropium 18 microg once daily (n = 33, M/F: 23/10); salmeterol/fluticasone (50/250 microg) twice daily (n = 32, M/F: 24/8); or tiotropium 18 microg once daily (n = 32, M/F: 23/9) for 12 months. Patients in the blank control group (n = 29, M/F: 22/7) did not receive any inhaled anticholinergic drugs, long-acting beta(2) agonists or glucocorticoid therapy. Intention-to-treat analysis (n = 161) and per-protocol analysis (n = 126, age 45 - 71 years) were performed.. Three active treatments significantly improved symptoms and health status. The use of rescue medication in the combination group [1 (0 - 7) time, 95% CI] was significantly decreased compared with those in the blank group [2 (0 - 29) times], salmeterol/fluticasone alone [2 (0 - 13) times], tiotropium alone [1 (0 - 11) time], F = 4.914, P < 0.01. The frequency of exacerbations in the combination group was (0.7 +/- 0.5) time, significantly lower than that in the blank group [(1.5 +/- 0.9) times], salmeterol/fluticasone alone [(1.2 +/- 0.6) times], and tiotropium alone [(1.1 +/- 0.5) times], F = 8.513, P < 0.01. The FEV(1) in the combination group after the trial was (1.19 +/- 0.03) L, significantly improved compared to that before treatment (1.09 +/- 0.04) L, a 9.5% increase, which was greater than the blank (0.9%), tiotropium alone (8.2%) and salmeterol/fluticasone alone (6.3%), t = -5.024 to -15.58, P < 0.01.. Combination therapy with salmeterol/fluticasone and tiotropium leads to better control of symptoms and improved lung function, with no greater risk of side-effects, as compared to salmeterol/fluticasone or tiotropium alone in the treatment of COPD.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Cholinergic Antagonists; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

A subset of patients with chronic obstructive pulmonary disease (COPD) may respond more favorably to inhaled corticosteroids (ICS), but no simple method is currently utilized to predict the presence or absence of ICS responses in patients with COPD.We evaluated the ability of exhaled nitric oxide (FENO) and serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], and interleukin-8 [IL-8]) to independently predict spirometric responses to ICS in patients with COPD.. Among 60 ex-smokers with severe COPD (mean FEV1 1.07 L, 36% of predicted), we conducted a single-arm, open-label study. Participants spent four weeks free of any ICS, followed by four weeks of ICS use (fluticasone propionate 500 mcg twice daily). FENO, CRP, IL-6, IL-8, and pre-bronchodilator spirometry were measured immediately before and after the four weeks of ICS use.. Baseline FENO, CRP, IL-6, and IL-8 showed no correlations to FEV1 responses to ICS. ICS responders (increase in FEV1 > or = 200 mL after four weeks of ICS) did have significantly higher baseline FENO levels compared with non-responders (46.5 parts per billion [ppb] vs. 25 ppb, p = 0.028). The receiver operating characteristic curve for FENO to discriminate responders from non-responders had an area under curve of 0.72. Baseline serum inflammatory markers did not differ between responders and non-responders.. In ex-smokers with severe COPD, a measure of local pulmonary inflammation, FENO, may be more closely associated with FEV1 responses to four weeks of ICS than are standard markers of systemic inflammation, serum CRP, IL-6, and IL-8.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Biomarkers; Bronchodilator Agents; C-Reactive Protein; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Nitric Oxide; Prospective Studies; Pulmonary Disease, Chronic Obstructive; ROC Curve; Salmeterol Xinafoate; Severity of Illness Index; Spirometry

The combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) are commonly used treatments in chronic obstructive pulmonary disease (COPD) but there are few data on their effectiveness when used together. We compared the effects of SFC 50/500 microg twice daily in addition to TIO 18 microg once daily with the individual treatments alone.. 41 patients with COPD participated in a randomised, double blind, double dummy, three way crossover study with 2 week washout periods between treatments. Lung function assessment included plethysmography and spirometry. The primary end point was post-dose specific airways conductance (sGaw) area under the curve (AUC(0-4 h)) on day 14.. AUC(0-4 h) sGaw was significantly higher on day 14 after SFC+TIO compared with TIO (22%) or SFC alone (27%) (both p<0.001). SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone (212 ml, p<0.001) and SFC alone (110 ml, p = 0.017) on day 14. Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14. Subjects receiving SFC+TIO had clinically relevant improvements in Transition Dyspnoea Index (TDI) total score of 2.2 compared with TIO alone (p<0.001) (but not SFC alone, 0.7; NS) and used significantly less rescue medication (1.0 occasion less daily than TIO (p<0.001) and 0.6 less than SFC (p = 0.01)).. SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone. The advantages of triple therapy are observed across a range of physiologically important parameters, including airway conductance and lung volumes. Triple therapy also led to patient related benefits by improving TDI and use of rescue medication.

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease (COPD).. To determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation.. We conducted a double-blind randomized placebo-controlled trial across 11 centers (n = 289 patients with FEV(1) of 47.8 +/- 16.2% of predicted) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks. The primary endpoint was C-reactive protein (CRP) level. Secondary molecules of interest were IL-6 and surfactant protein D (SP-D).. Neither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels. There was, however, a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo (P = 0.002). Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo, driven mostly by improvements in the symptom scores. Changes in the circulating SP-D levels were related to changes in health status scores. FEV(1) improved significantly only in the fluticasone/salmeterol group compared with placebo.. ICS in conjunction with long-acting beta(2)-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks. They do, however, significantly reduce serum SP-D levels. These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Biomarkers; C-Reactive Protein; Canada; Double-Blind Method; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Interleukin-6; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Respiratory Function Tests; Treatment Outcome

It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting beta2-agonists (LABAs) and combined administration of a LABA and an inhaled corticosteroid (ICS) reduces the potential for acute effects of LABA on blood-gas tensions. In this study, we have compared the acute effects of tiotropium 18 microg and salmeterol/fluticasone combination (SFC) 50/250 microg on arterial blood gases in 20 patients with stable COPD. Each subject was studied on 2 days, separated from one another by at least 4 days. Blood specimens were taken just before the inhalation and at 15, 30, 60, 180 and 360 min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV1 (greatest changes were 0.20 L, 95% CI: 0.13-0.27 at 360 min after tiotropium; and 0.13 L, 95% CI: 0.06-0.19 at 180 min after SFC). The greatest mean changes from baseline in PaO2 were -1.7 (95% CI: -4.0 to 0.6)mmHg, p=0.134, after tiotropium; -0.8 (95% CI: -2.2 to 0.6)mmHg, after SFC. Both changes were observed after 15 min. Both drugs caused a small decrease in PaCO2 (greater changes: -1.9 (95% CI -3.2 to -0.6)mmHg, p=0.005 at 60 min after tiotropium; and -2.4 (95% CI: -3.5 to -1.3) mmHg, p=0.0002 at 180 min after SFC). These results indicate that both tiotropium and SFC are able to induce a significant long-last bronchodilation without affecting arterial blood gases. Moreover, they confirm that the impact of tiotropium on PaO2 is small and without clinical significance and the addition of a LABA to an ICS can reduce the potentially dangerous acute effect of the LABA on blood gases.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Carbon Dioxide; Cross-Over Studies; Drug Combinations; Fluticasone; Forced Expiratory Volume; Humans; Oxygen; Partial Pressure; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

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, p < 0.0001). Also, peak responses were in favor of tiotropium plus formoterol (difference in peak FEV(1), 103 mL [p < 0.0001]; difference in peak FVC, 214 mL [p < 0.0001]), as were FEV(1) and FVC at each individual time point after dose (p < 0.05). 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.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethanolamines; Female; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

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 if the airway circulation is also affected and if airway treatment has an effect on endothelial function. Airway blood flow (Q(aw)) responses to inhaled albuterol as an index of endothelial function were measured in age-matched healthy current smokers, healthy ex-smokers, ex-smokers with COPD and healthy lifetime non-smokers; in the ex-smokers with COPD, the albuterol responsiveness was repeated after a 4-week treatment with an inhaled glucocorticoid/beta(2)-adrenergic agonist combination drug. Mean baseline Q(aw) was similar in the four groups. Albuterol inhalation increased mean Q(aw) in lifetime non-smokers (50.1+/-8.3%; p<0.05) and in healthy ex-smokers (37.2+/-3.4%; p<0.05) but not in healthy current smokers (13.9+/-3.2%; p=NS) and ex-smokers with COPD (9.7+/-4.5%; p=NS). While drug treatment per se did not change Q(aw) significantly, it restored albuterol responsiveness (+67.6+/-11.1%; p<0.05) in the ex-smokers with COPD. Thus, cigarette smoking is associated with endothelial dysfunction in the airway, with a partial recovery of endothelial function after smoking cessation in healthy ex-smokers but not in ex-smokers with COPD. In the latter, combined glucocorticoid/beta(2)-adrenergic agonist treatment restores albuterol responsiveness.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Endothelium, Vascular; Female; Fluticasone; Humans; Lung; Male; Middle Aged; Pulmonary Circulation; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Smoking

Exacerbations of chronic obstructive pulmonary disease (COPD) greatly contribute to declining health status and the progression of the disease, thereby incurring significant direct and indirect health care costs. The prevention of exacerbations, therefore, is an important treatment goal.. To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations.. Randomized, double-blind, parallel-group study. After a 4-wk run-in period, 994 clinically stable patients were randomized to one of two treatment groups: 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk.. The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group (p < 0.0001). The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group, corresponding to a 35% decrease. In addition, the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group (128 vs. 93 d, p < 0.0001). Other endpoints, including health-related quality of life, peak expiratory flow, and use of rescue medication, were significantly improved in the combination therapy group. Both treatments were well tolerated.. This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate

Previous studies on inhaled steroid and long-acting beta2-agonist combination products may not be representative for the asthma and chronic obstructive pulmonary disease (COPD) patients in family practice.. To compare in a group of doctor-diagnosed patients with asthma or COPD, the effects of a lower dose of fluticasone in a combination product with salmeterol with conventional treatment (i.e. a higher dose of fluticasone), both supplemented with as-needed use of a short-acting bronchodilator.. The study was a 12-week multicentre, randomized controlled, double-blind trial. In all, 41 family practices recruited 137 patients diagnosed with asthma and 40 patients diagnosed with COPD. Primary outcome was the forced expiratory volume in 1 second (FEV1) as percentage of predicted. Morning peak expiratory flow (PEF), symptom-free days, health status [Asthma Quality of Life Questionnaire (AQLQ) and St. George's Respiratory Questionnaire (SGRQ)], exacerbations, use of short-acting bronchodilators and adverse events were secondary outcomes.. FEV1% predicted increased 2.6% (SD 8.3) in fluticasone/salmeterol- and 0.01% (SD 6.6) in fluticasone-treated patients (overall: P=0.036, asthma: P=0.025 and COPD: P=0.700). PEF increased in favour of fluticasone/salmeterol in asthma patients only (P=0.016). Fluticasone/salmeterol-treated asthma patients had 1.1 more symptom-free days per week (P=0.044); no such effect was observed for COPD (P=0.769). There were no differences in total AQLQ and SGRQ scores, exacerbations, use of reliever puffs or adverse effects.. In family practice patients diagnosed with asthma, several treatment goals were better achieved with a lower dose of fluticasone and salmeterol in a combination product than with a higher dose of fluticasone. We found no differences between the two approaches for patients with COPD.

Topics: Adult; Aged; Albuterol; Androstadienes; Asthma; Bronchodilator Agents; Dose-Response Relationship, Drug; Family Practice; Female; Fluticasone; Humans; Male; Middle Aged; Netherlands; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Surveys and Questionnaires

Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.. To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.. Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.. 27 academic and community medical centers in Canada.. 449 patients with moderate or severe COPD.. 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.. The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.. The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.. More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists.. Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cause of Death; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Hospitalization; Humans; Male; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown.. We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed.. Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo).. The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216 [ClinicalTrials.gov].).

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk; Salmeterol Xinafoate; Smoking; Survival Analysis

Asthma is generally accepted as an inflammatory disease that needs steroid treatment. However, when to start with inhaled steroids remains unclear. A study was undertaken to determine when inhaled corticosteroids should be introduced as the first treatment step.. To investigate the effectiveness of early introduction of inhaled steroids on decline in lung function in steroid-naïve subjects with a rapid decline in lung function in general practice.. Patients with signs/symptoms suspect of asthma (i.e., persistent and/or recurrent respiratory symptoms) and a decline in forced expiratory volume in 1 s (FEV(1)) during 1-year monitoring of 0.080 l or more and reversible obstruction (> or =10% predicted) or bronchial hyperresponsiveness (PC(20)< or =8 mg/ml) were studied. They had been identified in a population screening aiming to detect subjects at risk for chronic obstructive pulmonary disease (COPD) or asthma.. A placebo-controlled, randomized, double-blind study.. 75 subjects out of a random population of 1155 were found eligible, and 45 were willingly to participate. Subjects were randomly treated with placebo or fluticasone propionate 250 microg b.i.d., and FEV(1) and PC(20) were monitored over a 2-year period.. The primary outcome measure was decline in FEV(1); the secondary outcome measure was bronchial hyperresponsiveness (PC(20)).. 22 subjects were randomly allocated to the active group with inhaled corticosteroids and 23 to placebo. Change of FEV(1) in the active treated group was +43 ml in post-bronchodilator FEV(1) (p =0.341) and +62 ml/year (p =0.237) in pre-bronchodilator FEV(1) after 1 year, and -22 ml (p =0.304) for post-bronchodilator FEV(1) and -9.4 ml (p =0.691) for pre-bronchodilator FEV(1) after 2 years, compared to placebo. The effect on PC(20) was almost one dose-step (p =0.627) after 1 year and one dose-step (p =0.989) after 2 years.. In this study, the early introduction of inhaled corticosteroids in newly diagnosed asthmatic subjects with rapid decline in lung function did not prove to be either clinically relevant or statistically significant in reversing the decline in FEV(1). For PC(20), no significant changes were detected.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Double-Blind Method; Fluticasone; Forced Expiratory Volume; Humans; Lung; Netherlands; Placebos; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Airway inflammation in chronic obstructive pulmonary disease (COPD) is characterised by infiltration of CD8+ T cells and CD68+ macrophages and an increased number of neutrophils, whereas few studies have described the presence of eosinophils. Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear, recent studies suggest that combination therapy could be beneficial. A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate (SFC) and fluticasone propionate (FP) alone on inflammatory cells in the airways of patients with COPD.. Patients were treated in a randomised, double blind, parallel group, placebo-controlled trial with either a combination of 50 microg salmeterol and 500 microg FP twice daily (SFC, n = 19, 19 men, mean age 62 years), 500 microg FP twice daily (n = 20, 15 men, mean age 64 years) or placebo (n = 21, 17 men, mean age 66 years) for 3 months. At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8+ T lymphocytes, CD68+ macrophages, neutrophils and eosinophils were measured.. CD8+ cells were significantly reduced by SFC compared with placebo (difference -98.05 cells/mm(2); 95% CI -143.14 to -52.9; p<0.001). Such a marked effect was not seen with FP alone (-44.67 cells/mm(2); 95% CI -90.92 to 1.57; p = 0.06). CD68+ macrophages were also reduced by SFC compared with placebo (difference -31.68 cells/mm(2); 95% CI -61.07 to -2.29; p = 0.03) but not by FP. SFC did not significantly change neutrophils and eosinophils compared with placebo.. SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchitis; Bronchodilator Agents; CD8-Positive T-Lymphocytes; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Immunohistochemistry; Lymphopenia; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome; Vital Capacity

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

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cause of Death; Double-Blind Method; Drug Combinations; Female; Fluticasone; Follow-Up Studies; Health Status; Humans; Lung; Male; Maximal Expiratory Flow-Volume Curves; Placebos; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk Assessment; Salmeterol Xinafoate; Survival Rate; Vital Capacity

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; p < 0.001) 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 p < 0.0001) in former or current smokers but not in never-smokers (p > 0.05). The mean improvement in the total SGRQ score for the SFC group was 5.74 (p < 0.01) 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; p < 0.01). 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.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; China; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Metered Dose Inhalers; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Smoking; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome

Topics: Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Fluticasone; Germany; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Survival Analysis

The evidence for the effectiveness and safety of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) is inconclusive. This study determined the cost effectiveness of withdrawing fluticasone propionate (FP) in outpatients with COPD.. The cost effectiveness analysis was based on a randomised, placebo controlled FP withdrawal study. After a 4 month run in period on FP, patients were randomly assigned to continue FP 500 microg twice daily or to receive placebo for 6 months. A decision analytical model evaluated the 6 month incremental cost effectiveness of the ICS versus ICS withdrawal strategy. One way sensitivity analyses and a Monte Carlo simulation were performed to evaluate the robustness of the findings.. The average patient with COPD in the FP group generated 511 in direct medical costs, including 238 for FP. The cost of the placebo strategy was 456. The higher direct drug cost of 212 per patient for the FP strategy during the 6 month follow up period compared with the placebo group was partially offset by a lower exacerbation and hospital admission cost of 157. The 6 month incremental cost effectiveness of the FP strategy compared with placebo was 110 per exacerbation prevented and 1286 per hospital admission prevented.. Over a 6 month period, withdrawing FP in a pre-selected trial population of COPD patients led to absolute cost savings but with a higher rate of exacerbations and hospital admissions.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Double-Blind Method; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Recurrence; Withholding Treatment

No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease.. We tested the hypothesis that inhaled combined long-acting beta2-agonist (salmeterol) and corticosteroid (fluticasone propionate) will reduce inflammation.. Bronchial biopsies and induced sputum were taken from 140 current and former smokers (mean age, 64 yr) with moderate to severe disease, randomized in a 13-wk double-blind study to placebo (n = 73) or salmeterol/fluticasone propionate 50/500 microg (n = 67) twice daily. Biopsies were repeated at 12 wk and sputa at 8 and 13 wk. After adjustment for multiplicity, comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8+ and CD68+ cells/mm2 and sputum neutrophils.. Combination therapy was associated with a reduction in biopsy CD8+ cells of -118 cells/mm2 (95% confidence interval [CI], -209 to -42; p = 0.02), a reduction of 36% over placebo (p = 0.001). CD68+ cells were unaffected by combination treatment. Sputum differential (but not total) neutrophils reduced progressively and, at Week 13, significantly with combination treatment (median treatment difference, 8.5%; 95% CI, 1.75%-15.25%; p = 0.04). The combination also significantly reduced biopsy CD45+ and CD4+ cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils (all p < or = 0.03). These antiinflammatory effects were accompanied by a 173-ml (95% CI, 104-242; p < 0.001) improvement in prebronchodilator FEV1.. The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease, which may contribute to clinical efficacy.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Anti-Inflammatory Agents; Biopsy; Bronchoscopy; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Sputum; Treatment Outcome

Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer and cardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduce exacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown. The Advair Biomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting beta2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease.. After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily), followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting beta2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500 micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), or placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada. Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predicted or less. Patients will be excluded if they have any known chronic systemic infections, inflammatory conditions, history of previous solid organ transplantation, myocardial infarction, or cerebrovascular accident within the past 3 months prior to study enrollment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function.. If inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Adult; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

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; p < 0.05) and healthy ex-smokers (37.2 +/- 3.4% predicted; p < 0.05), 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; p < 0.05) 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.

Topics: Adult; Albuterol; Androstadienes; Bronchodilator Agents; Case-Control Studies; Cross-Over Studies; Endothelium, Vascular; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Regional Blood Flow; Respiratory System; Salmeterol Xinafoate; Smoking; Vasodilation

It is now well recognised that heparin possesses numerous anti-inflammatory properties in addition to its anticoagulant properties. Thus, the aim of this study was to investigate the effects of the low molecular weight heparin, enoxaparin (ENX), as an add-on therapy for a period of 12 weeks, to inhaled salmeterol/fluticasone propionate (SLM/FP) combination in patients with stable chronic obstructive pulmonary disease (COPD). Forty-six patients were randomised to receive 12 weeks of treatment in one of two treatment groups: (1) fixed combination of SLM 50 microg and FP 500 microg Diskus, one inhalation twice daily; or (2) as group 1 plus 20 mg ENX administered subcutaneously once daily for 12 weeks. Patients attended the clinic before and after 4, 8 and 12 weeks of treatment for evaluations of lung function, blood gas tensions, dyspnoea and supplemental salbutamol use. Thirty-six patients completed the 12-week treatment period, 20 from group 1 and 16 from group 2. A significant increase in forced expiratory volume in 1 s (FEV1) over baseline was observed after 12 weeks of treatment in group 1 (0.145 L, 95% CI: 0.994-1.406, p<0.01), whilst significant increases in FEV1 over baseline were observed in group 2 after 4, 8 and 12 weeks of treatment with a maximum increase at 12 weeks of 0.244 L (95% CI: 1.175-1.596, p<0.01). Both treatment groups experienced similar improvements in blood gas tensions, dyspnoea and supplemental salbutamol use. Our results suggest that addition of ENX to conventional therapy of COPD may provide additional clinical benefit and must be further investigated as a treatment for COPD.

Topics: Aged; Albuterol; Androstadienes; Anticoagulants; Blood Gas Analysis; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Enoxaparin; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Vital Capacity

Reactive nitrogen species (RNS) are thought to be one of the important factors in the pathogenesis of chronic obstructive pulmonary disease (COPD). A study was undertaken to examine the effects of theophylline and fluticasone propionate (FP) on RNS production in subjects with COPD.. Sixteen COPD subjects participated in the study. Theophylline (400 mg/day orally) or FP (400 mug/day inhalation) were administered for 4 weeks in a randomised crossover manner with a washout period of 4 weeks. Induced sputum was collected at the beginning and end of each treatment period. 3-nitrotyrosine (3-NT), which is a footprint of RNS, was quantified by high performance liquid chromatography with an electrochemical detection method as well as by immunohistochemical staining.. Theophylline significantly reduced the level of 3-NT in the sputum supernatant as well as the number of 3-NT positive cells (both p<0.01). FP also reduced 3-NT formation, but the effect was smaller than that of theophylline. Theophylline also significantly reduced the neutrophil cell counts in the sputum (p<0.01), while FP treatment had no effect on the number of inflammatory cells in the sputum, except eosinophils.. Theophylline reduces nitrative stress and neutrophil infiltration in COPD airways to a larger extent than inhaled corticosteroid.

Topics: Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Aged; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Reactive Nitrogen Species; Theophylline; Vital Capacity

Currently, patients have to keep track of doses to determine when to replace their metered-dose inhalers (MDIs). This study evaluated the performance and patient satisfaction of a novel MDI with an integrated dose counter. In an open-label study at 38 outpatient centres, patients > or =12 years old with asthma or chronic obstructive pulmonary disease (COPD) received two actuations of fluticasone propionate/salmeterol 125/25 microg (115/21 microg ex-actuator) hydrofluoroalkane (ADVAIR) HFA) via MDI with counter twice a day until all 120 actuations were completed. Concordance between counter and diary recordings in patients who reported use of > or =90% of labelled actuations (completer population, n = 228) was high (discrepancy rate of 0.94%) and the incidence of device firing without changes in counter readings was low (0.13%). Mean expected actuations based on canister weights (114) were slightly lower than mean counter (121) and diary reported actuations (120). Upon study completion, 95% of patients were satisfied with the dose counter and 92% agreed it would help prevent them from running out of medication. Safety assessments (intent-to-treat population, n = 237) indicated that the drug was well tolerated. This integrated MDI counter may help patients maintain better disease control by enabling them to accurately track their medication supply.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Albuterol; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Female; Fluticasone; Humans; Hydrocarbons, Fluorinated; Male; Metered Dose Inhalers; Middle Aged; Patient Satisfaction; Powders; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

Inhaled corticosteroids have a high level of topical anti-inflammatory activity. However, in patients with COPD these drugs have been reported to exert limited effects. A reduction in histone deacetylase (HDAC) activity is suggested to prevent the anti-inflammatory action of corticosteroids. Cigarette smoke is known to reduce HDAC expression. The aim of this study is to compare the outcome of corticosteroid therapy in both smoking and non-smoking COPD patients. Twenty-three smoking patients and 18 ex-smoking patients with COPD were treated with inhaled corticosteroids for a period of 2 months. Blood and induced sputum samples were collected before and after treatment. Values of FEV(1) %-predicted did not change upon the therapy, but there was a trend to improve in the ex-smokers (63.1 -> 64.8%-pred.), compared with a decrease in the smokers (63.3 -> 61.6%-pred.). The levels of the pro-inflammatory cytokine IL-8 increased in the group of smokers from 379 +/-78 to 526 +/-118 ng/ml. Although not significant, a slight decrease from 382 +/-70 to 342 +/-62 ng/ml was observed in the group of ex-smokers. The neutrophil related elastase activity showed similar effects after steroid treatment, it went up from 36.4 +/-12.0 to 113.5 +/-9.7 nmol/l in smokers, and decreased from 346.2 +/-72.1 to 131.1 +/-6.5 nmol/l in ex-smokers with COPD. These results support the evidence that inhaled corticosteroids have no anti-inflammatory effects in COPD patients, but only when these patients are still smoking. Smoking cessation seems the best therapy for COPD patients.

Topics: Adrenal Cortex Hormones; Aged; Albumins; Androstadienes; Anti-Inflammatory Agents; Budesonide; Cell Count; Female; Fluticasone; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Neutrophils; Pancreatic Elastase; Peroxidase; Pulmonary Disease, Chronic Obstructive; Smoking; Smoking Cessation; Sputum; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is accompanied by both airway and systemic inflammation and by oxidative stress. This study aimed to characterise the relationship between oxidative stress and inflammatory components in induced sputum and blood.. We studied blood and sputum samples from stable COPD patients (mean FEV1 60.5+/-7.5% predicted) at baseline (no treatment) and after 10 weeks treatment with either inhaled steroid, fluticasone propionate (FP) (1000 microg/d) or 10 weeks treatment with N-acetylcysteine (600mg/d) (NAC). We assessed the inflammatory markers (IL-8, ECP, sICAM-1, NE) in sputum and serum and we compared them with blood markers of oxidative stress (SOD, GPx, TEAC, albumin, vitamin E and A).. At baseline blood sICAM-1 correlated with IL-8 levels (P<0.01, r = 0.62) and negatively with GPx (P<0.01, r = -0.63) and with TEAC (P<0.05, r = -0.53). TEAC correlated positively with GPx (P<0.01, r = 0.70). Correlation between sICAM and IL-8 disappeared after NAC treatment. The correlation between sICAM and GPx disappeared after FP treatment. The correlation between TEAC and GPx was maintained after both NAC and FP.. The relationship between markers of inflammation, adhesion and antioxidant capacity is significantly modulated by treatment with N-acetylcysteine or inhaled corticosteroids.

Topics: Administration, Inhalation; Aged; Androstadienes; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Bronchitis; Cross-Over Studies; Female; Fluticasone; Forced Expiratory Volume; Humans; Interleukin-8; Male; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Spirometry; Sputum; Vital Capacity

Bronchodilators are still the most effective drugs for controlling the symptoms of chronic obstructive pulmonary disease (COPD). Tiotropium bromide, a long-acting anticholinergic drug, has recently been added to the therapeutic arsenal for the disease. To date, there have been no studies combining 2 long-acting bronchodilators. The aim of the present trial was to determine whether the combination of salmeterol and tiotropium improved lung function in COPD patients more than either of them alone.. Twenty-two patients (20 men) diagnosed with COPD, with a mean age of 64 years, were enrolled in this cross-over trial. Active smokers were excluded. Mean (SD) forced expiratory volume in 1 second (FEV1) was 43% (14%) of predicted. All patients were experienced in the use of inhalers. The following 3 therapeutic combinations were randomly assigned to be administered for a 1-week period: a) fluticasone (500 microg/12 h), salmeterol (50 microg/12 h) and placebo; b) fluticasone, tiotropium (18 microg/24 h), and placebo; and c) fluticasone, salmeterol, and tiotropium. At the end of each period, forced spirometry was performed before inhalation of the therapeutic combination (between 8:30 am and 9:30 am) and 2 hours after inhalation. Throughout the week, morning peak flow rates measured immediately before inhalation were recorded, and there was a 48-hour wash-out period between each therapeutic combination.. All the patients completed the protocol. There were no significant differences in preinhalation or postinhalation FEV1 with salmeterol compared to tiotropium (preinhalation FEV1, 1.17 [0.55] L compared to 1.19 [0.49] L; postinhalation FEV1, 1.32 [0.65] L compared to 1.29 [0.61] L). In all cases postinhalation FEV1 was significantly higher than preinhalation FEV1. The combination of fluticasone, salmeterol, and tiotropium proved superior to the other 2 combinations with respect to both preinhalation FEV1 and postinhalation FEV1 (preinhalation FEV1, 1.32 [0.56] L, [P<.03 in both comparisons]; postinhalation FEV1, 1.49 [0.68] L [P<.001 in both comparisons]). Peak flow rate was also significantly higher with the combination of the 2 bronchodilators (345 L/min compared to 291 L/min and 311 mL, respectively [P <.04 in both cases]). There were no notable side effects.. In terms of improvement in lung function, the combination of salmeterol and tiotropium together with fluticasone is more effective in patients with moderate-to-severe COPD than either of the 2 bronchodilators administered alone.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Data Interpretation, Statistical; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome

Combined treatment with inhaled corticosteroids and long acting beta2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination.. Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores.. PEF was significantly higher after 1 day in patients treated with salmeterol 50 microg twice daily or the salmeterol/fluticasone propionate combination 50/500 microg twice daily than placebo. In patients treated with fluticasone propionate 500 microg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11 to 21), 11 l/min (95% CI 6 to 16), and 27 l/min (95% CI 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long term response in individual patients.. The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.

Topics: Administration, Inhalation; Albuterol; Analysis of Variance; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Dyspnea; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome; Vital Capacity

Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting beta2 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of ICS will result in disease deterioration.. The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 microg FP + 50 microg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study.. The drop out rate after randomisation was similar in the two groups. Withdrawal of FP resulted in a sustained decrease in FEV1: mean (SE) change from baseline -4.4 (0.9)% (S) v -0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were -3.7 (0.8)% (S) v 0.0 (0.8)% (SFC) (p = 0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p = 0.15). The mean annual incidence rate of mild exacerbations was 1.3 (S) v 0.6 (SFC), p = 0.020. An immediate and sustained increase in dyspnoea score (scale 0-4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone.. Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA.

Topics: Administration, Inhalation; Albuterol; Analysis of Variance; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Female; Fluticasone; Humans; Male; Medical Records; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Substance Withdrawal Syndrome

Inhaled corticosteroids (ICS) are widely used for the treatment of COPD despite of controversial statements concerning their efficacy. The use of N-acetylcysteine (NAC), a mucolytic drug with antioxidant properties, is less clear, but it may counteract the oxidant-antioxidant imbalance in COPD. The aim of this study was to evaluate whether treatment of COPD patients with ICS or NAC is able to improve inflammatory indices and to enhance lung function. ICS treatment enhanced protective markers for oxidative stress such as glutathione peroxidase (GPx) (51.2 +/-5.8 vs. 62.2 +/-8.6 U/g Hb, P<0.02) and trolox-equivalent antioxidant capacity (TEAC) (1.44 +/-0.05 vs. 1.52 +/-0.06 mM, P<0.05). NAC decreased sputum eosinophil cationic protein (318 +/-73 vs. 163 +/-30 ng/ml, P<0.01) and sputum IL-8 (429 +/-80 vs. 347 +/-70 ng/ml, P<0.05). The increased antioxidant capacity prevented an up-regulation of adhesion molecules, since the levels of intracellular adhesion molecule 1 (ICAM-1) correlated negatively with GPx (P<0.0001) and TEAC (P<0.0001). On the other hand, expression of adhesion molecules was promoted by inflammation, reflected by a positive correlation between the levels of IL-8 and ICAM-1 (P<0.0001). The effects of treatment on lung function were only reflected in the FEV(1) values. The absolute value of FEV(1), both before and after salbutamol inhalation, increased from 1690 +/-98 to 1764 +/-110 ml, and 1818 +/-106 to 1906 +/-116 ml, respectively, after ICS (P<0.05) . Ten weeks after treatment, FEV(1) values dropped to 1716 +/-120 ml post-salbutamol (P<0.05). When followed by treatment with NAC, these values decreased even further to 1666 +/-84 ml. These results suggest that ICS improved lung function in COPD patients with moderate airflow obstruction, beside a minor improvement in the oxidant-antioxidant imbalance leading to a lesser expression of ICAM-1. Treatment with NAC decreased some inflammatory parameters and had indirectly an inhibitory effect on the expression of adhesion molecules.

Topics: Acetylcysteine; Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Inflammatory Agents; Antioxidants; Double-Blind Method; Eosinophil Cationic Protein; Expectorants; Female; Fluticasone; Forced Expiratory Volume; Glutathione Peroxidase; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Treatment Outcome

To determine whether administration of glucocorticoids provides additional benefits to environmental management of horses with recurrent airway obstruction (RAO).. 28 horses with RAO.. Horses were classified as having mild, moderate, or severe RAO. Within each category, horses were randomly assigned to receive inhaled fluticasone propionate, inhaled control substance, or oral administration of prednisone. During the 4-week study, horses were maintained outdoors and fed a pelleted feed. Clinical scores, pulmonary function, results of cytologic examination of bronchoalveolar lavage fluid (BALF), and adrenal gland function were determined before and 2 and 4 weeks after initiation of treatment.. Clinical score and pulmonary function of all RAO-affected horses improved during the treatment period. After 4 weeks, clinical scores and pulmonary function of horses treated with a glucocorticoid were not different from those for the control treatment. In horses with severe RAO, treatment with fluticasone for 2 weeks resulted in significantly greater improvement in pulmonary function, compared with pulmonary function after treatment with prednisone or the control substance. Treatment with a glucocorticoid for 4 weeks and a low-dust environment did not have any effect on cellular content of BALF Treatment with prednisone for 2 weeks resulted in a significant decrease in serum cortisol concentration, compared with concentrations after administration of fluticasone or the control substance.. Environmental management is the most important factor in the treatment of horses with RAO. Early treatment with inhaled fluticasone can help accelerate recovery of horses with severe RAO.

Topics: Analysis of Variance; Androstadienes; Animals; Bronchoalveolar Lavage; Environment; Fluticasone; Horse Diseases; Horses; Hydrocortisone; Prednisone; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Contusions; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Substance Withdrawal Syndrome

To assess the systemic bioactivity of fluticasone proprionate (FP) 2000 micro g daily on sensitive adrenal and bone markers in severe chronic obstructive pulmonary disease (COPD) patients with or without significant emphysema.. Ten patients without emphysema (COPD group: age 55 years, FEV(1) 51% predicted and DL(CO) 83% predicted) and 10 patients with emphysema (COPDE group: age 59 years, FEV(1) 43% predicted and DL(CO) 49% predicted) received FP 2000 micro g daily via a spacer for 2 weeks. There was a 1-week washout period prior to FP treatment where patients were given salmeterol and oxitropium, after stopping their usual inhaled corticosteroids for the duration of the study. Measurements including overnight 10 h urinary cortisol excretion corrected for creatinine (OUCC) and serum osteocalcin concentrations were performed at baseline following washout and after 2 weeks of FP.. Values for OUCC and serum osteocalcin concentrations pre- and post-FP were not significantly different between the COPD and COPDE groups. There was significant suppression of OUCC (nmol mmol(-1)) by FP treatment within the COPD group (P = 0.03): 7.86 vs 4.64 (95% CI on the difference 0.47, 5.98), and within the COPDE group (P = 0.006): 7.13 vs 4.27 (95% CI on the difference: 1.03, 4.69). Likewise, there was significant suppression of osteocalcin concentration (nmol l(-1)) by FP treatment within the COPD group (P = 0.04): 7.24 vs 6.34 (95% CI on the difference: 0.01, 1.78), and within the COPDE group (P = 0.03): 6.92 vs 5.72 (95% CI on the difference: 0.12, 2.29).. Severe COPD patients who are receiving high dose FP are susceptible to the development of systemic adverse effects, irrespective of the presence of emphysema.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocortisone; Male; Middle Aged; Osteocalcin; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema

The aim of this study was to compare the relative efficacy in terms of improvement in symptoms and lung function of salmeterol/fluticasone propionate (SLM/FP) combination administered through the Diskus inhaler versus theophylline (THEO) added to FP Diskus in patients with stable chronic obstructive pulmonary disease (COPD).. Eighty patients were randomized to receive 4 months of treatment in one of two treatment groups: (1) fixed combination of SLM 50 microg and FP 500 microg Diskus, 1 inhalation twice daily; or (2) FP Diskus 500 microg, 1 inhalation twice daily, plus oral titrated THEO twice daily. Patients attended the clinic before and after 4, 8, 12 and 16 weeks of treatment for evaluations of pulmonary function, and dyspnea, which was assessed using an analogic visual scale. Also the supplemental salbutamol use was measured.. . Sixty-six patients completed the 4-month treatment period: 37 patients receiving SLM/FP and 29 patients receiving THEO+FP. Patients were withdrawn for various reasons, the most common of which were poor compliance with the protocol, exacerbation and GI events. A gradual increase in FEV(1) was observed with each treatment. Maximum significant increases in FEV(1) over baseline values that were observed after 4 months of treatment were as follows: SLM/FP 0.172 l (95% CI: 0.084-0.260) and THEO+FP 0.155 l (95% CI: 0.054-0.256). SLM/FP experienced significantly (p<0.05) greater improvements in dyspnea, and required significantly fewer supplemental salbutamol treatments than the THEO+FP group.. Our results suggest that SLM/FP combination may provide substantial benefits in both physiologic and clinical outcomes in symptomatic patients with COPD. It also causes a more effective control than THEO+FP.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Smoking; Theophylline

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aerosols; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Fluticasone; Humans; Internationality; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St George's Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent (<1.65 exacerbations x yr(-1)) and frequent (>1.65 exacerbations x yr(-1)). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.

Topics: Adult; Aged; Androstadienes; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Surveys and Questionnaires

This is the first comparison of two combination therapies, fluticasone propionate/salmeterol and ipratropium bromide/albuterol (salbutamol), for the treatment of patients with COPD.. A randomized, double-blind, double-dummy, parallel group, multicenter evaluation of fluticasone propionate/salmeterol 250/50 microg twice daily via DISKUS and ipratropium bromide/albuterol 36/206 microg four times daily via metered-dose inhaler over 8 weeks was conducted at 41 research sites in the US. Morning pre-dose FEV(1), 6-hour serial spirometry, PEF, dyspnea, night-time awakenings, supplemental albuterol use, and patient diary evaluations of symptoms were evaluated.. A total of 365 patients with symptomatic COPD were enrolled. The treatment groups were similar in mean age (63.3 and 63.9 years), screening pulmonary function (44.1% and 43.2% of predicted FEV(1)), race (96% and 95% White), and sex distribution (59% and 60% male). Both fluticasone propionate/salmeterol and ipratropium bromide/albuterol improved lung function, symptoms, and supplemental albuterol use compared with baseline. Fluticasone propionate/salmeterol was more effective than ipratropium bromide/albuterol for improvement in morning pre-dose FEV(1), morning PEF, 6-hour FEV(1) area under the curve (AUC(6)), Transition Dyspnea Index (TDI) focal score, daytime symptom score, night-time awakenings, sleep symptoms, and albuterol-free nights (p < or = 0.013). Compared with day 1, at week 8 the FEV(1) AUC(6) significantly increased with fluticasone propionate/salmeterol and significantly decreased with ipratropium bromide/albuterol (p < or = 0.003). The incidence of adverse events was similar between treatment groups, except for a higher incidence of oral candidiasis with fluticasone propionate/salmeterol.. Short-term treatment with the combined inhaled corticosteroid and long-acting beta(2)-adrenoceptor agonist fluticasone propionate/salmeterol resulted in greater control of lung function and symptoms than combined ipratropium bromide/albuterol bronchodilator therapy, in patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Dyspnea; Female; Fluticasone; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Time Factors; Treatment Outcome

Systemic inflammation is present in chronic obstructive pulmonary disease (COPD), which has been linked to cardiovascular morbidity and mortality. We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD. We recruited 41 patients with mild to moderate COPD. After 4 weeks during which inhaled corticosteroids were discontinued, patients were assigned to fluticasone (500 mcg twice a day), oral prednisone (30 mg/day), or placebo over 2 weeks, followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day. Withdrawal of inhaled corticosteroids increased baseline C-reactive protein (CRP) levels by 71% (95% confidence interval [CI], 16-152%). Two weeks with inhaled fluticasone reduced CRP levels by 50% (95% CI, 9-73%); prednisone reduced it by 63% (95% CI, 29-81%). No significant changes were observed with the placebo. An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline (a 29% reduction; 95% CI, 7-46%). Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD.

Topics: Administration, Inhalation; Administration, Oral; Aged; Aged, 80 and over; Androstadienes; Anti-Inflammatory Agents; Biomarkers; C-Reactive Protein; Chemokine CCL2; Double-Blind Method; Drug Administration Schedule; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Linear Models; Male; Middle Aged; Prednisone; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Only long-term home oxygen therapy has been shown in randomised controlled trials to increase survival in chronic obstructive pulmonary disease (COPD). There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators, alone or in combination, on mortality in patients with COPD, despite their known benefit in reducing symptoms and exacerbations. The "TOwards a Revolution in COPD Health" (TORCH) survival study is aiming to determine the impact of salmeterol/fluticasone propionate (SFC) combination and the individual components on the survival of COPD patients. TORCH is a multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Approximately 6,200 patients with moderate-to-severe COPD were randomly assigned to b.i.d. treatment with either SFC (50/500 microg), fluticasone propionate (500 microg), salmeterol (50 microg) or placebo for 3 yrs. The primary end-point is all-cause mortality; secondary end-points are COPD morbidity relating to rate of exacerbations and health status, using the St George's Respiratory Questionnaire. Other end-points include other mortality and exacerbation end-points, requirement for long-term oxygen therapy, and clinic lung function. Safety end-points include adverse events, with additional information on bone fractures. The first patient was recruited in September 2000 and results should be available in 2006. This paper describes the "TOwards a Revolution in COPD Health" study and explains the rationale behind it.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Albuterol; Androstadienes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Reference Values; Respiratory Function Tests; Risk Assessment; Salmeterol Xinafoate; Severity of Illness Index; Statistics, Nonparametric; Survival Analysis

The prevalence of chronic obstructive pulmonary disease (COPD) in women is increasing worldwide. Women may have greater susceptibility to COPD progression than men, and differences in efficacy and safety of respiratory medications by gender are largely unexplored. We aimed to determine whether the response to treatment in women with COPD differed from men in a large, 1-year double-blind trial ('TRISTAN'). In a sensitivity analysis, we compared 539 male and 180 female COPD patients, who were randomized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months. Combination therapy improved pre-treatment FEV1 significantly more than placebo in women by 152 ml (95% confidence interval 95-208) and in men by 127 ml (94-159). Similarly, a reduction in COPD exacerbation rates of 31% in women (9-48%) and of 23% in men (8-35%) was observed. Combination therapy reduced COPD exacerbations requiring treatment with oral corticosteroids by 36% in women and by 41% in men. Finally, combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 (-4.6 - 0.1) and in men by -2.1 (-3.5 to -0.8). No gender interaction was found for any outcome. Treatments were well tolerated with no difference in the frequency of adverse events in women and men. In this trial, therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women.

Topics: Adrenergic beta-Agonists; Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Sex Characteristics; Treatment Outcome

COPD leads to a progressive decline of pulmonary function. Family physicians treat a substantial number of patients with COPD and are encouraged to start treatment at as early a stage as is possible. This study analyzed the effectiveness of early inhaled corticosteroid treatment on the decline of pulmonary function in COPD patients.. Subjects with a rapid decline in lung function (ie, FEV(1) decline, > 80 mL/yr) who had never before received a diagnosis of asthma or COPD.. Two-year, randomized, controlled, double-blind clinical trial of fluticasone propionate (250 microg bid; 24 patients) or placebo (25 patients), followed by a 7-month open-label study in which all subjects received fluticasone propionate. The primary outcome was the post-bronchodilator therapy FEV(1,) and secondary outcomes were respiratory symptoms, exacerbations, health state, quality of life, and health-care utilization.. After 31 months, there were no statistical differences in post-bronchodilator therapy FEV(1) between the intervention group and the control group. No statistical differences were observed for symptoms, exacerbations, or quality of life, although tendencies were consistently in favor of treatment. There was no significant impact on the direct or indirect costs.. There are no indications that early treatment with inhaled corticosteroids modifies a rapid decline in lung function or respiratory symptoms and quality of life.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Female; Fluticasone; Forced Expiratory Volume; Health Services; Health Status; Humans; Lung; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk Factors

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with worse health and increased healthcare utilisation. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD showed a 26% reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate (FP) compared to placebo, but did not indicate which patients showed greatest benefit. In this study the patients were stratified into mild and moderate-to-severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second (FEV1) 50% predicted, and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined. There were 391 (195 FP) patients with mild COPD and 359 (180 FP) patients with moderate-to-severe disease. The exacerbation rate was highly skewed in mild disease, but more normally distributed in moderate-to-severe disease. FP reduced the overall exacerbation rate in moderate-to-severe disease (FP median rate 1.47 yr(-1), placebo 1.75 yr(-1)), but not in mild disease (FP 0.67 yr(-1), placebo 0.92 yr(-1)). FP use was associated with fewer patients with > or = 1 exacerbation x yr(-1) being treated with oral corticosteroids (mild: FP 8%, placebo 16%; moderate-to-severe: FP 17%, placebo 30%). Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second <50% predicted. These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate-to-severe chronic obstructive pulmonary disease who experience recurrent exacerbations.

Topics: Administration, Inhalation; Administration, Topical; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone.. 1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 microg salmeterol twice daily (n=372), 500 microg fluticasone twice daily (n=374), 50 microg salmeterol and 500 microg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol.. All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p<0.0001), salmeterol (73 mL, 46-101, p<0.0001), or fluticasone alone (95 mL, 67-122, p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration.. Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD.

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Contusions; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Hydrocortisone; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Substance Withdrawal Syndrome

Chronic obstructive pulmonary disease (COPD) is a debilitating disease and places a large financial burden on health-care systems and society. We prospectively evaluated the cost-effectiveness offluticasone propionate (FP) treatment in patients with moderate-to-severe COPD, who were symptomatic on regular bronchodilator therapy.. An economic analysis was performed in a 6-month, randomized, double-blind clinical trial comparing FP 1,000 microg/day with placebo in 281 patients aged 45-79 years with symptomatic moderate-to-severe COPD. Data on clinical efficacy, health-care resource use and productivity loss associated with the management of COPD were prospectively collected. The main outcome measures were the incremental cost-effectiveness of achieving a > or = 10% improvement in FEV1 and of remaining exacerbation-free throughout the study. The economic evaluation was costed from the perspective of the NHS (direct costs) and of society (direct and indirect costs).. FP was significantly more effective than placebo in terms of the proportions of patients demonstrating a > or = 10% improvement in FEV1 (32 vs. 19%; P = 0.02) and remaining free of moderate/severe exacerbations (75 vs. 63%; P = 0.02). The difference between the groups in total costs was not significantly different. Incremental cost-effectiveness analyses showed that the additional clinical benefits of FP relativeto placebo, in terms of a > or = 10% improvement in FEV1 or an increased number of patients free of moderate/severe exacerbations, were achieved at minimal additional costs from an NHS perspective (additional 0.25 pounds per day for bath) or at a net saving from a societal perspective. Sensitivity analysis showed that these results were robust to changes in the underlying assumptions.. Treatment with FP was associated with statistically significant clinical benefits in patients with moderate-to-severe COPD currently symptomatic on regular bronchodilator therapy. As the differences in direct and total costs compared with placebo were small and non-significant, this treatment can be considered cost-effective in this patient population.

Topics: Aged; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Health Care Costs; Health Expenditures; Health Resources; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Vital Capacity

We have previously shown that the systemic exposure to inhaled fluticasone propionate (FP) is reduced in asthmatics compared with healthy subjects. We have now compared its pharmacokinetics in patients suffering from chronic obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects (n = 13).. A double-blind, randomized, cross-over study design was used. Plasma FP and serum cortisol were measured for 12 h after subjects received hydrofluoroalkane FP 1000 microg day-1 inhaled (via an MDI and spacer) for 7 days and following a single 1000- microg intravenous dose.. The pharmacokinetics differed in the two groups. After inhalation, geometric least square means were significantly lower in the COPD group for the plasma AUC (1961 vs 2996 pg ml-1 h-1 for COPD and controls, respectively; P = 0.03) and the Cmax (235 vs 421 pg ml-1 for COPD and controls, respectively; P = 0.03). Suppression of serum cortisol concentration over 12 h was greater in healthy controls. Weighted mean serum cortisol concentration (nmol l-1) in healthy subjects and COPD was 93 and 170, respectively (P = 0.03). The intravenous pharmacokinetic parameters for FP were comparable in the two groups, resulting in similar suppression of serum cortisol.. We conclude that the altered pharmacokinetics of inhaled fluticasone propionate in COPD caused less hypothalamic-pituitary-adrenal suppression than in healthy controls. This is further evidence that the systemic effects of inhaled corticosteroids should be assessed in patients and not healthy subjects.

Topics: Administration, Inhalation; Administration, Topical; Androstadienes; Anti-Inflammatory Agents; Biological Availability; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Fluticasone; Humans; Hydrocortisone; Pulmonary Disease, Chronic Obstructive

In the present trial, we compared the broncholytic efficacy of the combination therapy with 50 microg salmeterol + 250 microg fluticasone and 12 microg formoterol + 400 microg budesonide, both in a single inhaler device, in 16 patients with moderate-to-severe COPD. The study was performed using a single-blind crossover randomized study. Lung function, pulse oximetry (SpO2) and heart rate were monitored before and 15, 30, 60, 120, 180, 240, 300, 360, 480, 600, and 720 min after bronchodilator inhalation. Both combinations were effective in reducing airflow obstruction. FEV1 AUC(0-12 h) was 2.83 l (95% CI: 2.13-3.54) after salmeterol/fluticasone and 2.57 l (95% CI: 1.97-3.2) after formoterol/budesonide. Formoterol/budesonide elicited the mean maximum improvement in FEV1 above baseline after 120 min (0.29 l; 95% CI: 0.21-0.37) and salmeterol/fluticasone after 300 min (0.32 l; 95% CI: 0.23-0.41). At 720 min, the increase in FEV1 over baseline values was 0.10 l (95% CI: 0.07-0.12) after salmeterol/fluticasone and 0.10 l (95% CI: 0.07-0.13) after formoterol/budesonide. The mean peak increase in heart rate occurred 300 min after formoterol/budesonide (1.5 b/min; 95% CI--2.3 to 5.3) and 360 min after salmeterol/fluticasone (2.6 b/min; 95% CI--1.9 to 7.0). SpO2 did not change. All differences between salmeterol/fluticasone and formoterol/budesonide were not significant (P > 0.05) except those in FEV1 at 120 and 360 min. The results indicate that an inhaled combination therapy with a long-acting beta2-agonist and an inhaled corticosteroid appears to be effective in improving airway limitation after acute administration in patients suffering from COPD.

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Cross-Over Studies; Drug Combinations; Ethanolamines; Female; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Heart Rate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Single-Blind Method

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

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.

Topics: Aged; Albuterol; Analysis of Variance; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Maximal Expiratory Flow Rate; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Theophylline

A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent "response" determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV(1)) after prednisolone, and whether the prednisolone response predicts 3 year changes in FEV(1), health status, or number of exacerbations during placebo or fluticasone propionate treatment.. Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV(1) after prednisolone were investigated using multiple regression. The response to prednisolone was entered into separate mixed effects models of decline in FEV(1) and health status during the 3 years of the study.. The post-bronchodilator FEV(1) increased by a mean 60 ml (CI 46 to 74) after prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV(1) after prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p<0.001). There was no relationship between the change in FEV(1) after prednisolone and the response to inhaled bronchodilators, baseline FEV(1), atopic status, age, or sex. The response to prednisolone, however expressed, was unrelated to the subsequent change in FEV(1) over the following 3 years on either placebo or fluticasone propionate. Regression to the mean effects explained much of the apparent prednisolone response. The significant effect of treatment on decline in health status was not predicted by the prednisolone response.. Patients with COPD cannot be separated into discrete groups of corticosteroid responders and non-responders. Current smoking reduces the FEV(1) response to prednisolone. Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients.

Topics: Administration, Oral; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Prednisolone; Pulmonary Disease, Chronic Obstructive; Vital Capacity

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate

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.

Topics: Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Humans; Lung Volume Measurements; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

To investigate the determinants of patient withdrawal from our study, and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD.. A double-blind, placebo-controlled, randomized trial.. Eighteen outpatient centers in the United Kingdom.. Seven hundred fifty-one patients with stable COPD defined clinically and as baseline postbronchodilator FEV(1) > or = 0.8 L and < 85% predicted, FEV(1)/FVC ratio < 70%, and FEV(1) change after albuterol < 10% of predicted.. Random assignment of either 500 microg bid of inhaled fluticasone propionate (FP) using a spacer device or an identical placebo inhaler. Treatment was continued for 3 years or until patients withdrew from follow-up.. Postbronchodilator FEV(1) was measured on three occasions before randomization and every 3 months thereafter. Health status was assessed by the disease-specific St. George Respiratory Questionnaire (SGRQ) and the modified short-form 36 questionnaire (SF-36) at baseline and every 6 months. Three hundred thirty-nine patients withdrew, of whom 156 patients received FP. Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol (69 patients in the FP group withdrew due to respiratory symptoms, compared with 93 patients in the placebo group). This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1) was < 50% predicted. Patients withdrawing had a significantly more rapid decline in health status, measured by both the SGRQ and the SF-36 (p < 0.001). Those withdrawing from the placebo group had a more rapid decline in FEV(1) and more exacerbations than the FP-treated groups. Baseline FEV(1) was lower in dropouts than in patients completing the study receiving placebo, but there was no difference between the respective groups receiving FP.. Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function. Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point.

Topics: Adult; Aged; Androstadienes; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Humans; Male; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Spirometry; Treatment Outcome

The aim of this study was to assess the effects of a comprehensive self-management intervention on health-related quality of life (HRQoL), symptoms and walking distance in patients with stable moderately severe chronic obstructive pulmonary disease (COPD). This study was part of the overall COPD study of the Dept of Pulmonary Medicine, Enschede, which consisted of an inhaled corticosteroid (ICS) trial and a self-management trial. After the ICS trial, all patients were randomised again to a self-management and a control group. The self-management intervention consisted of a skill-oriented patient education programme and a near-home fitness programme, on top of usual care. The control group received usual care by the treating chest physician. HRQoL was measured by the St George's Respiratory Questionnaire (SGRQ) and walking distance by the 6-min walking test. Patients recorded their symptoms in diaries and graded their health status from 1-10 in a weekly report. Altogether, 248 COPD patients were randomly allocated to either an intervention (127) or control (121) group. No differences in the SGRQ scores within and between both groups were observed over 1 yr. Similarly, no differences in symptom scores and 6-min walking distance were found within and between groups. The intervention group reported more exacerbations than the control group. The majority (69%) of the exacerbations in the intervention group were self-treated at home. This study failed to show positive effects of a self-management programme among moderately severe chronic obstructive pulmonary disease patients.

Topics: Administration, Inhalation; Adult; Aged; Androstadienes; Bronchodilator Agents; Exercise Therapy; Exercise Tolerance; Female; Fluticasone; Health Status; Humans; Male; Middle Aged; Patient Education as Topic; Pulmonary Disease, Chronic Obstructive; Quality of Life; Self Care; Surveys and Questionnaires

Early treatment with inhaled corticosteroids may prevent progression of irreversible obstruction in COPD, especially in patients with bronchial hyperresponsiveness. We investigated the clinical effects of early introduction of inhaled steroids in subjects showing early signs and symptoms of COPD without a prior clinical diagnosis.. Study subjects were detected in a general population screening and monitoring program. Those with a moderately accelerated annual FEV1 decline and persistent respiratory symptoms were invited to participate in a 2-year randomized controlled trial comparing fluticasone propionate DPI 250 microg b.i.d. with placebo. Pre- and post-bronchodilator (BD) FEV1, PC20 histamine, functional status (COOP/WONCA charts) and occurrence of exacerbations were periodically assessed. Subjects recorded respiratory symptoms. Post-BD FEV1 decline served as the main outcome. Multivariable repeated measurements analysis techniques were applied.. 48 subjects were randomized (24 fluticasone, 24 placebo). After 3 months, the post-BD FEV1 had increased with 125 ml (SE = 68, P = 0.075) and the pre-BD FEV1 with 174 ml (SE 90, P = 0.059) in the fluticasone relative to the placebo group. The subsequent post-BD and pre-BD FEV1 decline were not beneficially modified by fluticasone treatment. There were no statistically significant differences in respiratory symptoms, functional status, or exacerbations favoring fluticasone. Subgroup analysis indicated that the presence of bronchial hyperresponsiveness modified the initial FEV1 response on fluticasone, but not the subsequent annual FEV1 decline.. Early initiation of inhaled steroid treatment does not seem to affect the progressive deterioration of lung function or other respiratory health outcomes in subjects with early signs and symptoms of COPD. In subjects at risk for, or in an early stage of COPD, long-term inhaled steroid treatment should not be based on a single spirometric evaluation after 3 months.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Vital Capacity

Treatment of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma. It seems that only certain subgroups of patients with COPD benefit from steroid treatment. A study was undertaken to examine whether inhaled fluticasone propionate (FP) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness (BHR).. Twenty three patients with COPD were studied. Patients had to be persistent current smokers between 40 and 70 years of age. Non-specific BHR was defined as a PC(20) for histamine of

Topics: Adult; Aged; Androstadienes; Biopsy; Bronchial Hyperreactivity; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Functional Residual Capacity; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Vital Capacity

Inhaled corticosteroids (ICS) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease (COPD) is unknown.. A study of endobronchial biopsy samples was conducted as part of a double blind, placebo controlled, randomised trial of parallel design. Patients had mild to moderately severe COPD (FEV(1) 25-80% of predicted) and were given 3 months treatment with ICS, fluticasone propionate (FP; 500 micro g twice daily, n=14) or placebo (n=10). Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells.. Compared with their baseline values, FP resulted in a significant decrease (on average 65%) in the numbers of mucosal mast cells (median 7.8 (range 1-33) v 2.8 (1-14), p<0.05). The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared: 8.8 (1-24) v 2.8 (1-14) (p<0.05). Unexpectedly, there were significantly more neutrophils in the FP than in the placebo group: 4.0 (0-23) v 1.7 (0-8), respectively (p<0.05). There were no alterations to other cell types including mononuclear cells. Symptoms markedly improved in the patients treated with FP for 3 months.. Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa: the reduction in mast cell numbers may account for the improvement in symptoms over this time.

Topics: Aged; Androstadienes; Biopsy; Bronchi; Bronchitis; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Vital Capacity

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.

Topics: Administration, Inhalation; Administration, Topical; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Peak Expiratory Flow Rate; Powders; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Inhaled corticosteroids are often used in the treatment of stable chronic obstructive pulmonary disease (COPD), however, studies of these agents have had mixed results. Previous trials have often excluded subjects with bronchodilator response, have failed to evaluate effect on gas exchange, and have usually looked at only post- rather than prebronchodilator forced expiratory volume (FEV). Our objective was to better assess the efficacy of topical corticosteroids in the treatment of COPD. We used a prospective, randomized, double-blinded, placebo-controlled, crossover study at the Outpatient Department, Department of Veterans Affairs Medical Center. Thirty-six COPD patients with a mean (+/- SD) FEV1 of 1.10 +/- 0.43 L, with or without significant bronchodilator response participated in the study. Subjects received a 3-month course of inhaled fluticasone propionate (220 micro g/puff) or identical-appearing placebo by metered-dose inhaler at 2 puffs twice daily, followed by crossover to the alternative inhaler for an additional 3 months. Fluticasone treatment resulted in a higher prebronchodilator FEV1 (1.17 +/- 0.08 L [mean +/- SEM] versus 1.07 +/- 0.08 L, p = 0.001), a higher PaO2 (66.6 +/- 1.4 mmHg versus 63.6 +/- 1.6 mmHg, p = 0.002), and a better dyspnea score on the chronic respiratory questionnaire (3.70 +/- 0.18 versus 3.47 +/- 0.19, p = 0.03). A trend towards fewer exacerbations with fluticasone did not quite meet statistical significance (p = 0.11). Inhaled fluticasone over 3 months improved prebronchodilator airflow obstruction and oxygenation while decreasing dyspnea in moderate to severe COPD. Postbronchodilator FEV1 was not significantly changed.

Topics: Acute Disease; Administration, Inhalation; Adrenocorticotropic Hormone; Aged; Aged, 80 and over; Analysis of Variance; Androstadienes; Anti-Inflammatory Agents; Blood Gas Analysis; Cross-Over Studies; Double-Blind Method; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Idaho; Male; Middle Aged; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Severity of Illness Index; Smoking; Treatment Outcome; Vital Capacity

The aim of this double-blind single center study (the COPE study) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate (FP) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease. After 4 months of treatment with FP (1,000 microg/day), 244 patients were randomized to either continue FP or to receive placebo for 6 months: 123 patients continued FP (FP group), and 121 received placebo (placebo group). In the FP group, 58 (47%) patients developed at least one exacerbation compared with 69 (57%) in the placebo group. The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 (95% confidence interval [CI] 1.1-2.1). In the placebo group 26 patients (21.5%) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients (4.9%) in the FP group (relative risk = 4.4; 95% CI 1.9-10.3). Over a 6-month period, a significant difference in favor of the FP group was observed in the total score (+2.48 95% CI 0.37-4.58), activity domain (+4.64 95% CI 1.60-7.68), and symptom domain (+4.58 95% CI 1.05-8.10) of the St. George's Respiratory Questionnaire. This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Androstadienes; Double-Blind Method; Exercise Tolerance; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recurrence; Severity of Illness Index; Smoking; Substance Withdrawal Syndrome; Treatment Outcome

Inhaled corticosteroids (ICS) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies. However, the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease (COPD) is unknown. We have performed a double-blind, placebo-controlled, randomized study to compare fluticasone propionate (FP) 500 microg twice daily via a dry powder inhaler and placebo (P) over a 3-month period in subjects with COPD. Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment. Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis. Compared with P (n = 14), subjects on inhaled FP (n = 16) had no significant reductions in the primary endpoints: CD8+, CD68+ cells, or neutrophils, considered to be of importance in COPD. However, there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group. CD4+ cells were significantly raised in the P group in both subepithelium and epithelium. Symptoms significantly improved, and there were significantly fewer exacerbations in subjects on FP, compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD, and this may explain, in part, the decrease in exacerbations seen in long-term studies with fluticasone propionate.

Topics: Administration, Inhalation; Adult; Aged; Androstadienes; Anti-Inflammatory Agents; Biopsy; Bronchitis; Double-Blind Method; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Humans; Immunohistochemistry; London; Lung; Male; Mast Cells; Middle Aged; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Severity of Illness Index; Treatment Outcome

Dosing performance of dry powder inhalers is dependent on patient's inspiratory effort. This study compares the inhalation profiles generated by patients with severe obstructive lung disease using Diskus and Turbuhaler inhalers. The patient profiles are subsequently used to determine the dosing performance of fluticasone propionate Diskus and budesonide Turbuhaler inhalers. Inhalation profiles were recorded in COPD patients (FEV1 < or = 30% predicted) as they inhaled with maximal effort through the inhalers. The profiles were used in an inhalation simulator to assess the dosing performance by measuring the total emitted dose and the fine particle mass for each inhaler type. Peak inspiratory flow was significantly higher through the Diskus (mean 82.31 min(-1)) compared with Turbuhaler (mean 53.51 min(-1), difference = 28.8 l min(-1); P < 0.0001). In addition, in direct comparison of the two devices. the Diskus was shown to deliver a more consistent dose irrespective of flow than the Turbuhaler in this patient population. These findings may be of importance in optimising selection of devices for patients with severe airway obstruction.

Topics: Aged; Androstadienes; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Equipment Design; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

In a two-stage detection program, subjects with signs of obstructive airway disease were selected from a random sample of the general population. Subjects (n = 82) were randomly assigned to either fluticasone propionate 250 microg twice a day or placebo twice a day via pMDI in a 1-yr, double-blind trial if they met criteria for persistent airway obstruction, increased bronchial hyperresponsiveness, or a rapid decline in FEV(1). Main outcome measures were postbronchodilator FEV(1), quality-adjusted life years (QALYs), and direct medical cost. Secondary measures were prebronchodilator FEV(1), PC(20), health-related quality of life (CRQ), symptom-free weeks, episode-free weeks, exacerbations, and indirect cost. Subgroup analysis was based on reversibility of obstruction. Analysis revealed a significant gain in postbronchodilator FEV(1) (98 ml/yr; p = 0.01) in favor of fluticasone. Only subjects with reversible obstruction showed an improvement in PC(20) (1.4 doubling dose; p = 0.03). Early treatment resulted in 2.7 QALYs gained per 100 treated subjects (p = 0.17) and in a clinically relevant improvement in dyspnea (CRQ; p < 0.03). The incremental cost effectiveness ratios were US$13,016/QALY for early treatment and US$33,921/QALY for the combination of detection and treatment. The incremental cost for one additional subject with a clinically relevant difference in dyspnea was US$1,674. In conclusion, early intervention with fluticasone resulted in significant health gains at relatively low financial cost.

Topics: Absenteeism; Activities of Daily Living; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Cost-Benefit Analysis; Direct Service Costs; Double-Blind Method; Drug Administration Schedule; Drug Costs; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quality-Adjusted Life Years; Recurrence; Time Factors; Treatment Outcome

To examine the impact of initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in a single device on chronic obstructive pulmonary disease (COPD) exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related healthcare resource utilization (HCRU) and costs in patients with COPD.. Retrospective database analysis of patients with COPD aged ≥40 years who initiated FF/UMEC/VI between September 1, 2017, and December 31, 2018 (index date: first pharmacy claim for FF/UMEC/VI), following evidence of multiple-inhaler triple therapy (MITT) (≥30 consecutive days) in the year prior to index. COPD exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related HCRU and costs were compared between the baseline period (12 months prior to and including index) and follow-up period (12 months following index).. Data from 912 patients (mean [SD] age: 71.2 [8.1], 51.2% female) were included in the analyses. Among the overall cohort, mean count of total COPD exacerbations (moderate or severe) per patient was statistically significantly lower in the follow-up period compared to baseline (1.2 vs 1.4, p=0.001). The proportion of patients with ≥1 COPD exacerbation (moderate or severe) was also statistically significantly lower in the follow-up period compared to baseline (56.4% vs 62.4%, p=0.001). All-cause and COPD-related HCRU were similar during follow-up compared to baseline, although the proportion of patients with COPD-related ambulatory visits was lower during follow-up (p<0.001). COPD-related office visit costs, emergency room visit costs, and pharmacy costs were statistically significantly lower during follow-up compared to baseline (p<0.001; p=0.019; p<0.001, respectively).. In a real-world setting, patients on MITT who subsequently initiated FF/UMEC/VI in a single device had significant reductions in the rate of COPD exacerbations (moderate or severe). Switching to FF/UMEC/VI also resulted in improvements in some HCRU and cost outcomes. These data support the use of FF/UMEC/VI among patients at high risk of exacerbation to reduce future risk and improve outcomes.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Female; Fluticasone; Humans; Male; Patient Acceptance of Health Care; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies

ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history.. COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated.. Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup.. These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Patient Acceptance of Health Care; Pneumonia; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide

Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists (LABAs) over inhalers containing inhaled corticosteroids (ICSs) and LABAs. However, data from randomized clinical trials comparing these combination inhalers (LAMA-LABAs vs ICS-LABAs) have been conflicting and raised concerns of generalizability.. To assess whether LAMA-LABA therapy is associated with reduced COPD exacerbations and pneumonia hospitalizations compared with ICS-LABA therapy in routine clinical practice.. This was a 1:1 propensity score-matched cohort study using Optum's Clinformatics Data Mart, a large commercial insurance-claims database. Patients must have had a diagnosis of COPD and filled a new prescription for a combination LAMA-LABA or ICS-LABA inhaler between January 1, 2014, and December 31, 2019. Patients younger than 40 years were excluded, as were those with a prior diagnosis of asthma. The current analysis was performed from February 2021 to March 2023.. Combination LAMA-LABA inhalers (aclidinium-formoterol, glycopyrronium-formoterol, glycopyrronium-indacaterol, tiotropium-olodaterol, or umeclidinium-vilanterol) and combination ICS-LABA inhalers (budesonide-formoterol, fluticasone-salmeterol, fluticasone-vilanterol, or mometasone-formoterol).. The primary effectiveness outcome was first moderate or severe COPD exacerbation, and the primary safety outcome was first pneumonia hospitalization. Propensity score matching was used to control for confounding between the 2 groups. Logistic regression analysis was used to estimate propensity scores. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models stratified on matched pairs.. Among 137 833 patients (mean [SD] age, 70.2 [9.9] years; 69 530 [50.4%] female) (107 004 new ICS-LABA users and 30 829 new LAMA-LABA users), 30 216 matched pairs were identified for the primary analysis. Compared with ICS-LABA use, LAMA-LABA use was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation (HR, 0.92; 95% CI, 0.89-0.96) and a 20% reduction in the rate of first pneumonia hospitalization (HR, 0.80; 95% CI, 0.75-0.86). These findings were robust across a range of prespecified subgroup and sensitivity analyses.. In this cohort study, LAMA-LABA therapy was associated with improved clinical outcomes compared with ICS-LABA therapy, suggesting that LAMA-LABA therapy should be preferred for patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Cohort Studies; Drug Therapy, Combination; Female; Fluticasone; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Muscarinic Antagonists; Nebulizers and Vaporizers; Pneumonia; Pulmonary Disease, Chronic Obstructive

There is limited literature regarding real-world treatment patterns of patients with COPD, particularly since the introduction of once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol in 2017. Here, we evaluated treatment patterns of patients with COPD before and after a COPD exacerbation.. Retrospective, descriptive study using medical and pharmacy claims data and enrollment information from the Optum. COPD exacerbations were identified in 307,727 patients (125,942 severe; 181,785 moderate). Mean age at index was 72.8 years; 56.3% were female. Before and after first exacerbation, 37.7% and 48.2% of patients used ≥1 controller medication, respectively. In the 90 days pre-index, ICS, LABA, and LAMA medications were used by 27.5% of patients. Of these users, 64.3% remained on the same medication class, 21.7% discontinued, and 14.1% switched medication in the 90 days post-index. Among switchers, 44.0% switched to triple therapy. Most common switches were ICS/LABA to ICS/LABA/LAMA (20.7%) and LAMA to ICS/LABA/LAMA (16.4%).. Many COPD exacerbations occur among patients not on controller medications. Although the percentage of patients receiving a controller medication increased following a first exacerbation, it remained below 50%. Of patients receiving controller medications pre-exacerbation, only a small proportion escalated to triple therapy post-exacerbation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Disease Progression; Female; Fluticasone; Humans; Male; Medicare; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; United States

Three-dimensional airway models were produced from 20 patients with moderate-to-very severe COPD. Total, central, and regional small airways deposition as a percentage of delivered dose of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) 160/7.2/5 µg per actuation and fluticasone furoate/umeclidinium/vilanterol (FF/UM/VI) 100/62.5/25 µg were evaluated using in silico FRI based on in vitro aerodynamic particle size distributions of each device. Simulations were performed using multiple inhalation profiles of varying durations and flow rates representing patterns suited for a pressurized metered-dose inhaler or dry-powder inhaler (four for BGF, two for FF/UM/VI, with one common profile). For the common profile, deposition for BGF versus FF/UM/VI was compared post-hoc using paired t-tests.. Across inhalation profiles, mean total lung deposition was consistently higher with BGF (47.0-54.1%) versus FF/UM/VI (20.8-22.7%) and for each treatment component, with greater deposition for BGF also seen in the central large airways. Mean regional small airways deposition was also greater across inhalation profiles with BGF (16.9-23.6%) versus FF/UM/VI (6.8-8.7%) and for each treatment component. For the common profile, total, central, and regional small airways deposition were significantly greater for BGF versus FF/UM/VI (nominal p < 0.001), overall and for treatment components; notably, regional small airways deposition of the ICS components was approximately five-fold greater with budesonide versus fluticasone furoate (16.1% vs. 3.3%).. BGF was associated with greater total, central, and small airways deposition for all components versus FF/UM/VI. Importantly, using an identical inhalation profile, there was an approximately five-fold difference in small airways deposition for the ICS components, with only a small percentage of the ICS from FF/UM/VI reaching the small airways. Further research is needed to understand if the enhanced delivery of BGF translates to clinical benefits.

Topics: Budesonide; Dry Powder Inhalers; Fluticasone; Humans; Lung; Pulmonary Disease, Chronic Obstructive

Oral corticosteroids (OCS) play a role in the treatment of acute chronic obstructive pulmonary disease (COPD) exacerbations; however, chronic use is not recommended due to the high rate of systemic complications, development of comorbidities, and increased mortality. Data assessing the real-world impact of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) on OCS utilization rates are limited. This study assessed the impact of FF/UMEC/VI on OCS use among patients with COPD previously treated with OCS.. A total of 2013 patients were identified (mean age 63.5 years, 55.7% female). The proportion of patients with ≥1 OCS claim decreased by 32.2% between the pre- and post-index period (67.8% vs 100%; p < 0.001). Comparing the post-index period to the pre-index period, mean number of OCS pharmacy claims per patient decreased from 3.3 to 2.5 (p < 0.001) and mean daily dose was reduced from 3.1 to 2.6 mg/day (p = 0.004); 30.0% of patients reduced their daily dose by 90-100%. Reductions were also seen in COPD-related HCRU. The proportion of patients with an inpatient admission for COPD decreased from 11.4% to 7.1% (p < 0.001), emergency room visits decreased from 23.1% to 17.4% (p < 0.001), and office visits from 97.5% to 90.1% (p < 0.001). Similar results were seen for all-cause HCRU.. Among patients with COPD with prior OCS use, FF/UMEC/VI initiation resulted in significant reductions in OCS utilization, COPD-related HCRU (including hospitalization), and all-cause HCRU.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Female; Fluticasone; Humans; Male; Medicare; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; United States

Apart from the individual diseases, some patients also show overlapping manifestations of asthma and COPD. Nevertheless, the diagnosis of COPD is often delayed due to inaccessibility to spirometry; the prevalence of the asthma COPD overlap phenotype is rather high given the exposure to biomass smoke. Furthermore, the rates of exacerbations are twice as high compared to the patients with either of the diseases. A treatment strategy that would reduce the risk of exacerbations would contribute immensely to the management of such patients. Evidence of eosinophilia (marker of inflammation) in patients with asthma, asthma COPD overlap phenotype or COPD alone should prompt treatment with a combination of inhaled corticosteroids (ICS)/ long-acting β-agonists (LABA); several studies have shown improvement in the airflow limitation and reduction in the rate of exacerbations with salmeterol-fluticasone combination (SFC). Considering the association of COPD and cardiovascular diseases (CVD), it is critical to determine the cardiovascular safety of the LABA in such patients. Salmeterol is a highly selective partial b-2 agonist; the TORCH study and the studies comparing formoterol and salmeterol infer that there is no increased risk of new cardiovascular adverse events either with Salmeterol or SFC. Furthermore, the combination may provide certain degree of cardio-protection. Since COPD per se increases the risk of CVD, the cardio-safety of salmeterol outweighs its onset of action. SFC has well substantiated benefits in patients with asthma, COPD and high-risk patients such as those with an overlap of COPD and asthma symptoms, patients with elevated eosinophils and pre-existing CVD. An advisory board was hence conducted, which discussed the role of combination of salmeterol and fluticasone (SFC) not only in asthma and COPD but also in asthma COPD overlap phenotype. Based on the panel's clinical experience and the expertise derived thereof, the propositions regarding the place of SFC therapy in patients with stable and uncontrolled asthma, asthma COPD overlap phenotype and COPD has been put forth.

Topics: Asthma; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by long-term breathing problems and airflow limitations. International guidelines recommend using bronchodilators like long-acting beta- and muscarinic antagonists, and inhalational corticosteroids.. The cost-effectiveness of single-inhaler triple therapy containing fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) was compared to the treatments Fluticasone Furoate/Vilanterol (FF/VI), Umeclidinio/Vilanterol (UMEC/VI) and Fluticasone Propionate 250 mcg/Salmeterol 25mcg + Tiotropio 18 mcg (FP/SAL/TIO) for patients with COPD from the Chilean public health system perspective.. A cost-effectiveness analysis was performed, including a deterministic and probabilistic sensitivity analysis over a 25-year time horizon. Two scenarios were assessed to study the effect of a 3%-discount for costs and outcomes on FF/UMEC/VI.. The incremental cost-effectiveness (ICER) of FF/UMEC/VI versus FF/VI was $10,076/QALY, being a cost-effective alternative to a threshold of one Gross Domestic Product per capita (GDPpc), while versus FP/SAL/TIO the ICER increased to $50,288/QALY, showing to be a non-cost effective alternative to 1 GDPpc, but at a threshold of 3 GDPpc.. FF/UMEC/VI appears to be a cost-effective intervention for treating COPD compared to FF/VI. However, FF/UMEC/VI compared to FP/SAL/TIO showed an ICER above the threshold of 1 GDPpc, but, in comparison with lower price, the ICER was below 3 GDPpc.

Topics: Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chile; Chlorobenzenes; Cost-Benefit Analysis; Double-Blind Method; Drug Combinations; Fluticasone; Forced Expiratory Volume; Humans; Public Health; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Non-T2 severe asthma and chronic obstructive pulmonary disease (COPD) are airway chronic inflammatory disorders with a poor response to corticosteroids. LAS194046, a novel pan-Janus kinase (JAK) inhibitor, shows inhibitory effects on T2 allergic lung inflammation in rats. In this work we analyze the effects of LAS194046, fluticasone propionate and their combination in neutrophils from non-T2 severe asthma and COPD patients in vitro. Neutrophils from 23 healthy subjects, 23 COPD and 21 non-T2 severe asthma patients were incubated with LAS194046 (0.01 nM-1 µM), fluticasone propionate (0.1 nM-1 µM) or their combination and stimulated with lipopolysaccharide (LPS 1 µM). LAS194046 shows similar maximal % inhibition and potency inhibiting IL-8, MMP-9 and superoxide anion release in neutrophils from healthy, COPD and asthma. Fluticasone propionate suppresses mediator release only in neutrophils from healthy patients. The combination of LAS194046 with fluticasone propionate shows synergistic anti-inflammatory and anti-oxidant effects. The mechanisms involved in the synergistic effects of this combination include the increase of MKP1 expression, decrease of PI3Kδ, the induction of glucocorticoid response element and the decrease of ERK1/2, P38 and JAK2/STAT3 phosphorylation compared with monotherapies. In summary, LAS194046 shows anti-inflammatory effects in neutrophils from COPD and severe non-T2 asthma patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate.

Topics: Administration, Inhalation; Androstadienes; Animals; Anti-Inflammatory Agents; Asthma; Fluticasone; Humans; Janus Kinase Inhibitors; Neutrophil Activation; Pulmonary Disease, Chronic Obstructive; Rats

Triple therapy for chronic obstructive pulmonary disease (COPD) is recommended for some patients, but the inhaled corticosteroids (ICS) may differ in effectiveness and safety. We compared budesonide-based and fluticasone-based triple therapy given in two inhalers on the incidence of exacerbation, mortality and severe pneumonia, using an observational study approach. We identified a cohort of patients with COPD, new users of triple therapy given in two inhalers during 2002-2018, age 50 or older, from the UK's CPRD database, and followed for one year. The hazard ratio (HR) of exacerbation, all-cause death and pneumonia was estimated using the Cox regression model, weighted by fine stratification of the propensity score of treatment initiation. The cohort included 29,716 new users of fluticasone-based triple therapy and 9,646 of budesonide-based. The HR of a first moderate or severe exacerbation with budesonide-based triple therapy was 0.98 (95% CI: 0.94-1.03), relative to fluticasone-based, while for a severe exacerbation it was 0.97 (95% CI: 0.87-1.07). The incidence of all-cause death was lower with budesonide-based therapy among patients with no prior exacerbations (HR 0.80; 95% CI: 0.66-0.98). The HR of severe pneumonia with budesonide-based therapy was 0.84 (95% CI: 0.75-0.95). In a real-world clinical setting of COPD treatment, budesonide-based triple therapy given in two inhalers was generally as effective at reducing exacerbations as fluticasone-based triple therapy. However, the budesonide-based triple therapy was associated with a lower incidence of severe pneumonia and possibly also of all-cause death, especially among patients with no prior exacerbations for whom triple therapy is not recommended.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Budesonide; Fluticasone; Humans; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive

To compare adherence and persistence among adult patients with asthma receiving single-inhaler FF/UMEC/VI versus multiple-inhaler triple therapy (MITT) in the United States.. This retrospective cohort study used IQVIA PharMetrics Plus data to evaluate patients with asthma who initiated once-daily FF/UMEC/VI 100/62.5/25 mcg or MITT between September 18, 2017, and September 30, 2019. Inverse probability weighting and multivariable regression adjusted for differences in characteristics between the FF/UMEC/VI and MITT cohorts. Adherence was assessed using proportion of days covered (PDC) and proportion of patients achieving PDC ≥0.8 and PDC ≥0.5. Non-persistence was identified as a >45-day gap between fills.. The study included 1396 FF/UMEC/VI and 5115 MITT initiators. Three months after initiation, FF/UMEC/VI users had significantly higher mean PDC versus MITT users (0.68 vs 0.59; P < .001) and 31% more likely to be adherent (PDC ≥0.8; 40.6% vs 31.3%; adjusted risk ratio [95% confidence interval (CI)]: 1.31 [1.13-1.54]; P < .001). Similar patterns were observed at 6 and 12 months post initiation. In addition, FF/UMEC/VI users were 49% more likely to persist at 12 months than MITT users (25.9% vs 15.1%, adjusted hazard ratio [95% CI]: 1.49 [1.39-1.60]; P < .001).. Patients with asthma initiating triple therapy with FF/UMEC/VI had significantly better adherence and persistence compared with MITT initiators.

Topics: Administration, Inhalation; Adult; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Retrospective Studies

The most classic treatment recommended in the current chronic obstructive pulmonary disease (COPD) guidelines is glucocorticoid and β2 receptor agonist combination, such as salmeterol xinafoate and fluticasone propionate (Sal/Flu), causing many adverse reactions due to hormones. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating chronic inflammation, contributing to its structure is similar to steroidal anti-inflammatory drugs. In this study, we successfully established COPD rat model by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction, as characterized by lung function decline. We discovered that salmeterol xinafoate/MgIG combination could alleviated lung inflammation infiltration, airway wall thickness (AWT) and the secretion of bronchial mucin MUC5AC of COPD rats more than salmeterol xinafoate, MgIG, or salmeterol xinafoate and fluticasone propionate treatment did, as well as reduced inflammatory cells (white blood cells, neutrophils and lymphocytes) accumulation in bronchoalveolar lavage fluid and decreased TNF-α, IL-6 and IL-1β production in the serum of COPD rats. Finally, we found that Moreover, the mechanism involved might be related to the suppression of JAK/STAT signaling pathway. Overall, our studies suggested that MgIG might be a potential alternative adjuvant drug for fluticasone propionate for the clinical treatment of patients with COPD.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Animals; Anti-Inflammatory Agents; Bronchodilator Agents; Drug Combinations; Fluticasone; Pulmonary Disease, Chronic Obstructive; Rats; Salmeterol Xinafoate; Saponins; Triterpenes

In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting.. In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs.. Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals.. PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.

Topics: Administration, Inhalation; Androstadienes; Bayes Theorem; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delivery of Health Care; Double-Blind Method; Drug Combinations; Fluticasone; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Few studies have reported the association between the radiographic characteristics and the development of pneumonia in patients with chronic obstructive pulmonary disease (COPD) treated with inhaled corticosteroids (ICSs). Our study aimed to assess the effect of radiographic phenotypes on the risk of pneumonia in patients treated with ICSs.. This study retrospectively analysed all patients with COPD treated with ICSs in a subset of the Korea Chronic Obstructive Pulmonary Disorders Subgroup Study registry between January 2017 and December 2019. The association between radiographic phenotypes including the presence and severity of emphysema, airway wall thickening, or bronchiectasis on chest computed tomography were determined visually/qualitatively and the risk of pneumonia was analyzed using the Cox regression model.. Among the 90 patients with COPD treated with ICSs, 41 experienced pneumonia more than once during the median follow-up of 29 (interquartile range, 8-35) months. In univariate Cox regression analysis, older age, longer use of ICSs, use of fluticasone propionate or metered dose inhaler, and severe exacerbation events increased the risk of pneumonia. In multivariate analysis, the presence of emphysema (adjusted hazard ratio [aHR]=3.73, P=0.033), severity measured using the visual sum score (mild-to-moderate, aHR=8.58, P=0.016; severe, aHR=3.58, P=0.042), Goddard sum score (mild-to-moderate, aHR=3.31, P=0.058; severe, aHR=5.38, P=0.014), and the upper lobe distribution of emphysema (aHR=3.76, P=0.032) were associated with a higher risk of pneumonia. Subtypes of centrilobular and panlobular emphysema had a higher risk of pneumonia compared with paraseptal emphysema (aHR=3.98, P=0.033; HR=3.91, P=0.041 vs HR=2.74, P=0.304). The presence of bronchiectasis (aHR=2.41, P=0.02) and emphysema/bronchiectasis overlap phenotype (aHR=2.19, P=0.053) on chest CT was a risk factor for pneumonia in this population. However, severity of bronchiectasis and the presence or severity of bronchial wall thickening according to the visual sum score were not associated with the risk of pneumonia.. Among patients with COPD treated with ICSs, radiographic phenotypes including the presence of emphysema, bronchiectasis or emphysema/bronchiectasis overlap phenotype, severity with emphysema, subtypes of centrilobular or panlobular emphysema, and upper lobe distribution of emphysema may help predict the risk of pneumonia.

Topics: Adrenal Cortex Hormones; Bronchiectasis; Emphysema; Fluticasone; Humans; Phenotype; Pneumonia; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Retrospective Studies

Inhaled corticosteroids (ICS) are commonly prescribed first-line treatments for asthma and chronic obstructive pulmonary disease (COPD). Recent evidence has shown that ICS use is associated with changes in the airway microbiome, which may impact clinical outcomes such as potential increased risk for pneumonia in COPD. Although the immunomodulatory effects of corticosteroids are well appreciated, whether ICS could directly influence the behavior of respiratory tract bacteria has been unknown. In this pilot study we explored the effects of fluticasone proprionate, a commonly prescribed inhaled corticosteroid, on respiratory bacteria with an expanded focus on Klebsiella pneumoniae, a species previously implicated in fluticasone-associated pneumonia in COPD. We observed significant effects of fluticasone proprionate on growth responses of

Topics: Adrenal Cortex Hormones; Asthma; Fluticasone; Humans; Klebsiella pneumoniae; Pilot Projects; Pneumonia; Pulmonary Disease, Chronic Obstructive

Real-world data provide the potential for generating evidence on drug treatment effects in groups excluded from trials, but rigorous, validated methodology for doing so is lacking. We investigated whether non-interventional methods applied to real-world data could reproduce results from the landmark TORCH COPD trial.We performed a historical cohort study (2000-2017) of COPD drug treatment effects in the UK Clinical Practice Research Datalink (CPRD). Two control groups were selected from CPRD by applying TORCH inclusion/exclusion criteria and 1:1 matching to TORCH participants, as follows. Control group 1: people with COPD not prescribed fluticasone propionate (FP)-salmeterol (SAL); control group 2: people with COPD prescribed SAL only. FP-SAL exposed groups were then selected from CPRD by propensity score matching to each control group. Outcomes studied were COPD exacerbations, death from any cause and pneumonia.2652 FP-SAL exposed people were propensity score matched to 2652 FP-SAL unexposed people while 991 FP-SAL exposed people were propensity score matched to 991 SAL exposed people. Exacerbation rate ratio was comparable to TORCH for FP-SAL

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Cohort Studies; Drug Combinations; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Bronchodilator Agents; Budesonide; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Topics: Bronchodilator Agents; Budesonide; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Topics: Aged; Asthma; Bronchodilator Agents; Drug Combinations; Fluticasone; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Radiographic Image Enhancement; Radiography, Thoracic; Spirometry; Tiotropium Bromide; Treatment Outcome

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 β. This 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.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Beclomethasone; Bronchodilator Agents; Budesonide; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone; Formoterol Fumarate; Glucocorticoids; Humans; Male; Metered Dose Inhalers; Middle Aged; Pneumonia; Propensity Score; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Salmeterol Xinafoate; Taiwan

Spirometry is required to accurately diagnose chronic obstructive pulmonary disease (COPD). Following an acute exacerbation, it is recommended that spirometry be performed after a delay of 4-6 weeks to allow stability and a measure of 'baseline' lung function. However, poor attendance at these appointments can occur, leading to an inability to confirm the diagnosis of COPD or assess the severity of airflow obstruction. Portable spirometry (PS) is a proven surrogate device that may provide a convenient method to address these issues. The purpose of this study was to compare PS values, obtained prior to hospital discharge to laboratory-based spirometry (LS) results undertaken 4 weeks later.. Thirty-three eligible inpatients with a clinically determined exacerbation of COPD were recruited. Patients underwent PS prior to discharge and LS 4 weeks later.. Reliability of PS values at discharge compared with outpatient LS 4 weeks later was excellent (intraclass correlation coefficient > 0.9). The PS confirmed a new diagnosis of COPD at the bedside in 29% of patients and excluded COPD in 6% at both time points. Patients were found to have a similar severity of airflow obstruction on both PS and LS, with clinical stability maintained between visits. The PS and LS may be used interchangeably for earlier diagnosis of COPD. PS at the point of discharge from hospital offers a unique opportunity to diagnose and facilitate COPD management from hospital to primary care.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aftercare; Aged; Bronchodilator Agents; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Hospitalization; Humans; Male; Middle Aged; Minimal Clinically Important Difference; Muscarinic Antagonists; Point-of-Care Systems; Point-of-Care Testing; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Spirometry; Vital Capacity

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Beclomethasone; Budesonide; Disease Susceptibility; Female; Fluticasone; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Pulmonary Disease, Chronic Obstructive; Streptococcus pneumoniae

Inhaled corticosteroids are generally considered safe and do not usually lead to systemic adverse events since their plasma concentrations are low due to hepatic metabolism by the cytochrome P450 3A4. However, when associated with inhibitors of this cytochrome, such as ritonavir, they may lead to iatrogenic Cushing syndrome by the systemic accumulation of corticosteroids and consequent suppression of the hypothalamic-pituitary-adrenal axis. We present a case of iatrogenic Cushing syndrome complicated by multifocal osteonecrosis in a patient with HIV infection on antiretroviral therapy with protease inhibitors boosted with ritonavir, after the association of inhaled fluticasone. This clinical case highlights a relevant interaction between corticosteroids and inhibitors of the cytochrome P450 and the severe consequences that may occur.

Topics: Administration, Inhalation; Adult; Bronchodilator Agents; Cushing Syndrome; Drug Interactions; Fluticasone; HIV Infections; HIV Protease Inhibitors; Humans; Iatrogenic Disease; Male; Osteonecrosis; Pulmonary Disease, Chronic Obstructive; Ritonavir

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Budesonide; Fluticasone; Humans; Pneumococcal Infections; Pulmonary Disease, Chronic Obstructive

Chitosan (CS) is a natural polysaccharide, widely studied in the past due to its unique properties such as biocompatibility, biodegradability and non-toxicity. Chemical modification of CS is an effective pathway to prepare new matrices with additional functional groups and improved properties, such as increment of hydrophilicity and swelling rate, for drug delivery purposes. In the present study, four derivatives of CS with trans-aconitic acid (t-Acon), succinic anhydride (Succ), 2-hydroxyethyl acrylate (2-HEA) and acrylic acid (AA) were prepared, and their successful grafting was confirmed by FTIR and

Topics: Administration, Inhalation; Capsules; Delayed-Action Preparations; Fluticasone; Humans; Particle Size; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Animals; Antithrombins; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Chemokine CXCL1; Dabigatran; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fluticasone; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Mice, Inbred Strains; Osteopontin; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Topics: Adrenal Cortex Hormones; Aged; Animals; Antimicrobial Cationic Peptides; Bacterial Infections; Cathelicidins; Dysbiosis; Female; Fluticasone; Humans; Lung; Male; Mice; Pulmonary Disease, Chronic Obstructive; Streptococcus pneumoniae

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response.

Topics: Aminopyridines; Benzamides; Cyclopropanes; Exome Sequencing; Fluticasone; Formoterol Fumarate; Genomics; Humans; Lung; MicroRNAs; Models, Biological; Organ Culture Techniques; Pharmacogenomic Variants; Precision Medicine; Pulmonary Disease, Chronic Obstructive; State Medicine

Topics: Administration, Inhalation; Bronchodilator Agents; Drug Interactions; Fluticasone; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Muscular Diseases; Pulmonary Disease, Chronic Obstructive; Ritonavir

There have been concerns about the risk of inhaled corticosteroid (ICS)-related tuberculosis (TB) development.. We investigated the occurrence of TB among ICS users according to underlying respiratory diseases and type of ICS.. A 12-year population cohort comprising approximately 1 million subjects collected from the Korean claims database were used. Adult ICS users (budesonide or fluticasone) were enrolled. The temporal relationship between TB development and the last ICS prescription before TB development was evaluated. A nested case-control study was performed with 1:4 matching for age, sex, and the initiation date of the ICS.. There were 17,991 ICS users, and 175 developed TB during the study period. Approximately 80% (140/175) of patients who developed TB were diagnosed within 3 years after the last ICS prescription. In the nested case-control study, the occurrence of TB was not related to the type of ICS, but was related to a higher annual admission rate and a higher comorbidity score. The risk of TB was higher in patients with chronic obstructive pulmonary disease (COPD) than in those with asthma (odds ratio: 2.31; CI 95%: 1.39-3.38; P = .0011) after adjusting for covariates. The subgroup analysis revealed no difference between budesonide and fluticasone with respect to the risk of developing TB in patients with asthma, COPD, or asthma-COPD overlap syndrome.. An increased risk of TB development may persist for 3 years after stopping the ICS and the risk is higher in patients with COPD regardless of the type of ICS used.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Asthma; Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome; Budesonide; Case-Control Studies; Dose-Response Relationship, Drug; Female; Fluticasone; Humans; Logistic Models; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Republic of Korea; Risk Factors; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

Fluticasone propionate uptake in the presence of a proprietary cell-penetrating peptide (human stimulus factor, [HSF]) based on the N-terminal domain of lactoferrin was studied, alone and in combination with salmeterol, using an air interface Calu-3 epithelial model. The HSF enhanced uptake and transport of fluticasone propionate across the epithelial barrier when alone and in presence of salmeterol. This was attributed to transcellular-mediated uptake. This HSF is a promising peptide for delivery of therapeutics where enhanced epithelial penetrating is required.

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Cell Line, Tumor; Cell Membrane; Drug Carriers; Drug Combinations; Fluticasone; Humans; Lactoferrin; Peptides; Permeability; Protein Domains; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Salmeterol Xinafoate

Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and β2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and β2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients. Peripheral blood neutrophils from healthy and COPD patients were incubated with AZD8999 and fluticasone propionate, individually or in combination, for 1h followed by lipopolysaccharide (LPS) stimulation for 6h. The IL-8, MMP9, IL-1β, and GM-CSF release was measured in cell culture supernatants. AZD8999 shows ~ 50% maximum inhibitory effect and similar potency inhibiting the released cytokines in neutrophils from healthy and COPD patients. However, while fluticasone propionate suppresses mediator release in neutrophils from healthy patients, COPD neutrophils are less sensitive. The combination of non-effective concentrations of AZD8999 (0.01nM) with non-effective concentrations of fluticasone propionate (0.1nM) shows synergistic anti-inflammatory effects. The studied mechanisms that may be involved in the synergistic anti-inflammatory effects of this combination include the increase of glucocorticoid receptor (GR)α and MKP1 expression, the induction of glucocorticoid response element (GRE) activation and the decrease of ERK1/2, P38 and GR-Ser226 phosphorylations compared with monotherapies. In summary, AZD8999 shows anti-inflammatory effects in neutrophils from COPD patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate, supporting the use of MABA/ICS combination therapy in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Anti-Inflammatory Agents; Cyclohexanes; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Fluticasone; Healthy Volunteers; Humans; Male; Middle Aged; Muscarinic Antagonists; Neutrophils; Pulmonary Disease, Chronic Obstructive; Quinolines; Receptors, Adrenergic, beta-2; Receptors, Muscarinic; Thiophenes

Patients with COPD have an increased risk for community-acquired pneumonia, which is further increased by inhaled corticosteroids.. To assess effects of the corticosteroids, budesonide and fluticasone propionate, on macrophage bacterial responses in COPD.. Monocyte-derived macrophages (MDMs) generated from blood monocytes from 10 non-smoker controls (NoS), 20 smokers without COPD (Sm), and 40 subjects with moderate to severe COPD (21 ex-smokers (COPD-ES) and 19 current smokers (COPD-S)) were pre-treated with budesonide or fluticasone (10 nM-1 μM) and challenged with live non-typeable Haemophilus influenzae (NTHI) or Streptococcus pneumoniae (SP). Cell surface bacterial recognition receptor expression (flow cytometry) and cytokine release (bead array) were analyzed.. NTHI and SP reduced bacterial recognition receptor expression on MDMs from COPD and Sm, but not NoS (except TLR4). SR-AI and MARCO were reduced by both NTHI and SP, whereas other receptors by either NTHI or SP. Among COPD subjects, COPD-ES demonstrated a greater number of reductions as compared to COPD-S. NTHI reduced SR-AI, MARCO, CD11b, CD35 and CD206 in COPD-ES while only SR-AI and CD11b in COPD-S. SP reduced SRA-1, CD1d, TLR2 and TLR4 in both COPD-ES and COPD-S, and reduced MARCO and CD93 only in COPD-ES. All receptors reduced in COPD by NTHI and most by SP, were also reduced in Sm. Budesonide counteracted the receptor reductions induced by both NTHI (CD206 p = 0.03, MARCO p = 0.08) and SP (SR-AI p = 0.02) in COPD-ES. Fluticasone counteracted only SP-induced reductions in TLR2 (p = 0.008 COPD-ES and p = 0.04 COPD-S) and TLR4 (p = 0.02 COPD-ES). Cytokine release was equivalently reduced by both corticosteroids.. Reduction in macrophage bacterial recognition receptors during bacterial exposure could provide a mechanism for the increased pneumonia risk in COPD. Differential effects of budesonide and fluticasone propionate on macrophage bacterial recognition receptor expression may contribute to the higher pneumonia incidence reported with fluticasone propionate.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Budesonide; Cytokines; Female; Fluticasone; Haemophilus influenzae; Humans; Macrophages; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Smoking; Streptococcus pneumoniae; Up-Regulation

The aim was to investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatmentWe performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate/severe chronic obstructive pulmonary disease (COPD) patients at baseline and after 6- and 30-month treatment with the ICS fluticasone propionate or placebo. The effect of ICS on miRNA expression was validated in differentiated primary bronchial epithelial cultures, and functional studies were conducted in BEAS-2B cells. MiRNAs affected by ICS and their predicted targets were compared to an independent miRNA dataset of bronchial brushings from COPD patients and healthy controls.Treatment with ICS for both 6 and 30 months significantly altered the expression of four miRNAs, including miR-320d, which was increased during ICS treatment compared with placebo. The ICS-induced increase of miR-320d was confirmed in primary airway epithelial cells. MiR-320d negatively correlated targets were enriched for pro-inflammatory genes and were increased in the bronchial brushes of patients with lower lung function in the independent dataset. Overexpression of miR-320d in BEAS-2B cells dampened cigarette smoke extract-induced pro-inflammatory activity

Topics: Adrenal Cortex Hormones; Aged; Cross-Sectional Studies; Female; Fluticasone; Genome-Wide Association Study; Humans; Male; MicroRNAs; Middle Aged; Pulmonary Disease, Chronic Obstructive; Transcriptome

Clinical trials of COPD pharmacotherapy typically involve aging populations with moderate-to-severe COPD, but the latter is often diagnosed by spirometric criteria that are not age-appropriate across the continuum of lung function. We have therefore re-evaluated the clinical effect of combination therapy (salmeterol plus fluticasone) in moderate-to-severe COPD, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI) and trial data from Towards a Revolution in COPD Health (TORCH).. Of the 6112 TORCH participants, 5688 (93.1%) had GLI-based moderate-to-severe COPD (mean age 64.8 years). The primary outcome was all-cause mortality and the primary comparison was combination therapy vs. placebo. Secondary outcomes included COPD and cardiovascular (CV) mortality and pneumonia. A modified intention-to-treat analysis evaluated differences in time-to-event over a three-year period, using Cox proportional hazards models with statistical significance at p < 0.010 (acknowledging repeated significance testing).. Relative to placebo, combination therapy yielded a statistically non-significant reduction in all-cause mortality-adjusted hazard ratio [adjHR] 0.78 (95% confidence interval [CI]: 0.64, 0.95), p = 0.012. Relative to placebo, combination therapy also yielded statistically non-significant reductions in COPD and CV mortality-adjHR 0.75 (95% CI: 0.55, 1.02), p = 0.068 and adjHR 0.76 (95% CI: 0.53, 1.09), p = 0.135, respectively. In contrast, combination therapy yielded a statistically significant increased risk of pneumonia, relative to placebo-adjHR 1.80 (95% CI: 1.46, 2.21), p < 0.001.. In GLI-based moderate-to-severe COPD, combination therapy yields a statistically significant increased risk of pneumonia but the reductions in mortality are not statistically significant, although could potentially be clinically meaningful.

Topics: Aged; Bronchodilator Agents; Cardiovascular Diseases; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Male; Middle Aged; Multicenter Studies as Topic; Pneumonia; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Severity of Illness Index; Spirometry

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antifungal Agents; Bronchodilator Agents; Bronchopneumonia; Candidiasis; Diagnosis, Differential; Disease Progression; Drug Therapy, Combination; Fluticasone; Humans; Itraconazole; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Tiotropium Bromide

No studies have investigated genetic effects on quality of life (QoL) measurements like improvements in the St George's Respiratory Questionnaire (SGRQ) scores for chronic obstructive pulmonary disease treatments with fluticasone propionate/salmeterol (FSC). Therefore, in addition to testing genetic effects on change from baseline in trough forced expiratory volume in 1 s (FEV. One locus on chromosome 20 with seven variants with low minor allele frequencies significantly associated with change from baseline SGRQ score. The binary SGRQ response provided similar trends for association but did not attain genome-wide significance levels. No genetic association was detected with change from baseline in trough FEV. Common variants are unlikely to play a role in response to FSC.

Topics: Chromosomes, Human, Pair 20; Fluticasone; Forced Expiratory Volume; Gene Frequency; Genetic Association Studies; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Surveys and Questionnaires; Treatment Outcome

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

Topics: Administration, Inhalation; Asthma; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Models, Molecular; Protein Conformation; Pulmonary Disease, Chronic Obstructive

Topics: Bronchodilator Agents; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Topics: Bronchodilator Agents; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Inhaled therapies are the therapeutic mainstay in stable chronic obstructive pulmonary disease (COPD). They are represented by long-acting bronchodilators (anticholinergics or beta2-agonists) and by inhaled corticosteroids, currently available as a monotherapy or as combination therapies in one inhaler. Combinations of anticholinergics and beta2 agonists or beta2 agonists and inhaled corticosteroids are widely used per the prescription guidelines. The advantage of them are related with higher adherence and better acceptability by the patients as compared to both components dosed with individual inhalers. Bronchodilator combinations have also been demonstrated to exhibit a superior efficacy due to their synergistic mechanism of action when compared to either monotherapy. Triple therapies with anticholinergic-beta2 agonist-inhaled corticosteroid have been under investigation over the last few years and recently one such product became available in the EU for the treatment of stable COPD. Areas covered: The the FULFIL trial (Lung FUnction and quality of LiFe assessment in COPD with closed trIpLe therapy) investigated the efficacy and safety of fluticasone/vilanterol/umeclidinium once daily therapy in COPD patients. Expert opinion: The results discussed in this paper support the use of this combination in advanced COPD but also in earlier stages in patients with frequent exacerbation. However further and more long-term assessments are required.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cholinergic Antagonists; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines

Clinical trials of pharmacotherapy in chronic obstructive pulmonary disease (COPD) often include older persons with moderate-to-severe airflow-obstruction, as defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD). In this context, spirometric airflow-obstruction establishes COPD. Because GOLD misidentifies COPD and its severity in older persons, we set out to apply more age-appropriate spirometric criteria from the Global Lung function Initiative (GLI) in a prior clinical trial of COPD pharmacotherapy, specifically the Towards a Revolution in COPD Health (TORCH) trial - N = 6,112, mean age 65 years. In the TORCH trial, which enrolled GOLD-defined moderate COPD (26.2%, n = 1,200) and GOLD-defined severe COPD (73.8%, n = 4,511), the GLI reclassification yielded a higher frequency of severe COPD (89.6%, n = 5,474), the inclusion of restrictive-pattern (6.9%, n = 420) and, in turn, a very low frequency of moderate COPD (3.5%, n = 212). These GLI reclassification results suggest that GOLD-based enrollment criteria for the TORCH trial may have assembled a cohort that was: 1) less likely to respond to COPD pharmacotherapy, given the greater representation of severe COPD, very minor representation of moderate COPD, and inclusion of a non-obstructive spirometric impairment (restrictive-pattern); and 2) more likely to have medication-related adverse events, given the inappropriate use of COPD pharmacotherapy in misidentified COPD (restrictive-pattern). We therefore propose that future clinical trials of COPD pharmacotherapy should consider GLI criteria for defining COPD, including a greater representation of GLI-defined moderate COPD.

Topics: Age Factors; Aged; Bronchodilator Agents; Clinical Trials as Topic; Diagnostic Errors; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Severity of Illness Index; Spirometry; Vital Capacity

Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Animals; Bacterial Infections; Bacterial Load; Cell Line; Fluticasone; Humans; Immunity, Innate; Lung; Mice, Knockout; Mucus; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Receptor, Interferon alpha-beta; Rhinovirus

Topics: Fluticasone; Humans; Indans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate

The cost-effectiveness of long-acting muscarinic antagonist (LAMA) umeclidinium bromide (UMEC) 62.5 μg as add-on therapy to other maintenance COPD treatments is unknown.. For the lifetime horizon, compared with FF/VI, FP/SAL and ICS/LABAs, addition of UMEC was associated with incremental costs per quality-adjusted life-years (QALY) of £4050, £7210 and £5780, respectively, and incremental costs per life year gain of £3380, £6020 and £4940. All UMEC-containing regimens resulted in numerically lower exacerbation rates versus comparator regimens over a lifetime horizon.. Addition of UMEC to various ICS/LABA treatments was associated with higher cost than ICS/LABA alone, but was cost-effective in most scenarios.

Topics: Adrenergic beta-2 Receptor Agonists; Androstadienes; Cost-Benefit Analysis; Delayed-Action Preparations; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Humans; Maintenance Chemotherapy; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Therapeutic efficacy of pulmonary diseases is often limited and drug delivery systems offer new solutions to clinical problems. Solid lipid microparticles (SLMs) are suggested as systems for the delivery of therapeutics to the lung as, because of their size, they are able to deposit into secondary bronchi.. Here, we describe two novel different SLMs using chitosan and alginate such as mucoadhesive polymers and we also studied their biocompatibility and their effectiveness compared with the free drug in controlling senescence and inflammatory processes in cigarette smoke extracts.. Data reported show that fluticasone propionate (FP)-loaded SLMs are more effective than FP alone in controlling oxidative stress.. The therapeutic approach using FP-loaded microparticles could be a promising strategy for the treatment of the chronic inflammatory pulmonary diseases.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Alginates; Biocompatible Materials; Cell Survival; Chitosan; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Drug Stability; Epithelial Cells; Fluticasone; Glucuronic Acid; Hexuronic Acids; Humans; Lipids; Lung; Microscopy, Electron, Scanning; Microspheres; Oxidative Stress; Particle Size; Pulmonary Disease, Chronic Obstructive; Surface Properties

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Objective adherence to inhaled therapy by patients with chronic obstructive pulmonary disease (COPD) has not been reported.. To objectively quantify adherence to preventer Diskus inhaler therapy by patients with COPD with an electronic audio recording device (INCA).. This was a prospective observational study. On discharge from hospital patients were given a salmeterol/fluticasone inhaler with an INCA device attached. Analysis of this audio quantified the frequency and proficiency of inhaler use.. These data may inform clinicians in understanding why a prescribed inhaler is not effective and to devise strategies to promote adherence in COPD.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Drug Combinations; Female; Fluticasone; Humans; Male; Nebulizers and Vaporizers; Patient Compliance; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Unlike many other COPD studies, the 4-year UPLIFT trial permitted inhaled corticosteroid (ICS) use during run-in and treatment phases. This provided the opportunity to prospectively observe the continuing effects of ICS on respiratory events in closely observed COPD population.. We aimed to determine rate and number of episodes of pneumonia and exacerbations of COPD in patients entering the study on no ICS, fluticasone proprionate (FP), and other ICS.. The UPLIFT dataset was examined retrospectively, and patients were divided into three groups based on their medications at entry: no ICS, FP and other ICS. Poisson regression was used to compare the frequency of respiratory adverse events.. At entry, the groups were well matched apart from a higher FEV1% predicted (38 vs. 41%; ICS vs. no ICS, respectively) and prevalence of current smoking (26 vs. 36%; ICS vs. no ICS, respectively). Incidence rates of pneumonia were significantly higher in patients taking ICS compared to no ICS (0.068 vs. 0.056 respectively; p = 0.012). When the FP group was compared to the other ICS, the event rate was even higher (0.077 vs. 0.058, respectively; p < 0.001). COPD exacerbations were more frequent in patients taking ICS, with significantly greater rate in the FP group compared to that seen with other ICS (0.93 vs. 0.84 respectively; p = 0.013).. ICS use was associated an increase in respiratory adverse event rates, but whether this was due to more severe illness at entry is unknown. In subgroup analysis, the excess of morbidity in the ICS group appeared to be mainly associated with those receiving FP at randomisation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Cholinergic Antagonists; Disease Progression; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Time Factors; Tiotropium Bromide; Treatment Outcome

To validate outcomes of presently available chronic obstructive pulmonary disease (COPD) cost-effectiveness models against results of two large COPD trials-the 3-year TOwards a Revolution in COPD Health (TORCH) trial and the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial.. Participating COPD modeling groups simulated the outcomes for the placebo-treated groups of the TORCH and UPLIFT trials using baseline characteristics of the trial populations as input. Groups then simulated treatment effectiveness by using relative reductions in annual decline in lung function and exacerbation frequency observed in the most intensively treated group compared with placebo as input for the models. Main outcomes were (change in) total/severe exacerbations and mortality. Furthermore, the absolute differences in total exacerbations and quality-adjusted life-years (QALYs) were used to approximate the cost per exacerbation avoided and the cost per QALY gained.. Of the six participating models, three models reported higher total exacerbation rates than observed in the TORCH trial (1.13/patient-year) (models: 1.22-1.48). Four models reported higher rates than observed in the UPLIFT trial (0.85/patient-year) (models: 1.13-1.52). Two models reported higher mortality rates than in the TORCH trial (15.2%) (models: 20.0% and 30.6%) and the UPLIFT trial (16.3%) (models: 24.8% and 36.0%), whereas one model reported lower rates (9.8% and 12.1%, respectively). Simulation of treatment effectiveness showed that the absolute reduction in total exacerbations, the gain in QALYs, and the cost-effectiveness ratios did not differ from the trials, except for one model.. Although most of the participating COPD cost-effectiveness models reported higher total exacerbation rates than observed in the trials, estimates of the absolute treatment effect and cost-effectiveness ratios do not seem different from the trials in most models.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Computer Simulation; Cost-Benefit Analysis; Decision Making; Economics, Medical; Female; Fluticasone; Humans; Male; Middle Aged; Models, Econometric; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Topics: Androstadienes; Drug Combinations; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Lung; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

As expected, the vilanterol + fluticasone combination increases the risk of pneumonia in patients with COPD.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive

Topics: Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive

The objective of this study was to assess the cost effectiveness of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) compared with salmeterol/fluticasone combination (SFC) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who had a history of one or no exacerbations in the previous year, in Canada, France, Italy, and Portugal.. A patient-level simulation was developed to compare the costs and outcomes of IND/GLY versus SFC based on data from the LANTERN trial (NCT01709903). Monte-Carlo simulation methods were employed to follow individual patients over various time horizons. Population and efficacy inputs were derived from the LANTERN trial. Considering the payers' perspective, only direct costs were included. Costs and health outcomes were discounted annually at 3.0 % for all countries. Unit costs were taken from publically available sources with all costs converted to euros (€). The cost base year was 2015. Deterministic and probabilistic sensitivity analyses were undertaken to test the robustness of the model results.. IND/GLY was found to be the dominant (more effective and less costly) treatment option compared with SFC in all four countries. The use of IND/GLY was associated with mean total cost savings per patient over a lifetime of €6202, €1974, €1611, and €220 in Canada, France, Italy, and Portugal, respectively. Sensitivity analysis showed that exacerbation rates had the largest impact on incremental costs and quality-adjusted life-years (QALYs). The probability of IND/GLY being cost effective was estimated to be >95 % for thresholds above €5000/QALY.. In patients with moderate to severe COPD, IND/GLY is likely to be a cost-effective treatment alternative compared with SFC.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Canada; Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Fluticasone; France; Glycopyrrolate; Health Care Costs; Humans; Indans; Italy; Male; Portugal; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate

Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect.. Human sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM-1 μM), aclidinium bromide (0.1 nM-1 μM) or a combination thereof and stimulated with 1 μg of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1β were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation.. The non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-δ and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes.. LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD.

Topics: Aged; Anti-Inflammatory Agents; Bronchodilator Agents; Case-Control Studies; Choline O-Acetyltransferase; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Fluticasone; Humans; Inflammation Mediators; Male; Middle Aged; Muscarinic Antagonists; Neutrophils; Non-Neuronal Cholinergic System; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Sputum; Tropanes; Vesicular Acetylcholine Transport Proteins

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function associated with increased local and systemic inflammatory markers, such as TNFα and IL-1β. Glucocorticoids are used to treat this chronic disease, however their efficacy is low and new drugs are very much required. 17-oxo-DHA is a cyclooxygenase-2-dependent, electrophilic, α,β-unsaturated keto-derivative of docosahexaenoic acid with anti-inflammatory properties. We evaluated the action of 17-oxo-DHA alone or in combination with the steroid fluticasone propionate (FP) in peripheral blood mononuclear cells (PBMCs) from COPD patients and healthy individuals exposed to lipopolysaccharide. We show that PBMCs from COPD patients released higher levels of TNFα and IL-1β compared to controls. 17-oxo-DHA displayed strong anti-inflammatory effects. The addition of 17-oxo-DHA in combination with FP showed enhanced anti-inflammatory effects through the modulation of transcriptional and post-transcriptional mechanisms. 17-oxo-DHA, but not FP, was able to suppress the release of mature IL-1β through inhibition of the NLRP3 inflammasome. Furthermore, 17-oxo-DHA inhibited inflammasome-dependent degradation of the glucocorticoid receptor (GR). Our findings suggest that 17-oxo-DHA in combination with FP or other steroids might achieve higher therapeutic efficacy than steroids alone. Combined treatment might be particularly relevant in those conditions where increased inflammasome activation may lead to GR degradation and steroid-unresponsive inflammation.

Topics: Aged; Anti-Inflammatory Agents; Case-Control Studies; Caspase 1; Cell Line; Cell Separation; Docosahexaenoic Acids; Enzyme Activation; Female; Fluticasone; Humans; Inflammasomes; Interleukin-1beta; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Mitochondria; Nigericin; NLR Family, Pyrin Domain-Containing 3 Protein; Proteolysis; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Receptors, Glucocorticoid; RNA, Messenger; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tumor Necrosis Factor-alpha

Topics: Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Recent studies show that several Siglec receptors, such as Siglec-8 and Siglec-14, may be important therapeutic targets in asthma and COPD. Siglecs are a family of lectins belonging to the immunoglobulin superfamily and recognize sialic acid residues of glycoproteins. Most of Siglecs have intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIM), implicating them in the suppression of immunoreceptor signaling. Siglec-5/14 may be involved in the negative regulation of innate immune responses. The aim of this study was to analyze Siglec-5/14 expression in induced sputum cells of COPD patients in the following treatment combinations: (1) a long-acting beta2-agonist, formoterol; (2) formoterol combined with a long-acting antimuscarinic agent, tiotropium; and (3) formoterol combined with an inhaled corticosteroid or formoterol combined with tiotropium and with an inhaled corticosteroid. Siglec expression was assessed in sputum cells by flow cytometry using a specific monoclonal antibody. Double staining of cells indicated that Siglec-5/14 is expressed in monocyte/macrophages and neutrophils, but not in lymphocytes. Siglec-5/14 expression was significantly higher in patients receiving combined therapy including inhaled corticosteroids compared with patients taking only formoterol or formoterol + tiotropium. Our results suggest that inhaled corticosteroids may exert beneficial or negative effects, depending on the patients' phenotype, through increased immunosuppressive Siglec-5 or immunoactivatory Siglec-14 receptors, respectively.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Androstadienes; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bronchodilator Agents; Budesonide; Cell Separation; Cholinergic Antagonists; Drug Therapy, Combination; Ethanolamines; Fluticasone; Formoterol Fumarate; Gene Expression; Humans; Immunophenotyping; Lectins; Macrophages; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Scopolamine Derivatives; Sputum; T-Lymphocytes; Tiotropium Bromide

The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Pulmonary Disease, Chronic Obstructive; Recurrence; Republic of Korea; Salmeterol Xinafoate; Smoking; Spirometry; Treatment Outcome

Topics: Administration, Inhalation; Advisory Committees; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Humans; Incidence; Male; Primary Prevention; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

A new approach to the treatment of COPD includes controlling inflammation because of its important role in exacerbation of the disease. Recently, roflumilast has been added as a therapeutic option for COPD. Roflumilast is an oral phosphodiesterase-4 inhibitor that targets inflammatory cells involved in triggering exacerbations of COPD. The objective of the current study was to evaluate roflumilast for its contribution to phagocytic activity in COPD patients.. Twenty-one patients diagnosed with COPD received roflumilast once daily for 6 months in combination with fluticasone (an inhaled corticosteroid), salmeterol (a long-acting β2-agonist), and tiotropium (a long-acting muscarinic antagonist) or combinations of these agents. The main inclusion criterion was stable disease for at least the previous 30 days. Neutrophils and spirometric changes, ie, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), were measured in the COPD patients at indicated time points. The first sample was taken before receiving roflumilast, the second 3 months later, and the third after 6 months. Examination of defective phagocytosis was done by flow cytometry using a FagoFlowEx(®) kit. The statistical analysis was performed using Statistica software.. Our results indicate that phagocytic activity was increased after 3 and 6 months of treatment when compared with baseline (P<0.001). Similarly, FVC and FEV1 were also increased during the 6-month period, but only FVC differed significantly from baseline (P<0.001).. Although the number of patients in this study was limited, our results indicate that roflumilast induces phagocytic activity, which improves lung function.

Topics: Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aminopyridines; Anti-Inflammatory Agents; Benzamides; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Flow Cytometry; Fluticasone; Forced Expiratory Volume; Greece; Humans; Lung; Muscarinic Antagonists; Phagocytosis; Phosphodiesterase 4 Inhibitors; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Salmeterol Xinafoate; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Topics: Benzyl Alcohols; Biomedical Research; Bronchodilator Agents; Chlorobenzenes; Family Practice; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; United Kingdom

Topics: Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Fluticasone; Humans; Indans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate

Adipokines are protein mediators first described as products of adipose tissue regulating energy metabolism and appetite. Recently, adipokines have also been found to modulate inflammation and smooth muscle cell responses. Therefore we investigated the association of two adipokines, adiponectin and leptin, with the degree of emphysema, pulmonary function, symptoms and glucocorticoid responsiveness in patients with COPD.. Plasma adiponectin and leptin levels, spirometry, body plethysmography and symptoms were measured in 43 male COPD patients with smoking history ≥ 20 pack-years, post bronchodilator FEV1/FVC < 0.7 and pulmonary emphysema on HRCT. The measurements were repeated in a subgroup of patients after 4 weeks' treatment with inhaled fluticasone.. In patients with COPD, plasma adiponectin levels correlated positively with airway resistance (Raw) (r = 0.362, p = 0.019) and functional residual capacity (FRC) (r = 0.355, p = 0.046). Furthermore, the baseline adiponectin concentration correlated negatively with the fluticasone induced changes in St George's Respiratory questionnaire (SGRQ) symptom score (r = -0.413, p = 0.040) and in FRC % pred (r = -0.428, p = 0.003), i.e. a higher baseline plasma adiponectin level was associated with more pronounced alleviation of symptoms and dynamic hyperinflation. Plasma leptin levels were not related to the measures of lung function, symptoms or glucocorticoid responsiveness.. Plasma adiponectin levels were associated with peripheral airway obstruction and dynamic hyperinflation in patients with COPD. A higher adiponectin level predicted more favourable relief of symptoms and hyperinflation during glucocorticoid treatment. Adiponectin may have a role in the COPD pathogenesis; it may also be a biomarker of disease severity and treatment responses in this disease.

Topics: Adiponectin; Adipose Tissue; Administration, Inhalation; Androstadienes; Biomarkers; Bronchodilator Agents; Fluticasone; Glucocorticoids; Humans; Leptin; Male; Plethysmography, Whole Body; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Risk Factors; Sensitivity and Specificity; Smoking; Spirometry; Surveys and Questionnaires; Treatment Outcome

Glucocorticoids (GCs) have been used for more than 50 y as immunosuppressive drugs, yet their efficacy in macrophage-dominated disorders, such as chronic obstructive pulmonary disease, is debated. Little is known how long-term GC treatment affects macrophage responses in inflammatory conditions. In this study, we compared the transcriptome of human macrophages, matured in the presence or absence of fluticasone propionate (FP), and their ability to initiate or sustain classical activation, mimicked using acute LPS and chronic IFN-γ stimulation, respectively. We identified macrophage gene expression networks, modulated by FP long-term exposure, and specific patterns of IFN-γ- and LPS-induced genes that were resistant, inhibited, or exacerbated by FP. Results suggest that long-term treatment with GCs weakens adaptive immune signature components of IFN-γ and LPS gene profiles by downmodulating MHC class II and costimulatory molecules, but strengthens innate signature components by maintaining and increasing expression of chemokines involved in phagocyte attraction. In a mouse model of chronic obstructive pulmonary disease, GC treatment induced higher chemokine levels, and this correlated with enhanced recruitment of leukocytes. Thus, GCs do not generally suppress macrophage effector functions, but they cause a shift in the innate-adaptive balance of the immune response, with distinct changes in the chemokine-chemokine receptor network.

Topics: Adaptive Immunity; Androstadienes; Animals; Budesonide; Cells, Cultured; Cytokines; Fluticasone; Gene Expression Regulation; Gene Regulatory Networks; Humans; Immunity, Innate; Interferon-gamma; Lipopolysaccharides; Lung; Macrophage Activation; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Specific Pathogen-Free Organisms; Th1 Cells; Tobacco Smoke Pollution; Toll-Like Receptor 4; Transcriptome

Topics: Administration, Inhalation; Androstadienes; Female; Fluticasone; Glucocorticoids; Humans; Male; Pneumonia; Pulmonary Disease, Chronic Obstructive

COPD (chronic obstructive pulmonary disease) is a common lung disease characterized by airflow limitation and systemic inflammation. Recently, adipose tissue mediated inflammation has gathered increasing interest in the pathogenesis of the disease. In this study, we investigated the role of novel adipocytokines nesfatin-1 and visfatin in COPD by measuring if they are associated with the inflammatory activity, lung function, or symptoms. Plasma levels of NUCB2/nesfatin-1 and visfatin were measured together with IL-6, IL-8, TNF- α , and MMP-9, lung function, exhaled nitric oxide, and symptoms in 43 male patients with emphysematous COPD. The measurements were repeated in a subgroup of the patients after four weeks' treatment with inhaled fluticasone. Both visfatin and NUCB2/nesfatin-1 correlated positively with plasma levels of IL-6 (r = 0.341, P = 0.027 and rho = 0.401, P = 0.008, resp.) and TNF- α (r = 0.305, P = 0.052 and rho = 0.329, P = 0.033, resp.) and NUCB2/nesfatin-1 also with IL-8 (rho = 0.321, P = 0.036) in patients with COPD. Further, the plasma levels of visfatin correlated negatively with pulmonary diffusing capacity (r = -0.369, P = 0.016). Neither of the adipokines was affected by fluticasone treatment and they were not related to steroid-responsiveness. The present results introduce adipocytokines NUCB2/nesfatin-1 and visfatin as novel factors associated with systemic inflammation in COPD and suggest that visfatin may mediate impaired pulmonary diffusing capacity.

Topics: Adult; Aged; Androstadienes; Biomarkers; Calcium-Binding Proteins; Case-Control Studies; Cytokines; DNA-Binding Proteins; Fluticasone; Forced Expiratory Volume; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Lung; Male; Middle Aged; Nerve Tissue Proteins; Nicotinamide Phosphoribosyltransferase; Nitric Oxide; Nucleobindins; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Inhaled corticosteroids are anti-inflammatory medications that can down-regulate the immunologic response in patients with COPD; however, their role at onset of COPD exacerbation is still not understood. The aim of this study was to assess the early inflammatory response and clinical presentation of patients with COPD exacerbation mediated by inhaled corticosteroids.. Prospective data were collected on 123 hospitalized subjects with COPD exacerbation over a 30-month period at 2 Spanish university hospitals. Based on domiciliary use, comparative analyses were performed between subjects who did not use inhaled corticosteroids (n = 58) and subjects who did (n = 65). Measurements of serum biomarkers were recorded on admission to the hospital (day 1) and on day 3; clinical, physiological, microbiological, and severity data and mortality/readmission rates were also recorded.. At days 1 and 3, both groups showed a similar inflammatory response; fluticasone produced lower levels of interleukin-8 compared with budesonide (P < .01). All clinical features considered were similar in the 2 groups; multivariate analysis predicting clinical complications on hospitalization showed air-flow obstruction severity as the only predictive factor (odds ratio 3.13, 95% CI 1.13-8.63, P = .02).. Our study demonstrates a lack of inhaled corticosteroid influence in the early systemic inflammatory response to and clinical presentation of COPD exacerbation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Biomarkers; Budesonide; Comorbidity; Female; Fluticasone; Hospitalization; Humans; Interleukin-8; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spain

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Glucocorticoids; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2-4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD.. Smokers and ex-smokers with COPD ≥ 40 years old initiating or stepping-up their dose of extrafine beclomethasone or fluticasone were matched 1:1 for demographic characteristics, index prescription year, concomitant therapies, and disease severity during 1 baseline year. During 2 subsequent years, we evaluated treatment change and COPD exacerbations, defined as emergency care/hospitalization for COPD, acute oral corticosteroids, or antibiotics for lower respiratory tract infection.. Mean patient age was 67 years, 57%-60% being male. For both initiation (n=334:334) and step-up (n=189:189) patients, exacerbation rates were comparable between extrafine beclomethasone and fluticasone cohorts during the 2 year outcome period. Odds of treatment stability (no exacerbation or treatment change) were significantly greater for patients initiating extrafine beclomethasone compared with fluticasone (adjusted odds ratio 2.50; 95% confidence interval, 1.32-4.73). Median ICS dose exposure during 2 outcome years was significantly lower (P<0.001) for extrafine beclomethasone than fluticasone cohorts (315 μg/day versus 436 μg/day for initiation, 438 μg/day versus 534 μg/day for step-up patients).. We observed that small-particle ICS at significantly lower doses had comparable effects on exacerbation rates as larger-particle ICS at higher doses, whereas initiation of small-particle ICS was associated with better odds of treatment stability during 2-years' follow-up.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Androstadienes; Anti-Bacterial Agents; Beclomethasone; Disease Progression; Emergency Service, Hospital; Female; Fluticasone; Hospitalization; Humans; Lung; Male; Middle Aged; Particle Size; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Smoking; Smoking Cessation; Smoking Prevention; Time Factors; Treatment Outcome

Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.. We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.. Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.. We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.. Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.

Topics: Activating Transcription Factor 4; Aged; Analysis of Variance; Androstadienes; Bronchi; Bronchodilator Agents; Bronchoscopy; Epithelial Cells; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Respiratory Function Tests; Smoking; Transcriptome

The use of inhaled corticosteroids in patients with chronic obstructive pulmonary disease (COPD) has been associated with an increased risk of pneumonia in controlled clinical trials and case-control analyses.. Using claims databases as a research model of real-world diagnosis and treatment, to determine if the use and dose of inhaled corticosteroids (ICS) among patients with newly diagnosed COPD are associated with increased risk of pneumonia.. This was a retrospective cohort analysis of patients diagnosed with COPD between January 01, 2006 and September 30, 2010, drawn from databases (years 2006-2010). Patients (aged ≥45 years) were followed until first pneumonia diagnosis, end of benefit enrollment, or December 31, 2010, whichever was earliest. A Cox proportional hazard model was used to assess the association of ICS use and risk of pneumonia, controlling for baseline characteristics. Daily ICS use was classified into low, medium, and high doses (1 μg-499 μg, 500 μg-999 μg, and ≥1000 μg fluticasone equivalents daily) and was modeled as a time-dependent variable.. Among 135,445 qualifying patients with a total of 243,097 person-years, there were 1020 pneumonia incidences out of 5677 person-years on ICS (crude incidence rate, 0.180 per person-year), and 27,730 pneumonia incidences out of 237,420 person-years not on ICS (crude incidence rate, 0.117 per person-year). ICS use was associated with a dose-related increase in risk of pneumonia, with adjusted hazard ratios (versus no use; (95% confidence interval) of 1.38 (1.27-1.49) for low-dose users, 1.69 (1.52-1.88) for medium-dose users, and 2.57 (1.98-3.33) for high-dose users (P < 0.01 versus no use and between doses).. The use of ICS in newly diagnosed patients with COPD is potentially associated with a dose-related increase in the risk of pneumonia.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Androstadienes; Anti-Inflammatory Agents; Databases, Factual; Dose-Response Relationship, Drug; Female; Fluticasone; Humans; Incidence; Male; Middle Aged; Pneumonia; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; United States

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Fluticasone; Humans; Medication Therapy Management; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index

Chronic respiratory disease and inhaled corticosteroid (ICS) therapy for chronic obstructive pulmonary disease (COPD) increase the risk of pneumonia. Few data are available on the association of these risk factors with non-tuberculous mycobacterial (NTM) pulmonary disease.. This study examined chronic respiratory diseases and ICS use as risk factors in a population-based case-control study encompassing all adults in Denmark with microbiologically confirmed NTM pulmonary disease between 1997 and 2008. The study included 10 matched population controls per case. Conditional logistic regression was used to compute adjusted ORs for NTM pulmonary disease with regard to chronic respiratory disease history.. Overall, chronic respiratory disease was associated with a 16.5-fold (95% CI 12.2 to 22.2) increased risk of NTM pulmonary disease. The adjusted OR for NTM disease was 15.7 (95% CI 11.4 to 21.5) for COPD, 7.8 (95% CI 5.2 to 11.6) for asthma, 9.8 (95% CI 2.03 to 52.8) for pneumoconiosis, 187.5 (95% CI 24.8 to 1417.4) for bronchiectasis, and 178.3 (95% CI 55.4 to 574.3) for tuberculosis history. ORs were 29.1 (95% CI 13.3 to 63.8) for patients with COPD on current ICS therapy and 7.6 (95% CI 3.4 to 16.8) for patients with COPD who had never received ICS therapy. Among patients with COPD, ORs increased according to ICS dose, from 28.1 for low-dose intake to 47.5 for high-dose intake (more than 800 μg/day). The OR was higher for fluticasone than for budesonide.. Chronic respiratory disease, particularly COPD treated with ICS therapy, is a strong risk factor for NTM pulmonary disease.

Topics: Administration, Inhalation; Aged; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchiectasis; Budesonide; Case-Control Studies; Chronic Disease; Confidence Intervals; Denmark; Female; Fluticasone; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Odds Ratio; Pneumoconiosis; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases; Risk Factors; Tuberculosis, Pulmonary

A bioanalytical method for the quantitative determination of budesonide and fluticasone in human sputum was developed. Sputolysin(®) Reagent was added to the sputum samples. After incubation (37°C; 60-70 min under shaking) and automated solid phase extraction the extracts were analysed using LC-MS/MS. Budesonide and fluticasone showed good linearity (r>0.99) over the range 0.1-100 nM in the first and second validation batch, and over the range 0.25-10,000 nM in the third and fourth validation batch. The lower limit of quantification (LLOQ) achieved was 5 nM for budesonide and fluticasone in 100 μL human sputum. Intra-run and inter-run RSD for four quality control levels (5-100 nM) were within 6.9% (budesonide) and 8.0% (fluticasone). The accuracy ranged from -11.4% to -1.6% (budesonide), and from -11.8% to 0.4% (fluticasone). The validated method was applied to clinical sputum samples from COPD patients.

Topics: Androstadienes; Anti-Inflammatory Agents; Budesonide; Chromatography, Liquid; Drug Stability; Fluticasone; Humans; Linear Models; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Solid Phase Extraction; Sputum; Tandem Mass Spectrometry; Temperature

Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting β(2) -agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.. Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC(50) values on TNF-α-induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H(2) O(2) ) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma.. PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10(-9)  M) and salmeterol (SM, 10(-8)  M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H(2) O(2) exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H(2) O(2) -induced PI3Kδ-dependent (PKB) phosphorylation. H(2) O(2) decreased SM-induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H(2) O(2) was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3Kδ inhibitor.. FM reversed oxidative stress-induced corticosteroid insensitivity and decreased β(2) adrenoceptor-dependent cAMP production via inhibition of PI3Kδ signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD.

Topics: 1-Phosphatidylinositol 4-Kinase; Adenine; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Androstadienes; Asthma; Budesonide; Chromones; Dexamethasone; Drug Resistance; Ethanolamines; Female; Fluticasone; Formoterol Fumarate; Humans; Hydrogen Peroxide; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Morpholines; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Quinazolines; Receptors, Adrenergic, beta-2; Salmeterol Xinafoate; U937 Cells; Young Adult

Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC-SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC-SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC-SOD would be therapeutically beneficial for COPD.

Topics: Administration, Inhalation; Airway Resistance; Aminopyridines; Androstadienes; Animals; Benzamides; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Cyclopropanes; Fluticasone; Forced Expiratory Volume; Ipratropium; Lung; Mice; Pancreatic Elastase; Phosphatidylcholines; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Respiratory Physiological Phenomena; Superoxide Dismutase; Superoxides; Vital Capacity

This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Azabicyclo Compounds; Binding Sites; Cell Membrane Permeability; Crystallography, X-Ray; Dogs; Drug Stability; Humans; In Vitro Techniques; Kinetics; Leukocytes, Mononuclear; Methylurea Compounds; Models, Molecular; p38 Mitogen-Activated Protein Kinases; Protein Binding; Protein Conformation; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Rats; Solubility; Surface Plasmon Resonance; Tumor Necrosis Factor-alpha

Patients with chronic obstructive pulmonary disease (COPD) demonstrate variable responses to inhaled corticosteroids (ICS). The factors contributing to this variability are not well understood. Data from patients with asthma have suggested that low 25-hydroxyvitamin D [25(OH)D] levels contribute to a lack of ICS response in asthma. The objective of this study was to determine whether serum levels of 25(OH)D were related to ICS responses in patients with COPD.. A total of 60 exsmokers with severe COPD (mean forced expiratory volume in one second [FEV(1)] 1.07 L, 36% of predicted) spent 4 weeks free of any ICS, followed by 4 weeks of ICS use (fluticasone propionate 500 μg twice daily). Spirometry was performed prior to and after 4 weeks of ICS use. Blood 25(OH)D levels were measured prior to ICS use and examined for relationships to changes in FEV(1) following the 4 weeks of ICS use.. The mean 25(OH)D level was 23.3 ± 9.3 ng/mL. There was a high prevalence of vitamin D insufficiency (35%) and deficiency (40%). There was no relationship between baseline 25(OH)D and changes in FEV(1) following 4 weeks of ICS.. Baseline 25(OH)D does not contribute to the variation in short-term FEV(1) responses to ICS in patients with severe COPD.

Topics: Administration, Inhalation; Aged; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Minnesota; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and responses to therapies are highly variable. The aim of this study was to identify the predictors of pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD. A total of 127 patients with stable COPD from the Korean Obstructive Lung Disease (KOLD) Cohort, which were prospectively recruited from June 2005 to September 2009, were analyzed retrospectively. The prediction models for the FEV(1), FVC and IC/TLC changes after 3 months of treatment with salmeterol/fluticasone were constructed by using multiple, stepwise, linear regression analysis. The prediction model for the FEV(1) change after 3 months of treatment included wheezing history, pre-bronchodilator FEV(1), post-bronchodilator FEV(1) change and emphysema extent on CT (R = 0.578). The prediction models for the FVC change after 3 months of treatment included pre-bronchodilator FVC, post-bronchodilator FVC change (R = 0.533), and those of IC/ TLC change after 3 months of treatment did pre-bronchodilator IC/TLC and post-bronchodilator FEV(1) change (R = 0.401). Wheezing history, pre-bronchodilator pulmonary function, bronchodilator responsiveness, and emphysema extent may be used for predicting the pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Emphysema; Female; Fluticasone; Humans; Linear Models; Lung; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Republic of Korea; Respiratory Function Tests; Retrospective Studies; Salmeterol Xinafoate; Tomography Scanners, X-Ray Computed; Treatment Outcome

Currently available glucocorticoids are relatively short acting and may be less effective in patients with chronic obstructive pulmonary disease (COPD) where high levels of oxidative stress are seen. Here we show that a novel glucocorticoid, fluticasone furoate (FF), has a longer duration of action in several cell systems compared with fluticasone propionate (FP) and budesonide, and unlike FP, FF is resistant to oxidative stress. FF had similar or slightly higher potency to FP and was 2-9 fold more potent than budesonide, when assessed at 4h, in inhibiting inflammatory cytokine production in epithelial cell lines (BEAS2B, A549), primary bronchial epithelial cells and a monocytic cell line (U937). The potency of FF was sustained beyond 16 h with or without washout compared with FP or budesonide, such that it showed a greater duration of action in this range of cellular assays. The activated YFP-conjugated glucocorticoid receptor was detectable in nuclei of FF treated BEAS2B cells for at least for 30 h, and FF had a longer duration of action than FP in inhibiting activation of transcription factors such as NF-κB and AP-1. In addition, FF showed superior effects to FP in peripheral blood mononuclear cells from patients with COPD and also in U937 cells or primary bronchial epithelial cells under conditions of oxidative stress. The longer duration of action and oxidative stress insensitivity of FF compared with FP has potential clinical implications for the control of inflammation in respiratory diseases, such as COPD.

Topics: Active Transport, Cell Nucleus; Androstadienes; Asthma; Budesonide; Cell Line; Cell Nucleus; Fluticasone; Glucocorticoids; Humans; Leukocytes, Mononuclear; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Respiratory System; Time Factors; Transcription Factor RelA

High levels of exhaled nitric oxide (NO) predict favourable response to inhaled corticosteroids in asthma, but the ability of exhaled NO or inflammatory markers in exhaled breath condensate (EBC) to predict steroid responsiveness in chronic obstructive pulmonary disease (COPD) is not known. We measured alveolar and bronchial NO output, levels of leukotriene B(4) (LTB(4)), cysteinyl leukotrienes (cysLTs) and 8-isoprostane in EBC, spirometry, body plethysmography and symptoms in 40 subjects with COPD before and after 4 weeks of treatment with inhaled fluticasone (500 microg b.i.d.). Five subjects (12.5%) with COPD had significant improvement in lung function during fluticasone treatment, whereas 20 subjects (50%) had significant decrease in symptoms. High baseline bronchial NO flux was associated with higher increase in forced expiratory volume in 1 s to forced vital capacity ratio (r = 0.334, p = 0.038) and more symptom relief (r = -0.317, p = 0.049) during the treatment. Baseline EBC levels of LTB(4), cysLTs or 8-isoprostane were not related to response to fluticasone treatment. Inhaled fluticasone decreased bronchial NO flux but not alveolar NO concentration or markers in EBC. High levels of bronchial NO flux are related to symptom relief and improvement of airway obstruction during treatment with inhaled fluticasone in COPD. Markers of inflammation or oxidative stress in EBC are not related to steroid responsiveness in COPD.

Topics: Androstadienes; Biomarkers; Breath Tests; Bronchi; Bronchodilator Agents; Female; Fluticasone; Humans; Male; Nitric Oxide; Pulmonary Disease, Chronic Obstructive

The effect of the long acting beta(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 microg and fluticasone propionate 125 microg 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).. 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.. 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.. 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.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Electromyography; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung Volume Measurements; Male; Middle Aged; Muscle Contraction; Prognosis; Pulmonary Disease, Chronic Obstructive; Respiratory Muscles; Salmeterol Xinafoate; Severity of Illness Index

To assess the risk of pneumonia among COPD patients using salmeterol/fluticasone propionate combination inhalers (SFC), inhaled corticosteroids (ICS), or long-acting beta-agonists (LABA), alone or in combination, compared to those using only short-acting bronchodilators (SABD).. The study population comprised 5245 individuals using inhaled treatment for COPD, identified from the databases of three large regional managed care organisations from different parts of the USA. Longitudinally-collected administrative data were obtained on their clinical histories and treatments. Nested case-control methods were used to calculate adjusted odds ratios (OR) for the risk of pneumonia while on therapy.. 2154 patients had at least one diagnosed case of pneumonia between 1st September 2001 and 31st August 2003. Relative to SABD, the only treatment associated with a non-significant increased risk of pneumonia was ICS used alone (OR=1.29; 95%CI: 0.96-1.73; p=0.09). Users of LABA alone (OR=0.92; 95%CI: 0.69-1.22) or SFC (OR=1.03; 95%CI: 0.74-1.42) had no increased risk for pneumonia relative to SABD. Advanced age and severity of lung disease were strongly associated with increased risk for pneumonia.. Treatment with ICS or an ICS/LABA combination inhaler was not associated with a significantly increased risk of developing pneumonia.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Age Factors; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Case-Control Studies; Delayed-Action Preparations; Drug Therapy, Combination; Female; Fluticasone; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Severity of Illness Index

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Anti-Inflammatory Agents; Breathing Exercises; Bronchodilator Agents; Combined Modality Therapy; Drug Therapy, Combination; Fluticasone; Humans; Oxygen Inhalation Therapy; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Body Mass Index; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Smoking; Spirometry; Survival Analysis

According to evidence-based guidelines, the combination of inhaled corticosteroids and inhaled long-acting beta(2)-agonists in a single inhaler is recommended for patients with chronic obstructive pulmonary disease (COPD) who are experiencing exacerbations. The relative effectiveness of combination products such as budesonide/formoterol (BUD/FM) and fluticasone propionate/salmeterol (FP/SM) has not been well documented.. This study was conducted to investigate the different outcomes associated with the use of either BUD/FM or FP/SM in a single inhaler in patients with COPD. Outcomes included rates of exacerbations, emergency department (ED) visits and hospitalizations for COPD, medication utilization, and treatment adherence.. A 1-year, population-based, matched cohort study was conducted using administrative health care databases from the Canadian province of Quebec. Patients treated with BUD/FM were matched (1:1) to patients treated with FP/SM based on the following criteria: age group, sex, calendar year of treatment initiation, the number of COPD exacerbations in the year before treatment initiation, and use of inhaled short acting beta(2)-agonists (SABAs) and ipratropium bromide in the 3 months before treatment initiation. COPD exacerbations were defined as a claim for a short-course (< or =14 days) prescription of oral corticosteroids, or an ED visit or a hospitalization for COPD. Events occurring within 15 days were counted as a single exacerbation. Between-group comparisons of the number of exacerbations, ED visits, and hospitalizations for COPD, as well as claims for oral corticosteroids, were performed using Poisson regression models. Between-group comparisons of the mean number of doses of SABAs and ipratropium bromide per day were performed using linear regression models. Treatment adherence was also assessed.. Of the 2262 patients in the matched cohort, 78.1% were aged > or =65 years and 52.1% were men. COPD exacerbations, claims for oral corticosteroids, use of SABAs, and patient adherence to treatment did not differ significantly between the BUD/FM and FP/SM groups. However, the BUD/FM group was significantly less likely to have an ED visit (adjusted relative risk [RR] = 0.75; 95% CI, 0.58 to 0.97) or hospitalization (adjusted RR = 0.61; 95% CI, 0.47 to 0.81) for COPD and had fewer claims for prescriptions for tiotropium (adjusted RR = 0.71; 95% CI, 0.57 to 0.89). The BUD/FM group also used fewer doses of ipratroprium bromide than the FP/SM group (adjusted mean difference, -0.2 dose; 95% CI, -0.3 to -0.1).. These COPD patients treated with BUD/FM were less likely to have ED visits and hospitalizations for COPD and used fewer doses of anticholinergic medication than patients treated with FP/SM in the year after treatment initiation. However, due to the observational nature of the study design, we cannot conclude with certainty that the medication was the only factor responsible for the observed differences.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Cohort Studies; Databases, Factual; Drug Combinations; Emergency Service, Hospital; Ethanolamines; Female; Fluticasone; Formoterol Fumarate; Hospitalization; Humans; Male; Medication Adherence; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quebec; Retrospective Studies; Salmeterol Xinafoate

Topics: Androstadienes; Biomarkers; Breath Tests; Bronchi; Bronchodilator Agents; Fluticasone; Humans; Nitric Oxide; Pulmonary Disease, Chronic Obstructive

There has been inconsistent evidence on the association between use of inhaled corticosteroids (ICS) and increased risk of nonvertebral fractures in patients with asthma or chronic obstructive pulmonary disease (COPD). In a large population-based study in the United Kingdom, we estimated the association between fluticasone propionate/salmeterol fixed-dose combination (FSC) and other ICS use and nonvertebral fracture incidence among patients with COPD.. We identified a cohort of patients aged ≥ 45 years with COPD in the General Practice Research Database (GPRD) between 2003 and 2006. We used a nested case-control design to estimate the odds of incident nonvertebral fractures associated with prior prescriptions of FSC and other ICS, applying conditional logistic regression and controlling for potential confounders. Exposure to FSC and other ICS was assessed by recency, duration, and number of prescriptions. Average daily dose was defined as low, medium, high, or very high using fluticasone propionate equivalents.. We identified 1523 nonvertebral fracture cases among 53 191 patients with COPD at risk in the cohort. Use of FSC in the year prior to the index date was associated with a statistically significant increase in the odds of nonvertebral fractures (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.07-1.47); however, there was no increase in the odds of nonvertebral fractures for other ICS use (OR, 1.12; 95% CI, 0.97-1.30). When examining results by the recent use of prescriptions, an exposure that occurred farther from the index date was associated with a significant increase in nonvertebral fracture (26-52 days prior OR, 1.36; 95% CI, 1.04-1.77; 53-365 days prior OR, 1.39; 95% CI, 1.07-1.78), whereas categories of more recent use (0-12 days prior or 13-25 days prior) were not associated with nonvertebral fractures relative to no FSC use. No pattern of association between increasing levels of FSC or other ICS average daily dose and increased odds of nonvertebral fracture was observed.. We did not observe a consistent association between prescriptions of FSC or other ICS in terms of recent use or average daily dose in the prior year and increases in the odds of nonvertebral fractures in patients with COPD, although ever use of FSC was associated with a slight elevation in the odds.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Case-Control Studies; Comorbidity; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluticasone; Fractures, Bone; Humans; Incidence; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; United Kingdom

We examine the lifetime cost-effectiveness of treatment with fluticasone propionate/salmeterol (500/50 microg) compared with no maintenance treatment in COPD in the US.. A decision-analytic model was developed to estimate lifetime costs and outcomes associated with fluticasone propionate/salmeterol 500/50 microg treatment, salmeterol 50 microg, and fluticasone propionate 500 microg compared to no maintenance treatment in treating COPD from a third-party US payer perspective. The patient population was similar to that of the TORCH clinical trial. Model structure and inputs were obtained from published literature and clinical trial data. All costs are presented in 2006 US dollars. Outcomes included cost per life year (LY) saved and cost per quality-adjusted life year (QALY) gained. Costs and outcomes were discounted at 3% annually. Univariate and multivariate sensitivity analyses were conducted to assess model robustness.. Compared to no maintenance treatment, treatment with fluticasone propionate/salmeterol 500/50mug results in a lifetime incremental cost-effectiveness ratio (ICER) of $33,865/QALY. Treatment with salmeterol 50 microg was found to have an ICER of $20,797/QALY. These results are robust to changes in input parameters. Fluticasone propionate 500 microg was dominated by no treatment, though the results were not robust to changes in parameters.. Treatment of COPD with fluticasone propionate/salmeterol 500/50 microg appears to be cost-effective (

Topics: Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Anti-Asthmatic Agents; Cost-Benefit Analysis; Drug Costs; Female; Fluticasone; Humans; Male; Markov Chains; Middle Aged; Models, Economic; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recurrence; Risk; Salmeterol Xinafoate; Treatment Outcome

Inhaled corticosteroids are used to treat COPD and asthma. An association between sequence variants in the corticotrophin-releasing hormone receptor 1 (CRHR1) gene and improved lung function in asthmatics treated with inhaled corticosteroids was reported recently. This study investigated the association between the change in lung function in response to inhaled corticosteroids and single-nucleotide CRHR1 polymorphisms in patients with COPD.. COPD patients (n = 87) with a positive smoking history were recruited from the pulmonary clinics of 11 hospitals in Korea. Patients were treated with fluticasone propionate and salmeterol for 12 weeks and lung function was measured at baseline and after the 12-week treatment. Eighty-four of the 87 subjects were successfully genotyped.. Seventy-one patients with the wild-type GG genotype and 13 patients with the heterozygous GT genotype in rs242 941 were evaluated. After 12-week treatment, the change in FEV(1) was significantly higher in patients with wild-type GG genotype (6.0 +/- 0.8% of predicted FEV(1)) than in GT heterozygotes (-0.8 +/- 1.8, P = 0.003).. Improved FEV(1) following inhaled corticosteroid and a long-acting beta2-agonist was associated with CRHR1 genetic polymorphism in patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Genotype; Humans; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Receptors, Corticotropin-Releasing Hormone; Respiratory Function Tests; Salmeterol Xinafoate; Treatment Outcome

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

To assess the incremental cost-effectiveness of inhaled medication use in chronic obstructive pulmonary disease (COPD).. A Markov model was constructed to estimate the incremental quality-adjusted life-years (QALYs) gained of the alternative treatment arms used in the Towards a Revolution in COPD Health (TORCH) study (ie, salmeterol-fluticasone propionate combination [SFC], salmeterol, fluticasone, and placebo).. The cycle length for the model was set to 3 months, and the maximum time horizon was set to 3 years. The cost-effective analysis was conducted from a third-party payer's perspective in the US healthcare system. Future costs and effects were discounted at 3%. Multiple 1-way sensitivity analyses and a probabilistic sensitivity analysis using Monte Carlo simulation were performed to handle uncertainty.. The most cost-effective strategies are placebo (as-needed short-acting bronchodilator use with no maintenance therapy) when willingness to pay (WTP) is less than $52,800/QALY gained and SFC when WTP exceeds that threshold. When no maintenance therapy is not an acceptable option, the most cost-effective strategies are treatment with salmeterol when WTP is less than $49,500/QALY gained and treatment with SFC when WTP exceeds that threshold. The base-case analysis showed that incremental cost-effectiveness ratios of salmeterol, fluticasone, and SFC relative to placebo were $56,519, $62,833, and $52,046/QALY gained, respectively.. The most cost-effective strategy in moderate-to-severe COPD depends on how much society is willing to pay to achieve health improvements. When treatment with as-needed short-acting bronchodilator use does not provide adequate control, salmeterol or SFC would be the drug of choice depending on WTP.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Markov Chains; Monte Carlo Method; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate

Several studies suggest that inhaled and oral corticosteroids repress systemic inflammation in chronic obstructive pulmonary disease (COPD). However, the cytokines that may respond to these medications are unclear.. We used data from 41 patients with a history of stable moderate COPD (average age 64 years) who were randomised to inhaled fluticasone (500 microg twice daily from a Diskus inhaler), oral prednisone (30 mg daily) or placebo for 2 weeks. Using a multiplexed array system, different serum cytokines that have been implicated in COPD pathogenesis were measured.. We found that compared with placebo, inhaled fluticasone significantly reduced levels of soluble tumour necrosis factor receptor-2 (sTNF-R2) by 24% (95% CI, 7-38%; p = 0.01), monocyte chemoattractant protein-1 by 20% (95% CI, 5-32%; p = 0.01), interferon gamma inducible CXCL10 (IP-10) by 43% (95% CI, 3-66%; p = 0.04), and soluble L-selectin levels by 15% (95% CI, 1-28%; p = 0.04). Compared with placebo, oral prednisone reduced levels of sTNF-R2 by 26% (95% CI, 15-36%; p < 0.001), L-selectin by 22% (95% CI, 8-34%; p = 0.004), intercellular adhesion molecule-1 by 31% (95% CI, 9-48%; p = 0.01), pulmonary and activation-regulated chemokine (PARC) by 18% (95% CI, 2-32%; p = 0.03) and IP-10 by 40% (95% CI, 0-64%; p = 0.05). sTNF-R2, L-selectin and IP-10 were significantly reduced by both oral and inhaled corticosteroids. The other cytokines were not significantly repressed by either oral or inhaled corticosteroids.. In summary, inhaled and oral corticosteroids significantly repressed a selected number of systemic cytokines in patients with stable, moderate COPD; most of the steroid-responsive cytokines appear to be chemoattractants.

Topics: Administration, Inhalation; Administration, Oral; Aged; Androstadienes; Biomarkers; Cytokines; Female; Fluticasone; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

To compare, in elderly Medicare beneficiaries, chronic obstructive pulmonary disease (COPD)-related healthcare costs for patients initiating treatment with fluticasone propionate/salmeterol 250 μg/50 μg (FSC) with those for patients initiating treatment with ipratropium bromide/albuterol (IPA), ipratropium bromide (IPR), and tiotropium bromide (TIO).. In this retrospective, observational, cohort study, COPD-related medical costs (inpatient/emergency department, outpatient) and pharmacy costs were assessed in Medicare beneficiaries ≥ 65 years old who were enrolled in a commercial Medicare health maintenance organization plan and had a diagnosis of COPD (ICD-9-CM codes 491.xx, 492.xx, or 496.xx) within 12 months before initial treatment with FSC, IPA, IPR, or TIO.. In these ≥ 65-year-old patients (N=14,689), initial maintenance treatment with FSC was associated with total COPD-related cost savings (medical + pharmacy) of $295 versus IPA, $1,235 versus IPR, and $110 versus TIO (p<0.05, each comparison) over a 1-year follow-up period.. Initiation of maintenance therapy with FSC was associated with significant reduction in total costs (medical + pharmacy) relative to costs associated with the short-acting anticholinergic bronchodilators IPR and IPA and the long-acting anticholinergic bronchodilator TIO in an elderly Medicare-eligible population. These data considered in the context of the substantial efficacy and effectiveness data suggest that early introduction of maintenance treatment with FSC has both clinical and economic benefits. Limitations inherent in handling of administrative data include lack of objective clinical measures such as spirometry and smoking status. Furthermore, accuracy of diagnosis codes cannot be verified.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Health Care Costs; Health Services; Humans; Insurance Claim Review; Ipratropium; Male; Medicare; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; United States

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

Topics: Administration, Inhalation; Androstadienes; Budesonide; Fluticasone; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

The aim of this study was to determine the mineral status of mandibles, femurs, and spines in chronic obstructive pulmonary disease (COPD) patients under long-term inhaled corticosteroid therapy.. Pulmonary function tests were conducted on patients (n = 30) with COPD under inhaled corticosteroid therapy for at least 1 year. The results were compared to sex- and age-matched controls (n = 30). Analyses of blood gases were also carried out relative to COPD, and bone mineral densities (BMD) of the mandible, lumbar spine, femoral neck, trochanter, and Ward's triangle were also measured by dual-energy X-ray absorptiometry (DEXA). Levels of serum osteocalcin, alkaline phosphatase, calcium, phosphorus, and cortisol were also assessed.. In accordance with the Global Initiative for Chronic Obstructive Lung Disease criteria, 8 of the COPD patients had moderate, 11 patients had severe, and 11 patients had very severe forms of the disease. All BMD measurements were lower in the COPD patients than in the control group. The serum osteocalcin levels in COPD patients were significantly lower than those in the control group (p < 0.0001). Serum calcium (p < 0.004) and cortisol levels (p < 0.026) in the COPD patients were also significantly lower than those in the control subjects. Although serum alkaline phosphatase level was higher and the phosphorus level was lower in the treatment group than in the control group, the differences were not statistically significant.. Regular evaluation of the biochemical markers of bone metabolism and BMD would be helpful for detecting any detrimental changes of bone in COPD patients under long-term inhaled corticosteroid therapy. In this study, mandibular BMD was observed to be lower in COPD patients under long-term inhaled corticosteroid therapy than in healthy subjects. Thus, dental implant treatment may require preventive measures in COPD patients under long-term inhaled corticosteroid therapy.

Topics: Absorptiometry, Photon; Administration, Inhalation; Adrenal Cortex Hormones; Aged; Alkaline Phosphatase; Androstadienes; Biomarkers; Body Mass Index; Bone Density; Bronchodilator Agents; Budesonide; Calcium; Carbon Dioxide; Case-Control Studies; Female; Femur; Femur Neck; Fluticasone; Glucocorticoids; Humans; Hydrocortisone; Longitudinal Studies; Lumbar Vertebrae; Male; Mandible; Middle Aged; Osteocalcin; Oxygen; Phosphorus; Pulmonary Disease, Chronic Obstructive; Smoking

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte. In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils. Human neutrophils were preincubated with salmeterol or FP or the combination. The amount of interleukin-8 (IL-8), elastase and matrix metalloproteinases (MMP)-2 and -9 releases, and reactive oxygen species (ROS) generation and expression of MAP kinase phosphatase (MKP-1) and glucocorticoid receptor (GR) were determined. Cigarette smoke medium (CSM) induces an increased expression of CXC receptors and the production of ROS that may explain the strong production of IL-8 by neutrophils. The expression of CXC receptors, the production of ROS, and the release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP, or the combination. Interestingly, the combination therapy had an additive suppressive effect on the CSM-induced production of IL-8. The latter could be explained by an increased mRNA expression of MKP-1, the GR and an increased translocation of the GR to the nucleus. This leads eventually to suppression of both the NF-kappaB and MAPK pathways and, hence, to less IL-8 production by the neutrophil. These data are in support for the use of a combination therapy in COPD patients.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Animals; Bronchodilator Agents; Dual Specificity Phosphatase 1; Fluticasone; Humans; Interleukin-8; Matrix Metalloproteinases; Mitogen-Activated Protein Kinases; Neutrophils; NF-kappa B; Nicotiana; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Receptors, Glucocorticoid; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Salmeterol Xinafoate; Signal Transduction; Smoke

To compare the effects of initial maintenance therapy with fluticasone 250 microgram plus salmeterol 50 microgram in a single inhaler versus other inhaled medications on exacerbation risks and treatment costs among chronic obstructive pulmonary disease (COPD) patients.. A retrospective observational analysis was conducted by using medical/pharmacy claims from a large managed care database between January 2000 and February 2004. Patients age 40 years or older with a primary diagnosis of COPD (International Classification of Diseases, Ninth Revision, Clinical Modification code 490, 491, 492, or 496), at least 18 months of continuous eligibility, and an index prescription for fluticasone/salmeterol combination, salmeterol alone, inhaled corticosteroid alone, ipratropium/albuterol combination, or ipratropium alone (reference) were identified.. Time to first COPD-related hospitalization or emergency department (ED) visit was estimated by using Cox proportional hazard models. All-cause and COPD-related treatment costs were estimated by using generalized linear models with a gamma distribution and log link. Multivariable regressions were used, controlling for age, sex, comorbidities, COPD subtype, preindex medications, and hospitalizations and ED visits.. Initial maintenance therapy with fluticasone/salmeterol combination was associated with a 31% to 56% lower risk of hospitalization or ED visit compared with ipratropium alone, adjusting for baseline characteristics and preindex resource utilization. Fluticasone/salmeterol combination therapy was related to lower medical costs, higher pharmacy costs, and almost similar total costs in all populations studied.. Fluticasone/salmeterol combination therapy was considered to be cost-effective compared with ipratropium alone because it achieved better clinical outcomes with similar or lower treatment costs.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Salmeterol Xinafoate

The Inhaled Steroids in Obstructive Lung Disease (ISOLDE) study was a trial that randomised 752 patients with moderate to severe COPD to fluticasone propionate 1000 mcg/day or placebo for three years. We aimed to examine the causes of death of the ISOLDE participants after the original three up to 13 years post-randomisation. Death certificates were obtained either from the NHS Strategic Tracing Service or from the Office of National statistics. Deaths were classified according to the trial protocol. In the subsample of 375 participants from the seven ISOLDE original centers where complete extended follow-up was conducted, the factors associated with observed higher mortality (p<0.05) were male gender, older age and more severe COPD. Causes of death were; 107 (52%) respiratory, 38 (18%) cardiac, 29 (14%) lung cancer, 16 (8%) other cancer and 16 (8%) other causes. The percentage of respiratory-related deaths increased during the follow-up period; from 46% within the three-year trial, to 48% after 3-6 years, 57% after 6-9 years, and 60% after 9-13 years of follow-up (p for trend<0.05). We conclude that participants' survival is poor (only 44% in the 13 years after the ISOLDE trial), and that respiratory-related illnesses were the most frequent causes of death in patients with moderate to severe COPD.

Topics: Age Factors; Aged; Androstadienes; Female; Fluticasone; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Lung Diseases; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk; Sex Factors; Smoking

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

Fluticasone propionate reduces the frequency and severity of the episodes of exacerbation of chronic obstructive pulmonary disease (COPD). Streptococcus pneumoniae and Haemophilus influenzae are frequently isolated in these episodes. Both express phosphorylcholine, an epitope that mediates their interaction with airway epithelial cells via the platelet-activating factor receptor (PAFR). The present work studies the effects of fluticasone propionate on the expression of PAFR on human airway epithelial cells, the invasion of these cells by S. pneumoniae and H. influenzae, and the course of pneumococcal infection in vivo. The following were used in the experiments: S. pneumoniae and H. influenzae isolated from patients with COPD, cell cultures of type II pneumocytes and bronchoepithelial cells, and a mouse model of lung infection. Fluticasone propionate was found to reduce PAFR expression on the surface of the two cells types studied. All S. pneumoniae and H. influenzae isolates expressed phosphorylcholine. Treatment of both cells lines with fluticasone propionate reduced invasion of both microorganisms and reduced the bacterial load of mice infected with S. pneumoniae. Fluticasone propionate reduces the invasion of airway epithelial cells by Streptococcus pneumoniae and Haemophilus influenzae through its effect on platelet-activating factor receptor. These results may help explain the beneficial effects of fluticasone propionate on chronic obstructive pulmonary disease exacerbations.

Topics: Androstadienes; Animals; Bronchi; Bronchodilator Agents; Cell Line, Tumor; Epithelial Cells; Fluticasone; Haemophilus influenzae; Humans; Lung; Male; Mice; Platelet Membrane Glycoproteins; Pulmonary Disease, Chronic Obstructive; Receptors, G-Protein-Coupled; Streptococcus pneumoniae; Trachea

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Research Design; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Cost-effective treatments for chronic obstructive pulmonary disease (COPD) are needed to reduce the burden on the Medicare system.. The objectives of this retrospective study were to compare the effects of fluticasone propionate 500 microg/salmeterol 50 microg (FSC 500/50) with those of ipratropium (IPR) in older adult patients with COPD on the following factors: (1) the risk of all-cause and COPD-related hospitalization and emergency department (ED) visits; and (2) all-cause and COPD-related treatment costs.. This retrospective, observational cohort study assessed commercially insured patients aged > or =65 years (Medicare eligible) with COPD-related medical costs (International Classification of Diseases, Ninth Revision, Clinical Modification codes 490.xx, 491.xx, 492.xx, or 496.xx), 18 months of continuous enrollment (12 months' pre-study and 6 months' poststudy), and > or =1 prescription claim (ie, the index event) for FSC 500/50 or IPR between January 2, 2001, and August 12, 2003. Exacerbation events (hospitalizations/ED visits) were assessed using Cox proportional hazards regression models controlling for baseline factors and preindex events. Treatment costs were estimated using multivariate generalized linear models to adjust for baseline characteristics and preindex utilization and costs. A propensity-matched comparison was conducted as a sensitivity analysis.. A total of 1051 patients (540 women, 511 men) were identified: 952 in the IPR group (mean age, 74.26 years) and 99 in the FSC 500/50 group (mean age, 72.38 years). Treatment with FSC 500/50 was not associated with a reduction in the risk of all-cause hospitalization or ED visit compared with IPR (adjusted hazards ratio [HR], 0.913 [95% CI, 0.673-1.238]); however, FSC 500/50 was associated with a significantly lower risk (45%) of a COPD-related event (adjusted HR, 0.547 [95% CI, 0.301-0.995]). Although treatment with FSC 500/50 was associated with significantly lower annual mean all-cause medical costs compared with IPR ($18,642 vs $25,556, P < 0.05), the use of FSC 500/50 was also associated with significantly higher annual all-cause pharmacy costs ($2813 vs $2244, P < 0.05). Compared with the IPR cohort, the FSC 500/50 cohort had lower mean annual COPD-related medical costs (-$464 [P = NS]) and higher COPD-related pharmacy costs ($260 [P < 0.01]). However, increased pharmacy costs may be compensated for by decreased medical costs in both all-cause and COPD-related services. Results from the sensitivity analysis with the propensity score-matched sample of 194 patients were similar.. Compared with the IPR cohort, the FSC 500/50 cohort was 45% less likely to have a COPD-related exacerbation event and had similar medical costs. FSC 500/50 was a more effective initial maintenance therapy than IPR for this Medicare population, and, despite the $260 increase in COPD-related pharmacy costs, there was no significant difference in COPD-related medical costs.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cohort Studies; Costs and Cost Analysis; Databases, Factual; Drug Combinations; Emergency Service, Hospital; Female; Fluticasone; Hospitalization; Humans; Ipratropium; Male; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk; Risk Assessment; Salmeterol Xinafoate; Treatment Outcome

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Hospitalization; Humans; Male; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Interleukin-6 (IL-6) is a proinflammatory cytokine up-regulated by rhinovirus infection during acute exacerbations of asthma and chronic obstructive pulmonary disease. The role of IL-6 during exacerbations is unclear; however, it is believed IL-6 could contribute to airway and systemic inflammation. In this study we investigate the effects of common asthma treatments fluticasone propionate and beta(2) agonists salmeterol and salbutamol on IL-6 production in BEAS-2B and primary bronchial epithelial cells. Salmeterol and salbutamol enhanced rhinovirus- and IL-1beta-induced IL-6 production; however, fluticasone treatment caused a reduction of IL-6 protein and mRNA. Combined activity of salmeterol and fluticasone at equimolar concentrations had no effect on rhinovirus or IL-1beta induction of IL-6. The induction of IL-6 by salmeterol was dependent upon the beta(2) receptor and could also be induced by cAMP or cAMP-elevating agents forskolin and rolipram. Using transfection of IL-6 promoter reporter constructs, dominant negative mutants, and electromobility shift assays, it was found that NF-kappaB was the only transcription factor required for rhinovirus induction of IL-6 gene expression. Salmeterol caused an augmentation of rhinovirus-induced promoter activation via a mechanism dependent upon the c/EBP and/or CRE (cyclic AMP response element) cis-acting sites. The suppressive effect of FP was dependent upon distinct glucocorticoid response element sequences proximal to the transcriptional start site within the IL-6 promoter. The data demonstrate that beta(2) agonists can augment IL-6 expression by other stimuli in an additive manner via cyclic AMP and that the negative effect of steroids is mediated by glucocorticoid response elements within the IL-6 promoter.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchi; CCAAT-Enhancer-Binding Proteins; Colforsin; Cyclic AMP; Epithelial Cells; Fluticasone; Gene Expression Regulation; HeLa Cells; Humans; Interleukin-1beta; Interleukin-6; NF-kappa B; Phosphodiesterase Inhibitors; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Response Elements; Rhinovirus; Rolipram; Salmeterol Xinafoate; Transcription, Genetic

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Germany; Hospitalization; Humans; Incidence; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Severity of Illness Index

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Human Experimentation; Humans; Placebos; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Data Interpretation, Statistical; Drug Therapy, Combination; Fluticasone; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Factor Analysis, Statistical; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Fluticasone; Humans; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Limited information is available on the relative outcomes and treatment costs of various pharmacotherapies for chronic obstructive pulmonary disease (COPD) in a Medicaid population.. This study compared the effects of initial medication regimens for COPD on COPD-related and all-cause events (hospitalizations and/or emergency department [ED] visits) and COPD-related and all-cause costs.. The study population was a historical cohort of Texas Medicaid beneficiaries aged 40 to 64 years with COPD-related medical costs (International Classification of Diseases, Ninth Revision, Clinical Modification codes 491.xx, 492.xx, 496.xx), 24 months of continuous Medicaid enrollment (12 months before and after the index prescription), and at least 1 prescription claim (index) for a combination product containing fluticasone propionate + salmeterol, an inhaled corticosteroid, salmeterol, or ipratropium between April 1, 2001, and March 31, 2003. The analyses of events employed Cox proportional hazards regression, controlling for baseline factors and preindex events. The analyses of costs used a 2-part model with logistic regression and generalized linear model to adjust for baseline characteristics and preindex utilization and costs.. The study population included 6793 patients (1211 combination therapy, 968 inhaled corticosteroid, 401 salmeterol, and 4213 ipratropium). Only combination therapy was associated with a significantly lower risk for any COPD-related event (hazard ratio [HR] = 0.733; 95% CI, 0.650-0.826) and any all-cause event (HR = 0.906; 95% CI, 0.844-0.972) compared with ipratropium. COPD-related prescription costs were higher in all cohorts compared with the ipratropium cohort, but COPD-related medical costs were lower, offsetting the increase in prescription costs. For all-cause costs, prescription costs were higher in the combination-therapy cohort (+$415; P < 0.05) and the salmeterol cohort (+$247; P < 0.05) compared with the ipratropium cohort, but significant reductions in all-cause medical costs in the combination-therapy cohort (-$1735; P < 0.05) and salmeterol cohort (-$1547; P < 0.05) more than offset the increase in prescription costs.. In this historical population of Texas Medicaid beneficiaries, the combination-therapy cohort was 27% less likely to have a COPD-related event than the ipratropium cohort, 10% less likely to have any all-cause event, had similar COPD-related costs, and had reduced all-cause costs. Thus, compared with the ipratropium cohort, the combination-therapy cohort had an improvement in outcomes (based on the decreased time to a hospitalization or ED visit), with similar or decreased direct medical costs. Future research is needed in other patient groups.

Topics: Adrenal Cortex Hormones; Adult; Albuterol; Androstadienes; Bronchodilator Agents; Cohort Studies; Cost-Benefit Analysis; Drug Therapy, Combination; Emergency Service, Hospital; Female; Fluticasone; Hospitalization; Humans; Ipratropium; Male; Medicaid; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Texas; Treatment Outcome

Bronchodilators, including long-acting beta(2)-adrenoceptor agonists and anticholinergic bronchodilators, are effective in the treatment of chronic obstructive pulmonary disease. Evidence suggests that the addition of a long-acting beta(2)-agonist to an inhaled corticosteroid is associated with a reduced rate of exacerbations compared with either treatment alone or placebo. However, it is not known whether a long-acting beta(2)-agonist/inhaled corticosteroid combination is more effective than an anticholinergic bronchodilator alone in reducing exacerbations. The Investigating New Standards for Prophylaxis In Reduction of Exacerbations (INSPIRE) trial will study salmeterol (a long-acting beta(2)-agonist) in combination with fluticasone propionate (an inhaled corticosteroid) compared with tiotropium bromide (an anticholinergic bronchodilator) in patients with moderate-to-severe chronic obstructive pulmonary disease. The INSPIRE study is a multicentre, randomised, double-blind, double dummy, parallel group study conducted over 104 weeks. This is the first study to use two parallel definitions of an exacerbation; an event-based exacerbation is defined as one that requires use of healthcare resources, including additional treatment and hospitalization, whereas a symptom-based exacerbation is defined as one that satisfies the 1987 Anthonisen criteria. It is also the first study to compare the long-term effects of salmeterol/fluticasone propionate with tiotropium bromide on the rate of event-based exacerbations. Endpoints include rate of exacerbations (primary endpoint), time to first exacerbation, and duration of exacerbations. Health outcomes will be assessed via the St George's Respiratory Questionnaire. If the innovative methodology of utilizing 2 definitions of exacerbation proves successful, it will set the benchmark for future studies in chronic obstructive pulmonary disease.

Topics: Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Fluticasone; Humans; Middle Aged; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Research Design; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Fluticasone; Guideline Adherence; Humans; Practice Guidelines as Topic; Prognosis; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Severity of Illness Index; Spirometry

Topics: Adrenal Cortex Hormones; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Early Diagnosis; Fluticasone; Health Education; Humans; Influenza Vaccines; Pneumococcal Vaccines; Pneumonectomy; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Smoking; Spirometry; Surveys and Questionnaires; Survival Analysis; Theophylline; Tiotropium Bromide; Treatment Outcome

The use of inhaled corticosteroids (ICS) is one of the most controversial issues in COPD treatment. There is evidence that ICS with or without long-acting beta-2-adrenergics (LABA) reduce exacerbation rates and improve the health status of severe COPD patients. The effects on FEV1 are limited and their effect on survival is unknown. Recently, a worldwide double-blind placebo-controlled study 'Towards a revolution in COPD health' (TORCH) was published in which salmeterol 50 microg and fluticasone 500 microg twice daily was compared with placebo, salmeterol alone or fluticasone alone. Of the 6112 included patients 875 died within 3 years after the start of treatment. Death rate, defined as the primary outcome parameter, was not significantly reduced (p = 0.052) while exacerbation frequency and health status improved in the combination therapy group. The TORCH trial therefore does not change current guidelines regarding trial treatment with ICS in severe COPD patients.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Treatment Outcome

The toll-like receptors (TLRs) are a key component of host defense in the respiratory epithelium. Cigarette smoking is associated with increased susceptibility to infection, while COPD is characterised by bacterial colonisation and infective exacerbations. We found reduced TLR4 gene expression in the nasal epithelium of smokers compared with non-smoking controls, while TLR2 expression was unchanged. Severe COPD was associated with reduced TLR4 expression compared to less severe disease, with good correlation between nasal and tracheal expression. We went on to examine the effect of potential modulators of TLR4 expression in respiratory epithelium pertinent to airways disease. Using an airway epithelial cell line, we found a dose-dependent downregulation in TLR4 mRNA and protein expression by stimulation with cigarette smoke extracts. Treatment with the corticosteroids fluticasone and dexamethasone resulted in a dose-dependent reduction in TLR4 mRNA and protein. The functional significance of this effect was demonstrated by impaired IL-8 and HBD2 induction in response to LPS. Stimulation with salmeterol (10-6 M) caused upregulation of TLR4 membrane protein presentation with no upregulation of mRNA, suggesting a post-translational effect. The effect of dexamethasone and salmeterol in combination was additive, with downregulation of TLR4 gene expression, and no change in membrane receptor expression. Modulation of TLR4 in respiratory epithelium may have important implications for airway inflammation and infection in response to inhaled pathogens.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Albuterol; Androstadienes; beta-Defensins; Case-Control Studies; Cell Line; Dexamethasone; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluticasone; Gene Expression Regulation; Humans; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Nasal Mucosa; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; RNA, Messenger; Salmeterol Xinafoate; Severity of Illness Index; Smoke; Smoking; Toll-Like Receptor 4

Topics: Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Confounding Factors, Epidemiologic; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Withholding Treatment

The objective of this in-vitro study was to determine whether mixtures of three nebulizable drugs are physicochemically compatible. Drug combinations were prepared by mixing the content of one respule Flutide forte "ready to use" (fluticasone propionate) with 2 milliliter Atrovent LS (ipratropium bromide) and 0.5 milliliter Sultanol inhalation solution (albuterol sulfate). Test suspensions were stored at room temperature and exposed to normal laboratory light for 5 hours. Concentrations of fluticasone- 17-propionate, ipratropium bromide, and albuterol sulfate were determined by using stability-indicating high-performance liquid chromatography assays with ultraviolet detection. Physical compatibility was determined by measuring pH and osmolality. Main outcome measures were the drug concentrations of the active components of the mixtures. All drug concentrations retained nearly 100% of the initial drug concentrations after mixing and storage in glass containers at room temperature. Osmolality and pH of the mixtures exhibited no significant changes and no visible changes of the mixtures were detectable over the inspection period. Mixtures of fluticasone propionate, ipratropium bromide, and albuterol sulfate inhalation drug products were shown to be physicochemically compatible over a period of 5 hrs. In order to avoid contamination and microbiological instability, mixing should only take place immediately before administration. Further investigations are needed to determine whether or not drug delivery is affected by mixing the nebulizer suspensions and to ensure that simultaneous nebulization is recommendable.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Combinations; Drug Incompatibility; Drug Storage; Fluticasone; Germany; Humans; Ipratropium; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Bronchodilator Agents; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive

Pharmacy database medication refill studies provide a panoramic view of medication-taking behavior in patients nationally.. To investigate fluticasone propionate/salmeterol combination (FSC) adherence, including the factors associated with refill adherence in a large national pharmacy database.. Adherence and persistence were documented for 12 months from date of initial FSC prescription in 5504 patients who filled their medication at a nationwide pharmacy chain.. On average, patients filled enough medication to cover 22.2% of days. More than half the patients filled a 30-day prescription only once over the 1-year interval. Higher adherence levels were associated with being male, being older than 35 years, having a comorbid disorder, a having a copay of 1.01 dollar to 10 dollars, previous beta2-agonist use, and a prescription for higher-dose FSC.. This pharmacy database study portrays medication adherence levels to be considerably lower than those reported in most clinical trials, suggests that most adults taking FSC obtain a single fill before abandoning their controller medication, and indicates a need for a reappraisal of current treatment guidelines and educational strategies for both providers and patients.. For many patients, filling of a controller medication is markedly discrepant with practice guidelines. Reappraisal of both the guidelines and strategies to implement them is in order.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Albuterol; Androstadienes; Asthma; Bronchodilator Agents; Child; Child, Preschool; Cohort Studies; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Salmeterol Xinafoate; Sex Factors

Topics: Androstadienes; Anti-Inflammatory Agents; Arteriosclerosis; C-Reactive Protein; Coronary Artery Disease; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Treatment Outcome

Topics: Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Biological Availability; C-Reactive Protein; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

To develop a Markov model that allows the cost effectiveness of interventions in patients with chronic obstructive pulmonary disease (COPD) to be estimated, and to apply the model to investigate the cost effectiveness of an inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist (beta(2)-agonist) combination (salmeterol/fluticasone propionate) versus usual care.. A Markov model consisting of four mutually exclusive disease states was constructed (mild, moderate and severe disease, and death). The transition probabilities of disease progression (for smokers and ex-smokers) and death were derived from the published medical literature. The model outputs were costs, exacerbations, survival, QALYs and cost effectiveness. The model was made fully probabilistic to reflect the joint uncertainty in the model parameters. Efficacy data for the combination of inhaled salmeterol/fluticasone propionate 50/500microg twice daily in poorly reversible COPD patients with a history of exacerbations were obtained from the 1-year TRISTAN (TRial of Inhaled STeroids ANd long-acting beta-agonists) study and applied to the model, based on patient profiles representative of COPD clinical trials.. According to the model, the mean life expectancy with usual care alone (placebo group) was 8.95 years, which decreased to 4.08 QALYs once adjusted for quality and discounted, at a lifetime discounted cost of Can 16,415 dollars per patient (year 2002 values). Assuming that salmeterol/fluticasone propionate reduced exacerbation frequency only (base case analysis), the estimated mean survival time remained unchanged but there was an increase in the number of QALYs (4.21) for an estimated lifetime cost of Can 25,780 dollars, resulting in a cost-effectiveness ratio of Can 74,887 dollars per QALY (95% CI 21,985, 128,671) versus usual care. If a survival benefit was assumed for salmeterol/fluticasone propionate, the incremental cost per QALY was Can11,125 dollars (95% CI 8710, dominated) versus usual care. If the combination achieved around a 10% improvement in forced expiratory volume in 1 second, leading to delayed progression to more severe disease states, the benefits translated into an incremental cost per QALY of Can 49,928 dollars (95% CI 37 269, 66,006) versus usual care.. This Markov model allows, for the first time, a means of estimating the long-term cost effectiveness and cost utility of interventions for COPD. Initial evidence suggests that for patients with poorly reversible COPD and a documented history of frequent COPD exacerbations, the addition of salmeterol (a long-acting beta(2)-agonist) to fluticasone propionate (an inhaled corticosteroid) is potentially cost effective from the Canadian healthcare payer's perspective. However, the precision of this estimate will be improved when additional data are available from clinical trials such as the ongoing TORCH (TOwards a Revolution in COPD Health) study.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Drug Combinations; Fluticasone; Humans; Markov Chains; Models, Economic; Prognosis; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Survival Analysis

The aim of this study was to investigate the effects of long-term inhaled corticosteroids on bone mineral density (BMD) of the mandible in relation with the tooth loss.. Cross sectional analytic study.. Patients (n = 30) with chronic obstructive pulmonary disease under inhaled corticosteroid therapy for at least 1 year were compared with sex- and age-matched healthy controls (n = 30). BMD of the mandible was measured by dual-energy X-ray absorptiometry. The clinical examination included recording the number of teeth present together with periodontal condition. Levels of serum osteocalcin, alkaline phosphatase, calcium, phosphorus and cortisol were also assessed.. BMD of the mandible in patients on corticosteroid treatment was significantly lower than that in the control group (P = 0.001). Patients under treatment had more missing teeth than the control group but the difference did not reach statistical significance. The two groups exhibited similar clinical parameters of periodontal condition. Significantly lower levels of osteocalcin (P < 0.0001), calcium (P = 0.004) and cortisol (P = 0.03) were observed in the patients on corticosteroid treatment.. Long-term use of inhaled corticosteroids may impair bone metabolism and lead to a marked decrease in the mandibular BMD.

Topics: Absorptiometry, Photon; Administration, Inhalation; Adrenal Cortex Hormones; Aged; Alveolar Bone Loss; Androstadienes; Anti-Inflammatory Agents; Bone Density; Budesonide; Calcium; Case-Control Studies; Cross-Sectional Studies; Female; Fluticasone; Humans; Hydrocortisone; Male; Mandible; Middle Aged; Osteocalcin; Periodontal Index; Pulmonary Disease, Chronic Obstructive; Statistics, Nonparametric; Tooth Loss

Topics: Administration, Inhalation; Androstadienes; Clinical Trials as Topic; Female; Fluticasone; Humans; Male; Patient Selection; Pulmonary Disease, Chronic Obstructive; Risk Factors; Sensitivity and Specificity; Treatment Outcome; Treatment Refusal

Topics: Albuterol; Androstadienes; Asthma; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

A review of graphical and test based methods for evaluating assumptions underlying the use of least squares analysis with the general linear model is presented along with some discussion of robustness. Alternative analyses are described for situations where there is evidence that the assumptions are not reasonable. Evaluation of the assumptions is illustrated through the use of an example from a clinical trial used for US registration purposes. It is recommended that: (1) most assumptions required for the least squares analysis of data using the general linear model can be judged using residuals graphically without the need for formal testing, (2) it is more important to normalize data or to use nonparametric methods when there is heterogeneous variance between treatment groups, and (3) nonparametric analyses can be used to demonstrate robustness of results and that it is best to specify these analyses prior to unblinding.

Topics: Aging; Albuterol; Androstadienes; Bronchodilator Agents; Data Interpretation, Statistical; Drug Industry; Fluticasone; Forced Expiratory Volume; Humans; Least-Squares Analysis; Linear Models; Pulmonary Disease, Chronic Obstructive; Research Design; Salmeterol Xinafoate; United States

Chronic obstructive pulmonary disease (COPD) has multiple pathophysiologic effects that are not confined to the lungs. Similarly, treatment for COPD may have a number of different beneficial effects, and although each of these may be small, their cumulative effect may add up to a worthwhile overall outcome. Many of the effects of COPD are only weakly related to FEV(1), and there is good evidence that health status questionnaires are the best overall measures of disease severity. Recently it has been shown, using such instruments, that health status in patients with COPD deteriorates progressively and at a measurable rate. Fluticasone reduces that decline, an effect that may take months to be detectable but continues to develop over 3 years. The effect of fluticasone on health appears to be due to a reduction in exacerbations coupled with its small effect on FEV(1).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Dose-Response Relationship, Drug; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Prognosis; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Respiratory Function Tests; Risk Assessment; Secondary Prevention; Severity of Illness Index; Sickness Impact Profile; Treatment Outcome

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

Topics: Administration, Inhalation; Albuterol; Androstadienes; Cause of Death; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Risk Assessment; Salmeterol Xinafoate; Severity of Illness Index; Survival Analysis

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Drug Therapy, Combination; Endpoint Determination; Fluticasone; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Fluticasone; Humans; Patient Dropouts; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Reproducibility of Results; Salmeterol Xinafoate

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Theophylline; Vital Capacity

Topics: Adenosine Monophosphate; Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Diagnosis, Differential; Dose-Response Relationship, Drug; Fluticasone; Humans; Kinetics; Pulmonary Disease, Chronic Obstructive; Research

Topics: Administration, Inhalation; Administration, Oral; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Placebos; Pulmonary Disease, Chronic Obstructive; Radiography, Thoracic; Salmeterol Xinafoate; Time Factors

To evaluate the levels of hydrogen peroxide (H(2)O(2)) and 8-isoprostane in the expired breath condensate (EBC) of patients with COPD, and to assess the relationship between the above markers of oxidative stress and parameters expressing inflammatory process and disease severity.. Inpatient respiratory unit and outpatient clinic in tertiary care hospital.. Cross-sectional study.. Thirty stable COPD patients (all smokers) with disease severity ranging from mild to severe. Ten subjects who were smokers with stage 0 disease (ie, at risk for COPD; mean [+/- SD] FEV(1), 88 +/- 5% predicted) were studied as a control group.. H(2)O(2) and 8-isoprostane levels were measured in EBC, and the values were correlated with variables expressing COPD severity (ie, FEV(1) percent predicted, dyspnea severity score (ie, Medical Research Council scale) and airway inflammation (ie, differential cell counts from induced sputum).. The mean concentration of H(2)O(2) was significantly elevated in COPD patients compared to control subjects (mean, 0.66 micromol/L [95% confidence interval (CI), 0.54 to 0.68 micro mol/L) vs 0.31 micro mol/L [95% CI, 0.26 to 0.35 micromol/L], respectively; p < 0.0001). The difference was primarily due to the elevation of H(2)O(2) in patients with severe and moderate COPD, whose expired breath H(2)O(2) levels were significantly higher than those of patients with mild disease (mean, 0.96 micromol/L [95% CI, 0.79 to 1.13 micromol/L], 0.68 micromol/L [95% CI, 0.55 to 0.81 micromol/L], and 0.33 micromol/L [95% CI, 0.24 to 0.43 micromol/L], respectively, p < 0.0001). The mean concentration of 8-isoprostane was significantly elevated in patients with COPD compared to that of the control group (47 pg/mL [95% CI, 41 to 53 pg/mL] vs 29 pg/mL [95% CI, 25 to 33 pg/mL], respectively; p < 0.0001) but did not differ significantly among the different stages of the disease (p = 0.43). Repeatability and stability data within measurements showed that H(2)O(2) has a better repeatability and stability than 8-isoprostane. Furthermore, we observed significant correlations of H(2)O(2) with FEV(1), neutrophil count, and dyspnea score. Those correlations existed only in patients with moderate and severe disease. No correlations were found between levels of 8-isoprostane and the above parameters.. We conclude that levels of H(2)O(2) and 8-isoprostane are elevated in the EBC of patients with COPD, but that H(2)O(2) seems to be a more repeatable and a more sensitive index of the inflammatory process and the severity of the disease.

Topics: Adult; Aged; Androstadienes; Anti-Inflammatory Agents; Breath Tests; Bronchodilator Agents; Exhalation; Fluticasone; Humans; Male; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Theophylline

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Clinical Trials as Topic; Drug Combinations; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Placebos; Pulmonary Disease, Chronic Obstructive; Respiratory Therapy; Retrospective Studies; Salmeterol Xinafoate; Time Factors

To compare the impact of fluticasone propionate versus three leukotriene modifiers-montelukast, zafirlukast, and zileuton-on the cost of asthma within a managed care organization.. Retrospective quasi-experimental comparison.. Managed care organization with approximately 350,000 enrollees.. Three hundred forty-seven patients with asthma who received at least two prescriptions for either fluticasone or a leukotriene modifier. Patients receiving both fluticasone and a leukotriene modifier were excluded.. Multivariate analysis was used to compare total asthma-related costs between treatment groups. A significant difference in total asthma-related costs was found between patients receiving fluticasone (adjusted mean cost $511) compared with those receiving a leukotriene modifier ($1,092; p=0.0001). Other significant predictors of postindex asthma-related costs were pre-index asthma-related costs, a severity adjustment score, and the diagnosis of chronic obstructive pulmonary disease. Patients taking a leukotriene modifier obtained more short-acting beta-agonists than patients receiving fluticasone (6.49 +/- 4.05 vs 4.30 +/- 3.41, p < 0.0001). A survival analysis of time to receive any additional controller therapy revealed that patients receiving fluticasone were significantly less likely to receive another controller than were those receiving a leukotriene modifier (p=0.0014).. These results suggest that fluticasone is associated with lower asthma-related costs than leukotriene modifiers.

Topics: Adult; Algorithms; Analysis of Variance; Androstadienes; Anti-Asthmatic Agents; Arizona; Asthma; Cost of Illness; Female; Fluticasone; Humans; Leukotriene Antagonists; Linear Models; Male; Managed Care Programs; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Survival Analysis

Topics: Albuterol; Androstadienes; Clinical Trials as Topic; Drug Combinations; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Female; Fluticasone; Humans; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Severity of Illness Index; Survival Rate; Treatment Outcome; United Kingdom; World Health Organization

Despite substantial evidence regarding the benefits of combined use of inhaled corticosteroids and long-acting beta2-agonists in asthma, such evidence remains limited for chronic obstructive pulmonary disease (COPD). Observational data may provide an insight into the expected survival in clinical trials of fluticasone propionate (FP) and salmeterol in COPD. Newly physician-diagnosed COPD patients identified in primary care during 1990-1999 aged > or = 50 yrs, of both sexes and with regular prescriptions of respiratory drugs were identified in the UK General Practice Research Database. Three-year survival in 1,045 COPD patients treated with FP and salmeterol was compared with that in 3,620 COPD patients who regularly used other bronchodilators but not inhaled corticosteroids or long-acting beta2-agonists. Standard methods of survival analysis were used, including adjustment for possible confounders. Survival at year 3 was significantly greater in FP and/or salmeterol users (78.6%) than in the reference group (63.6%). After adjusting for confounders, the survival advantage observed was highest in combined users of FP and salmeterol (hazard ratio (HR) 0.48 (95% confidence interval 0.31-0.73)), followed by users of FP alone (HR 0.62 (0.45-0.85)) and regular users of salmeterol alone (HR 0.79 (0.58-1.07)) versus the reference group. Mortality decreased with increasing number of prescriptions of FP and/or salmeterol. In conclusion, regular use of fluticasone propionate alone or in combination with salmeterol is associated with increased survival of chronic obstructive pulmonary disease patients managed in primary care.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Case-Control Studies; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Family Practice; Female; Fluticasone; Humans; Male; Middle Aged; Probability; Prognosis; Pulmonary Disease, Chronic Obstructive; Reference Values; Respiratory Function Tests; Retrospective Studies; Salmeterol Xinafoate; Survival Analysis; Treatment Outcome; United Kingdom

Topics: Administration, Inhalation; Administration, Topical; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Hospitalization; Humans; Placebos; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Time Factors

Topics: Administration, Topical; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Asthma; Awards and Prizes; Bronchodilator Agents; Clinical Trials as Topic; Drug Combinations; Fluticasone; Germany; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

Efficient inhalation therapy depends on successful delivery of the drug to the lung. The efficacy of drug delivery is not only influenced by the characteristics of the inhalation device, but also by the patient's handling of the device and by the inspiratory maneuver achieved through the device. We analyzed the output characteristics of three different chlorofluorocarbon (CFC)-free breath-actuated inhalers for inhaled glucocorticosteroids (BUD Turbohaler, FP Diskus/Accuhaler and HFA-BDP Autohaler, respectively). Mass output and particle size distribution of drug aerosol delivered by the inhalers were determined depending on different inhalation parameters in vitro using an Andersen cascade impactor. We found that, beside the peak inspiratory flow (PIF), other factors such as flow acceleration and inhalation volume also have significant effects on aerosol generation with respect to mass output and particle size distribution. Thus, these parameters should be taken into account when a suitable device for an individual patient is to be selected. The dependency on inspiratory parameters was most pronounced for the dry powder inhalers. The Turbohaler showed by far the highest variance in particle output (fine particle fraction ranging from 3.4% to 22.1% of label claim), whereas the Diskus was less dependent on variations in inhalation (10.6% to 18.5% of label claim). The most constant aerosol output was found for the Autohaler, which also released the highest fine particle fraction (43.1% to 56.6% of label claim).

Topics: Administration, Inhalation; Adult; Aerosols; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Child; Fluticasone; Humans; Inhalation; Lung; Nebulizers and Vaporizers; Particle Size; Pulmonary Disease, Chronic Obstructive; Respiratory Mechanics

Topics: Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome