pulmicort and Pulmonary-Disease--Chronic-Obstructive

Inhaled corticosteroids (ICSs) have been used widely in the maintenance therapy of COPD. However, whether inhaled therapy containing ICSs can reduce the all-cause mortality risk and the possible benefited patient subgroups is unclear.. Does inhaled therapy containing ICSs reduce the all-cause mortality risk in patients with COPD compared with other inhaled therapies not containing ICSs?. We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for relevant randomized clinical trials (RCTs). Pooled results were calculated using Peto ORs with corresponding 95% CIs.. Inhaled therapy containing ICSs, especially triple therapy, of longer than 6 months was associated with a reduction in the all-cause mortality risk in patients with COPD. The predictors of this association included medication factors and patient characteristics, among which eosinophil counts of ≥ 200/μL were the strongest predictor.. PROSPERO; No.: CRD42022304725; URL: https://www.crd.york.ac.uk/prospero/.

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

The fracture risk of patients with chronic obstructive pulmonary disease (COPD) treated with inhaled corticosteroids is controversial. And some large-scale randomized controlled trials have not solved this problem. The purpose of our systematic review and meta-analysis including 44 RCTs is to reveal the effect of inhaled corticosteroids on the fracture risk of COPD patients.. Two reviewers independently retrieved randomized controlled trials of inhaled corticosteroids or combinations of inhaled corticosteroids in the treatment of COPD from PubMed, Embase, Medline, Cochrane Library, and Web of Science. The primary outcome was a fracture event. This study was registered at PROSPERO (CRD42022366778).. Forty-four RCTs were performed in 87,594 patients. Inhaled therapy containing ICSs (RR, 1.19; 95%CI, 1.04-1.37; P = 0.010), especially ICS/LABA (RR, 1.30; 95%CI, 1.10-1.53; P = 0.002) and triple therapy (RR, 1.49; 95%CI, 1.03-2.17; P = 0.04) were significantly associated with the increased risk of fracture in COPD patients when compared with inhaled therapy without ICSs. Subgroup analyses showed that treatment duration ≥ 12 months (RR, 1.19; 95%CI, 1.04-1.38; P = 0.01), budesonide therapy (RR, 1.64; 95%CI., 1.07-2.51; P = 0.02), fluticasone furoate therapy (RR, 1.37; 95%CI, 1.05-1.78; P = 0.02), mean age of study participants ≥ 65 (RR, 1.27; 95%CI, 1.01-1.61; P = 0.04), and GOLD stage III(RR, 1.18; 95%CI, 1.00-1.38; P = 0.04) were significantly associated with an increased risk of fracture. In addition, budesonide ≥ 320 ug bid via MDI (RR, 1.75; 95%CI, 1.07-2.87; P = 0.03) was significantly associated with the increased risk of fracture.. Inhalation therapy with ICSs, especially ICS/LABA or triple therapy, increased the risk of fracture in patients with COPD compared with inhaled therapy without ICS. Treatment duration, mean age of participants, GOLD stage, drug dosage form, and drug dose participated in this association. Moreover, different inhalation devices of the same drug also had differences in risk of fracture.

Topics: Adrenal Cortex Hormones; Budesonide; Duration of Therapy; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease with considerable clinical and socioeconomic impact. Budesonide/glycopyrrolate/formoterol fumarate (BGF) is a newly approved pharmacotherapy for COPD in China that has been shown to improve lung function and reduce the risk of exacerbations, but the cost-effectiveness of BGF remains unknown. The objective of this study was to evaluate the cost-effectiveness of BGF in patients with moderate to very severe COPD from a Chinese healthcare system perspective.. A semi-Markov model was developed to compare the costs and benefit of treatment with BGF versus a composite comparator of long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) therapies. Clinical inputs for BGF and the composite comparator were based on the KRONOS study (NCT02497001) and a network meta-analysis. Cost inputs were derived from published literature and Chinese government documents, supplemented by expert opinion where necessary. Health-related quality-of-life inputs were also obtained based on the KRONOS study. Lifetime costs, number of exacerbations, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. Costs were measured in 2020 Chinese Yuan (CN¥) and converted into US dollars (US$). Scenario analyses and sensitivity analyses were conducted.. Over the lifetime horizon, BGF treatment led to fewer moderate and severe exacerbations (4.01 and 0.87, respectively) versus the composite comparator (8.42 and 2.04, respectively), with a base-case ICER of CN¥13,685.94 (US$1983.47) per QALY gained. Scenario analyses considering different population and utilities resulted in ICERs ranging from dominant to CN¥13,673.91 (US$1981.73). Extensive sensitivity analyses indicated robust base-case results since all analyses yielded ICERs below the conservative cost-effectiveness threshold of one times the Chinese per capita gross domestic product (CN¥72,447.00 [US$10,499.57], 2020).. Triple therapy with BGF was predicted to improve outcomes and be a cost-effective treatment option compared with LAMA/LABA therapies for patients with moderate to very severe COPD in China.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Clinical Studies as Topic; Cost-Benefit Analysis; Drug Combinations; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is a major and difficult disease of the chronic respiratory system that is common and frequent, with a huge disease burden. The aim of this study was to investigate the efficacy and safety of budesonide/glyburide/formoterol fumarate (BGF) in the treatment of COPD.. A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The basic features of the seven pieces of literature were identified using the search strategy. The sample size range was 130∼1264.. The effects of BGF increased FEV1 in patients with COPD (mean difference = 2.86, 95%CI: 2.71-3.01,. This study elucidates the efficacy and safety of BGF in the treatment of COPD with a view to providing a clinical reference.

Topics: Aged; Bronchodilator Agents; Budesonide; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive

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

To review current evidence on the use of a fixed-dose combination (FDC) of budesonide/glycopyrrolate/formoterol fumarate (BGFF) triple therapy delivered via metered dose inhaler (MDI) in patients with chronic obstructive pulmonary disease (COPD) and offer clinical practice insights.. We used PubMed to conduct the literature search from 1946 through June 30, 2021, using budesonide, glycopyrrolate or glycopyrronium, and formoterol.. We included clinical trials in patients with COPD along with pharmacokinetic or pharmacodynamic studies.. In all, 19 citations were included. BGFF MDI reduces the risk of exacerbations regardless of exacerbation history compared with dual bronchodilators or inhaled corticosteroid/long-acting β-agonist. Rescue inhaler use decreased, and patient-reported outcomes of symptoms and well-being improved with triple therapy. Mortality was decreased with the higher-dose BGFF MDI in comparison to dual bronchodilator therapy. Dysphonia and candidiasis were more common with BGFF MDI compared with dual bronchodilators, as was pneumonia.. BGFF MDI is the second FDC triple therapy approved for COPD treatment. BGFF MDI improves important patient outcomes in COPD, including exacerbation risk. The unique co-suspension technology allows delivery of 3 active ingredients in 1 inhaler, a potential benefit to overcome adherence and technique-related barriers. These benefits must be gently weighed against the increased risk of pneumonia.. The findings from phase 3 trials support the efficacy and safety of triple therapy in COPD. Future studies are needed to confirm potential mortality benefit and the role of triple therapy in patients without an exacerbation history.

Topics: Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bayes Theorem; Bronchodilator Agents; Budesonide; Drug Combinations; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quality of Life

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Budesonide; Drug Combinations; Formoterol Fumarate; Glucocorticoids; Glycopyrrolate; Humans; Metered Dose Inhalers; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive

To systematically observe the curative efficacy and safety of budesonide inhalation in the treatment of acute exacerbation of chronic obstructive pulmonary disease, and to find a suitable dose of aerosolized budesonide for Chinese patients.. The meta-analysis study was conducted at Wenjiang District People's Hospital, Chengdu City, Sichuan Province, China from May 2019 to August 2019 and comprised randomised controlled trials of glucocorticoids for acute exacerbation of chronic obstructive pulmonary disease on the databases of the China National Knowledge Infrastructure, Wanfang Medical Network, PubMed, Medline, Embase, Cochrane Library and Google Scholar. Data extraction and quality evaluation of the studies was done and meta-analysis was then performed using RevMan 5.3.. There were 25 studies identified that comprised 1959 patients. When the budesonide dose was 6mg/d and the methylprednisolone dose was 40mg/d, no significant difference was found in partial pressure of carbon dioxide and oxygen post-treatment (p>0.05). When the nebulized budesonide dose was <6mg/d, methylprednisolone was more effective than budesonide (p<0.05), while >6mg/d was not significantly more effective (p>0.05). At 4mg/d, the difference in the dyspnoea score post-treatment was significant (p<0.05). No significant difference was found in dyspnoea scores after intravenous glucocorticoid treatment when the dose was greater than or equal to 4mg/d. In terms of adverse reactions, the response rate of blood glucose, blood pressure, excitement, insomnia and stomach discomfort in the intravenous group was higher than that in the nebulised group (p<0.05). Oropharyngeal discomfort in the nebulized group was higher than that the intravenous group (p<0.05).. The optimal dose for the inhalation of budesonide in Chinese patients was between 4mg/d and 6mg/d. The adverse reactions of nebulised budesonide were lower than those of intravenous methylprednisolone.

Topics: Budesonide; China; Glucocorticoids; Humans; Methylprednisolone; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Dry Powder Inhalers; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive

A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV. Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario.. This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bayes Theorem; Bronchodilator Agents; Budesonide; Drug Combinations; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Agonists; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Treatment Outcome

Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Electronic Nicotine Delivery Systems; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Tropanes

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

BACKGROUND The 2018 Global Initiative for Chronic Obstructive Lung Disease publication suggested that the combination of bronchodilator therapy of inhaled glucocorticoid/long-acting β₂ adrenoceptor agonist is more effective in improving pulmonary function and health status in the treatment of patients with acute exacerbations than the individual components; however, it is not known whether this also the case for stable chronic obstructive pulmonary disease (COPD). The purpose of this meta-analysis was to evaluate the effectiveness of budesonide/formoterol in the maintenance and relief therapy of patients with stable COPD. MATERIAL AND METHODS An electronic search of the literature in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials was undertaken to identify published randomized controlled trials (RCTs) of ≥12 weeks duration comparing the budesonide/formoterol, with budesonide, formoterol, or placebo in the treatment of patients with stable COPD. The identified RCTs were reviewed. The mean difference (MD) with corresponding 95% confidence interval (CI) was used to pool the results. RESULTS Seven high quality studies with RCTs met the inclusion criteria for meta-analysis. Compared with budesonide alone, the combination therapy of budesonide/formoterol showed significant improvement in the following spirometric indices: pre-dose forced expiratory volume in 1 second (FEV₁) (SMD: 0.26, 95% CI: 0.18, 0.34; P=0.000). In addition, versus formoterol alone, budesonide/formoterol was associated with a significant increase in pre-dose FEV₁ (SMD: 0.12, 95% CI: 0.07, 0.17; P=0.000). A similar pattern was also evident in the comparison to placebo, where budesonide/formoterol yielded greater increase in pre-dose FEV₁ (SMD: 0.24, 95% CI: 0.18, 0.30; P=0.000). Moreover, compared with other controls, the combination of budesonide-formoterol significantly improved morning peak expiratory flow and evening peak expiratory flow, significantly reduced the total score of St. George's Respiratory Questionnaire. CONCLUSIONS For stable COPD patients, compared with controls (monocomponents or placebo), budesonide/formoterol improved pulmonary function and health status. Future larger long-term RCTs are warranted to assess the beneficial clinical efficacy of budesonide/formoterol in COPD patients.

Topics: Aged; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests

COPD guidelines report that systemic corticosteroids are preferred over inhaled corticosteroids in the treatment of exacerbations, but the inhaled route is considered to be an option.. To conduct a systematic review and meta-analysis regarding the efficacy and safety of inhaled corticosteroids for COPD exacerbations. The second objective was to provide pharmacologic and clinical perspectives of inhaled corticosteroids for COPD exacerbations.. The primary outcome was a change in FEV. Each of the 9 studies included in the meta-analysis was conducted in subjects who were hospitalized and not critically ill. Our meta-analysis indicated that high-dose nebulized budesonide 4-8 mg/d was noninferior to systemic corticosteroids on the change in FEV. Based on our meta-analysis with a change in FEV

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Bronchodilator Agents; Budesonide; Carbon Dioxide; Disease Progression; Forced Expiratory Volume; Humans; Hyperglycemia; Nebulizers and Vaporizers; Oxygen; Partial Pressure; Pulmonary Disease, Chronic Obstructive

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

There is a considerable amount of evidence that supports the possibility of an increased risk of pneumonia associated with prolonged use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD). However, as yet, no statistically significant increase in pneumonia-related 30-day mortality in patients on ICS has been demonstrated. The lack of objective pneumonia definitions and radiological confirmations have been a major source of bias, because of the similarities in clinical presentation between pneumonia and acute exacerbations of COPD. One of the newer fluticasone furoate studies overcomes these limitations and also provides an assessment of a range of doses, suggesting that the therapeutic window is quite narrow and that conventional dosing has probably been too high, although the absolute risk may be different compared to other drugs. Newer studies were not able to rule out budesonide as responsible for pneumonia, as previous evidence suggested, and there is still need for evidence from head-to-head comparisons in order to better assess possible intra-class differences. Although the exact mechanisms by which ICS increase the risk of pneumonia are not fully understood, the immunosuppressive effects of ICS on the respiratory epithelium and the disruption of the lung microbiome are most likely to be implicated. Given that COPD represents such a complex and heterogeneous disease, attempts are being made to identify clinical phenotypes with clear therapeutic implications, in order to optimize the pharmacological treatment of COPD and avoid the indiscriminate use of ICS. If deemed necessary, gradual withdrawal of ICS appears to be well tolerated. Vaccination against pneumococcus and influenza should be emphasized in patients with COPD receiving ICS. Physicians should keep in mind that signs and symptoms of pneumonia in COPD patients may be initially indistinguishable from those of an exacerbation, and that patients with COPD appear to be at increased risk of developing pneumonia as a complication of ICS therapy.

Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Budesonide; Formoterol Fumarate; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Increasing evidence suggests pharmacological treatments may impact on overall survival in Chronic Obstructive Pulmonary Disease (COPD) patients. Individual clinical trials are rarely powered to detect mortality differences between treatments and may not include all treatment options relevant to healthcare decision makers.. A systematic review was conducted to identify RCTs of COPD treatments reporting mortality; evidence was synthesised using network meta-analysis (NMA). The analysis included 40 RCTs; a quantitative indirect comparison between 14 treatments using data from 55,220 patients was conducted.. The analysis reported two treatments reducing all-cause mortality; salmeterol/fluticasone propionate combination (SFC) was associated with a reduction in mortality versus placebo in the fixed effects (HR 0.79; 95 % Crl 0.67, 0.94) but not the random effects model (0.79; 0.56, 1.09). Indacaterol was associated with a reduction in mortality versus placebo in fixed (0.28; 0.08 to 0.85) and random effects (0.29; 0.08, 0.89) models. Mean estimates and credible intervals for hazard ratios for indacaterol versus placebo are based on a small number of events; estimates may change when the results of future studies are included. These results were maintained across a variety of assumptions and provide evidence that SFC and indacaterol may lead to improved survival in COPD patients.. Results of an NMA of COPD treatments suggest that SFC and indacaterol may reduce mortality. Further research is warranted to strengthen this conclusion.

Topics: Albuterol; Aminopyridines; Beclomethasone; Benzamides; Benzyl Alcohols; Bronchodilator Agents; Budesonide; Chlorobenzenes; Cyclopropanes; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Glucocorticoids; Humans; Indans; Ipratropium; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quinolones; Survival Rate; Theophylline; Tiotropium Bromide; Triamcinolone

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

The inhaled route is considered to be the best route to administer drugs for treating respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), for both safety and efficacy. Inhalation devices are classified into four types - pressuriszed metered dose inhalers (pMDIs), dry powder inhalers, breath actuated inhalers and nebulizers. pMDIs are portable, convenient, multi-dose devices and these advantages have made them very popular with patients. They were introduced in the 1950s as the first portable, multi-dose delivery system for bronchodilators. Even though pMDIs are the most widely used devices for inhalation therapy in asthma and COPD, studies establishing their use and providing clinical data with bronchodilators and combination therapies in patients with COPD are limited. A summary of the use of pMDI with spacers in patients with COPD in terms of lung deposition and impact on lung function are presented in this review article. A review of use of the pMDI device in patients with COPD with different available and prescribed medications (bronchodilators-β2-agonists and anticholinergics, and their combination with inhaled corticosteroids) is discussed.

Topics: Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Equipment Design; Ethanolamines; Formoterol Fumarate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F).. To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD).. We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers.. Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component.. Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs.. A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials.. Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Steroids

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous, progressive inflammatory disease that imposes considerable economic and healthcare burdens on society, with the disease predicted to remain a leading cause of morbidity and mortality worldwide in the future. Current pharmacological treatment can improve symptoms of the disease, but not progression. Global Initiative for Chronic Obstructive Lung Disease guidelines recommend that patients with moderate COPD should use one or more long-acting bronchodilators (e.g. a long-acting β(2)-agonist) as required and, for those with severe and very severe disease who are experiencing repeated COPD exacerbations, an inhaled corticosteroid should be added as required. Budesonide/formoterol Turbuhaler® (Symbicort® Turbuhaler®) is a dry powder inhaler (DPI) that combines these two classes of drugs in a single inhaler, thereby making administration easier and more convenient. Budesonide/formoterol Turbuhaler® (delivered dose 320 μg/9 μg) is recommended for the symptomatic treatment of adult patients with severe COPD (forced expiratory volume in 1 second <50% of predicted value) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators. This article reviews the pharmacological properties and clinical use of budesonide/formoterol Turbuhaler® in adult patients with moderate to severe COPD. Budesonide/formoterol Turbuhaler® (320 μg/9 μg twice daily) was effective and well tolerated in adult patients with moderate to severe COPD participating in large, multicentre trials of up to 12 months' duration. Budesonide/formoterol Turbuhaler® improved lung function, exacerbation rates, COPD symptom scores and health status from baseline to a significantly greater extent than placebo and, in general, than the individual monotherapies in these trials. Moreover, as reflected in the faster onset of action of formoterol than salmeterol, budesonide/formoterol Turbuhaler® was more effective than salmeterol/fluticasone propionate DPI at improving the patient's ability to perform morning activities in a short-term study. In the 12-week CLIMB trial, adding budesonide/formoterol Turbuhaler® to inhaled tiotropium bromide therapy was significantly more effective than adding placebo to tiotropium bromide therapy. Thus, inhaled budesonide/formoterol, either alone or as add-on therapy to other medications, continues to be a useful option for the management of COP

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Forced Expiratory Volume; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index

The purpose of this study was to update our network meta-analysis in order to compare the efficacy of indacaterol 75 μg with that of a fixed-dose combination of formoterol and budesonide (FOR/BUD) and a fixed-dose combination salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on evidence identified previously in addition to two new randomized clinical trials.. Fifteen randomized, placebo-controlled clinical trials including COPD patients were evaluated: indacaterol 75 μg once daily (n = 2 studies), indacaterol 150 μg once daily (n = 5), indacaterol 300 μg once daily (n = 4), FOR/BUD 9/160 μg twice daily (n = 2), FOR/BUD 9/320 μg twice daily (n = 2), SAL/FP 50/500 μg twice daily (n = 4), and SAL/FP 50/250 μg twice daily (n = 1). All trials were analyzed simultaneously using a Bayesian network meta-analysis and relative treatment effects between all regimens were obtained. Treatment-by-covariate interactions were included where possible to improve the similarity of the trials. Outcomes of interest were trough forced expiratory volume in 1 second (FEV(1)) and transitional dyspnea index at 12 weeks.. Based on the results without adjustment for covariates, indacaterol 75 μg resulted in a greater improvement in FEV(1) at 12 weeks compared with FOR/BUD 9/160 μg (difference in change from baseline 0.09 L [95% credible interval 0.04-0.13]) and FOR/BUD 9/320 μg (0.07 L [0.03-0.11]) and was comparable with SAL/FP 50/250 μg (0.00 L [-0.07-0.07]) and SAL/FP 50/500 μg (0.01 L [-0.04-0.05]). For transitional dyspnea index, data was available only for indacaterol 75 μg versus SAL/FP 50/500 μg (-0.49 points [-1.87-0.89]).. Based on results of a network meta-analysis with and without covariates, indacaterol 75 μg is expected to be at least as efficacious as FOR/BUD (9/320 μg and 9/160 μg) and comparable with SAL/FP (50/250 μg and 50/500 μg) in terms of lung function. In terms of breathlessness (transitional dyspnea index) at 12 weeks, the results are inconclusive given the limited data.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Drug Therapy, Combination; Dyspnea; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Indans; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic

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

Treatment with inhaled steroids is related to pneumonia and acute respiratory infection. The aim of this review is to quantify the effect inhaled steroids in pneumonia in stable chronic obstructive pulmonary disease (COPD) patients.. We performed a systematic review of the systematic reviews that have studied inhaled corticosteroids in stable COPD patients.. Inhaled steroid therapy in patients with clinically stable COPD causes an increase in the number of pneumonia. The NNTH of the analysed systematic reviews ranged from 12 subjects exposed to more than three years, to 80 subjects with one year follow up. Budesonide did not show this side effect.. It would be advisable to inform patients about the risk/benefit of these therapies.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Budesonide; Disease Susceptibility; Drug Combinations; Evidence-Based Medicine; Humans; Immunosuppression Therapy; Meta-Analysis as Topic; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk

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

To compare efficacy of indacaterol to that of fixed-dose combination (FDC) formoterol and budesonide (FOR/BUD) and FDC salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on the available randomized clinical trials (RCTs).. Fifteen placebo-controlled RCTs were included that evaluated: indacaterol 150 μg (n = 5 studies), indacaterol 300 μg (n = 4), FOR/BUD 9/160 μg (n = 2), FOR/BUD 9/320 μg (n = 3), SAL/FP 50/500 μg (n = 5), and SAL/FP 50/250 μg (n = 1). Outcomes of interest were trough forced expiratory volume in 1 second (FEV(1)), total scores for St. George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI). All trials were analyzed simultaneously using a Bayesian network meta-analysis and relative treatment effects between all regimens were obtained. Treatment-by-covariate interactions were included where possible to improve the similarity of the trials.. Indacaterol 150 μg resulted in a higher change from baseline (CFB) in FEV(1) at 12 weeks compared to FOR/BUD 9/160 μg (difference in CFB 0.11 L [95% credible intervals: 0.08, 0.13]) and FOR/BUD 9/320 μg (0.09 L [0.06, 0.11]) and was comparable to SAL/FP 50/250 μg (0.02 L [-0.04, 0.08]) and SAL/FP 50/500 μg (0.03 L [0.00, 0.06]). Similar results were observed for indacaterol 300 μg at 12 weeks and indacaterol 150/300 μg at 6 months. Indacaterol 150 μg demonstrated comparable improvement in SGRQ total score at 6 months versus FOR/BUD (both doses), and SAL/FP 50/500 μg (-2.16 point improvement [-4.96, 0.95]). Indacaterol 150 and 300 μg demonstrated comparable TDI scores versus SAL/FP 50/250 μg (0.21 points (-0.57, 0.99); 0.39 [-0.39, 1.17], respectively) and SAL/FP 50/500 μg at 6 months.. Indacaterol monotherapy is expected to be at least as good as FOR/BUD (9/320 and 9/160 μg) and comparable to SAL/FP (50/250 and 50/500 μg) in terms of lung function. Indacaterol is also expected to be comparable to FOR/BUD (9/320 and 9/160 μg) and SAL/FP 50/500 μg in terms of health status and to SAL/FP (50/250 and 50/500 μg) in terms of breathlessness.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Treatment Outcome

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

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

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

Two large, 12-month clinical trials have been performed with budesonide-formoterol in patients with stable COPD and have shown clear data on the efficacy of this combination in improving pulmonary function, symptoms and health-related quality of life and in reducing the number of exacerbations. Before these trials, information was already available on the efficacy of both monocomponents in this disease, although the main clinical data obtained with formoterol and budesonide separately in the treatment of COPD come from the respective branches of these drugs in the two large clinical trials described in the present article. Improvement in pulmonary function variables [forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF)] was always greater with the combination of budesonide-formoterol. The scores obtained in quality of life questionnaires were also more favorable in the combination treatment branches as early as the first week of treatment and persisted at 12 months of follow-up. Improvement in symptoms and in the use of reliever medication was also greater in the combination branch. The frequency of mild and severe exacerbations, as well as the use of oral corticosteroids, was lower in the budesonide-formoterol branch. The time to first exacerbation was also more prolonged in this group. The present review discusses the main findings on the efficacy of the combination of budesonide-formoterol in stable COPD.

Topics: Bronchodilator Agents; Budesonide; Clinical Trials as Topic; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 μg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Animals; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Evidence-Based Medicine; Formoterol Fumarate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Treatment Outcome; United States

Budesonide/formoterol in two dosage strengths (80/4.5 µg and 160/4.5 µg), each administered as two inhalations twice daily, was previously developed as a fixed-dose inhaled corticosteroid/long-acting β-agonist combination in a pressurized metered-dose inhaler for use in asthma. More recent double-blind, randomized controlled trials of 6 and 12 months duration (referred to, respectively, as SHINE and SUN) have demonstrated the efficacy and safety of the higher-dose formulation in patients with severe and very severe chronic obstructive pulmonary disease. Specifically, budesonide/formoterol 160/4.5 µg (two inhalations twice daily) has demonstrated additive benefits over one or the other of its monocomponents with respect to improvements in morning predose and 1-h postdose lung function, as well as greater improvements in respiratory symptoms, health status and rescue medication use, and greater reductions in exacerbations of chronic obstructive pulmonary disease than placebo. It also has a satisfactory safety profile and has not been shown to increase the risk of pneumonia.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Evidence-Based Medicine; Formoterol Fumarate; Glucocorticoids; Humans; Lung; Metered Dose Inhalers; Pressure; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Assessment of patients with COPD has changed in the last few years by adding subjective patient evaluations to traditional measurements based on pulmonary function. One of the most recently studied variables is symptom variability during the day and, specifically, patients' perceptions of these symptoms in the first few hours of the day. To evaluate this feature, two new symptom questionnaires, the Capacity of Daily Living in the Morning (CDLM) questionnaire and the Global Chest Symptoms Questionnaire (GCSQ), have recently been developed. Recent studies have begun to provide data on the effect of the available treatments on these morning symptoms, yielding information on the rapidity of action of budesonide/formoterol with a significant and nearly clinically relevant effect on morning activities. Confirmation of these results could lead to future strategies designed to earlier symptomatic improvement, which could lead to greater treatment adherence.

Topics: Activities of Daily Living; Adrenergic beta-2 Receptor Agonists; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Diagnostic Self Evaluation; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Dyspnea; Ethanolamines; Fatigue; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index; Surveys and Questionnaires

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

Systemic corticosteroids are strongly recommended in the treatment of exacerbations of chronic obstructive pulmonary disease (COPD). As COPD patients are usually elderly and are relatively immobile, side effects of systemic corticosteroids frequently outweigh their beneficial effects. On the contrary, nebulized corticosteroid solutions have a negligible systemic side-effect profile. In this review, as an alternative to systemic corticosteroids, the place of nebulized corticosteroids in exacerbation periods of COPD was summarized.. The number of trials in the literature is increasing. Regarding the available data, high dose nebulized budesonide was found as effective as systemic corticosteroids in exacerbations of COPD. The side-effect profile, blood glucose level in particular, is better for nebulized budesonide.. Findings from recent studies are giving a positive impression on the role of high dose nebulized budesonide in exacerbations of COPD. However, larger and statistically high powered trials testing different types of nebulized corticosteroid solutions with varying dosages are still lacking. Before recommending the routine use of nebulized corticosteroids in exacerbations, present findings need to be confirmed with further studies of high quality.

Topics: Adrenal Cortex Hormones; Blood Glucose; Budesonide; Dose-Response Relationship, Drug; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

The corticosteroid budesonide and the rapid-onset, long-acting beta(2)-adrenoceptor agonist formoterol have been combined into a single pressurized metered-dose inhaler (pMDI) for use in patients with chronic obstructive pulmonary disease (COPD). Well designed 6- and 12-month clinical trials, twice-daily budesonide/formoterol pMDI 320 microg/9 microg effectively improved lung function in patients with moderate to very severe COPD. The co-primary endpoints of adjusted mean morning predose forced expiratory volume in 1 second (FEV(1)) and 1-hour post-dose FEV(1) improved from baseline to a significantly greater extent with twice-daily budesonide/formoterol pMDI 320 microg/9 microg than with twice-daily placebo, budesonide pMDI 320 microg and formoterol dry powder inhaler 9 microg. Budesonide/formoterol pMDI was also associated with improvements from baseline in other measures of lung function, COPD control (including the time to first COPD exacerbation in the 12-month trial), symptoms and health status. These improvements were significantly greater than those observed with placebo and, for some endpoints, monotherapy with the individual components. Budesonide/formoterol pMDI was well tolerated in clinical trials in patients with COPD. Its overall adverse event profile is consistent with the known tolerability profiles of formoterol and budesonide, and is generally similar to that with placebo.

Topics: Bronchodilator Agents; Budesonide; Clinical Trials as Topic; Drug Combinations; Ethanolamines; Formoterol Fumarate; Health Status; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Concern is continuing about increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) who use inhaled corticosteroids. We aimed to establish the effects of inhaled budesonide on the risk of pneumonia in such patients.. We pooled patient data from seven large clinical trials of inhaled budesonide (320-1280 mug/day), with or without formoterol, versus control regimen (placebo or formoterol alone) in patients with stable COPD and at least 6 months of follow-up. The primary analysis compared treatment groups for the risk of pneumonia as an adverse event or serious adverse event during the trial or within 15 days of the trial end. Cox proportional hazards regression was used to analyse the data on an intention-to-treat basis. Data were adjusted for patients' age, sex, smoking status, body-mass index, and postbronchodilator percent of predicted forced expiratory volume in 1 s (FEV(1)).. We analysed data from 7042 patients, of whom 3801 were on inhaled budesonide and 3241 were on control treatment, with 5212 patient-years of exposure to treatment. We recorded no significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs 3% [n=103]; adjusted hazard ratio 1.05, 95% CI 0.81-1.37) or a serious adverse event (1% [n=53] vs 2% [n=50]; 0.92, 0.62-1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (0.61). Increasing age and decreasing percent of predicted FEV(1) were the only two variables that were significantly associated with occurrence of pneumonia as an adverse event or a serious adverse event.. Budesonide treatment for 12 months does not increase the risk of pneumonia in patients with COPD during that time and therefore is safe for clinical use in such patients.. Michael Smith Foundation for Health Research.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Ethanolamines; Female; Follow-Up Studies; Forced Expiratory Volume; Formoterol Fumarate; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pneumonia; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Safety; Smoking; Time Factors

This systematic review examines the published evidence on the pharmacoecomonics of Symbicort. Symbicort is a combination inhaler used in asthma and chronic obstructive pulmonary disease (COPD) that contains budesonide and formoterol. In asthma, Symbicort can be used as fixed or adjustable dose maintenance therapy as well as for both maintenance and reliever therapy (SMART).. A literature search of PubMed was carried out to find all publications on the pharmacoeconomics of Symbicort. Additional studies were searched for in the reference lists of the papers retrieved and by searching tables of contents of relevant journals. A total of 13 studies on Symbicort in asthma and 2 studies on Symbicort in COPD were found.. Total costs were lower with Symbicort than with separate inhalers containing budesonide and formoterol. Adjustable dosing maintained control of asthma using less medication and was associated with lower treatment costs than fixed dosing with Symbicort or the combination of fluticasone/salmeterol. SMART improves asthma control, reduces exacerbations and reduces direct and indirect costs compared to fixed maintenance therapy with either Symbicort or fluticasone/salmeterol. In COPD, Symbicort offers clinical advantages over therapy with the monocomponents and these are achieved at little or no extra cost.

Topics: Asthma; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Economics, Pharmaceutical; Ethanolamines; Formoterol Fumarate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting beta-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient's perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchoconstrictor Agents; Budesonide; Drug Administration Schedule; Drug Combinations; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Inhaled bronchodilators, particularly short-acting inhaled beta(2)-agonists, and systemic glucocorticosteroids are effective treatments for acute exacerbations of chronic obstructive pulmonary disease (COPD). However, in the treatment of these episodes there may be some advantages to the longer-acting agents in that there will be prolonged bronchodilation. Moreover, high doses of systemic glucocorticosteroids are associated with a significant risk of side effects. In the last few years, evidence is mounting that nebulized budesonide and inhaled formoterol might be an alternative to oral prednisolone and short-acting beta(2)-agonists, respectively, in the treatment of acute exacerbations of COPD. Interestingly, some new data suggest that a combination therapy with single inhaler containing budesonide and formoterol may be an alternative to traditional therapy in the treatment of acute exacerbations of this disorder. However, since individual studies are typically statistically underpowered and are remarkably heterogeneous with regard to their conclusions, larger studies are needed to confirm these preliminary findings and determine conclusively any impact of budesonide/formoterol combination in acutely ill COPD patients.

Topics: Acute Disease; Administration, Inhalation; Adrenergic beta-Agonists; Bronchodilator Agents; Budesonide; Clinical Trials as Topic; Drug Combinations; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used as maintenance therapy in patients with moderate to severe asthma or chronic obstructive pulmonary disease (COPD). The main effect of inhaled corticosteroids is thought to be mediated through suppression of airway inflammation, while long-acting beta2-adrenoceptor agonists are thought to work by inducing bronchodilation. However, there is emerging data to indicate that these two classes of drugs interact positively with each other, leading to added or perhaps synergistic benefits for patients. Corticosteroids enhance the expression of beta2-adrenoceptor, thus providing protection against desensitization and development of tolerance to beta2-adrenoceptor agonists, which may occur with prolonged use of these medications. Long-acting beta2-adrenoceptor agonists, on the other hand, may amplify the anti-inflammatory effects of corticosteroids by accelerating nuclear translocation of the glucocorticoid receptor complex, and enhancing transcription and expression of steroid-inducible genes in pro-inflammatory cells. In clinical trials, corticosteroids in combination with long-acting beta2-adrenoceptor agonists reduce exacerbation rates, and improve lung function and health status of patients with moderate to severe asthma or COPD beyond that achieved by individual component therapy. Their effects on mortality are unknown. There is a large clinical trial currently underway, which will provide mortality data by the year 2006. On balance, clinical evidence supports the use of combination therapy in moderate to severe asthma and COPD.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Albuterol; Androstadienes; Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Budesonide; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Gene Expression Regulation; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Receptors, Adrenergic, beta-2; Receptors, Glucocorticoid

Long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combination therapy is recommended by international treatment guidelines for COPD. The current literature concerning the safety of LABAs and ICS, both as monotherapies and in combination, in patients with COPD is reviewed. Bronchodilators such as LABAs are key treatments for COPD due to their effects on bronchial smooth muscle and airflow limitation. LABAs are well-tolerated in patients with COPD, with a low incidence of reported adverse events (AEs). Most AEs associated with LABA use are due to systemic exposure and include muscle tremor and cardiac effects. Placebo-controlled studies in patients with COPD demonstrate that there is no increase in risk of cardiac AEs with LABA therapy. ICS therapy targets airway inflammation in COPD, and is associated with a reduction in the frequency of COPD exacerbations, and improvements in symptoms, lung function and health status. Localized effects such as oropharyngeal irritation are common with ICS, but are not considered to be serious. Potential ocular effects with ICS therapy in patients with COPD have been identified and require further investigation. Rare, but more serious AEs related to ICS use are the effects on bone and the suppression of endogenous cortisol production; however, the clinical relevance of these effects is unclear. Clinical data indicate that LABA/ICS combination therapy is more effective in COPD than either agent used alone and is not associated with any additional AEs.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Heart Rate; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Treatment Outcome

The budesonide-formoterol dry powder inhaler (Symbicort Turbuhaler 160/ 4.5-640/18 microg/day) contains the long-acting beta2-adrenoreceptor agonist formoterol and the inhaled corticosteroid budesonide. Two large, 12-month trials examined the effect of budesonide-formoterol 160/4.5 microg twice daily in COPD patients who met these criteria. The studies were identical, except one in which the patients had received oral prednisolone 30 mg/ day and had inhaled formoterol 4.5 microg twice daily for 2 weeks before randomization. In terms of the FEV1, budesonide-formoterol produced an effect greater than that of both budesonide alone and formoterol alone reported in previous studies. The combination was generally more effective than either of the components in terms of peak expiratory flow, symptoms, and exacerbations. These advantages of the combination over those of either budesonide alone or formoterol alone were quite consistent. Improving lung function and decreasing symptoms significantly, budesonide-formoterol combination therapy provides significant clinical improvements in COPD, despite the limited reversibility of impaired lung function in the disease.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Humans; Powders; Pulmonary Disease, Chronic Obstructive; Quality of Life; Treatment Outcome

Inhaled corticosteroids (ICSs) have become the mainstay of chronic controller therapy to treat airways inflammation in asthma and to reduce exacerbations in chronic obstructive pulmonary disease. An array of ICSs are now available that are aerosolized by a range of delivery systems. Such devices include pressurized (or propellant) metered-dose inhalers (pMDIs), pMDIs plus valved holding chambers or spacers, breath-actuated inhalers, and nebulizers. More recently, dry-powder inhalers (DPIs) were developed to help overcome problems of hand-breath coordination associated with pMDIs. The clinical benefit of ICSs therapy is determined by a complex interplay between the nature and severity of the disease, the type of drug and its formulation, and characteristics of the delivery device together with the patient's ability to use the device correctly. The ICSs budesonide is available by pMDI, DPI, and nebulizer-allowing the physician to select the best device for each individual patient. Indeed, the availability of budesonide in three different delivery systems allows versatility for the prescribing physician and provides continuity of drug therapy for younger patients who may remain on the same ICSs as they mature.

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Bronchodilator Agents; Budesonide; Child; Choice Behavior; Dose-Response Relationship, Drug; Equipment Design; Female; Humans; Long-Term Care; Male; Metered Dose Inhalers; Particle Size; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Treatment Outcome

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

The effective prevention of exacerbations in patients with chronic obstructive pulmonary disease (COPD) has the potential to improve patients' health-related quality of life, reduce rates of hospitalisation and mortality and lower healthcare costs. Several pharmacological agents, including inhaled corticosteroid/long-acting beta2-agonist combination therapies, have demonstrated beneficial effects on COPD exacerbations. The number needed to treat (NNT) analysis is a simple, concise method that allows physicians to quantify directly the benefits that alternative treatment options have on disease outcomes in terms of the number of patients who need to be treated before a benefit is observed. This review evaluates the applicability and clinical relevance of NNT analysis for determining the effectiveness of combination therapies against COPD exacerbations, focusing on budesonide/ formoterol in the same inhaler. Physicians are encouraged to consider NNT data within the context of their limitations and in conjunction with other analytical methods when selecting treatments for patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Data Interpretation, Statistical; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. Current guidelines recommend the addition of inhaled steroids to bronchodilators, which are central to the symptomatic management of COPD in patients with severe disease. Budesonide/formoterol is a combination inhaled steroid and long-acting bronchodilator delivered by a dry-powder inhaler, approved for use in COPD. Two large, randomised, double-blind, 12-month studies found that combination budesonide/formoterol is more effective than either component alone in addressing many important aspects of the disease, such as pulmonary function, symptoms, use of relief medication, health-related quality of life and exacerbation in patients suffering from severe COPD. This review discusses the pharmacological and clinical properties of the drug.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Respiratory Function Tests

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

Budesonide/formoterol is a fixed-dose combination of the corticosteroid budesonide and the long-acting beta2-agonist formoterol, and is inhaled via the Turbuhaler device. In two large, randomised, double-blind, 12-month studies, patients with severe chronic obstructive pulmonary disease (COPD) receiving budesonide/formoterol 320/9 microg twice daily had a significantly higher forced expiratory volume in 1 second (FEV1) and significantly higher morning and evening peak expiratory flow at trial endpoint than recipients of budesonide or placebo; FEV1 was significantly higher than with formoterol in the larger study. In both studies, the rate of COPD exacerbations and exacerbations requiring oral corticosteroids was significantly reduced with budesonide/formoterol versus formoterol and placebo. Moreover, the time to first exacerbation was significantly prolonged with budesonide/formoterol versus all other treatment arms in the larger study. At 12 months, significant improvements in health-related quality-of-life scores were seen with budesonide/formoterol versus placebo in both studies. The reduction in total and individual symptom scores was significantly greater with budesonide/formoterol than with budesonide or placebo in the smaller study. Budesonide/formoterol was generally well tolerated by patients with severe COPD. The tolerability profile of the combination was similar to that of the individual components with no increase in the incidence of adverse events.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Anti-Inflammatory Agents; Budesonide; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life

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

Seretide (fluticasone + salmeterol--Allen & Hanburys) and Symbicort (budesonide + formoterol--AstraZeneca) inhalers have recently been licensed in the UK for the symptomatic treatment of patients with severe chronic obstructive pulmonary disease (COPD) and a history of repeated exacerbations. Advertising for Seretide depicts a man and states that the drug "has improved his ability to breathe and reduced his risk of exacerbations", while promotional claims for Symbicort include benefits in "reducing symptoms" and "improving quality of life". Here we assess the place of these fixed-dose combination inhalers containing a corticosteroid and a long-acting beta 2 agonist in the management of patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Treatment Outcome

Inhalation therapy delivers therapeutic agents directly into the lungs of patients with asthma, and is likely to remain the route of delivery of choice for the foreseeable future. The majority of patients with asthma suffer from mild intermittent to mild persistent disease for which regular low dose inhaled corticosteroids and on demand short-acting beta2-agonists have been recommended. These highly effective anti-asthma medications are readily available, and so in the future improvement in asthma therapy will most Likely derive from improvements in inhaler technology. Dry powder inhalers (DPIs) have many advantages compared to chlorofluorocarbon pressurised metered dose inhalers. Most notably, with DPIs patients no longer need to co-ordinate activation of the inhaler with inspiration. The Novolizer (VIATRIS, Germany) which is one of the latest developments in DPI technology offers a number of features required to increase the safety and efficacy of inhaled therapy. It is the first DPI to include an inspiratory trigger threshold, which helps to prevent sub-optimal dose administration. Repeated activation without inhalation is mechanically inhibited by an overdose prevention mechanism. In conclusion, there is good evidence that technically refined DPIs are more likely to advance inhaled anti-asthmatic therapy than newly developed inhaled drugs. This is important when inhalation therapy is considered not only for asthma but also for chronic obstructive pulmonary disease.

Topics: Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Forced Expiratory Volume; Humans; Metered Dose Inhalers; Practice Guidelines as Topic; Product Surveillance, Postmarketing; Professional Practice; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Vital Capacity

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

Asthma is a chronic inflammatory disease of the bronchial tree, characterised by reversible obturation, bronchial mucosal inflammation and bronchial hyperresponsiveness. In the treatment of asthma, most important is avoidance of provoking allergens and regular anti-inflammatory treatment with inhaled glucocorticosteroids. For patients, very important is quick relief from asthma symptoms, this is why they prefer fast and long acting beta 2-agonists as a symptomatic treatment. Optimal control of asthma symptoms can be achieved with combination treatment consisting of inhaled glucocorticosteroid and beta 2-agonist. Budesonide is a corticosteroid that treats the underlying airway inflammation in asthma; formoterol is a fast and long-acting beta 2-agonist that prevents and reverses airway obstruction. Thus budesonide and formoterol have complementary effects, treating two different components of asthma. Clinical studies show that in the treatment of asthma Symbicort is more effective than double dose GCS, due to the budesonide/formoterol synergy. It is at least as effective, well tolerated and safe as its mono-products in corresponding doses given via separate inhalers. More convenient treatment represents an important benefit for patients with asthma. Symbicort is recommended for regular treatment and could also be used "as needed" due to the rapid onset of the bronchodilatory effect of formoterol.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Drug Synergism; Ethanolamines; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive

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

Novolizer is a multidose breath-actuated dry powder inhaler (DPI) approved for use with salbutamol (albuterol) and budesonide. It has multiple patient feedback mechanisms and an inspiratory flow rate threshold designed to optimise dosage. In two studies, children aged 4-11 years with asthma correctly used Novolizer and generated mean peak inspiratory flow rates (PIFRs) through Novolizer of 76 and 92.7 L/min, well above the Novolizer threshold of 35-50 L/min. In healthy volunteers, median lung deposition of budesonide administered via Novolizer was 19.9-32.1% at mean PIFRs of 54-99 L/min. In a randomised, double-blind, single-dose study in patients with chronic obstructive pulmonary disease (COPD) and asthma, the 1-hour improvement from baseline in mean maximum forced expiratory volume in 1 second (FEV(1)) was 21.3% with inhalation of salbutamol through Novolizer, and 19.5% through Sultanol pressurised metered-dose inhaler (MDI). FEV(1) increased significantly in patients with asthma and COPD treated for 4 weeks in a randomised, open-label comparison of salbutamol through either Novolizer or Sultanol MDI. A randomised open-label study in adults with asthma treated with inhaled budesonide found equivalent improvements in FEV(1) and symptoms with Novolizer and Turbuhaler. Novolizer was well accepted overall. Most patients preferred it to previously used MDIs or DPIs. Only 4-5% found the taste feedback unacceptable. Physicians observed improved compliance over 4 weeks in 80% of patients with asthma using Novolizer.

Topics: Administration, Inhalation; Adult; Albuterol; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Clinical Trials as Topic; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Nebulizers and Vaporizers; Powders; Pulmonary Disease, Chronic Obstructive

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

Maintenance and reliever therapy (MART) with inhaled corticosteroid (ICS)/formoterol effectively reduces exacerbations in asthma. We aimed to investigate its efficacy compared with fixed-dose fluticasone/salmeterol in chronic obstructive pulmonary disease (COPD).. Patients with COPD and ≥1 exacerbation in the previous 2 years were randomly assigned to open-label MART (Spiromax budesonide/formoterol 160/4.5 µg 2 inhalations twice daily+1 prn) or fixed-dose therapy (Diskus fluticasone propionate/salmeterol combination (FSC) 500/50 µg 1 inhalation twice daily+salbutamol 100 µg prn) for 1 year. The primary outcome was rate of moderate/severe exacerbations, defined by treatment with oral prednisolone and/or antibiotics.. In total, 195 patients were randomised (MART Bud/Form n=103; fixed-dose FSC n=92). No significant difference was seen between MART and FSC therapy in exacerbation rates (1.32 vs 1.32 /year, respectively, rate ratio 1.05 (95% CI 0.79 to 1.39); p=0.741). No differences in lung function parameters or health status were observed. Total ICS dose was significantly lower with MART than FSC therapy (budesonide-equivalent 928 µg/day vs 1747 µg/day, respectively, p<0.05). Similar proportions of patients reported adverse events (MART Bud/Form: 73% vs fixed-dose FSC: 68%, p=0.408) and pneumonias (MART: 5% vs FSC: 1%, p=0.216).. This first study of MART in COPD found that budesonide/formoterol MART might be similarly effective to fluticasone/salmeterol fixed-dose therapy in moderate to severe patients with COPD, at a lower daily ICS dosage. Further evidence is needed about long-term safety.

Topics: Adrenal Cortex Hormones; Androstadienes; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Inhaled glucocorticoid corticosteroid (ICS), long-acting β2-adrenoceptor agonist (LABA), and other drugs have limited therapeutic effects on COPD with significant individual differences. Traditional Chinese medicine (TCM)-modified Bushen Yiqi formula (MBYF) demonstrates advantages in COPD management in China. This study aims to evaluate the efficacy and safety of MBYF as an add-on to budesonide/formoterol in COPD patients and confirm the related genes affecting the therapeutic effect in the treatment of COPD.. In this multicentre, randomised, double-blind, placebo-controlled, parallel-group study, eligible patients with COPD will randomly receive a 360-day placebo or MBYF as an adjuvant to budesonide/formoterol in a 1:1 ratio and be followed up with every 2 months. The primary outcomes will be the frequency, times, and severity of acute exacerbation of COPD (AECOPD), COPD assessment test (CAT) score, and pulmonary function tests (PFTs). The secondary outcomes will include the modified Medical Research Council (mMRC) dyspnoea scale, 6-min walking test (6MWT), BODE index, quantitative scores of syndromes classified in TCM, inflammation indices, and hypothalamic-pituitary-adrenaline (HPA) axis function. We will also test the genotype to determine the relationship between drugs and efficacy. All the data will be recorded in case report forms (CRFs) and analysed by SPSS V.20.0.. A randomized clinical trial design to evaluate the efficacy and safety of MBYF in COPD is described. The results will provide evidence for the combination therapy of modern medicine and TCM medicine, and individual therapy for COPD.. ID:  ChiCTR1900026124 , Prospective registration.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Therapy, Combination; Formoterol Fumarate; Humans; Multicenter Studies as Topic; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

In the Phase III ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid (ICS) doses reduced moderate/severe exacerbation rates and improved symptoms, health-related quality of life (HRQoL), and lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) dual therapy in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD). Here, we assessed whether the benefit for BGF versus GFF was driven by patients who received ICS before randomization to GFF.. ETHOS was a 52-week, randomized, double-blind, multicenter, parallel-group study in symptomatic patients with COPD and ≥1 moderate/severe exacerbation in the previous year. Patients received BGF 320/14.4/10 μg, BGF 160/14.4/10 μg, GFF 14.4/10 μg, or BFF 320/10 μg twice daily via a single metered dose Aerosphere™ inhaler. In these subgroup analyses, efficacy and safety were assessed in patients with or without prior ICS use in the 30 days before screening.. The modified intent-to-treat population comprised 8509 patients (prior ICS use, n = 6810 [80%]; no prior ICS use, n = 1699 [20%]). Moderate/severe exacerbation rates were reduced by 24% and 23% in patients with and without prior ICS use, respectively, with BGF 320 versus GFF. Benefits of BGF 320 versus GFF were also similar in patients with and without prior ICS use across other endpoints relating to exacerbations, symptoms, HRQoL, lung function, and safety. Trends were similar for BGF 160 versus GFF.. Benefits on exacerbations, symptoms, HRQoL, and lung function with BGF versus GFF were observed, irrespective of prior ICS use in the 30 days before screening.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Lung; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Quality of Life

Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count.. Patients (40-80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 µg, BGF 160/14.4/10 µg, GFF 14.4/10 µg, or BFF 320/10 µg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (<100, ≥100, ≥100-<300, ≥300 cells/mm. Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥100 cells/mm³.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Quality of Life

For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm. Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study.. A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV.  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tomography, X-Ray Computed

Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, is a triple fixed-dose combination in late-stage clinical development for chronic obstructive pulmonary disease (COPD).. We conducted two studies to characterize the pharmacokinetic (PK) profile of BGF MDI in patients with COPD: (i) a phase I, open-label, single and chronic (7-day) dosing study (NCT03250182) with one treatment arm (BGF MDI 320/18/9.6 μg); and (ii) a PK sub-study of KRONOS (NCT02497001), a phase III, randomized, double-blind study in which patients received 24 weeks' treatment with BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 μg. PK parameters in both studies included maximum observed plasma concentration (C. Steady-state PK parameters of budesonide, glycopyrronium, and formoterol were similar after 7 days' dosing in the phase I PK study and after 24 weeks in the KRONOS PK sub-study. Systemic exposure to budesonide, glycopyrronium, and formoterol was generally comparable across treatments in the KRONOS PK sub-study, suggesting no meaningful drug-drug or within-formulation PK interactions.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Drug Delivery Systems; Female; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Random Allocation

This pre-specified subgroup analysis evaluated the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) triple therapy versus corresponding dual therapies in the China subgroup of the phase III, double-blind KRONOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).. In the China subgroup (n = 432; 22.7% of the KRONOS population), BGF MDI demonstrated nominally significant improvements in the primary endpoint versus BFF MDI (least squares mean (LSM) difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference - 4 mL; P = 0.8316). BGF MDI demonstrated at least numerical improvements versus comparators in secondary lung function and symptom endpoints. BGF MDI reduced the rate of moderate/severe COPD exacerbations versus GFF MDI (rate ratio 0.41; P = 0.0030), with numerical benefits versus BFF MDI and BUD/FORM DPI. All treatments were well tolerated.. Results demonstrated that BGF MDI showed benefits on lung function (vs inhaled corticosteroid/long-acting β. ClinicalTrials.gov NCT02497001.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Budesonide; China; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests

Clinical studies have suggested nebulized budesonide (NB) as an alternative to systemic corticosteroids for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the optimal budesonide dose for AECOPD remains unclear.. To compare the efficacy and safety of different doses of NB in the management of AECOPD.. A total of 321 AECOPD patients with moderate-to-severe exacerbation were randomly divided into three groups and treated with NB. The low dose group (L) was given 4 mg/day (n=95, 1 mg Q6h), while high-dose group 1 (H1, n=111, 2 mg Q6h) and high-dose group 2 (H2, n=115, 4 mg Q12h) were given 8 mg/day. Patients also received routine treatment including oxygen therapy, expectorant, nebulization bronchodilators, antibiotics, and fluid rehydration. The COPD assessment test (CAT), lung function, and artery blood gas were evaluated before and after 3 hrs and 5 days of treatment. In addition, hospital stay, frequency of acute exacerbations within 3 months of discharge, and adverse events during treatment were compared.. H1 and H2 showed improved spirograms and CAT score faster than L. In H2, forced expiratory volume in 1 s (FEV. Compared to the conventional dose (4 mg/day), a high dose (8 mg/day) of NB improved pulmonary function and symptoms more effectively in the early treatment of AECOPD, especially when given as 4 mg twice daily.

Topics: Administration, Inhalation; Aerosols; Aged; Bronchodilator Agents; Budesonide; China; Disease Progression; Drug Administration Schedule; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Lung; Male; Maximal Midexpiratory Flow Rate; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Time Factors; Treatment Outcome; Vital Capacity

Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β. In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.. The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group.. Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Budesonide; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Glycopyrrolate; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Budesonide; Case-Control Studies; Dose-Response Relationship, Drug; Female; Formoterol Fumarate; Gene Expression Profiling; Humans; Lung; Male; Middle Aged; Nasal Cavity; Placebos; Pulmonary Disease, Chronic Obstructive

The Phase III KRONOS study (NCT02497001) found the fixed-dose combination triple therapy budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) to be efficacious and well tolerated versus corresponding dual therapies in patients with moderate-to-very severe COPD from North America, China and Japan. However, pharmacokinetic (PK) studies of other drugs have shown that ethnic factors (e.g. genetic factors affecting drug metabolism) can affect the bioavailability of drugs which may impact upon efficacy and safety outcomes.. The analyses included data from 64 Chinese, 31 Japanese and 169 Western subjects. Overall, PK properties following single or repeated dosing of BGF MDI were similar across Chinese, Japanese and Western subjects. After single dosing at either dose level, AUC. Overall, these analyses suggest no appreciable ethnic differences in the PK of BGF MDI across Chinese, Japanese and Western healthy subjects.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Formoterol Fumarate; Fumarates; Glycopyrrolate; Healthy Volunteers; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive

Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).. Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.. The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6-82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0-2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9-5.7%). Six deaths were reported (0.7-2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.

Topics: Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Drug Monitoring; Drug Tolerance; Female; Formoterol Fumarate; Glycopyrrolate; Humans; Japan; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Time; Treatment Outcome

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality all over the world. Acute exacerbation of COPD (AECOPD) not only accelerates the progression of disease, but also causes hospital administration and death events. Epidemiologic studies have shown air pollution is a high risk factor of AECOPD. However, there are rare technics or treatment strategies recommended to reduce severe air pollution related AECOPD.. This is a multi-center, prospective, randomized and standard treatment parallel control clinical trial. Seven hundred sixty-four stable COPD patients in group B, C and D according to GOLD 2017 will be recruited and equally divided into two parallel groups, salvational intervention (SI group) and control group (CT group). Original treatments for participants include tiotropium (18μg once q.d), budesonide/formoterol (160μg/4.5μg once or twice b.i.d) or budesonide/formoterol (160μg/4.5μg once or twice b.i.d) with tiotropium (18μg once q.d). The savational intervention for SI group is routine treatment plus budesonide/formoterol (160μg/4.5μg once b.i.d) from the first day after severe air pollution (air quality index, AQI ≥200) to the third day after AQI < 200. CT group will maintain the original treatment. The intervention will last for 2 years. Primary outcome is the frequency of AECOPD per year and the secondary outcomes include the incidence of unplanned outpatient visits, emergency visits, hospitalization, medical cost and mortality associated with AECOPD per year.. The salvational intervention is a novel strategy for COPD management under severe air pollution. Results of the present study will provide reference information to guide clinical practice in reducing the air pollution related exacerbation of COPD.. This study has been registered at www.ClinicalTrials.gov (registration identifier: NCT03083067 ) in 17 March, 2017.

Topics: Adult; Aged; Aged, 80 and over; Air Pollution; Beijing; Bronchodilator Agents; Budesonide; Disease Progression; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Regression Analysis; Tiotropium Bromide

Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes.. To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients.. We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured.. Budesonide significantly reduced the number of days on MV (days-to-weaning=4.6±1.6days) compared to that seen in the control group (7.2±2.7days, p=0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p=0.018) and 5 (p=0.011) The levels of CXCL-8 and IL-6 diminished on days 3-5 after start of budesonide (p<0.05).. In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning.

Topics: Adult; Aged; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Budesonide; Cell Count; Cytokines; Female; Humans; Inflammation Mediators; Lymphocytes; Macrophages; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Ventilator Weaning

The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease (COPD) who will experience fewer exacerbations when taking inhaled corticosteroids (ICS). Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response. We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD.. We analysed data from three AstraZeneca randomised controlled trials of budesonide-formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts. Patients with any history of asthma were excluded. Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design. The trials are registered with ClinicalTrials.gov, NCT00206167, NCT00206154, and NCT00419744.. In patients with COPD treated with formoterol, blood eosinophil count predicts exacerbation risk and the clinical response to ICS.. AstraZeneca.

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Eosinophils; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk; Therapeutics

Topics: Administration, Inhalation; Aged; Budesonide; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Formoterol Fumarate; Humans; Male; Pulmonary Disease, Chronic Obstructive; Switzerland

Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β. We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.. The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV. These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

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

The systemic inflammation is associated with clinical outcome and mortality in chronic obstructive pulmonary disease (COPD) patients. To investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D, a randomized, open-label clinical trial was conducted.. Eligible participants (n = 324) were randomized and received either Tio 18ug once daily (group I), Bud/Form 160/4.5ug twice daily (group II), Bud/Form 320/9ug twice daily (group III), or Tio 18ug once daily with Bud/Form 160/4.5ug twice daily (group IV) for 6 months. Systemic inflammation biomarkers were measured before randomization and during the treatment, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), and white blood cell (WBC).. After 6-month treatment, CRP levels in group II, group III and group IV changed by a median (interquartile range) of -1.25 (-3.29, 1.18) mg/L, -1.13 (-2.55, 0.77) mg/L, and -1.56 (-4.64, 0.22) mg/L respectively, all of which with statistical differences compared with group I. In addition, there were no treatment differences in terms of IL-8, SAA, TNF-α, Fib and WBC levels.. A long-term treatment with Bud/Form alone or together with Tio can attenuate circulating CRP levels in COPD patients of group D, compared with Tio alone.

Topics: Aged; Aged, 80 and over; Biomarkers; Bronchodilator Agents; Budesonide; C-Reactive Protein; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

Exhaled breath condensate (EBC) has emerged as a noninvasive method for assessing inflammation in lung diseases. Our aim is to investigate the correlation between tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) in EBC and in lung tissue, and between these values in EBC with pulmonary function tests in patients with chronic obstructive pulmonary disease (COPD).. To ensure the availability of lung tissue, 60 patients undergoing resection for early lung cancer were divided into 3 groups: a COPD treatment group, a COPD control group and a non-COPD group. Patients in the COPD treatment group received what was termed "lung-protective treatment" including ambroxol, budesonide and ipratropium bromide in addition to chest physiotherapy. Patients underwent pulmonary function testing and EBC collection, and TNF-α and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). TNF-α and IL-1β in lung tissues were evaluated by immunoflorescense. Correlations were analyzed by Pearson correlation coefficients.. The TNF-α and IL-1β levels in EBC were significantly higher in the COPD groups compared with the non-COPD group before surgery (all P < 0.01), and the levels were significantly decreased after lung-protective treatment was received before surgery (all P < 0.01). TNF-α and IL-1β levels in EBC were significantly decreased in all patients after surgery with lung-protective treatment (P = 0.027, P = 0.004). TNF-α and IL-1β content in lung tissues was significantly higher in the COPD groups (all P < 0.05), and the histologic analysis showed similar results. Negative correlations between FEV1/FVC and expression of TNF-α and IL-1β were observed. There was a positive correlation between TNF-α and IL-1β in lung tissues and in EBC.. TNF-α and IL-1β in EBC are potential biomarkers for evaluating pulmonary function and inflammation in patients with COPD. Furthermore, lung-protective treatment is effective in reducing inflammation in patients with COPD.

Topics: Aged; Ambroxol; Breath Tests; Budesonide; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1beta; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Tumor Necrosis Factor-alpha

We investigated the effects of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of acute exacerbation COPD (AECOPD) on circulating levels of inflammatory factors and prognosis.. A total of 86 cases of patients on ventilator support were randomly divided into control group and observation group with 43 cases each. The control group was administered routine treatment including basic disease treatment, anti-infection, maintenance of a stable internal environment, nutritional support, oxygen inhalation and so on. The control group was administered saline through a ventilator mask. The observation group was treated with atomized inhalation of ipratropium bromide and budesonide suspension and oxygen flow 3-5 L/min, 15-20 min/time and twice a day for 1 week. The treatment effects were compared.. Serum TNF-α, IL-6, and CRP levels were decreased in both groups after treatment, but levels in the observation group were significantly lower than those of the control group; differences were statistically significant (p < 0.05). Forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC and maximal expiratory flow rate in the observation group were significantly higher than those in the control group after treatment (p < 0.05). After treatment, the PaO2, SpO2 and respiratory failure index (RFI) of the observation group were significantly higher than those of the control group. The PaCO2 levels of the observation group were lower than those of the control group. The differences were statistically significant (p < 0.05). The clinical efficacy of the observation group was better than that of the control group; the ventilation time and total treatment time was significantly shorter and the differences were statistically significant (p < 0.05).. The ventilator mask atomizing inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of AECOPD can significantly improve circulating inflammatory reaction, improve lung function and blood gas levels, increase the treatment efficiency, and shorten the treatment time.

Topics: Administration, Inhalation; Aged; Blood Gas Analysis; Bronchodilator Agents; Budesonide; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-6; Ipratropium; Male; Masks; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Respiratory Function Tests; Suspensions; Tumor Necrosis Factor-alpha

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

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

Early treatment response markers, for example, improvement in forced expiratory volume in 1 second (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score, may help clinicians to better manage patients with chronic obstructive pulmonary disease (COPD). We investigated the prevalence of clinically important improvements in FEV1 and SGRQ scores after 2-month budesonide/formoterol or formoterol treatment and whether such improvements predict subsequent improvements and exacerbation rates.. This post hoc analysis is based on data from three double-blind, randomized studies in patients with moderate-to-very-severe COPD receiving twice-daily budesonide/formoterol or formoterol alone for 6 or 12 months. Prebronchodilator FEV1 and SGRQ total score were measured before treatment and at 2 and 12 months; COPD exacerbation rates were measured during months 2-12. Responders were defined by ≥100 mL improvement in prebronchodilator FEV1 and ≥4-point decrease in SGRQ total score.. Overall, 2,331 and 1,799 patients were included in the 0-2- and 0-12-month responder analyses, respectively, and 2,360 patients in the 2-12-month exacerbation rate analysis. At 2 months, 35.1% of patients were FEV1 responders and 44.3% were SGRQ responders. The probability of response was significantly greater with budesonide/formoterol than with formoterol or placebo for both parameters. Two-month responders had a greater chance of 12-month response than 2-month nonresponders for both FEV1 (odds ratio, 5.57; 95% confidence interval, 4.14-7.50) and SGRQ (odds ratio, 3.87; 95% confidence interval, 2.83-5.31). Two-month response in FEV1 (P<0.001), but not SGRQ (P=0.11), was associated with greater reductions in exacerbation risk.. Early FEV1 and SGRQ treatment responses relate to their changes at 12 months. FEV1 response, but not SGRQ response, at 2 months predicts the risk of a future COPD exacerbation in some, but not all patients. This is potentially useful in clinical practice, although more sensitive and specific markers of favorable treatment response are required.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Risk Assessment; Risk Factors; Severity of Illness Index; Symptom Flare Up; Time Factors

To investigate the efficacy and safety of nebulized budesonide and systemic glucocorticosteroids (GCS) (SGCS) in the treatment of an exacerbation of chronic obstructive pulmonary disease (COPD) and their effects on the serum concentration of soluble leukocyte differentiation antigens.. Seventy-eight hospitalized patients with an acute exacerbation of COPD were randomized into two groups: 1) 37 patients took nebulized budesonide 4 mg/day; 2) 41 patients received intravenous prednisolone. The symptoms of COPD, forced expiratory volume in one second (FEV1) and other spirometric indicators, peripheral blood oxygen saturation (SpO2), and adverse events were studied. The serum levels of the soluble adhesion molecules CD50 (sCD50) and CD54 (sCD54) and the lymphocyte activation molecules CD38 (sCD38) and CD25 (sCD25) were investigated by an enzyme immunoassay.. There was a significant resolution of the symptoms of COPD, FEV1, and SpO2 in both groups after treatment. The incidence of hyperglycemia episodes was lower in the budesonide group than in the sGCS group. GCSs caused a decrease in the serum level of soluble interleukin-2 receptor (sCD25) in both groups. A prednisolone cycle, unlike a budesonide one, was found to reduce the concentrations of sCD54, sCD50, and sCD38.. Nebulized budesonide is an effective and safe alternative to SGCS in treating an exacerbation of COPD. Inhaled GCSs, unlike SGCSs, exhibit anti-inflammatory activity, but exert no immunosuppressive activity.. Цель исследования. Изучить эффективность и безопасность небулизированного будесонида и системных глюкокортикостероидов (СГКС) при обострении хронической обструктивной болезни легких (ХОБЛ), а также их влияние на концентрацию растворимых дифференцировочных лейкоцитарных антигенов в сыворотке крови. Материалы и методы. Госпитализированных пациентов с обострением ХОБЛ (n=78) рандомизировали на 2 группы. Пациенты 1-й группы (n=37) получали будесонид 4 мг/сут через небулайзер; пациенты 2-й группы (n=41) - преднизолон внутривенно. Изучали симптомы, объем форсированного выдоха за 1-ю секунду (ОФВ1) и другие показатели спирометрии, насыщение периферической крови кислородом (SpO2), нежелательные явления. Содержание в сыворотке крови растворимых форм молекул адгезии CD50, CD54 (sCD50, sCD54) и молекул активации лимфоцитов CD38, CD25 (sCD38, sCD25) исследовали иммуноферментным методом. Результаты. Достоверное разрешение симптомов, ОФВ1 и SpO2 отмечено в обеих группах после лечения. Частота развития эпизодов гипергликемии в группе будесонида ниже, чем при лечении СГКС. В обеих группах ГКС вызывали снижение содержания в сыворотке крови растворимого рецептора интерлейкина-2 (sCD25). После курса преднизолона обнаружено уменьшение концентраций sCD54, sCD50, sCD38 в отличие от курса будесонида. Заключение. Небулизированный будесонид представляет собой эффективную и безопасную альтернативу СГКС при обострении ХОБЛ. Ингаляционные ГКС проявляют противовоспалительную активность, но не оказывают иммуносупрессивного действия в отличие от сГКС.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Antigens, CD; Bronchodilator Agents; Budesonide; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Outcome Assessment, Health Care; Prednisolone; Pulmonary Disease, Chronic Obstructive

Almost all international guidelines recommend corticosteroids for management of exacerbations of chronic obstructive pulmonary disease (COPD), because it leads to improved outcomes of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Nevertheless, due to its side effects, there are still concerns regarding the use of systemic corticosteroid (SC). Inhaled corticosteroids (IC) can be used as an alternative to SC, while reducing the risk of occurrence of side effects.. To measure the clinical efficacy and side effects of nebulized budesonide and systemic methylprednisolone in AECOPD.. Valid data from 410 AECOPD patients in 10 hospitals was collected. Patients were randomly divided into 2 groups; budesonide group, treated with nebulized budesonide (2 mg 3 times/day); and methylprednisolone group, treated with intravenously injected methylprednisolone (40 mg/day). COPD assessment test (CAT), arterial blood gas analysis, hospitalization days, adverse effects, fasting blood glucose, serum creatinine, alanine aminotransferase levels, and blood drug were measured and analyzed in both groups.. Symptoms, pulmonary function and arterial blood gas analysis were significantly improved after treatment in both groups (P < 0.05), with no significant differences between them (P > 0.05), while incidence of adverse events in the budesonide group was lower (P < 0.05). No significant differences in CAT score, days of admission, blood gas analysis results and physiological and biochemical indexes were found between the two groups. Patients treated with methylprednisolone showed a higher degree of PaO. Results show that inhalation of budesonide (2 mg 3 times/day) and systemic methylprednisolone (40 mg/day) had similar clinical outcome in AECOPD. In conclusion, inhaled budesonide is an alternative to systemic corticosteroids in AECOPD treatment.

Topics: Acute Disease; Administration, Inhalation; Aged; Bronchodilator Agents; Budesonide; Carbon Dioxide; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Injections, Intravenous; Male; Methylprednisolone; Middle Aged; Oxygen; Partial Pressure; Pulmonary Disease, Chronic Obstructive; Single-Blind Method; Vital Capacity

Corticosteroids have been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, whether inhaled corticosteroids (IC) alone have similar effects with systemic corticosteroid (SCS) is still unclear.. To compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD.. 30 AECOPD patients were randomly divided into two group. Budesonide group (15 cases) were treated with inhaled budesonide (3 mg Bid); methylprednisolone group (15 cases) were treated with systemic methylprednisolone (methylprednisolone acetate injectable suspension 40 mg Qd for three days and then methylprednisolone tablets 8 mg Bid). Observe symptoms, lung function, blood gas analysis and adverse effects of the patients in two groups. Peripheral blood samples were collected before and after treatment for 1 day, 4 days and 7 days. Interleukin-8 (IL-8) and TNF-α levels were determined by an enzyme linked immunosorbent assay (ELISA). Hs-CRP levels were detected by automatic biochemical analyzer. Western blotting was used to determine histone deacetylase 2 (HDAC2) protein expression.. Symptoms, pulmonary function and blood gas analysis were significantly improved after treatment in the two groups (P < 0.05) and no significant differences between the two groups (P > 0.05). There were no significant differences of IL-8, TNF-α and hs-CRP levels in the two groups (P > 0.05). Besides, the levels of HDAC2 protein expression before treatment were significantly lower comparing to that after treatment for 4 and 7 days. Incidence of adverse events (heart rate, blood pressure, glycemic, sleep condition, gastrointestinal symptoms) in budesonide group was lower than methylprednisolone group (P < 0.05).. Inhaled budesonide and systemic methylprednisolone have the same effects on systemic inflammation of AECOPD. Inhaled corticosteroid alone could instead systemic corticosteroid in AECOPD treatment.

Topics: Aged; Anti-Inflammatory Agents; Blood Gas Analysis; Budesonide; C-Reactive Protein; Drug Administration Routes; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-8; Male; Methylprednisolone; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Tumor Necrosis Factor-alpha

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous disorders encompassing different phenotypes of airflow obstruction, which might differ in their response to treatment.. The aim of this study was to determine distinct phenotypes comprising the syndromes of asthma and COPD and the treatment responsiveness of these phenotypes to inhaled β-agonist, antimuscarinic, and corticosteroid therapy.. We undertook a cross-sectional study with 3 phases. In phase 1, 1,264 participants aged 18 to 75 years with self-reported current wheeze and breathlessness were identified from a random population sample of 16,459. In phase 2, 451 participants attended for detailed assessment, including responsiveness to inhaled salbutamol and ipratropium bromide. In phase 3, 168 steroid-naive participants were enrolled in a 12-week trial of inhaled budesonide. Cluster analysis was performed in 389 participants who completed phase 2 with full data. Treatment responsiveness was compared between phenotypes.. Cluster analysis identified 5 phenotypes: moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, obese-comorbid, mild childhood-onset atopic asthma, and mild intermittent. Bronchodilation after salbutamol was equal to or greater than that after ipratropium for all phenotypes. The moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, and obese-comorbid phenotypes had greater efficacy with inhaled corticosteroid treatment than the mild intermittent group.. Cluster analysis of adults with symptomatic airflow obstruction identifies 5 disease phenotypes, including asthma-COPD overlap and obese-comorbid phenotypes, and provides evidence that patients with the asthma-COPD overlap syndrome might benefit from inhaled corticosteroid therapy.

Topics: Adolescent; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Airway Obstruction; Albuterol; Anti-Asthmatic Agents; Asthma; Budesonide; Cluster Analysis; Female; Glucocorticoids; Humans; Ipratropium; Male; Middle Aged; Muscarinic Antagonists; Obesity; Phenotype; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Budesonide; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Smoking; Treatment Outcome

The efficacy and tolerability of budesonide/formoterol versus formoterol in patients with moderate to severe chronic obstructive pulmonary disease (COPD) was evaluated.. In this randomized, double-blind, parallel-group, phase III study (NCT01069289), patients with moderate to severe COPD for ≥2 years received either budesonide/formoterol 160/4.5 μg two inhalations twice daily via Turbuhaler® or formoterol 4.5 μg two inhalations twice daily via Turbuhaler® for 12 weeks. Salbutamol was available as reliever medication. Primary outcome variable: change from baseline to average during treatment in pre-dose forced expiratory volume in 1 s (FEV1 ).. One thousand two hundred ninety-three patients were randomized (budesonide/formoterol n = 636; formoterol n = 657). Both budesonide/formoterol and formoterol increased pre-dose FEV1 versus baseline (improvements of 4.6% and 1.5% over baseline, respectively), with the increase from baseline being significantly greater with budesonide/formoterol versus formoterol (budesonide/formoterol:formoterol ratio 1.032; 95% confidence interval: 1.013-1.052; P = 0.0011). The budesonide/formoterol group had a significantly prolonged time to first exacerbation versus the formoterol group (hazard ratio: 0.679; 95% confidence interval: 0.507-0.909; P = 0.0094) and significantly greater improvements in many secondary outcome measures. Both treatments were well tolerated; the incidence and type of adverse events were similar: most commonly reported (budesonide/formoterol vs formoterol): COPD (8.0% vs 9.4%) and nasopharyngitis (5.5% vs 4.9%).. Budesonide/formoterol 160/4.5 μg two inhalations twice daily was effective and well tolerated in patients with moderate to severe COPD, offering benefits over formoterol alone in terms of improved lung function and reduced risk of exacerbation.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Treatment Outcome

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

Assess the cost effectiveness of budesonide/formoterol (BUD/FORM) Turbuhaler(®)+tiotropium (TIO) HandiHaler(®) vs. placebo (PBO)+TIO in patients with chronic obstructive pulmonary disease (COPD) eligible for inhaled corticosteroids/long-acting β2-agonists (ICS/LABA).. The cost-effectiveness analysis was based on the 12-week, randomised, double-blind CLIMB trial. The study included 659 patients with pre-bronchodilator forced expiratory volume in 1 s ≤ 50% and ≥1 exacerbation requiring systemic glucocorticosteroids or antibiotics the preceding year. Patients received BUD/FORM 320/9 μg bid + TIO 18 μg qd or PBO bid + TIO 18 μg qd. Effectiveness was defined as the number of severe exacerbations (hospitalisation/emergency room visit/systemic glucocorticosteroids) avoided. A sub-analysis included antibiotics in the definition of an exacerbation. Resource use from CLIMB was combined with Danish (DKK), Finnish (€), Norwegian (NOK) and Swedish (SEK) unit costs (2010). The incremental cost-effectiveness ratios (ICERs) for BUD/FORM + TIO vs. PBO + TIO were estimated using descriptive statistics and uncertainty around estimates using bootstrapping. Analyses were conducted from the societal and healthcare perspectives in Denmark, Finland, Norway and Sweden.. From a societal perspective, the ICER was estimated at €174/severe exacerbation avoided in Finland while BUD/FORM + TIO was dominant in the other countries. From the healthcare perspective, ICERs were DKK 1580 (€212), €307 and SEK 1573 (€165) per severe exacerbation avoided for Denmark, Finland and Sweden, respectively, while BUD/FORM + TIO was dominant in Norway. Including antibiotics decreased ICERs by 8-15%. Sensitivity analyses showed that results were overall robust.. BUD/FORM + TIO represents a clinical and economic benefit to health systems and society for the treatment of COPD in the Nordic countries. (ClinicalTrials.gov Identifier: NCT00496470).

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Bronchodilator Agents; Budesonide; Cost of Illness; Cost-Benefit Analysis; Double-Blind Method; Drug Combinations; Drug Costs; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Health Care Costs; Health Resources; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scandinavian and Nordic Countries; Scopolamine Derivatives; Sick Leave; Tiotropium Bromide; Treatment Outcome

Pulmonary surfactants are essential components of lung homeostasis. In chronic obstructive pulmonary disease (COPD), surfactant expression decreases in lungs whereas, there is a paradoxical increase in protein expression in plasma. The latter has been associated with poor health outcomes in COPD. The purpose of this study was to determine the relationship of surfactants and other pneumoproteins in bronchoalveolar lavage (BAL) fluid and plasma to airflow limitation and the effects of budesonide/formoterol on this relationship.. We recruited (clinical trials.gov identifier: NCT00569712) 7 smokers without COPD and 30 ex and current smokers with COPD who were free of exacerbations for at least 4 weeks. All subjects were treated with budesonide/formoterol 400/12 µg twice a day for 4 weeks. BAL fluid and plasma samples were obtained at baseline and the end of the 4 weeks. We measured lung-predominant pneumoproteins: pro-Surfactant Protein-B (pro-SFTPB), Surfactant Protein-D (SP-D), Club Cell Secretory Protein-16 (CCSP-16) and Pulmonary and Activation-Regulated Chemokine (PARC/CCL-18) in BAL fluid and plasma.. BAL Pro-SFTPB concentrations had the strongest relationship with airflow limitation as measured by FEV1/FVC (Spearman rho=0.509; p=0.001) and FEV1% of predicted (Spearman rho= 0.362; p=0.028). Plasma CCSP-16 concentrations were also significantly related to airflow limitation (Spearman rho=0.362; p=0.028 for FEV1% of predicted). The other biomarkers in BAL fluid or plasma were not significantly associated with airflow limitation. In COPD subjects, budesonide/formoterol significantly increased the BAL concentrations of pro-SFTPB by a median of 62.46 ng/ml (p=0.022) or 48.7% from baseline median value.. Increased severity of COPD is associated with reduced Pro-SFTPB levels in BAL fluid. Short-term treatment with budesonide/formoterol increases these levels in BAL fluid. Long term studies will be needed to determine the clinical relevance of this observation.

Topics: Aged; Biomarkers; Bronchoalveolar Lavage; Budesonide; Drug Interactions; Ethanolamines; Female; Formoterol Fumarate; Gene Expression Regulation; Humans; Lung; Male; Protein Precursors; Proteolipids; Pulmonary Disease, Chronic Obstructive

Treatment with an inhaled corticosteroid (ICS) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease (COPD) patients with repeated exacerbations. This randomized, double-blind, double-dummy, parallel-group, 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler (pMDI) on COPD exacerbations.. Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs, 1219 patients were randomized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg, budesonide/formoterol pMDI 160/9 μg, or formoterol dry powder inhaler 9 μg. An exacerbation was defined as COPD worsening requiring oral corticosteroids and/or hospitalization. A post hoc analysis, with antibiotic treatment added to the exacerbation definition, was also performed.. Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates (number per patient-treatment year) by 34.6% and 25.9%, respectively, versus formoterol (p ≤ 0.002). Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol, corresponding to a 21.2% reduction in hazard ratio (0.788 [95% CI: 0.639, 0.972]; p = 0.026). Exacerbation rates (number per patient-treatment year) including antibiotic treatment (post hoc analysis) were reduced by 25.9% and 18.7% with budesonide/formoterol 320/9 and 160/9, respectively, versus formoterol (p ≤ 0.023). Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol. Pneumonia adverse events occurred in 6.4%, 4.7%, and 2.7% of patients in the budesonide/formoterol 320/9, 160/9, and formoterol groups.. Over 12 months, both budesonide/formoterol doses reduced the exacerbation rate (defined with or without antibiotic treatment) versus formoterol. Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations. (NCT00419744).

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Smoking; Treatment Outcome; Vital Capacity

To evaluate the efficacy and safety of budesonide (BUD)/formoterol (FORM) compared with BUD, both administered by way of a dry powder inhaler (Turbuhaler * ). * Turbuhaler is a registered trade name of AstraZeneca, Södertälje, Sweden.. This was a 6-month, multicenter, randomized, parallel-group, double-blind, double-dummy design study (NCT 00421122). Patients were randomized to either BUD/FORM 160/4.5 μg, two inhalations twice daily, or BUD 200 μg, two inhalations twice daily. Improvement of lung function, daily symptoms, reliever use and health-related quality-of-life (St George's Respiratory Questionnaire [SGRQ] score) were compared between the two treatment groups.. A total of 308 patients with moderate to very severe COPD from 12 centers in China were randomized to BUD/FORM (n = 156) or BUD (n = 152). The primary endpoint, 1-hour post-dose forced expiratory volume in 1 second (FEV1), in the BUD/FORM group improved by 0.18 L (from 0.83 L at baseline to 1.01 L) and this was significantly better (p < 0.001) than the small increase (0.03 L) observed in the BUD group after 24 weeks' treatment. Increases in pre-dose and 15-min post-dose FEV(1) together with 1-hour post-dose forced vital capacity were also significantly larger with BUD/FORM than BUD (p < 0.001 for all). Compared with BUD alone, BUD/FORM improved COPD total symptom scores (-1.04 ± 0.16 vs. -0.55 ± 0.17; p = 0.03), reduced reliever use (-0.85 ± 0.16 puffs/day vs. -0.31 ± 0.16 puffs/day; p = 0.012) and improved health-related quality-of-life (mean change of total SGRQ score -4.5 points (p = 0.0182). Overall, both treatments were well tolerated.. In Chinese patients with moderate to very severe COPD, fixed combination treatment with BUD/FORM resulted in clinically meaningful improvements in lung function, health-related quality-of-life, COPD symptoms and a reduction in reliever use, compared with BUD alone and both treatments were well tolerated. Treatment of BUD/FORM for milder patients with COPD and head to head comparison of Chinese and Caucasians in future studies will be helpful to expand upon the findings of the current clinical trial.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; China; Double-Blind Method; Drug Combinations; Dry Powder Inhalers; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Treatment Outcome

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of chronic obstructive pulmonary disease (COPD) does not always match with other clinical disease descriptors such as exacerbation frequency and quality of life, indicating that forced expiratory volume in 1 s (FEV(1)) is not a perfect descriptor of the disease. The aim of this study was to find out whether changes in airway geometry after inhalation of the most commonly used inhalation therapy in severe COPD can more adequately be described with an image-based approach than with spirometry. 10 COPD GOLD stage III patients were assessed in a double-blind crossover study. Airway volumes were analysed using segmentation of multi-slice computed tomography (MSCT) images; airway resistance was determined using computational fluid dynamics (CFD). Distal airway volume significantly increased (p=0.011) in patients 4 h after receiving a budesonide/formoterol combination from 9.6±4.67 cm(3) to 10.14±4.81 cm(3). Also CFD-determined airway resistance significantly decreased (p=0.047) from 0.051±0.021 kPa·s·L(-1) to 0.043±0.019 kPa·s·L(-1). None of the lung function parameters showed a significant change. Only functional residual capacity (FRC) showed a trend to decline (p=0.056). Only the image-based parameters were able to predict the visit at which the combination product was administered. This study showed that imaging is a sensitive, complementary tool to describe changes in airway structure.

Topics: Aged; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Hydrodynamics; Image Processing, Computer-Assisted; Lung; Male; Middle Aged; Multidetector Computed Tomography; Placebos; Predictive Value of Tests; Pressure; Pulmonary Disease, Chronic Obstructive; Spirometry; Time Factors

Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60 mg bid during Phase I/IIa development.. This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60 mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George's respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments.. Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo.. Three months' treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Leukocyte Elastase; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pyridones; Quality of Life; Respiratory Mechanics; Sulfones; Treatment Outcome

Effects of β(2)-adrenergic receptor gene (ADRB2) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials. We aimed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD.. Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I (NCT00206167) or the 6-month trial II (NCT00206154) were randomly assigned to bid budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9 μg or 160/9 μg, budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg (trial II), budesonide pMDI 320 μg (trial II), formoterol dry powder inhaler 9 μg, or placebo. The effect of Gly16Arg on predose FEV(1) and 1-h postdose FEV(1), exacerbations, diary variables, and adverse events were analyzed.. No significant interaction between genotype and treatment response was observed for predose (P ≥ .197) or postdose FEV(1) (P ≥ .125) in either pharmacogenetic study (n = 2,866). The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups (both studies). Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment.. Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Tolerance; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2; Treatment Outcome

The use of inhaled corticosteroids in mild to moderate COPD is controversial. The aim of this study was to determine whether airway hyperresponsiveness to mannitol might identify patients who are likely to respond to add-on inhaled corticosteroids.. Ninety subjects with mild to moderate COPD were recruited and 68 subsequently randomized in a double-blind manner to receive inhaled budesonide (1,600 μg/d, n = 31) or placebo (n = 37) for 3 months. Thirty-eight subjects had airway hyperresponsiveness to mannitol (17 received budesonide, 21 placebo). All subjects received tiotropium throughout the study, including 4 weeks before randomization. Spirometry, quality of life (St. George Respiratory Questionnaire), degree of dyspnea, airway responsiveness to mannitol, and exhaled nitric oxide were assessed at week 0 (recruitment), week 4 (baseline prior to randomization), and week 16 (posttreatment).. Compared with placebo, budesonide was associated with improved quality of life in subjects showing airway hyperresponsiveness to mannitol (difference of changes in quality of life score between randomization and study completion, −9.1; 95% CI, −15.8 to −2.3; P < .01). Treatment with inhaled budesonide also led to a reduction in airway responsiveness to mannitol compared with placebo (difference in log10 response-dose ratio, −0.3; 95% CI, −0.6 to −0.04; P < .01). However, postrandomization changes in FEV1 % predicted, quality of life, and exhaled nitric oxide showed no difference between budesonide and placebo.. In subjects with mild to moderate COPD and airway hyperresponsiveness to mannitol, quality of life and airway responsiveness improved after treatment with inhaled corticosteroids added to long-acting bronchodilator therapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Bronchial Hyperreactivity; Budesonide; Diuretics, Osmotic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Mannitol; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Treatment Outcome

In the present study, we examined whether there is a difference in the onset of bronchodilatation between formoterol/beclomethasone 12/200 μg Modulite and formoterol/budesonide 9/320 μg Turbuhaler in patients with COPD. We enrolled 28 patients with stable COPD. Both formoterol/beclomethasone and formoterol/budesonide elicited a larger mean FEV₁-AUC₀₋₁₅min than formoterol alone, whereas there was no significant difference between their FEV₁-AUC₀₋₁₅min. Also the change in FEV₁ 15 min after inhalation of formoterol/beclomethasone combination or formoterol/budesonide combination was greater than that induced by formoterol alone. This study confirms the rapid effect of the inhaled corticosteroid component when combined with formoterol and indicates that the onset of bronchodilation of formoterol/beclomethasone Modulite and formoterol/budesonide Turbuhaler are similar and greater than formoterol alone in patients with COPD.

Topics: Aged; Beclomethasone; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

A new diagnosis of chronic obstructive pulmonary disease (COPD) is often made during the evaluation of patients requiring a surgical intervention for lung cancer. Based on initial impaired lung function, these untreated patients are often considered not fit for lung surgery. There is limited information on the short-term effectiveness of preoperative pharmacologic treatment strategies in patients with newly diagnosed COPD before lung surgery.. A prospective randomized study was conducted comparing 1-week-treatment periods of tiotropium/formoterol/budenoside (GR1) with tiotropium/formoterol (GR2) in conjunction with smoking cessation and chest physiotherapy. No patients had been previously treated for COPD. The primary end point was body plethysmography (forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and airway resistance (RAW)) at the end of each treatment period. Secondary end points were improvement of ≥ 10% in FEV1 (% predicted) and improvement of the severity of COPD after the 1-week treatment, as well as the rate of pulmonary complications after surgery.. A total of 46 patients were randomized in GR1 (n=24) and GR2 (n=22). Both groups were comparable with regard to age, height, weight, smoking history, baseline body plethysmography (FVC, FEV1, and RAW), and the severity of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) staging, respectively. However, the short-term effects of the treatment with regard to FEV1 (2.0 l vs 1.7 l; p=0.031) and increase of FEV1 (0.31 l vs 0.10 l; p=0.02) were better in GR1. More patients in GR1 had an improvement of ≥ 10% in FEV1 (p=0.004) and improvement of the severity of COPD (p=0.012) after the 1-week treatment. Fewer pulmonary complications (11.1% vs 42.9%, p=0.04) were observed in GR1 after surgery.. Both therapies resulted in an improvement of lung function. There is benefit from adding inhalative budenoside to tiotropium and formoterol in terms of an improvement in FEV1 and the severity of COPD. These beneficial results might lead to less pulmonary complications in the postoperative period.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Airway Resistance; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Drug Therapy, Combination; Epidemiologic Methods; Ethanolamines; Forced Expiratory Volume; Humans; Lung Neoplasms; Middle Aged; Plethysmography, Whole Body; Pneumonectomy; Preoperative Care; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Chronic obstructive pulmonary disease (COPD) patients are thought to have limited bronchodilator response, determined by changes in forced expiratory volume in 1s (FEV(1)). In this study, we assessed bronchodilator response in patients with COPD using not only FEV(1) but also changes in lung volume expressed as forced vital capacity (FVC) and inspiratory capacity (IC). We also evaluated the speed of onset of bronchodilation.. Data were from 2 randomized, double-blind, placebo-controlled studies (6-months [NCT00206154]; 12-months [NCT00206167]) in patients with moderate to very severe COPD.. twice daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9μg, budesonide/formoterol pMDI 160/9μg, formoterol dry powder inhaler (DPI) 9μg, placebo.. The percentage of patients with FEV(1) improvement (≥12% and ≥200mL; American Thoracic Society [ATS] criterion) was 34-39% post-albuterol (screening). On day of randomization (DOR), a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min: FEV(1) (57-59%). Similar results were seen for IC (50-61%) and FVC (57-67%) using the same improvement criteria. The time to ≥15% FEV(1) improvement on DOR was 5.0, 4.8, and 7.3min for budesonide/formoterol 320/9, budesonide/formoterol 160/9, and formoterol, respectively. Time to ≥15% FEV(1) improvement was better maintained with budesonide/formoterol than formoterol at treatment end (6 and 12 months).. Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment. Budesonide/formoterol pMDI also has a rapid (within 5min) onset of bronchodilation that is maintained over time compared with formoterol alone.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Spirometry; Vital Capacity

Our study of early intratracheal instillation of budesonide using surfactant as vehicle showed a significant decrease in death or chronic lung disease (CLD) in preterm infants with severe respiratory distress syndrome (RDS). We now report the long-term outcome at about 2 to 3 years of age.. Of the 75 potential survivors, 67 (90%) were studied (35 budesonide-treated, 32 control). All infants had birth weight <1500 g and had severe RDS requiring intermittent mechanical ventilation shortly after birth. The treated group received a mixture of budesonide and surfactant every 8 hours. The control group received only surfactant.. The physical growth and the neurological examinations were comparable between the groups at follow-up. Infants in the group treated with budesonide tended to have higher PDI and MDI scores than infants in the control group (79 +/- 20 vs 74 +/- 18 and 80 +/- 19 vs 75 +/- 20), but these differences were not statistically significant. The incidence of neurodevelopmental impairment was 11 (31%) in the treated group and 13 (40%) in the control group (P = .367).. Early intratracheal instillation of budesonide using surfactant as a vehicle significantly improved pulmonary outcome without causing long-term adverse effects.

Topics: Biological Products; Budesonide; Child Development; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Drug Compounding; Female; Follow-Up Studies; Glucocorticoids; Humans; Infant; Infant, Newborn; Infant, Premature; Instillation, Drug; Male; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactants; Retrospective Studies; Time Factors; Trachea; Treatment Outcome

Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.. Nineteen patients with COPD (FEV(1)/FVC ratio < 0.7; FEV(1) < 60%) completed a double-blind randomized crossover trial of tiotropium 18 microg/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/6 2 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).. Mean +/- SEM for age and FEV(1) were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV(1) (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P= .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.. Budesonide/formoterol caused an unexpected worsening of IOS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result.

Topics: Adrenal Cortex Hormones; Aged; Biological Availability; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Cross-Over Studies; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Humans; Male; Middle Aged; Oscillometry; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Breathlessness and exercise intolerance frequently impact the daily life of patients with COPD.. This double-blind, multicentre, three-period crossover study randomised 111 patients with COPD (mean age 64 years, mean FEV(1) 38% of predicted normal) to budesonide/formoterol 320/9 microg, formoterol 9 microg or placebo, twice daily for 1 week, following a 1-week run-in period with 1-week wash-out between treatments. Terbutaline (0.5 mg/dose) was used as needed. The primary efficacy variable was exercise endurance time (EET) at 75% peak work capacity with cycle ergometry assessed 1 h post-morning dose.. Budesonide/formoterol prolonged EET 1 h post-morning dose versus formoterol by 69 s (P < 0.005) and placebo by 105 s (P < 0.0001) and improved inspiratory capacity (IC) at isotime during exercise versus formoterol by 8% (P = 0.011) and placebo by 16% (P < 0.0001). Borg score at isotime was reduced by 0.48 (P = 0.12) and 0.78 (P = 0.014) compared with formoterol and placebo, respectively. At the repeated cycle test 6 h after morning dose, the effect on EET still favoured budesonide/formoterol over formoterol and placebo, while the isotime IC and Borg score were similar but better than placebo for the active study drugs. Budesonide/formoterol and formoterol improved health status (St George's Respiratory Questionnaire total score: mean difference versus placebo -2.4 and -2.2, respectively). All treatments were well tolerated.. Budesonide/formoterol resulted in a significant improvement in endurance time 1 h after the last morning dose in a 1-week treatment period versus formoterol and placebo. This study demonstrates, for the first time, the benefit of inhaled corticosteroids in addition to long-acting beta(2)-agonists on exercise tolerance in COPD patients. www.clinicaltrials.gov registration number: NCT00489853.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Ethanolamines; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires; Treatment Outcome

Oral corticosteroids and inhaled bronchodilators with or without antibiotics represent standard treatment of COPD exacerbations of moderate severity. Frequent courses of oral steroids may be a safety issue. We wanted to evaluate in an out-patient setting whether a 2-week course of inhaled budesonide/formoterol would be equally effective for treatment of acute COPD exacerbations as standard therapy in patients judged by the investigator not to require hospitalisation.. This was a double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatment strategies; two weeks' treatment with inhaled budesonide/formoterol (320/9 microg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 microg bid) in patients with acute exacerbations of COPD attending a primary health care centre. Inclusion criteria were progressive dyspnoea for less than one week, FEV1 30-60% of predicted normal after acute treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromide and no requirement for subsequent immediate hospitalisation, i.e the clinical status after the acute treatment allowed for sending the patient home.A total of 109 patients (mean age 67 years, 33 pack-years, mean FEV1 45% of predicted) were randomized to two weeks' double-blind treatment with budesonide/formoterol or prednisolone plus formoterol and subsequent open-label budesonide/formoterol (320/9 microg bid) for another 12 weeks. Change in FEV1 was the primary efficacy variable. Non-inferiority was predefined.. Non-inferiority of budesonide/formoterol was proven because the lower limit of FEV1-change (97.5% CI) was above 90% of the efficacy of the alternative treatment. Symptoms, quality of life, treatment failures, need for reliever medication (and exacerbations during follow-up) did not differ between the groups. No safety concerns were identified.. High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in non-hospitalized COPD patients. An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids are used.. NCT00259779.

Topics: Administration, Inhalation; Administration, Oral; Aged; Ambulatory Care; Bronchodilator Agents; Budesonide; C-Reactive Protein; Double-Blind Method; Drug Combinations; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Germany; Glucocorticoids; Humans; Lung; Male; Middle Aged; Prednisolone; Pulmonary Disease, Chronic Obstructive; Quality of Life; Surveys and Questionnaires; Sweden; Time Factors; Treatment Failure; Treatment Outcome

Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study.. This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD.. This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1, 964 patients aged >or =40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo.. The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1. .. Budesonide/formoterol 320/9 microg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001). The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p

Topics: Adult; Aerosol Propellants; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Follow-Up Studies; Forced Expiratory Volume; Formoterol Fumarate; Humans; Hydrocarbons, Fluorinated; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease. Combining these medications may provide additional benefits.. To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting beta(2)-agonist combination therapy.. In this 12-week, randomized, double-blind, parallel-group, multicenter study, after a 2-week run-in, 660 subjects (75% male; mean age, 62 yr; FEV(1), 1.1 L; 38% predicted normal), 40 years of age or older, received tiotropium (18 microg once daily) plus either budesonide/formoterol (320/9 microg) (n = 329) or placebo (n = 331) twice daily.. Clinic predose (primary outcome) and postdose FEV(1), predose and postdose forced vital capacity and inspiratory capacity, and health status were measured. Other outcomes included daily measurements taken at home (pre- and postdose morning FEV(1) and peak expiratory flow, morning symptoms and activities, and morning reliever use), severe exacerbations, and tolerability. Over the treatment period, budesonide/formoterol plus tiotropium significantly increased predose FEV(1) by 6% (65 ml) and postdose by 11% (123 and 131 ml at 5 and 60 min postdose, respectively) versus tiotropium alone (both P < 0.001). Other outcomes all significantly improved with budesonide/formoterol plus tiotropium versus tiotropium alone. The number of severe exacerbations decreased by 62% (rate ratio, 0.38; 95% confidence interval, 0.25-0.57; P < 0.001). Both treatments were well tolerated.. In patients with chronic obstructive pulmonary disease, budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function, health status, morning symptoms and activities, and reduces severe exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT00496470).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Budesonide; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Patients with chronic obstructive pulmonary disease (COPD) often experience symptoms and problems with activities early in the morning. This is the first study to compare the effect of budesonide/formoterol and salmeterol/fluticasone on lung function, symptoms and activities early in the morning.. Lung function (peak expiratory flow [PEF] and forced expiratory volume in 1 second [FEV( 1)]) and symptoms were measured at bedside and activities were measured during the morning using a six-item questionnaire concerning basic morning routines. In a randomised, double-blind, multicentre, cross-over study, 442 patients with COPD aged >or=40 years (pre-bronchodilator FEV(1)

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Surveys and Questionnaires

Airway absorption and bioavailability of inhaled corticosteroids (ICSs) may be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting beta2-agonists, formoterol and salmeterol.. This was a randomized, double-blind, double-dummy, two-way crossover, multicenter study. Following a run-in period, 28 patients with severe COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 37.5% predicted normal) and 27 healthy subjects (mean age 31 years, FEV1 103.3% predicted normal) received two single-dose treatments of budesonide/formoterol (400/12 microg) and salmeterol/fluticasone (50/500 microg), separated by a 4-14-day washout period. ICS concentrations were measured over 10 hours post-inhalation in plasma in all subjects, and over 6 hours in spontaneously expectorated sputum in COPD patients. The primary end point was the area under the curve (AUC) of budesonide and fluticasone plasma concentrations in COPD patients relative to healthy subjects.. Mean plasma AUC values were lower in COPD patients versus healthy subjects for budesonide (3.07 microM x hr versus 6.21 microM x hr) and fluticasone (0.84 microM x hr versus 1.50 microM x hr), and the dose-adjusted AUC (geometric mean) ratios in healthy subjects and patients with severe COPD for plasma budesonide and fluticasone were similar (2.02 versus 1.80; primary end point). In COPD patients, the Tmax and the mean residence time in the systemic circulation were shorter for budesonide versus fluticasone (15.5 min versus 50.8 min and 4.41 hrs versus 12.78 hrs, respectively) and Cmax was higher (1.08 microM versus 0.09 microM). The amount of expectorated fluticasone (percentage of estimated lung-deposited dose) in sputum over 6 hours was significantly higher versus budesonide (ratio 5.21; p = 0.006). Both treatments were well tolerated.. The relative systemic availabilities of budesonide and fluticasone between patients with severe COPD and healthy subjects were similar. In patients with COPD, a larger fraction of fluticasone was expectorated in the sputum as compared with budesonide.. Trial registration number NCT00379028.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Area Under Curve; Biological Availability; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Combinations; England; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2; Severity of Illness Index; Sputum; Sweden; Young Adult

Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation as a result of chronic inflammation of the airways and lung parenchyma. COPD patients always have airway hyperreactivity (AHR), so how to reduce AHR becomes the key purpose of clinical treatment. It is hypothesized that combined inhalation of corticosteroids and beta2-agonists can reduce the AHR in COPD. In this study, atomization inhalation of budesonide and terbutaline plus conventional therapies was applied to treat AECOPD (acute exacerbation of chronic obstructive pulmonary disease) patients for two weeks. The results showed that additional inhalation of budesonide and terbutaline could upregulate serum IL-2 levels, the percentages of CD3+ T and CD4+ T cells, and CD4/CD8 ratio, and decrease eosinophils and serum CRP level more efficiently than conventional treatment in patients with AECOPD. And the lung function of the atomization inhalation group was improved more obviously after the treatment compared with the conventional treatment group. Thus, atomization inhalation of terbutaline and budesonide can control AECOPD effectively, and has wide clinical perspective in controlling and preventing the exacerbation of COPD.

Topics: Administration, Inhalation; Aged; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; C-Reactive Protein; Eosinophils; Female; Humans; Interleukin-2; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; T-Lymphocyte Subsets; Terbutaline

The combination of an inhaled corticosteroid (ICS) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. Budesonide/formoterol dry powder inhaler (DPI) has demonstrated efficacy and tolerability in patients with COPD.. To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) in patients with COPD.. This was a 6-month, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre study (NCT00206154) of 1704 patients aged > or =40 years with moderate to very severe COPD conducted in 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa. After 2 weeks of treatment based on previous therapy (ICSs and short-acting bronchodilators allowed during the run-in period), patients received one of the following treatments administered twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) plus formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo.. The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV(1)) and 1-hour post-dose FEV(1).. Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1) versus formoterol (p = 0.026; pre-specified primary comparator) and 1-hour post-dose FEV(1) versus budesonide (p < 0.001; pre-specified primary comparator); budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide (p < 0.001) for 1-hour post-dose FEV(1) but not versus formoterol for pre-dose FEV(1). Dyspnoea (measured using the Breathlessness Diary) and health-related quality-of-life (HR-QOL) scores (based on the St George's Respiratory Questionnaire total score) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide, formoterol and placebo (p < or = 0.044 for all). Although not powered a priori for comparisons, the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and/or hospitalization was numerically (20-25%) lower with the budesonide-containing treatments (0.710-0.884) versus formoterol (1.098) and placebo (1.110). This result was driven by the exacerbations requiring treatment with oral corticosteroids (79-120 events). The number of exacerbations resulting in hospitalization was very low across treatment groups (11-22); the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg (0.158) versus other treatment groups (0.081-0.108) except budesonide/formoterol 160/9 microg (0.139), and for budesonide/formoterol 160/9 microg versus formoterol (0.081) [p < or = 0.05]. All treatments were generally well tolerated. The incidence of individual non-fatal serious adverse events was similar across all treatment groups, except COPD, which was highest in the budesonide/formoterol 320/9 microg group (6.1%) and lowest in the budesonide (3.6%) and formoterol (3.9%) groups, with a range of 4.3-4.6% in the budesonide/formoterol 160/9 microg, budesonide plus formoterol and placebo groups. Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo. There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo.. Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co-primary endpoints versus the pre-specified comparators (formoterol DPI 9 microg for pre-dose FEV(1) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1)). Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1) versus budesonide pMDI 320 microg. Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo. Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo.

Topics: Adult; Aerosol Propellants; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests

Systemic corticosteroids and additional short-acting beta2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting beta2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV(1)), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV(1) 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 microg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV(1) by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16%; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations.

Topics: Administration, Inhalation; Administration, Oral; Aged; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Eosinophils; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Prednisolone; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Treatment Outcome

A beneficial effect of long-term corticosteroid treatment in patients with COPD may be linked to suppressing inflammation, in particular neutrophilic inflammation. Effects on neutrophilic and eosinophilic inflammation and on lung function of long-term inhaled budesonide treatment (800 microg daily, 6 months, double-blind, randomised, cross-over versus placebo) were studied and compared to the effects of 3 weeks oral prednisolone (30 mg daily) in 19 patients with COPD (mean age 63 y, FEV(1) 65% of predicted). Neither treatment influenced neutrophilic inflammation. Inhaled budesonide compared to placebo significantly reduced sputum % eosinophils at 3 months (-42%, p = 0.036), but not significantly at 6 months (-31%, p = 0.78). Eosinophil count per g sputum was decreased with 30% at 3 months (p = 0.09) and with 9% at 6 months (p = 0.78). FEV(1) was slightly higher after 6 months budesonide (+2.5% predicted, p = 0.09). Prednisolone significantly reduced sputum % eosinophils (-87%, p = 0.007), but did not affect eosinophil count per g sputum and did not improve FEV(1) (-0.6% predicted, p = 0.40). A higher baseline FEV(1) (%) correlated with effects of budesonide on FEV(1) (p < 0.001), effects on sputum interleukin-8 and eosinophil cationic protein (both p < 0.05) and tended to correlate with effects on sputum % eosinophils (p = 0.056). Baseline inflammatory data and effects of prednisolone did not correlate with effects of budesonide. Effects of inhaled budesonide in COPD are not restricted to patients with severe disease and may be linked to a suppression of eosinophilic inflammation. Investigating effects of prednisolone has no predictive value for long-term treatment.

Topics: Administration, Inhalation; Administration, Oral; Aged; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Eosinophils; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Male; Middle Aged; Neutrophils; Prednisolone; Pulmonary Disease, Chronic Obstructive; Sputum

The present study was designed to evaluate the hypothesis that nebulised budesonide (NB) might be an alternative to systemic corticosteroids (SC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (ECOPD). Patients hospitalised with ECOPD (n = 159) were randomised into three groups. Group 1 received only standard bronchodilator treatment (SBDT), group 2 received SC (40 mg prednisolone) plus SBDT, and group 3 received NB (1,500 microg q.i.d.) plus SBDT. Improvement during 10-day hospitalisation was compared with exacerbation and rehospitalisation rates after discharge. While mean+/-sd age was 64.1+/-8.9 yrs (female/male = 0.1), mean forced expiratory volume in one second (FEV(1)) at admission was found to be 37.2+/-12.2% predicted. Arterial blood gases and spirograms recovered faster in groups 2 and 3. While improvements in arterial oxygen tension (P(a,O(2))) and forced vital capacity (FVC) in group 2, and improvements in P(a,O(2)), FVC and FEV(1) in group 3, became significant at 24-h control, the first significant improvement in group 1 appeared in arterial oxygen saturation at 72-h control. The mean improvement of P(a,O(2)) after 10 days was 1.20 and 1.06 kPa (9 and 8 mmHg) higher in group 2 and 3, respectively, than in group 1. Blood glucose exhibited an upward trend only in group 2. The study demonstrates that nebulised budesonide may be an effective and safe alternative to systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease.

Topics: Aged; Blood Gas Analysis; Bronchodilator Agents; Budesonide; Disease Progression; Female; Forced Expiratory Volume; Humans; Inpatients; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Spirometry; Treatment Outcome

Data on the onset of action of COPD medications are lacking. This study compared the onset of bronchodilation following different inhaled therapies in patients with moderate-to-severe COPD and reversible airway obstruction.. In this double-blind, double-dummy, crossover study, 90 patients (aged >or=40 years; FEV(1) 30-70% predicted) were randomized to a single dose (two inhalations) of budesonide/formoterol 160/4.5 microg, salmeterol/fluticasone 25/250 microg, salbutamol 100 microg or placebo (via pressurized metered-dose inhalers) on four visits. The primary end-point was change in FEV(1) 5 min after drug inhalation; secondary end-points included inspiratory capacity (IC) and perception of onset of effect.. Budesonide/formoterol significantly improved FEV(1) at 5 min compared with placebo (P < 0.0001) and salmeterol/fluticasone (P = 0.0001). Significant differences were first observed at 3 min. Onset of effect was similar with budesonide/formoterol and salbutamol. Improvements in FEV(1) following active treatments were superior to placebo after 180 min (all P < 0.0001); both combinations were better than salbutamol at maintaining FEV(1) improvements (P

Topics: Adrenal Cortex Hormones; Adult; Aged; Airway Obstruction; Albuterol; Androstadienes; Anti-Asthmatic Agents; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Cross-Over Studies; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Spirometry; Time Factors

Because additive effects of inhaled corticosteroids and long-acting anticholinergics are unclear, we undertook this study to compare the efficacy of tiotropium alone and tiotropium plus budesonide in patients with chronic obstructive pulmonary disease. The study subjects were randomized to receive either tiotropium 18 microg once daily with or without budesonide 200 microg twice daily for 6 weeks. The efficacy variables were changes in trough forced expiratory volume in one second (FEV1), St. George's Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), and use of rescue medication. One hundred patients were randomized and 81 completed the study. The mean age was 64.0 yr, and the mean FEV1 was 39.7% predicted. Compared with tiotropium alone (N=40), the tiotropium/budesonide combination (N=41) was related to an improvement in the SGRQ total score (tiotropium -2.8 units and tiotropium/budesonide -5.6 units, p=0.003). 6MWD was improved by 13.5 m in the tiotropium group and by 22.5 m in the tiotropium/budesonide group (p=0.031). Changes in trough FEV1 and the use of rescue medication were similar between two groups. In conclusion, compared with tiotropium alone, the tiotropium/budesonide combination was related to an improved health-related quality of life. These data support that low-dose budesonide may enhance the efficacy of tiotropium.

Topics: Aged; Bronchodilator Agents; Budesonide; Exercise; Female; Humans; Male; Middle Aged; Models, Statistical; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Patients with severe chronic airway obstruction might suffer dangerous hypoxemia after administration of a beta-agonist despite bronchodilation.. We first compared the acute effects on gas exchange of two doses of formoterol Turbuhaler (9 and 18 microg) in 10 patients with acute exacerbation of COPD. Afterwards, we compared the acute effects of formoterol Turbuhaler 9 microug with those of formoterol/budesonide combination in a single inhaler (Turbuhaler) 9/320 microg in 10 other patients with acute exacerbation of COPD. Finally, we compared the changes in PaO(2) induced by formoterol Turbuhaler 9 microg or formoterol/budesonide combination in a single inhaler (Turbuhaler) 9/320 microg with those in FEV(1) in 10 other patients with acute exacerbation of COPD. Each agent was given on separate days, and the patients' arterial blood gases were measured at baseline and at intervals of 120 min.. Small but statistically significant declines in PaO(2) were found after administration of both formoterol 9 and 18 microg. In the second group of patients, formoterol 9 microg alone again induced a significant decrease in PaO(2). However, the simultaneous administration of budesonide 320 microg significantly reduced the acute effect of formoterol on PaO(2). In a third group of 10 patients we confirmed a small but significant decrease in PaO(2) after formoterol alone and the reduction of this effect when budesonide was administered simultaneously. Moreover, we also documented that addition of budesonide amplified the fast onset of action of formoterol.. These results suggest that when treating patients suffering from acute exacerbation of COPD with formoterol, it is prudent to check their arterial blood gases. In any case, combined administration of formoterol and budesonide reduces the potential for acute effects of formoterol on blood-gas tensions.

Topics: Acute Disease; Administration, Inhalation; Adrenergic beta-Agonists; Aged; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Combinations; Ethanolamines; Forced Expiratory Volume; Formoterol Fumarate; Humans; Middle Aged; Nebulizers and Vaporizers; Oxygen; Partial Pressure; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

In 20 COPD patients (FEV(1) < or =65% predicted, IC<80% predicted), we evaluated changes in the degree of pulmonary hyperinflation after acute administration of tiotropium 18 microg or budesonide/formoterol 320/9 microg. The study consisted of a screening visit and two study days separated by at least one week. Functional parameters were measured before and 30, and 120 min after inhalation of single study drug. Both tiotropium and budesonide/formoterol induced significant changes in functional parameters after 30 and 120 min. However, the impact of tiotropium on the degree of pulmonary hyperinflation was larger than that of budesonide/formoterol, although only differences in IC and TGV between the two treatments were significant (P<0.05), at least after 120 min, whereas those in RV were not significant. The documentation that tiotropium is able to modify IC even after an acute administration indicates its capacity of influencing expiratory flow limitation in a very fast manner and this is an important finding. In fact, changes in IC after bronchodilators in patients with COPD with expiratory flow limitation at rest may represent an objective tool for prescribing these drugs to attain symptomatic improvement and better quality of life, even in the absence of a significant increase in FEV(1).

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Ethanolamines; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Inspiratory Capacity; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease (COPD) remains controversial. The purpose of this study was to evaluate whether sputum eosinophilia (defined as eosinophils > or = 3%) predicts clinical benefit from inhaled corticosteroid treatment in patients with smoking-related clinically stable moderate-to-severe COPD. Forty consecutive patients with effort dyspnoea (mean age 67 yrs; 52 pack-yr smoking history; post-bronchodilator forced expiratory volume in one second (FEV1) <60% predicted, consistent with moderate-to-severe smoking-related chronic airflow limitation) were enrolled. Subjects were treated with inhaled placebo followed by inhaled budesonide (Pulmicort Turbuhaler 1,600 microg.day(-1)), each given for 4 weeks. While the treatment was single-blind (subject level), sputum cell counts before and after treatment interventions were double-blind, thus removing bias. Outcome variables included spirometry, quality-of-life assessment and 6-min walk test. Sputum eosinophilia was present in 38% of subjects. In these, budesonide treatment normalised the eosinophil counts and, in comparison to placebo treatment, resulted in clinically significant improvement in the dyspnoea domain of the disease-specific chronic respiratory questionnaire (0.8 versus 0.3) and a small but statistically significant improvement in post-bronchodilator spirometry (FEV1 100 mL versus 0 mL; p<0.05). In conclusion, sputum eosinophilia predicts short-term clinical benefit from high-dose inhaled corticosteroid treatment in patients with stable moderate-to-severe chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Budesonide; Cross-Over Studies; Eosinophilia; Eosinophils; Female; Glucocorticoids; Humans; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Single-Blind Method; Smoking; Sputum

Although chronic obstructive pulmonary disease (COPD) patients frequently report symptoms, it is not known which factors determine the course of symptoms over time and if these differ according to the sex of the patient. The current study investigated predictors for presence, development and remission of COPD symptoms in 816 males and 312 females completing 3-yr-follow-up in the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP). The following were included in generalised estimating equations logistic regression analyses: explanatory variables of treatment; pack-yrs smoking; age, forced expiratory volume in one second % predicted (FEV1 % pred); annual increase in FEV1 and number of cigarettes smoked; body mass index; and phadiatop. Interaction terms of sex multiplied by explanatory variables were tested. Over 3 yrs, similar proportions of males and females reported symptoms. In males only, higher FEV1 % pred was associated with reduction in new symptoms of wheeze and dyspnoea, and symptom prevalence was reduced with annual FEV1 improvement and phlegm prevalence reduced with budesonide treatment (odds ratio 0.66; 95% confidence interval 0.52-0.83). Additionally an increase in the number of cigarettes smoked between visits increased the risk of developing phlegm (1.40 (1.14-1.70)) and wheeze (1.24 (1.03-1.51)) in males but not females. The current study shows longitudinally that symptom reporting is similar by sex. The clinical course of chronic obstructive pulmonary disease can differ by sex, as males show greater response to cigarette exposure and treatment.

Topics: Adult; Aged; Body Mass Index; Bronchodilator Agents; Budesonide; Dyspnea; Europe; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Remission Induction; Respiratory Sounds; Sex Factors; Smoking

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 characterised by a chronic inflammatory process in the large and small airways, as well as in the lung parenchyma. Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented, its role in stable COPD is not clear. We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 (IL-8) levels in bronchoalveolar lavage (BAL) and their correlation with spirometry and symptom scores. Twenty-six patients with stable COPD were randomised, in a double-blinded, placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period. The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy (mean+/-sem, 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months, P=0.004) and a reduction in the mean percentages of neutrophils (17.16+/-2.67% vs. 13.25+/-2.28% P=0.002). The improvement in sputum production was of borderline (P=0.058) significance but there was no improvement in lung function. In stable patients with COPD, treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation, as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL.

Topics: Administration, Inhalation; Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Glucocorticoids; Humans; Interleukin-8; Lymphocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Spirometry; Statistics, Nonparametric; Time Factors

Bronchodilator therapy is the first step treatment in patients with COPD. The beneficial effects of corticosteroids either in health status or in airway inflammation in COPD have been previously studied. The aim of this study was to evaluate whether adding inhaled corticosteroids to combined bronchodilator therapy has additive clinical and anti-inflammatory effects in COPD patients.. Thirty patients with COPD were included in the study. All patients were receiving inhaled anticholinergic and long-acting beta-2 agonist. Inhaled corticosteroid (budesonide 800 microg daily) was added to their current medications for 12 weeks. Before and after this treatment period, spirometric values and arterial blood gas parameters were determined, blood was drawn for measurement of serum inflammatory markers and sputum was induced.. All patients were male, mean age was 67.7+/-8.7 years and duration of disease was 9.7+/-4.3 years. The induced sputum total cell counts, eosinophil and neutrophil counts decreased with corticosteroid treatment. The induced sputum IL-8 and TNF-alpha levels decreased significantly (IL-8; 835.9+/-217 versus 378.4+/-105 pg/ml, p=0.0001, TNF-alpha; 320.7+/-129 versus 201.3+/-52 pg/ml, p=0.003). Serum inflammatory markers and sputum LTB4 levels did not change with treatment.. These results suggested that the addition of inhaled corticosteroids to combined bronchodilator therapy might have anti-inflammatory effects in patients with COPD.

Topics: Administration, Inhalation; Aged; Biomarkers; Bronchodilator Agents; Budesonide; Combined Modality Therapy; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Treatment Outcome

Budesonide/formoterol is a fixed-dose combination of the corticosteroid budesonide and the long-acting beta2-agonist formoterol, and is inhaled via the Turbuhaler device. In two large, randomised, double-blind, 12-month studies, patients with severe chronic obstructive pulmonary disease (COPD) receiving budesonide/formoterol 320/9 microg twice daily had a significantly higher forced expiratory volume in 1 second (FEV1) and significantly higher morning and evening peak expiratory flow at trial endpoint than recipients of budesonide or placebo; FEV1 was significantly higher than with formoterol in the larger study. In both studies, the rate of COPD exacerbations and exacerbations requiring oral corticosteroids was significantly reduced with budesonide/formoterol versus formoterol and placebo. Moreover, the time to first exacerbation was significantly prolonged with budesonide/formoterol versus all other treatment arms in the larger study. At 12 months, significant improvements in health-related quality-of-life scores were seen with budesonide/formoterol versus placebo in both studies. The reduction in total and individual symptom scores was significantly greater with budesonide/formoterol than with budesonide or placebo in the smaller study. Budesonide/formoterol was generally well tolerated by patients with severe COPD. The tolerability profile of the combination was similar to that of the individual components with no increase in the incidence of adverse events.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Anti-Inflammatory Agents; Budesonide; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life

Formoterol is a beta(2)-agonist bronchodilator that combines a fast onset of action with a long duration of broncholytic effect. An increasing documentation is showing that the combination of a long acting beta(2)-adrenoceptor agonist bronchodilator and an inhaled corticosteroid targets the airways obstruction in patients with COPD. In this study, we have explored whether the acute addition of an inhaled corticosteroid influences the fast bronchodilator response to formoterol. A total of 20 patients with stable COPD were randomized. Single doses of formoterol/budesonide 2 x (4.5/160)microg or formoterol 2 x 4.5 microg were given via Turbuhaler. Serial measurements of FEV(1) were performed over 60 min. Formoterol/budesonide elicited a significantly larger mean FEV(1)-AUC(0-15 min) than formoterol alone. Also the change in FEV(1) 15 min after inhalation of formoterol/budesonide combination (0.197 l; 95% CI: to 0.142-0.252) was greater than that induced by formoterol alone (0.147 l; 95% CI: to 0.092-0.201). The mean increases in FEV(1) were always higher after budesonide/formoterol than formoterol alone, although both treatments induced a significant improvement over baseline at each explored time point. Even the FEV(1)-AUC(0-60 min) after formoterol/budesonide was significantly larger than that after formoterol. Both treatments induced a significant reduction in VAS score but did not modify heart rate in a statistically significant manner. This study indicates that the addition of budesonide influences the fast onset of action of formoterol, but does not induce systemic effects, in patients with stable COPD.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

Withdrawal of corticosteroid is associated with a deterioration of health status in COPD. In this study the aim was to determine whether high dose inhaled corticosteroid improves quality of life in patients with COPD.. In total, 38 male patients with moderate COPD were included in the study. Baseline quality of life scores were determined using a Turkish version of the St George's Respiratory Questionnaire (SGRQ). Patients were randomly divided into two groups. Group 1 consisted of 20 patients who received existing bronchodilator therapy plus inhaled corticosteroid (800 micro g budesonide) for 12 weeks, while 18 patients in group 2 received bronchodilator and placebo. The SGRQ was repeated after the treatment period.. All patients were male and mean age was 67 +/- 8.2 years. Symptom, activity, impact, and total scores were assessed and a difference of four units with treatment was considered to be clinically significant. Total score and activity score were decreased by six units and eight units, respectively, in the placebo group while symptom and impact scores did not change significantly. Total scores and the three component scores improved significantly in the corticosteroid group compared to the placebo group (Deltatotal score: -22 in corticosteroid group, -6 in placebo group, P < 0.01).. Inhaled corticosteroid improved quality of life scores in patients with COPD, without significant improvement in airflow obstruction parameters. Since improvement of health status is one of the important aims in COPD treatment, use of inhaled corticosteroids should be considered from this perspective.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Budesonide; Carbon Dioxide; Double-Blind Method; Drug Therapy, Combination; Health Status; Humans; Male; Middle Aged; Oxygen; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests

The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo, budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In a 12-month, randomised, double-blind, placebo-controlled, parallel-group study in 812 adults (mean age 64 yrs, mean forced expiratory volume in one second (FEV1) 36% predicted normal), patients received two inhalations twice daily of either budesonide/formoterol (Symbicort) 160/4.5 microg (delivered dose), budesonide 200 microg (metered dose), formoterol 4.5 microg or placebo. Severe exacerbations and FEV1 (primary variables), peak expiratory flow (PEF), COPD symptoms, health-related quality of life (HRQL), mild exacerbations, use of reliever beta2-agonist and safety variables were recorded. Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24% versus placebo and 23% versus formoterol. FEV1 increased by 15% versus placebo and 9% versus budesonide. Morning PEF improved significantly on day 1 versus placebo and budesonide; after 1 week, morning PEF was improved versus placebo, budesonide and formoterol. Improvements in morning and evening PEF versus comparators were maintained over 12 months. Budesonide/formoterol decreased all symptom scores and use of reliever beta2-agonists significantly versus placebo and budesonide, and improved HRQL versus placebo. All treatments were well tolerated. These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Time Factors

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

Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown. COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV1) 36% predicted) initially received formoterol (9 microg b.i.d.) and oral prednisolone (30 mg o.d.) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 microg, budesonide 400 microg, formoterol 9 microg or placebo for 12 months. Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254 versus 96 days) and maintained higher FEV1 (99% versus 87% of baseline), both primary variables versus placebo. They had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (-7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables. Budesonide/formoterol in a single inhaler (Symbicort) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Budesonide; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Powders; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

There is a need for studying the effects of long-term inhaled corticosteroid therapy on bone mineral density (BMD) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease (COPD). Patients (n=912, mean age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV1) 77% of predicted; mean FEV1/slow vital capacity ratio 62%) were randomized to receive budesonide 400 microg, or placebo twice daily via Turbuhaler. BMD was measured at the L2-L4 vertebrae and the femoral neck, trochanter and Ward's triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24 and 36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment (n=653). Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%). New fractures occurred in five budesonide-treated patients, compared with three in the placebo group (p=0.50). There were no significant changes in BMD at any site in budesonide-treated patients, compared with the placebo group, during the course of the study. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin. In the present study, involving a large group of patients with chronic obstructive pulmonary disease, long-term treatment with budesonide 800 microg x day(-1) via Turbuhaler had no clinically significant effects on bone mineral density or fracture rates.

Topics: Administration, Inhalation; Adult; Aged; Anti-Inflammatory Agents; Bone Density; Budesonide; Female; Humans; Male; Middle Aged; Osteocalcin; Osteoporosis; Pulmonary Disease, Chronic Obstructive; Radiography; Risk Factors; Spinal Fractures

Nebulized budesonide has been used successfully to treat acute asthma exacerbation, and we hypothesized that it could also be effective for exacerbations of chronic obstructive pulmonary disease (COPD). In this multicenter, double-blind, randomized, placebo-controlled trial, the efficacy of nebulized budesonide (Pulmicort Respules/Nebuamp), oral prednisolone, and placebo was compared in 199 patients with acute exacerbations of COPD requiring hospitalization. Patients received from randomization (H(0)) to 72 h (H(72)), 2 mg of budesonide every 6 h (n = 71), 30 mg of oral prednisolone every 12 h (n = 62), or placebo (n = 66). All received standard treatment, including nebulized beta(2)-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. The mean change (95% confidence interval) in postbronchodilator FEV(1) from H(0) to H(72) was greater with active treatments than with placebo: budesonide versus placebo, 0.10 L (0.02 to 0.18 L); prednisolone versus placebo, 0.16 L (0.08 to 0.24 L). The difference in FEV(1) between budesonide and prednisolone was not significant, -0.06 L (-0.14 to 0.02 L). The occurrence of serious adverse events was similar for all groups. Budesonide had less systemic activity than prednisolone as indicated by a higher incidence of hyperglycemia observed with prednisolone. Both budesonide and prednisolone improved airflow in COPD patients with acute exacerbations when compared with placebo. Nebulized budesonide may be an alternative to oral prednisolone in the treatment of nonacidotic exacerbations of COPD but further studies should be done to evaluate its long-term impact on clinical outcomes after an initial episode of COPD exacerbation.

Topics: Acute Disease; Administration, Oral; Aged; Budesonide; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Prednisolone; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Vital Capacity

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

The aim ofthe study was to investigate changes in inflammatory markers following emergency treatment of obstructive pulmonary disease. The study comprised 43 patients. After acute treatment, they were given either 30 mg of prednisolone p.o. or 1600 microg of inhaled budeson de daily for 1 week. Over the following 3 weeks, all the patients were given 1600 microg of inhaled budesonide daily. Blood samples for measurements of eosinophil cationic protein (S-ECP), eosinophil peroxidase (S-EPO), total eos nophil count (B-Eos), myeloperoxidase (S-MPO) and human neutrophil lipocaline (HNL) were taken and spirometry was performed before emergency treatment and after 1 and 4 weeks. There was no difference in the improvement in forced expiratory volume in 1 sec (FEV1) between patients given prednisolone or budesonide. Patients with an improvement in FEV1 of >20% of baseline after 1 and 4 weeks displayed a larger decrease in eosinophil markers. The correlation between deltaFEV1 and deltaS-ECP was r= -0.37, P < 0.05, deltaS-EPO -0.40, P < 0.01 and deltaB-Eos -0.44, P < 0.01, after 4 weeks. This correlation was highly significant in patients who had smoked < or = 5 pack-years, while the correlation was not significant in patients with a longer smoking history and chronic airflow limitation (best FEV <80% of predicted). We conclude that the change in eosinophil markers is correlated to the improvement in lung function in non-smokers or short-term smokers following the emergency treatment of obstructive pulmonary disease. This study indicates that following eosinophil markers is more useful in patients with asthma than patients with COPD.

Topics: Acute Disease; Acute-Phase Proteins; Adult; Aged; Anti-Inflammatory Agents; Biomarkers; Blood Proteins; Bronchodilator Agents; Budesonide; Carrier Proteins; Chi-Square Distribution; Eosinophil Granule Proteins; Eosinophil Peroxidase; Eosinophils; Female; Forced Expiratory Volume; Humans; Lipocalin-2; Lipocalins; Male; Middle Aged; Oncogene Proteins; Peroxidase; Peroxidases; Prednisolone; Proto-Oncogene Proteins; Pulmonary Disease, Chronic Obstructive; Ribonucleases; Smoking; Statistics, Nonparametric

To investigate the clinical efficacy of combining budesonide formoterol with tiotropium bromide for treating asthma-chronic obstructive pulmonary disease overlap syndrome (AOCS).. The data of 104 patients with AOCS admitted to our hospital from December 2019 to December 2020 were assessed, randomly and divided into an experimental group (comprising 52 patients, receiving drug combination therapy) and a conventional group (comprising 52 patients, receiving drug therapy alone). Patients' clinical efficacy, pulmonary function, fractioned exhaled nitric oxide (FeNO), immune function, endothelial function, serum lipid peroxidation injury indexes, adverse reactions, and quality of life scores were compared.. Prior to treatment, no significant differences were observed in various pulmonary function indicators, FeNO, immune function, endothelial function, and lipid peroxidation injury indexes between the two groups (. The combination of budesonide formoterol to tiotropium bromide in treating asthma-COPD overlap syndrome may significantly improve pulmonary function, endothelial function, and immune status of patients and encourage the recovery of serum lipid peroxidation injury; therefore, this may deserve widespread adoption and application.

Topics: Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Bronchiolitis obliterans syndrome (BOS) is the lung manifestation of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We assessed whether inhaled tiotropium add-on to the combination regimen including budesonide/formoterol improve pulmonary function and the chronic obstructive pulmonary disease assessment test (CAT) scores in patients with BOS.. Post-HSCT patients diagnosed as BOS in Seoul St. Mary's Hospital were reviewed retrospectively. Patients defined as BOS and treated with budesonide/formoterol/tiotropium combination therapy after budesonide/formoterol therapy from January 2011 to June 2019 were enrolled.. Total of 86 patients were evaluated. After tiotropium add-on, the absolute FEV1 increased significantly from 1.47 ± 0.49 to 1.53 ± 0.57 L (p = 0.023) and the % predicted FEV1 from 45.0 ± 12.8 to 46.8 ± 14.5% (p = 0.031). The % predicted DLCO increased significantly after tiotropium add-on (from 61.6 ± 16.7 to 64.3 ± 16.3%, p = 0.028). Among 56 patients with complete CAT scores, no significant change was present in total CAT scores. In all, 30 of the 72 patients (41.7%) evidenced FEV1 increases > 100 mL, and 20 of 56 patients (35.7%) had CAT score decreases of ≥ 2 points. When the FEV1 and CAT scores were combined, the overall response rate to tiotropium add-on was 56.2% (41/73). The response group evidenced a significantly greater FVC increase, and a significant decrease in the RV/TLC ratio compared to the no-response group.. Inhaled tiotropium add-on to combination budesonide/formoterol significantly improved lung function, but not respiratory symptoms, in patients with post-HSCT BOS.

Topics: Bronchiolitis Obliterans; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Hematopoietic Stem Cell Transplantation; Humans; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Tiotropium Bromide

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

Triple therapy to prevent exacerbations from chronic obstructive pulmonary disease (COPD) is associated with improved health compared to single and dual-agent therapy in some populations. This study assessed the benefits of prompt administration of budesonide/glycopyrrolate/formoterol fumarate (BGF) following a COPD exacerbation.. EROS was a retrospective analysis of people with COPD using the MORE. 2409 patients were identified: 434 prompt, 1187 delayed, and 788 very delayed. The rate (95% CI) of total exacerbations post-index increased as time to BGF initiation increased: prompt 1.52 (1.39-1.66); delayed 2.00 (1.92-2.09); and very delayed 2.30 (2.20-2.40). Adjusting for patient characteristics, each 30-day delay in receiving BGF was associated with a 5% increase in the average number of subsequent exacerbations (rate ratio, 95% CI: 1.05, 1.01-1.08;. Following a COPD exacerbation, promptly initiating BGF was associated with a reduction in subsequent exacerbations and reduced healthcare utilization and costs.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Metered Dose Inhalers; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Retrospective Studies

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

Here we present pharmacological and clinical properties of a new fixed triple inhaled combination including an inhaled corticoid, a long acting ?2 agonist and a long acting anticholinergic for the treatment of severe chronic obstructive pulmonary disease (COPD). Trixeo Aerosphere® is the name of this triple combination which contains 160 µg budesonide, 4,8 µg formoterol and 9 µg glycopyrronium delivered by a pMDI. As compared to a budesonide/formoterol combination, Trixeo Aerosphere® improves forced expiratory volume in the first second (FEV1). As compared to glycopyrronium/formoterol combination, Trixeo Aerosphere® reduces exacerbation rate, improved quality of life and most importantly reduces mortality with a benefit increasing with blood eosinophil count. Trixeo Aerosphere® 320/18/9.6 is delivered twice daily 2 inhalations and is indicated in moderate to severe COPD insufficiently controlled by LABA/LAMA (long-acting ?2-adrenergic receptor agonist/ long-acting ?2-muscarinic receptor agonist) or ICS/LABA (inhaled corticosteroid/long-acting ?2-adrenergic receptor agonist).. Nous présentons dans cet article les propriétés pharmacologiques et les effets cliniques d’une nouvelle triple combinaison fixe inhalée comprenant un corticoïde inhalé, un ?2 mimétique à longue durée d’action et un anticholinergique à longue durée d’action, destinée au traitement de la bronchopneumopathie chronique obstructive (BPCO) sévère. Cette combinaison qui porte le nom de Trixeo Aerosphere® regroupe, dans le même dispositif, 160 µg de budésonide, 4,8 µg de formotérol et 18 µg de glycopyrronium. Par rapport à une combinaison budésonide/formotérol, le Trixeo Aerosphere® améliore la valeur du volume expiratoire maximum par seconde (VEMS). Par rapport à une combinaison formotérol/glycopyrronium, le Trixeo Aerosphere® réduit la fréquence des exacerbations et réduit la mortalité avec un bénéfice qui augmente avec le taux des éosinophiles circulants. Le Trixeo Aerosphere®, à la dose de 2X2 bouffées/24h, est indiqué dans le traitement des patients BPCO modérés à sévères insuffisamment contrôlés par une bithérapie LABA/LAMA (long-acting ?2-adrenergic receptor agonist/ long-acting ?2-muscarinic receptor agonist) ou ICS/LABA (inhaled corticosteroid/long-acting ?2-adrenergic receptor agonist).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic Agonists; Bronchodilator Agents; Budesonide; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Quality of Life

Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterase-4 in advanced clinical development for chronic obstructive pulmonary disease (COPD). Tanimilast is known to exert prominent anti-inflammatory activity when tested in preclinical experimental models as well as in human clinical studies. Recently, we have demonstrated that it also finely tunes, rather than suppressing, the cytokine network secreted by activated dendritic cells (DCs). This study was designed to characterize the effects of tanimilast on T-cell polarizing properties of DCs and to investigate additional functional and phenotypical features induced by tanimilast.. DCs at day 6 of culture were stimulated with LPS in the presence or absence of tanimilast or the control drug budesonide. After 24 h, DCs were analyzed for the expression of surface markers of maturation and activation by flow cytometry and cocultured with T cells to investigate cell proliferation and activation/polarization. The regulation of type 2-skewing mediators was investigated by real-time PCR in DCs and compared to results obtained in vivo in a randomized placebo-controlled trial on COPD patients treated with tanimilast.. Taken together, these findings demonstrate distinct immunomodulatory properties of tanimilast associated with a type 2 endotype and CD141 upregulation in DCs and provide a mechanistic rationale for the administration of tanimilast on top of inhaled corticosteroids.

Topics: Budesonide; Cells, Cultured; Cytokines; Dendritic Cells; Humans; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Thrombomodulin; Up-Regulation

Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression.. We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes.. We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells.. Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling.

Topics: Animals; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Emphysema; Endothelial Cells; Formoterol Fumarate; Fumarates; Glycopyrrolate; Hypertension, Pulmonary; Mice; NF-kappa B; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Budesonide; Humans; Pseudomonas Infections; Pulmonary Disease, Chronic Obstructive; Toll-Like Receptor 2

To evaluate the cost-effectiveness of Budesonide/Glycopyrronium/Formoterol (BUD/GLY/FOR) versus LAMA/LABA and ICS/LABA, respectively, in patients with moderate to severe COPD, from the Spanish National Healthcare System (NHS) perspective.. A lifetime Markov model with monthly cycle length was developed with baseline and treatment effect data from ETHOS clinical trial, together with utility values from literature and Spanish healthcare resource costs (€, 2021). A 3% annual discount rate was used for costs and benefits. The model comprised ten health states: nine forced expiratory volume in 1 second (FEV1)-related, which were divided by three levels of severity: moderate (FEV1 ≥50% and <80%); severe (FEV1 ≥30% and <50%) and very severe (FEV1 <30%) and a death state. Each FEV1-health state was divided into no exacerbation, moderate exacerbation, and severe exacerbations. An expert panel validated data and assumptions. Outcomes were measured as incremental cost per exacerbation avoided, per life year (LY) gained, and per quality-adjusted life-year (QALY) gained (ICUR). One-way (OWSA), scenario, and probabilistic sensitivity analyses (PSA) were performed.. According to this cost-effectiveness analysis based on a Markov model, BUD/GLY/FOR was associated with a lower totals exacerbation per patient (12.80) compared to LAMA/LABA (13.36) and ICS/LABA (13.23) and higher LYs (10.32 vs 10.14 and 10.06, respectively) and QALYs (7.55 vs 7.41 and 7.32, respectively). The incremental costs were €850.95, and €2422.26, respectively, per exacerbation avoided, €2733.38 and €4111.15, respectively, per LY gained and €3461.19 and €4545.24 per QALY gained. OWSA showed that the model was most sensitive to the costs of treatments following discontinuation, but the ICUR remained below the cost-effectiveness threshold of €25,000 per QALY gained. In the PSA, the probability of BUD/GLY/FOR being cost-effective was 91.32% vs LAMA/LABA and 99.29% vs ICS/LABA.. BUD/GLY/FOR is a cost-effective treatment strategy for Spanish NHS patients with COPD compared to dual therapies.

Topics: Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Cost-Benefit Analysis; Formoterol Fumarate; Fumarates; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive; Spain

Costs, exacerbations, quality-adjusted life-years (QALYs), and LYs were extrapolated using a Markov model that considered disease severity progression, risk of moderate and severe exacerbations, adverse events, and treatment discontinuation in patients with moderate-to-very severe COPD receiving BGF 320/14.4/10 µg, the LAMA/LABA glycopyrronium/formoterol fumarate dihydrate 14.4/10 µg (GFF), or the ICS/LABA budesonide/formoterol fumarate dihydrate 320/10 µg (BFF). Utilities for COPD severity states were estimated using EuroQol 5-dimension 5-level data from ETHOS. Exacerbation disutilities were sourced from published literature. Healthcare resource utilization was based on ETHOS data, published literature, key external experts' input, and informed assumptions. Unit costs came from the UK National Health Service Schedule of Reference Costs, Unit Costs of Health and Social Care from the Personal Social Services Research Unit, and published literature. A lifetime horizon was considered, with costs, QALYs, and LYs discounted at 3.5% per annum.. The incremental cost-utility ratio (ICUR; per QALY gained) was £9901 for BGF versus GFF and £2164 for BGF versus BFF. The probability of treatments being cost-effective at the conventional UK-adopted willingness-to-pay threshold of ICUR <£20,000 was 85.1% for BGF, 14.3% for GFF, and 0.6% for BFF.. Based on ETHOS data, BGF was demonstrated to be cost-effective versus LAMA/LABA and ICS/LABA dual therapies at the conventional UK-adopted willingness-to-pay threshold (ICUR <£20,000). The main cost-effectiveness driver for BGF versus LAMA/LABA and ICS/LABA therapies was reduction in rate of exacerbations, which reduced costs and preserved quality of life.

Topics: Budesonide; Cost-Benefit Analysis; Formoterol Fumarate; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; State Medicine

In the present study, the effect of nortriptyline (1 and 10 μM), budesonide (10 nM) and their combination on the migration of peripheral blood lymphocytes and monocytes from patients with chronic obstructive pulmonary disease (COPD) towards chemokines CCL5 and CXCL10 was evaluated by flow cytometry. Nortriptyline (10 μM), both alone and in combination with budesonide, inhibited the migration of T helper cells, cytotoxic T lymphocytes, NK cells and B lymphocytes towards CCL5 and CXCL10, as well as enhanced monocyte migration towards these chemokines. The combination of nortriptyline (1 μM) and budesonide suppressed the chemotaxis of lymphocyte subpopulations towards CXCL10, but not towards CCL5, more effectively than budesonide alone. The combination of nortriptyline (10 μM) and budesonide inhibited the migration of lymphocyte subpopulations towards CCL5 and CXCL10 and activated monocyte chemotaxis towards both chemokines more effectively than budesonide alone. The results of this study demonstrate the ability of nortriptyline alone to modulate the migration of peripheral blood lymphocytes and monocytes from patients with COPD and to potentiate the effects of budesonide.

Topics: Budesonide; Chemokines; Humans; Killer Cells, Natural; Monocytes; Nortriptyline; Pulmonary Disease, Chronic Obstructive

Topics: Administration, Inhalation; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Dry Powder Inhalers; Humans; Patient Preference; Pulmonary Disease, Chronic Obstructive

Topics: Adrenal Cortex Hormones; Budesonide; Double-Blind Method; Formoterol Fumarate; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive

A variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective.. Patient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD.. For all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 μg/5 μg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 μg/2.5 μg) soft mist inhaler had the highest PrCP (42.3%).. Patient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Asthma; Benzoxazines; Budesonide; Delayed-Action Preparations; Disease Progression; Drug Combinations; Drug Therapy, Combination; Formoterol Fumarate; Maintenance Chemotherapy; Nebulizers and Vaporizers; Patient Preference; Patient-Centered Care; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Tiotropium Bromide

Topics: Budesonide; Double-Blind Method; Formoterol Fumarate; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Drug Combinations; Female; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

Topics: Budesonide; Double-Blind Method; Formoterol Fumarate; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive

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

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

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

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

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

Although corticosteroids have been widely used in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD), few studies have evaluated the effectiveness of nebulized corticosteroids (NCS), systemic corticosteroids (SCS), and NCS plus SCS in the management of AECOPD in China. This study aimed to evaluate the effectiveness of NCS, SCS, and NCS plus SCS in Chinese patients with AECOPD.. This was a real-world study of AECOPD patients at 43 sites from January to September 2014. During hospitalization, patients treated with nebulized budesonide (NCS group, n=1091), SCS (SCS group, n=709), or both (NCS+SCS group, n=1846) were included. Propensity score matching (PSM) and subgroup analyses were performed. The primary outcomes were the length of hospital stay, mortality, and change in arterial blood gases from baseline.. Multivariable analysis showed that the three treatments at the same severity of AECOPD were not significantly different regarding intubation rates, rates of pneumonia improvement at discharge, rates of new-onset pneumonia in hospital, and mortality. Following PSM, NCS+SCS was associated with greater length of hospital stay than both NCS and SCS (in patients without respiratory failure [RF,. NCS is effective for patients with AECOPD, which may be an alternative treatment option. Further clinical trials are urgently needed to better understand the efficacy of NCS, SCS, and NCS+SCS in AECOPD management in China.

Topics: Adrenal Cortex Hormones; Budesonide; China; Disease Progression; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease (COPD) typically includes neutrophilic airway inflammation and eosinophilic inflammation in some cases. Inhaled corticosteroid (ICS) suppresses eosinophilic inflammation of the airway and reduces acute exacerbation (AE). The present study investigated the relationship between ICS and AE in patients with COPD classified by blood eosinophil counts.. Overall, 244 patients with COPD were retrospectively evaluated between 2014 and 2017 and classified into two groups based on blood eosinophil counts (≥ 300/μL and < 300/μL). These patients were then reclassified into subgroups of those with and without ICS. Differences in the characteristics and incidence of AE and pneumonia with AE in each subgroup were evaluated retrospectively.. All patients with ICS used 320 μg budesonide twice daily. In the group with blood eosinophil counts ≥ 300/μL, patients with ICS had a significantly lower incidence of AE than those without ICS (P = 0.023). Meanwhile, no significant differences were observed in incidence of AE in the group with blood eosinophil counts < 300/μL. In the group with blood eosinophil counts < 300/μL, patients with ICS had a higher incidence of pneumonia with AE (P = 0.009). Conversely, no significant differences were observed in the group with blood eosinophil counts ≥ 300/μL.. ICS significantly reduced AE in COPD patients with blood eosinophil counts ≥ 300/μL. Meanwhile, ICS significantly increased pneumonia rate in patients with blood eosinophil count < 300/μL. Blood eosinophil count may be a useful indicator to identify the benefits and risks of ICS in COPD.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Budesonide; Eosinophils; Female; Glucocorticoids; Humans; Leukocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk Assessment; Treatment Outcome

Topics: Administration, Inhalation; Adrenal Insufficiency; Budesonide; Glucocorticoids; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Vascular Surgical Procedures

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

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

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aerosols; Aged; Budesonide; China; Disease Progression; Drug Costs; Female; Glucocorticoids; Health Expenditures; Hospital Costs; Hospitalization; Humans; Inpatients; Lung; Male; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Treatment Outcome

Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week. The peribronchial collagen deposition was measured. The protein levels of MMP8 and MMP9 in bronchoalveolar lavage fluid (BALF) and lungs were assessed. Western blot analysis was used to detect the levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), a-smooth muscle actin (α-SMA), glycogen synthase kinase-3β (GSK-3β). The expression of VEGF and histone deacetylase 2 (HDAC2) in the lung were determined by Immunohistochemical analyses. We observe that progesterone attenuates the peribronchial collagen deposition, as well as the expression of MMP8, MMP9, HIF-1α, VEGF, α-SMA, and GSK-3β in BALF or lung tissues. Progesterone or BUD monotherapy has no effect on HDAC2 production. Progesterone combines with BUD induce dramatically enhanced effects. Thus, these results demonstrate novel roles of progesterone for the pathogenesis and airway remodeling in COPD. Progesterone plus BUD administration exerts more significant inhibition on airway remodeling with dose-independent. Additionally, progesterone may, to some extent, improve the glucocorticoid insensitivity.

Topics: Airway Remodeling; Animals; Anti-Inflammatory Agents; Budesonide; Disease Models, Animal; Drug Resistance; Glucocorticoids; Male; Mice; Mice, Inbred C57BL; Ozone; Progesterone; Pulmonary Disease, Chronic Obstructive

A high percentage of patients with COPD report chronic nasal symptoms. The study aims to evaluate the clinical impact of a 2-month treatment with inhaled nasal budesonide (100 µg per nostril twice daily) in patients affected by COPD with chronic rhinitis comorbidity.. Fifty-three stable COPD patients in therapy according to the Global initiative for chronic Obstructive Lung Disease recommendations were enrolled; 49 completed the study. At enrollment (visit 0), patients underwent skin prick test and rhinoscopy. At visit 0 and after 1 month (visit 1) and 2 months (visit 2) of therapy with nasal budesonide, patients underwent spirometry, and COPD assessment test (CAT), Sinonasal Outcome Test (SNOT 22), and modified Medical Research Council dyspnea scale were administered. Differences in continuous variables, after 2 months of treatment with nasal budesonide, were evaluated using a paired. Two months of treatment with nasal budesonide showed a significant statistical improvement in the total scores of CAT, SNOT 22, and modified Medical Research Council (. The results of the present study indicate the importance of careful evaluation of the presence of chronic nasal symptoms in all COPD patients and suggest beneficial clinical effect from treatment with nasal budesonide in terms of COPD symptoms and quality of life.

Topics: Administration, Intranasal; Aged; Anti-Inflammatory Agents; Budesonide; Female; Humans; Italy; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Rhinitis

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Topics: Bronchodilator Agents; Budesonide; Double-Blind Method; Formoterol Fumarate; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive

Concerns have been raised that treatment of COPD with inhaled corticosteroids may increase pneumonia risk. Responding to a request from the European Medicines Agency Pharmacovigilance Risk Assessment Committee, a pooled analysis of interventional studies compared pneumonia risk with inhaled budesonide-containing versus non-budesonide-containing treatments and the impact of other clinically relevant factors.. AstraZeneca-sponsored, parallel-group, double-blind, randomized controlled trials meeting the following criteria were included: >8 weeks' duration; ≥60 patients with COPD; inhaled budesonide treatment arm (budesonide/formoterol or budesonide); and non-budesonide-containing comparator arm (formoterol or placebo). Primary and secondary outcomes were time to first pneumonia treatment-emergent serious adverse event (TESAE) and treatment-emergent adverse event (TEAEs), respectively, analyzed using Cox regression models stratified by study.. Eleven studies were identified; 10,570 out of 10,574 randomized patients receiving ≥1 dose of study treatment were included for safety analysis (budesonide-containing, n=5,750; non-budesonide-containing, n=4,820). Maximum exposure to treatment was 48 months. The overall pooled hazard ratio (HR), comparing budesonide versus non-budesonide-containing treatments, was 1.15 for pneumonia TESAEs (95% confidence interval [CI]: 0.83, 1.57) and 1.13 for pneumonia TEAEs (95% CI: 0.94, 1.36). The annual incidence of pneumonia TESAEs was 1.9% and 1.5% for budesonide-containing and non-budesonide-containing treatments, respectively. Comparing budesonide/formoterol with non-budesonide-containing treatment, the HRs for pneumonia TESAEs and TEAEs were 1.00 (95% CI: 0.69, 1.44) and 1.21 (95% CI: 0.93, 1.57), respectively. For budesonide versus placebo, HRs were 1.57 for pneumonia TESAEs (95% CI: 0.90, 2.74) and 1.07 for pneumonia TEAEs (95% CI: 0.83, 1.38).. This pooled analysis found no statistically significant increase in overall risk for pneumonia TESAEs or TEAEs with budesonide-containing versus non-budesonide-containing treatments. However, a small increase in risk with budesonide-containing treatment cannot be ruled out; there is considerable heterogeneity in study designs and patient characteristics, particularly in the early budesonide studies, and each study contributes <40 pneumonia TESAEs.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Budesonide; Female; Glucocorticoids; Humans; Lung; Male; Middle Aged; Pneumonia; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Administration, Oral; Adrenal Cortex Hormones; Bias; Budesonide; Disease Progression; Drug Therapy; Europe; Humans; Incidence; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Fixed-dose combinations of inhaled corticosteroids and long-acting β. A model was developed to estimate the budget impact of reducing poor inhalation technique by switching asthma and COPD patients from BF Turbuhaler. In Scenario 1, per patient cost savings amounted to €60.10, €49.67, €94.14 and €38.20 in Germany, Italy, Sweden and the UK, respectively. Total cost savings in each country were €100.86 million, €19.42 million, €36.65 million and €15.44 million over three years, respectively, with an estimated 597,754, 151,480, 228,986 and 122,368 healthcare events avoided. In Scenario 2, cost savings totalled €8.07 million, €1.55 million, €2.93 million and €1.23 million over three years, respectively, with 47,850, 12,118, 18,319, and 9789 healthcare events avoided. Savings per patient were €4.81, €3.97, €7.53 and €3.06.. We demonstrated that reductions in poor inhalation technique by switching patients from BF Turbuhaler

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Dry Powder Inhalers; Formoterol Fumarate; Germany; Glucocorticoids; Health Care Costs; Humans; Italy; Pulmonary Disease, Chronic Obstructive; Sweden

Chronic obstructive pulmonary disease is associated with a high healthcare resource and cost burden. Healthcare resource utilization was analyzed in patients with symptomatic chronic obstructive pulmonary disease at risk of exacerbations in the FULFIL study. Patients received either once-daily, single inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol) 100 µg/62.5 µg/25 µg or twice-daily dual inhaled corticosteroid/long-acting beta agonist therapy (budesonide/formoterol) 400 µg/12 µg.. FULFIL was a phase III, randomized, double-blind, double-dummy, multicenter study. Unscheduled contacts with healthcare providers were recorded by patients in a daily electronic diary; the costs of healthcare resource utilization were calculated post hoc using UK reference costs.. Over 24 weeks, slightly fewer patients who received fluticasone furoate/umeclidinium/vilanterol (169/911; 18.6%) required contacts with healthcare providers compared with budesonide/formoterol (180/899; 20.0%). Over 52 weeks in an extension population, fewer patients who received fluticasone furoate/umeclidinium/vilanterol required unscheduled contacts with healthcare providers compared with budesonide/formoterol (25.2% vs. 32.7%). Non-drug costs per treated patient per year were lower in the fluticasone furoate/umeclidinium/vilanterol group than the budesonide/formoterol group over 24 and 52 weeks (£653.80 vs. £763.32 and £749.22 vs. £988.03, respectively), with the total annualized cost over 24 weeks being slightly greater for fluticasone furoate/umeclidinium/vilanterol than budesonide/formoterol (£1,289.35 vs. £1,267.45).. This healthcare resource utilization evidence suggests that, in a clinical trial setting over a 24- or 52-week timeframe, non-drug costs associated with management of a single inhaler fluticasone furoate/umeclidinium/vilanterol are lower compared with twice-daily budesonide/formoterol.. ClinicalTrials.gov number: NCT02345161.. GSK.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Androstadienes; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; United Kingdom

Chronic ozone exposure leads to a model of mice with lung inflammation, emphysema and oxidative stress. Progesterone plays an important role in attenuating the neuroinflammation. We assume that progesterone will reduce the chronic airway inflammation exposed to ozone and evaluate whether combination of progesterone with glucocorticoids results in synergistic effects. C57/BL6 mice were exposed to ozone (2.5ppm, 3h) 12 times over 6 weeks, and were administered with progesterone (0.03 or 0.3mg/L; inhaled) alone or combined with budesonide (BUD) (0.2g/L) after each exposure until the tenth week. Mice were studied 24h after final exposure, cells and inflammatory mediators were assessed in bronchoalveolar lavage fluid (BALF) and lungs used for evaluation of glucocorticoids receptors (GR), p38 mitogen-activated protein kinase (MAPK) phosphorylation and nuclear transcription factor κB (NF-κB) activation. Exposure to ozone resulted in a marked lung neutrophilia. Moreover, in ozone-exposed group, the levels of oxidative stress-related interleukin (IL)-1β, IL-6, IL-8, IL-17A, activated NF-κB and p38MAPK, airway inflammatory cells infiltration density, mean linear intercept (Lm) were greatly increased, FEV

Topics: Administration, Inhalation; Animals; Blotting, Western; Budesonide; Chronic Disease; Disease Models, Animal; Glucocorticoids; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Ozone; Pneumonia; Progesterone; Pulmonary Disease, Chronic Obstructive

Bilateral proximal femoral fractures without trauma are very rare conditions. They have been reported in connection with osteoporosis, renal osteodystrophy, parathyroid disease, tumors, epileptic seizures, electroconvulsive therapy, and postirradiation.. We present a case of a 75-year-old man with bilateral hip fractures. No trauma, neurological, endocrinological disorder, or malignancy was reported in his history. He had a background of chronic obstructive pulmonary disease (COPD) and had been taking inhaled steroids (budesonide) 800 µg per day for 10 years. He was a heavy smoker with a smoking history of 120 packs/year. His complaints had initially started as pain on the left hip and groin and then had progressed to the right in 10 days. Plain x-rays of the pelvis showed left femoral neck and right subtrochanteric femoral fractures. Fixation with proximal femoral nail of the right hip and partial arthroplasty of the left hip was performed on the following day after his admission. Pathological examination revealed osteoporosis in bone samples from both hips.. COPD and osteoporosis have some common risk factors. Smoking, decreased exercise capacity, inhaled, or oral steroid therapy may increase osteoporosis and risk of bone fractures by decreasing bone mineral density. Non-traumatic femoral fractures may occur in patients on long-term inhaled steroid treatment for chronic airway diseases such as asthma and COPD.. History of COPD with corticosteroid use may be used as a diagnostic tool to identify patients having osteoporosis. Preventive measures can be performed by monitoring high-risk patients with bone mineral densitometry, WHO fracture risk assessment tool (FRAX tool), serum calcium, and vitamin D levels to prevent bone fractures. Treating those patients with the lowest effective dose of corticosteroids should be targeted.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bone Density; Budesonide; Femoral Neck Fractures; Hip Fractures; Humans; Male; Osteoporosis; Pulmonary Disease, Chronic Obstructive; Risk Factors; Smoking

Chronic obstructive pulmonary disease (COPD) affects approximately 15 million people in the United States and accounts for approximately $36 billion in economic burden, primarily due to medical costs. To address the increasing clinical and economic burden, the Global Initiative for Chronic Obstructive Lung Disease emphasizes the use of therapies that help prevent COPD exacerbations, including inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA).. To evaluate health care costs and utilization among COPD patients newly initiating ICS/LABA combination therapy with budesonide/formoterol (BFC) or fluticasone/salmeterol (FSC) in a managed care system.. COPD patients aged 40 years and older who initiated BFC (160/4.5 μg) or FSC (250/50 μg) treatment between March 1, 2009, and March 31, 2012, were identified using claims data from major U.S. health plans. BFC and FSC patients were propensity score matched (1:1) on age, sex, prior asthma diagnosis, prior COPD-related health care utilization, and respiratory medication use. COPD-related, pneumonia-related, and all-cause costs and utilization were analyzed during the 12-month follow-up period. Post-index costs were assessed with generalized linear models (GLMs) with gamma distribution. Health care utilization data were analyzed via logistic regression (any event vs. none) and GLMs with negative binomial distribution (number of visits) and were adjusted for the analogous pre-index variable as well as pre-index characteristics that remained imbalanced after matching.. After matching, each cohort had 3,697 patients balanced on age (mean 64 years), sex (female 52% BFC and 54% FSC), asthma and other comorbid conditions, prior COPD-related health care utilization, and respiratory medication use. During the 12-month follow-up, COPD-related costs averaged $316 less for BFC versus FSC patients ($4,326 vs. $4,846; P = 0.003), reflecting lower inpatient ($966 vs. $1,202; P < 0.001), pharmacy ($1,482 vs. $1,609; P = 0.002), and outpatient/office ($1,378 vs. $1,436; P = 0.048) costs, but higher emergency department ($257 vs. $252; P = 0.033) costs. Pneumonia-related health care costs were also lower on average for BFC patients ($2,855 vs. $3,605; P < 0.001). Similarly, initiating BFC was associated with lower all-use health care costs versus initiating FSC ($21,580 vs. $24,483; P < 0.001, respectively). No differences in health care utilization were found between the 2 groups.. In this study, although no difference was observed in rates of health care utilization, COPD patients initiating BFC treatment incurred lower average COPD-related, pneumonia-related, and all-cause costs versus FSC initiators, which was driven by cumulative differences in inpatient, outpatient, and pharmacy costs.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Asthma; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Health Care Costs; Humans; Male; Middle Aged; Patient Acceptance of Health Care; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; United States

Topics: Asthma; Budesonide; Dry Powder Inhalers; Formoterol Fumarate; Humans; Medication Adherence; Pulmonary Disease, Chronic Obstructive

Alveolar macrophages (AMs) are equipped with innate immune receptors such as toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4). In primary bronchial epithelial cells, exposure of toll-like receptor (TLR) ligands or tumor necrosis factor-alpha (TNF-α) increased TLR2 mRNA expression and reduced interleukin-8 (IL-8) release when coincubated with glucocorticosteroids. The aim of this study was to compare TLR2 and TLR4 expression levels and the effect of a glucocorticosteroid after stimulation with TLR ligands on AMs from smokers with and without COPD compared with the healthy controls.. Bronchoalveolar lavage was performed, and AMs were isolated from smokers with (n=10) and without COPD (n=11) and healthy controls (n=10) and stimulated ex vivo with peptidoglycan (PGN), lipopolysaccharide (LPS), or TNF-α ± budesonide (Bud). Blocking antibodies to TLR2 or TLR4 were added before stimulation with LPS or PGN ± Bud, respectively. The release of proinflammatory cytokine (TNF-α), chemoattractant (CXCL8), and TLR expression was analyzed by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction.. LPS, PGN, and TNF-α induced an increased release of IL-8 and TNF-α in the AMs in all the groups independent of smoking or disease. These responses were inhibited by a glucocorticosteroid (Bud) in all the three groups, except PGN-induced IL-8 secretion in smokers without COPD. Bud increased TLR2 expression in the healthy controls and smokers without COPD. Costimulation of TLR ligands and Bud significantly enhanced TLR2 mRNA expression in both groups of smokers compared with TLR ligands alone. In smokers, costimulation with PGN and Bud significantly increased TLR2 expression when compared with Bud alone. On stimulation with the TLR4 agonist, LPS downregulated TLR4 mRNA expression in all the three groups.. The combination of glucocorticosteroids with TLR ligands can increase TLR2 expression, thereby improving host defense in smokers. Also this combination can decrease the secretion of proinflammatory cytokines and chemokines as an anti-inflammatory response. Our findings indicate that glucocorticosteroid therapy strengthens immune defense pathways, which may have implication during exacerbation caused by microorganisms.

Topics: Adult; Aged; Anti-Inflammatory Agents; Budesonide; Case-Control Studies; Female; Glucocorticoids; Humans; Immunity, Innate; Interleukin-8; Ligands; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Peptidoglycan; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoking; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Asthma and chronic obstructive pulmonary disease (COPD) are common chronic inflammatory respiratory diseases, which impose a substantial burden on healthcare systems and society. Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β2 agonists (LABA), often administered using dry powder inhalers (DPIs), are frequently prescribed to control persistent asthma and COPD. Use of DPIs has been associated with poor inhalation technique, which can lead to increased healthcare resource use and costs.. A model was developed to estimate the healthcare resource use and costs associated with asthma and COPD management in people using commonly prescribed DPIs (budesonide + formoterol Turbuhaler(®) or fluticasone + salmeterol Accuhaler(®)) over 1 year in Spain, Sweden and the United Kingdom (UK). The model considered direct costs (inhaler acquisition costs and scheduled and unscheduled healthcare costs), indirect costs (productive days lost), and estimated the contribution of poor inhalation technique to the burden of illness.. The direct cost burden of managing asthma and COPD for people using budesonide + formoterol Turbuhaler(®) or fluticasone + salmeterol Accuhaler(®) in 2015 was estimated at €813 million, €560 million, and €774 million for Spain, Sweden and the UK, respectively. Poor inhalation technique comprised 2.2-7.7 % of direct costs, totalling €105 million across the three countries. When lost productivity costs were included, total expenditure increased to €1.4 billion, €1.7 billion and €3.3 billion in Spain, Sweden and the UK, respectively, with €782 million attributable to poor inhalation technique across the three countries. Sensitivity analyses showed that the model results were most sensitive to changes in the proportion of patients prescribed ICS and LABA FDCs, and least sensitive to differences in the number of antimicrobials and oral corticosteroids prescribed.. The cost of managing asthma and COPD using commonly prescribed DPIs is considerable. A substantial, and avoidable, contributor to this burden is poor inhalation technique. Measures that can improve inhalation technique with current DPIs, such as easier-to-use inhalers or better patient training, could offer benefits to patients and healthcare providers through improving disease outcomes and lowering costs.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Asthma; Bronchodilator Agents; Budesonide; Chronic Disease; Drug Combinations; Dry Powder Inhalers; Ethanolamines; Europe; Female; Formoterol Fumarate; Health Care Costs; Humans; Models, Economic; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid

Multi-dose dry powder inhalers (DPIs) are commonly used in asthma and chronic obstructive lung disease (COPD) treatment. A disadvantage is their sensitivity to humidity. In real life, DPIs are periodically exposed to humid conditions, which may affect aerosol characteristics and lung deposition. This study compared DPI aerosol performance after exposure to humidity. Budesonide (BUD) inhalers (Turbuhaler; Novolizer; Easyhaler) and budesonide/formoterol (BUD/FORM) inhalers (Turbuhaler; Spiromax; Easyhaler) were stored in 75% relative humidity (RH) at both ambient temperature and at -0 °C. Delivered dose (DD) and fine-particle dose (FPD) were tested in vitro before and after storage. BUD inhalers: Turbuhaler and Novolizer showed only small decreases (<15%) in FPD in 40 °C/75% RH, whereas FPD for Easyhaler decreased by >60% (P=0.01) after 1.5 months of storage. Easyhaler also decreased significantly after 6 months of storage in ambient/75%RH by 25% and 54% for DD and FPD, respectively, whereas only small decreases were seen for Turbuhaler and Novolizer (<15%). BUD/FORM inhalers: Turbuhaler and Spiromax DD were unchanged in 40 °C/75% RH, whereas Easyhaler showed a small decrease. FPD (budesonide) decreased for Turbuhaler, Spiromax and Easyhaler by 18%, 10% and 68% (all significant), respectively, at 40 °C/75% RH. In ambient/75%RH, DD was unchanged for all inhalers, whereas FPD (budesonide) decreased for Spiromax (7%, P=0.02) and Easyhaler (34%, (P<0.01)). There are significant differences in device performance after exposure to humid conditions. A clinically relevant decrease of more than half FPD was seen for one of the inhalers, a decrease that may affect patients' clinical outcomes. Prescriber and patient knowledge on device attributes are essential to ensure optimal drug delivery to the lungs.

Topics: Administration, Inhalation; Anti-Asthmatic Agents; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Dry Powder Inhalers; Humans; Humidity; In Vitro Techniques; Pulmonary Disease, Chronic Obstructive

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

There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.. Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0-100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.. The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).. SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Area Under Curve; Bronchodilator Agents; Budesonide; Decision Support Techniques; Disease Progression; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Logistic Models; Lung; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; ROC Curve; Severity of Illness Index; Sex Factors; Time Factors; Treatment Outcome; Vital Capacity

Successful delivery of inhalation medication to the lungs can be affected by the inhalation manoeuvre used. Conventional in-vitro testing of the emitted dose from a dry powder inhaler (DPI) uses a vacuum pump to simulate an inhalation. We have adapted this method by replacing the pump with patient inhalation profiles and an anatomical throat. Three anatomical throat sizes and three inhalation profiles were used. The profiles represented the 10th, 50th and 90th percentiles of peak inhalation flow and acceleration of flow from a population of 50 COPD patients inhaling through empty Spiromax and Turbuhaler devices. Combining the dose emission results for the three throat sizes, the mean (SD) budesonide fine-particle dose (FPD) from budesonide-formoterol Spiromax 320/9 μg was 78.91 (20.18), 79.91 (15.36) and 75.10 (19.91)μg and the total emitted dose (TED) of budesonide was 263.69 (40.74), 261.20 (21.65) and 261.61 (45.65)μg. Similarly, the FPD from 320/9 μg Turbuhaler was 22.45 (3.24), 52.20 (12.57) and 69.11 (75.10)μg with a TED of 143.80 (14.90), 149.50 (26.61) and 158.61 (43.04)μg. Spiromax showed greater consistency than Turbuhaler over a range of inspiratory flow profiles. The results demonstrate the value of this new method to assess the doses that patients receive during real-life use of their DPI.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Dry Powder Inhalers; Formoterol Fumarate; Humans; Lung; Models, Anatomic; Particle Size; Pharynx; Pulmonary Disease, Chronic Obstructive

Topics: Asthma; Budesonide; Comorbidity; Drug Combinations; Dry Powder Inhalers; Formoterol Fumarate; Pulmonary Disease, Chronic Obstructive

Inhaled corticosteroid/long-acting β2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD) exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting β2-agonist combination) vs tiotropium (long-acting muscarinic antagonist) in the US has not yet been studied.. Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma) ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs.. The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR) of 0.78 (95% CI =[0.70, 0.87], P<0.001), indicating a 22% reduction in risk of COPD exacerbation associated with initiation of BFC versus tiotropium. A post hoc sensitivity analysis found similar effects in those who had a prior asthma diagnosis (HR =0.72 [0.61, 0.86]) and those who did not (HR =0.83 [0.72, 0.96]). BFC initiation was associated with lower COPD-related health care resource utilization and costs ($4,084 per patient-year compared with $5,656 for tiotropium patients, P<0.001).. In COPD patients new to controller therapies, initiating treatment with BFC was associated with improvements in health and economic outcomes compared with tiotropium.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Asthma; Bronchodilator Agents; Budesonide; Comorbidity; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Health Care Costs; Hospitalization; Humans; Insurance Claim Reporting; Male; Middle Aged; Muscarinic Antagonists; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Inhaled corticosteroids (ICS) are widely used in the treatment of obstructive lung diseases. Recent data suggest a higher pneumonia risk in chronic obstructive pulmonary disease (COPD) patients treated with ICS.. Since non-typeable Haemophilus influenzae (NTHi) is the most common pathogen associated with acute exacerbations of COPD, we investigated the effects of budesonide (BUD) on NTHi-induced inflammation and invasive infection.. The alveolar epithelial cell line A549 and specimens of human lung tissue (HLT) were used in our experiments. Intracellular infection was determined by a lysis/culture assay of infected cells. Activated p38 mitogen-associated protein kinase (MAPK) was assessed using Western blotting and immunohistochemistry, expression of toll-like receptor 2 (TLR2) was determined by PCR, and CXCL-8 levels were measured using ELISA. Immunohistochemistry was used for detection of CXCL-8, platelet-activating factor receptor (PAF-R) and NTHi.. BUD significantly reduced CXCL-8 secretion in A549 cells and lung tissue infected with NTHi. Furthermore, BUD decreased the expression of PAF-R in HLT and A549 cells. In A549 cells and HLT, BUD inhibited intracellular infection and - synergistically with NTHi - increased the expression of TLR2 (in A549 cells). TLR2 stimulation did not influence the intracellular infection of A549 cells, but p38 MAPK inhibition resulted in a significant reduction of infection.. The present study adds new insights into the effects of glucocorticoids on pulmonary host defence after NTHi infection. Although the inflammatory response to infection is suppressed by BUD, interestingly, the intracellular infection is also inhibited. This effect seems to depend on the inhibition of p38 MAPK - a key enzyme in many pro-inflammatory pathways - as well as of PAF-R expression.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Blotting, Western; Budesonide; Cells, Cultured; Culture Media, Conditioned; Enzyme Induction; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Haemophilus Infections; Haemophilus influenzae; Humans; Immunohistochemistry; p38 Mitogen-Activated Protein Kinases; Polymerase Chain Reaction; Pulmonary Disease, Chronic Obstructive; Sensitivity and Specificity

To compare the clinical characteristics and the therapeutic responses in chronic obstructive pulmonary disease (COPD) subgroups, classified by diffusing capacity of the lung for carbon monoxide (D(L)CO) and inspiratary capacity (IC).. A total of 105 mild-severe patients (70 males, 35 females, 44 to 85 years of age), with stable COPD were recruited in Cangzhou Central Hospital from June 2012 to June 2014. According to baseline D(L)CO and IC, the patients were divided into normal D(L)CO/IC group (group A, n=10), low D(L)CO/normal IC group (group B, n=18), normal D(L)CO/low IC group (group C, n=22) and low D(L)CO/IC group (group D, n=55). We compared the clinical characteristics, induced sputum cells and the therapeutic responses to 3-month treatment of budesonide/formoterol(320 µg/9 µg, inhale, bid)among the 4 groups.. Group D showed the highest CAT scores(27.6 ± 6.4). Group C showed a higher prevalence of patients with wheezing(81.8)% and the highest percentage of sputum eosinophils (7.6 ± 3.2)%. Group C showed the greatest FEV(1) increase(0.214 ± 0.053)L. Group D showed a greater FEV(1) increase than Group B [(0.137 ± 0.063) vs (0.092 ± 0.048)L]. Group C showed a greater FVC[(0.342 ± 0.073), (0.190 ± 0.081), (0.223 ± 0.094)L] increase and CAT[(4.4 ± 2.0), (2.3 ± 1.3), (3.9 ± 1.9)] decrease than Group B and Group D(P<0.05).. These findings suggest that COPD subgroups classified by D(L)CO and IC show several clinical characteristics and may be helpful to predict responses to treatment.

Topics: Adult; Aged; Aged, 80 and over; Budesonide; Eosinophils; Ethanolamines; Female; Formoterol Fumarate; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum

We hypothesised that increased oxidative stress, as present in the airways of asthma and chronic obstructive pulmonary disease (COPD) patients, induces epithelial damage and reduces epithelial responsiveness to suppressive effects of corticosteroids on proinflammatory cytokine production and barrier function.. We induced oxidative stress by H2O2 and/or cigarette smoke extract (CSE) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBEC) derived by brushings from asthma patients, COPD patients, and smoking and non-smoking control individuals. We investigated effects of budesonide on barrier function (electrical resistance) and TNF-α-induced proinflammatory cytokine production (IL-8/CXCL8, granulocyte macrophage-colony stimulating factor (GM-CSF)).. We observed that H2O2 and CSE reduce epithelial resistance. Budesonide significantly counteracted this effect, likely by protection against epidermal growth factor receptor-dependent cell-cell contact disruption. Furthermore, budesonide suppressed proinflammatory cytokine production. H2O2 pretreatment reduced this effect of budesonide on cytokine production in both 16HBE cells and PBECs. Importantly, PBECs from asthma and COPD patients were less sensitive to budesonide with respect to cytokine production and barrier function than PBECs from control subjects.. Together, our data indicate that budesonide suppresses epithelial proinflammatory responses and barrier dysfunction and that oxidative stress reduces these effects in airway epithelium from asthma and COPD patients. Therefore, restoration of corticosteroid responsiveness in asthma and COPD may act to improve the airway epithelial barrier.

Topics: Adult; Asthma; Bronchi; Budesonide; Cells, Cultured; Epithelial Cells; Female; Glucocorticoids; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Oxidative Stress; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Smoking

Steroid psychosis has been well described with oral glucocorticoids, however, our search of the literature did not identify an association between delirium and the combination of inhaled glucocorticoids and long-acting beta-agonists. We describe the occurrence of delirium with the combination of an inhaled glucocorticoid and bronchodilator. An elderly male described confusion and hallucinations within 1 week after initiation of budesonide/formoterol for chronic obstructive pulmonary disease. The combination inhaler was discontinued with resolution of symptoms. Several weeks later, the patient was hospitalized and restarted on the combination inhaler. The patient was alert and oriented on admission, however, confusion and hallucinations progressed throughout his hospital stay. The combination inhaler was discontinued and his confusion and hallucinations resolved by discharge. The temporal relationship of these events and a probable Naranjo association allows for reasonable assumption that the use of the budesonide/formoterol combination inhaler caused or contributed to the occurrences of delirium in this elderly patient. The onset of delirium was likely due to the systemic absorption of the glucocorticoid from lung deposition, complicated in an individual with several predisposing risk factors for delirium. Health care providers should be aware of this potential adverse drug reaction when prescribing inhaled medications to older patients at risk for delirium.

Topics: Administration, Inhalation; Aged, 80 and over; Bronchodilator Agents; Budesonide; Delirium; Drug Combinations; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Hallucinations; Humans; Male; Pulmonary Disease, Chronic Obstructive; Risk Factors

In patients with chronic obstructive pulmonary disease (COPD), pulmonary macrophages increase in number, release increased levels of inflammatory mediators, and respond poorly to glucocorticosteroids. Whether this is due to a change in macrophage phenotype or localized activation is unknown.. We sought to investigate whether macrophages from patients with COPD are a distinct phenotype.. Macrophage populations were isolated from human lung tissue from nonsmokers, smokers, and patients with COPD by using Percoll density gradients. Five macrophage populations were isolated on the basis of density (1.011-1.023, 1.023-1.036, 1.036-1.048, 1.048-1.061, and 1.061-1.073 g/mL), and cell-surface expression of CD14, CD16, CD163, CD40, and CD206 was assessed by using flow cytometry. Release of active matrix metalloproteinase 9, TNF-α, CXCL8, and IL-10 was measured by using ELISA.. The 2 least dense fractions were more than 90% apoptotic/necrotic, with the remaining fractions greater than 70% viable. Macrophages from nonsmokers and smokers were CD163(+), CD206(+), CD14(+), and CD40(-), whereas macrophages from patients with COPD were less defined, showing significantly lower expression of all receptors. There were no differences in receptor expression associated with density. Macrophages from patients with COPD of a density of 1.036 to 1.048 g/mL released higher levels of active matrix metalloproteinase 9 compared with cells from nonsmokers, with no difference between the remaining fractions. This population of macrophages from patients with COPD was less responsive to budesonide compared with those from nonsmokers and smokers when stimulated with LPS. Glucocorticosteroid insensitivity was selective for proinflammatory cytokines because budesonide inhibition of LPS-stimulated IL-10 release was similar for all macrophages.. This study identifies a specific macrophage phenotype in the lungs of patients with COPD who are glucocorticosteroid insensitive with a density of 1.036 to 1.048 g/mL but do not correspond to the current concept of macrophage phenotypes.

Topics: Antigens, CD; Budesonide; Cell Separation; Drug Resistance; Female; Flow Cytometry; Humans; Immunophenotyping; Interleukin-10; Interleukin-8; Macrophages, Alveolar; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

To examine the relationships between inhaler satisfaction, treatment compliance and health status in patients with chronic obstructive pulmonary disease (COPD).. In a large, multinational, cross-sectional, real-world survey, respiratory specialists and primary care physicians provided information on six consecutive patients with COPD, who were then asked to complete a questionnaire. Physician-assessed compliance was scored (5-point Likert scale) and patients rated overall satisfaction with their maintenance inhaler (7-point Likert scale). Health status assessments included frequency of exacerbations and hospitalizations due to exacerbations in the past 12 months.. The analysis included 1443 patients (71.8% male; mean age 65.2 years). Patients' overall satisfaction with their inhaler was significantly associated with treatment compliance (χ(2) - df = 89.7; p < 0.001). Male gender (χ(2) - df = 2.9; p < 0.05) and fewer maintenance drugs (χ(2) - df = 17.7; p < 0.001) were also associated with compliance; age and breathlessness severity were not. Attributes influencing inhaler satisfaction mainly related to durability, ergonomics and ease of use. Small but statistically significant associations were observed between increasing treatment compliance and fewer exacerbations (R(2) = 0.037; p < 0.001) and fewer hospitalizations due to exacerbations (R(2) = 0.025; p < 0.001). There was a direct association between inhaler satisfaction and fewer exacerbations (R(2) = 0.03; p < 0.001).. Treatment compliance appears to be modestly associated with inhaler satisfaction, better health status and less frequent COPD exacerbations, although other factors are also likely to be involved. Durability, ergonomics and ease-of-use are inhaler attributes that influence patient satisfaction.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Budesonide; Cross-Sectional Studies; Female; Health Status; Humans; Male; Medication Adherence; Nebulizers and Vaporizers; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Quality of Life; Sleep; Treatment Outcome

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common condition, which affects not only the quality of life of patients but also their prognosis. The purpose of this study was to explore the effects of an inhaled salbutamol sulfate solution and an inhalation suspension of the glucocorticoid budesonide that were atomized with heliox to treat patients with AECOPD.. Twenty-three patients with AECOPD were divided into a treatment group (He/O2 = 70%/30%) and a control group (N2/O2 = 70%/30%). The salbutamol sulfate and budesonide were administered by inhalation twice a day for 7 days. Vital signs, arterial blood gas levels, pulmonary function and the levels of serum myostatin (sMSTN) were measured and lung vibration imaging was performed.. We found that the PaO2 and PaCO2 values were not significantly different between the two groups at the various time points (P > 0.05). There were also no significant differences in any of the parameters of pulmonary function between the two groups. However, after baseline correction, the increase rate of the forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and the maximum minute ventilation (MVV) appeared to be significantly increased at some time points compared with the baseline (before treatment) in both groups (P < 0.05). Although the values of quantitative lung distribution (QLD) for different regions and the levels of sMSTN were slightly different between the two groups, the repeated measures analysis of variance (ANOVA) revealed that there were no significant differences between the two groups or within any group (P > 0.05).. Although the use of heliox as a driving gas can improve symptoms and benefit patients with AECOPD, the heliox treatment group did not have significant differences in arterial blood gases, lung function, lung vibration response imaging or the levels of sMSTN compared with the control group. (Chinese Clinical Trial Register Center ChiCTRTRC-00000273).

Topics: Administration, Inhalation; Aged; Albuterol; Budesonide; Drug Interactions; Female; Helium; Humans; Male; Middle Aged; Oxygen; Prospective Studies; Pulmonary Disease, Chronic Obstructive

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: Asthma; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Europe; Formoterol Fumarate; Humans; Legislation, Drug; Pulmonary Disease, Chronic Obstructive; United States

The Easyhaler(®) (EH) device-metered dry powder inhaler containing budesonide and formoterol is being developed for asthma and chronic obstructive pulmonary disease (COPD). As a part of product optimization, a series of in vitro and in vivo studies on flow rate dependency were carried out.. Inspiratory flow parameters via EH and Symbicort(®) Turbuhaler(®) (TH) inhalers were evaluated in 187 patients with asthma and COPD. The 10(th), 50(th), and 90(th) percentile flow rates achieved by patients were utilized to study in vitro flow rate dependency of budesonide/formoterol EH and Symbicort TH. In addition, an exploratory pharmacokinetic study on pulmonary deposition of active substances for budesonide/formoterol EH in healthy volunteers was performed.. Mean inspiratory flow rates through EH were 64 and 56 L/min in asthmatics and COPD patients, and through TH 79 and 72 L/min, respectively. Children with asthma had marginally lower PIF values than the adults. The inspiratory volumes were similar in all groups between the inhalers. Using weighted 10(th), 50(th), and 90(th) percentile flows the in vitro delivered doses (DDs) and fine particle doses (FPDs) for EH were rather independent of flow as 98% of the median flow DDs and 89%-93% of FPDs were delivered already at 10(th) percentile air flow. Using±15% limits, EH and TH had similar flow rate dependency profiles between 10(th) and 90(th) percentile flows. The pharmacokinetic study with budesonide/formoterol EH in healthy subjects (n=16) revealed a trend for a flow-dependent increase in lung deposition for both budesonide and formoterol.. Comparable in vitro flow rate dependency between budesonide/formoterol EH and Symbicort TH was found using the range of clinically relevant flow rates. The results of the pharmacokinetic study were in accordance with the in vitro results showing only a trend of flow rate-dependant increase in lung deposition of active substances with EH.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Bronchodilator Agents; Budesonide; Child; Equipment Design; Ethanolamines; Female; Formoterol Fumarate; Humans; In Vitro Techniques; Inhalation; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Young Adult

To compare clinical and demographic characteristics, resource utilization and costs of chronic obstructive pulmonary disease (COPD) patients prior to initiating budesonide-formoterol combination (BFC) or tiotropium-maintenance therapy.. This cross-sectional study used claims-based diagnosis to identify COPD patients in the HealthCore Integrated Research Database who initiated BFC or tiotropium therapy between March 1, 2009 and January 31, 2012 (intake period); the index date was defined as the initial prescription fill for either agent. Patients diagnosed with respiratory tract cancer or receiving inhaled corticosteroids/long-acting β2-adrenergic agonists or tiotropium in 12 months prior to index date were excluded. Categorical variables were evaluated with χ(2) tests; mean cost differences were evaluated using γ-regression.. Overall, 6,940 BFC and 10,831 tiotropium patients were identified. The BFC group was younger (mean age 64 versus 67 years), with a greater proportion of females (54% versus 51%). BFC-treated patients had more comorbid respiratory conditions, including asthma (25% versus 13%), but fewer comorbid cardiovascular conditions, including atherosclerosis (7% versus 10%) and myocardial infarction (4% versus 6%). A greater proportion of BFC patients received prior respiratory medication, including oral corticosteroids (46% versus 35%) and short-acting β2-agonists (44% versus 35%). Tiotropium-treated patients had a greater mean number of COPD-related outpatient visits (4.6 versus 4.1). BFC-treated patients had lower total all-cause ($17,259 versus $17,926) and COPD-related ($1,718 versus $1,930) health care costs, driven by lower all-cause and COPD-related inpatient expenditures.. Initiators of BFC or tiotropium showed differences in clinical and demographic characteristics and health care utilization and costs prior to starting COPD maintenance therapy.

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Age Factors; Aged; Bronchodilator Agents; Budesonide; Chi-Square Distribution; Cholinergic Antagonists; Comorbidity; Cross-Sectional Studies; Data Mining; Databases, Factual; Drug Combinations; Drug Costs; Ethanolamines; Female; Formoterol Fumarate; Glucocorticoids; Health Expenditures; Humans; Male; Middle Aged; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sex Factors; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

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: Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive

Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests.. COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9μg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9μg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function.. OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies.. In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a β2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

Topics: Adrenal Cortex Hormones; Bronchodilator Agents; Budesonide; Drug Combinations; Feasibility Studies; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Combinations of inhaled corticosteroids (ICSs) and long-acting β2 -agonists (LABAs) are recommended for patients with moderate and severe chronic obstructive pulmonary disease (COPD). However, it is not known whether different fixed combinations are equally effective. The aim of this study was to investigate exacerbation rates in primary care patients with COPD treated with budesonide/formoterol compared with fluticasone/salmeterol.. Patients with physician-diagnosed COPD and a record of postdiagnosis treatment with a fixed combination of budesonide/formoterol or fluticasone/salmeterol were included. Data from primary care medical records were linked to those from Swedish national hospital, drug and cause of death registers. Pairwise (1 : 1) propensity score matching was carried out at the index date (first prescription) by prescribed fixed ICS/LABA combination. Exacerbations were defined as hospitalizations, emergency visits and collection of oral steroids or antibiotics for COPD. Yearly event rates were compared using Poisson regression.. Matching of 9893 patients (7155 budesonide/formoterol and 2738 fluticasone/salmeterol) yielded two cohorts of 2734 patients, comprising 19 170 patient-years. The exacerbation rates were 0.80 and 1.09 per patient-year in the budesonide/formoterol and fluticasone/salmeterol groups, respectively (difference of 26.6%; P < 0.0001); yearly rates for COPD-related hospitalizations were 0.15 and 0.21, respectively (difference of 29.1%; P < 0.0001). All other healthcare outcomes were also significantly reduced with budesonide/formoterol versus fluticasone/salmeterol.. Long-term treatment with fixed combination budesonide/formoterol was associated with fewer healthcare utilization-defined exacerbations than fluticasone/salmeterol in patients with moderate and severe COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Formoterol Fumarate; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Registries; Respiratory Function Tests; Retrospective Studies; Secondary Prevention; Time Factors; Treatment Outcome

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

In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT.. Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD.. The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment.. MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Lung; Male; Middle Aged; Multidetector Computed Tomography; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

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

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung, and is the fifth leading cause of morbidity worldwide. A novel proinflammatory factor, interleukine-32 (IL-32), is suggested as a risk factor of COPD. Budesonide is widely used for COPD treatment as anti-inflammatory drug. However, the inflammatory inhibition mechanism of budesonide is not fully understood. In this study, we used a rat model with COPD to investigate the effect of budesonide on IL-32 expression in lung tissue. We found that cigarette smoking (CS) strongly induced IL-32 expression in lung tissue, seriously weakened lung function, and damaged pulmonary tissue. Budesonide inhibited the expression of IL-32 in lung tissue. In budesonide-treated rats, we observed no repair of damaged lung tissue but the pulmonary function was partly recovered. To our knowledge, this is the first report that budesonide inhibits the expression of IL-32 in lung tissues, which is strongly induced by CS.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Inflammation; Interleukins; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Risk Factors; Smoking

A role in pulmonary immunity has been ascribed to Natural Killer (NK) cells and several in vitro studies have shown a corticosteroid-induced inhibition of NK cells mediated cytotoxicity. Several clinical trials on chronic obstructive pulmonary disease (COPD) have suggested a relationship between COPD treatment and occurrence of respiratory infections. Aims of our study were to investigate if real life COPD treatment affects peripheral blood NK cells total count and their receptors expression and to assess if different doses of formoterol and budesonide, administered alone or in combination, are able to modulate the surface expression of activating (NKp30, NKp44, NKp46 and NKG2D) and inhibitory (KIR2DL2/L3, KIR3DL1 and NKG2A) receptors on peripheral blood NK cells of COPD patients. Moreover, we evaluated the potential effect of treatment with budesonide and/or formoterol on IFN-γ secretion in vitro. NK cells were isolated from peripheral blood of 7 healthy volunteers, 9 chronic bronchitis (CB) and 11 COPD patients. Total NK cells count and activating and inhibitory receptors expression were evaluated. NK cells were cultured for 20h in 96-well plates with IL-2 (100IU/ml)+IL-12 (2.5ng/ml), with or without budesonide (Bud; 1 and 0.01μM) and formoterol (For; 30 and 0.3nM) alone or in combination. Cells were analyzed by flow cytometry and IFN-γ was measured in cell supernatants by ELISA test. No difference between real life treated COPD, CB and healthy subjects was found concerning NK total count and NK cell receptors expression. When cells were stimulated over night with cytokines and treated with drugs, only NKG2D receptor was modulated. Its expression was significantly downregulated by budesonide alone and in combination with formoterol in COPD patients. IFN-γ production induced by stimulation with IL-2+IL-12 was decreased in a highly significant way (p<0.01) by all treatments in all groups. Even if in vitro experiments with budesonide, alone or in combination with formoterol, showed a modulation of NKG2D receptor expression and IFN-γ production, our ex vivo results show that real life LABA and ICS treatment does not influence peripheral NK cells count and their receptors phenotype.

Topics: Aged; Budesonide; Ethanolamines; Formoterol Fumarate; Humans; Interferon-gamma; Interleukin-2; Killer Cells, Natural; NK Cell Lectin-Like Receptor Subfamily K; Pulmonary Disease, Chronic Obstructive

The formulation of multi-drug pressurised metered dose inhalers (pMDIs) opens up exciting therapeutic opportunities for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We have investigated the formulation of a solution-based triple therapy pMDI containing ipratropium, formoterol, budesonide and ethanol as co-solvent.. This system was characterised for in-vitro performance and compared with marketed pMDIs (Atrovent and Symbicort).. No significant difference was found in the stage deposition of each drug from the triple therapy formulation, suggesting that the droplets contained a fixed ratio of the three components used. Stage deposition of formoterol and budesonide from the suspension-based marketed Symbicort were significantly different, suggesting that the two drugs were deposited as separate entities. Calculation of the mass median aerodynamic diameter (MMAD) of each formulation suggested Atrovent (ipratropium, MMAD = 0.9 ± 0.0 µm) to have a small particle size, similar to the triple therapy formulation. Atrovent, like the triple therapy formulation was solution based and it contained ethanol as a co-solvent (triple therapy formulation, MMAD = 1.3 ± 0.0 µm).. This study demonstrated the feasibility of formulating a solution-based pMDI containing a triple therapy with identical deposition pattern for the treatment of several respiratory diseases where multi-drug cell targeting is required.

Topics: Administration, Inhalation; Aerosols; Bronchodilator Agents; Budesonide; Chemistry, Pharmaceutical; Drug Combinations; Drug Delivery Systems; Ethanol; Ethanolamines; Feasibility Studies; Formoterol Fumarate; Humans; Ipratropium; Metered Dose Inhalers; Microscopy, Electron, Scanning; Particle Size; Pharmaceutical Vehicles; Pulmonary Disease, Chronic Obstructive; Solubility; Solutions; Solvents

Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by a largely irreversible airflow obstruction and a persistent, excessive inflammatory response. Alveolar macrophages (AMs) are increased in the lungs of COPD patients, and act as orchestrators of the inflammatory response, releasing a range of mediators to coordinate recruitment and activation of leukocytes. Attempts to treat the inflammatory component of COPD with anti-inflammatory drugs such as steroids has met with limited success. In this study, we compared the ability of the phosphodiesterase IV (PDEIV) inhibitor Cilomilast, the steroid Budesonide, and the p38 mitogen activated protein kinase inhibitor BIRB-796 to inhibit tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) releases from AMs isolated from COPD lung transplant tissue. All studies were carried out with appropriate ethical approval and written, informed consent was obtained from each subject. Cilomilast had little effect on cytokine release from AMs. There was considerable variability in the responsiveness of AMs to Budesonide, with a subset of AMs responding poorly to Budesonide. BIRB-796 inhibited TNFα release from all AM donors, including those that responded poorly to steroids. Treatment with BIRB-796 and Budesonide together gave an additive decrease in TNFa release. These results suggest that a p38 inhibitor may provide advantages over existing anti-inflammatory treatments for COPD, either as an add-on to existing therapy, or to treat patients who respond poorly to steroids.

Topics: Anti-Inflammatory Agents; Budesonide; Cells, Cultured; Cyclohexanecarboxylic Acids; Female; Humans; Interleukin-6; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Naphthalenes; Nitriles; p38 Mitogen-Activated Protein Kinases; Phosphodiesterase 4 Inhibitors; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Tumor Necrosis Factor-alpha

The present study was designed to evaluate inhaler techniques and patient satisfaction with fixed-combination budesonide/formoterol dry-powder inhaler chronic obstructive pulmonary disease (COPD) in Turkey in real-life clinical practice.. A total of 442 patients with COPD [mean (SD) age: 63.2 (10.6) years, 76.5% were males] were included in this cross-sectional study conducted at 25 outpatient clinics across Turkey. Data on socio-demographic characteristics, characteristics of COPD, inhaler technique and satisfaction with dry-powder inhaler were recorded at a single crosssectional visit performed at the study enrolment.. Patients were characterized by prominence of moderate to severe (78.1%) COPD, high rate of regular use of overall COPD medications (89.4%) and Turbuhaler® for an average of 33.7 months, predominance of males (76.5%), primary education (85.7%), urban location (68.3), ex-smokers (61.1%) and spending time outdoors for ≥ 4 hour/day (62.0%). Use of correct techniques was evident in majority of patients (≥ 94%), whereas inhalation maneuvers including breathing out gently away from mouthpiece without blowing into it (71.9%) and holding the breath for 5-10 seconds (78.3%) were performed correctly by lesser percent of patients especially in the older group (≥ 65 years, p< 0.05). Overall percent of patients with the feeling that she/he used the inhaler very/fairly correctly was 73.3%, while 86% of patients identified that they were very/fairly satisfied with the inhaler, irrespective of age and educational status.. In conclusion, our findings revealed the majority of patients are able to use Turbuhaler® correctly regardless of the educational status, while older age was associated with higher rate of errors in inhalation maneuvers in the real clinical practice in Turkey. Majority of our patients identified Turbuhaler® to be very/fairly convenient regarding ease of use, portability, and usability with an overall self-confidence in using the inhaler correctly among 73% and the satisfaction rate of 86%; irrespective of age and educational level.

Topics: Administration, Inhalation; Age Factors; Aged; Bronchodilator Agents; Budesonide; Cross-Sectional Studies; Drug Combinations; Dry Powder Inhalers; Educational Status; Ethanolamines; Formoterol Fumarate; Humans; Male; Middle Aged; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Turkey

Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate. We used computed tomography (CT) to evaluate the effect of smoking cessation on lung density in patients with COPD.. Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests (LFT) for 2?4 years as part of a randomised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density. Lung density was expressed as the 15th percentile density (PD15) and relative area of emphysema below -910 HU (RA-910). From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities.. Following smoking cessation RA-910 increased by 2.6% (p = 0.003) and PD15 decreased by -4.9 HU (p = 0.0002). Furthermore, changes were larger in the budesonide group than the placebo group (PD15: -7.1 vs -2.8 HU. RA-910 3.7% vs 1.7%). These differences were, however, not statistically significant. The LFT parameters (FEV(1) and diffusion capacity) were not significantly influenced by smoking cessation.. Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density, which resembles rapid progression of emphysema. This fall in density is probably due to an anti-inflammatory effect of smoking cessation.

Topics: Aged; Anti-Inflammatory Agents; Budesonide; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Smoking Cessation; Tomography, Spiral Computed; Tomography, X-Ray Computed

Corticosteroid insensitivity represents a major barrier to the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma. It is caused by oxidative stress, leading to reduced histone deacetylase-2 (HDAC2) function through activation of phosphoinositide-3-kinase-δ (PI3Kδ). The tricyclic antidepressant nortriptyline has been identified in high-throughput screens as an agent that increases corticosteroid responsiveness. The aim of this study was to identify the molecular mechanism whereby nortriptyline increases corticosteroid sensitivity. Phosphorylation of Akt, a footprint of PI3K activation, and HDAC activity were evaluated by Western blotting and fluorescent activity assay in U937 monocytic cells. Corticosteroid sensitivity was evaluated by the inhibition of tumor necrosis factor α (TNFα)-induced interleukin 8 (IL-8) production by budesonide. Hydrogen peroxide (H(2)O(2)) or cigarette smoke extract (CSE) increased the level of phosphorylated Akt (pAkt) and reduced HDAC activity. Pretreatment with nortriptyline inhibited pAkt induced by CSE and H(2)O(2) as well as restored HDAC activity that had been decreased by H(2)O(2) and CSE. In addition, nortriptyline inhibited PI3Kδ activity, but had no effect on the PI3Kα and PI3Kγ isoforms. Although CSE reduced the effects of budesonide on TNFα-induced IL-8 production in U937 cells, nortriptyline reversed CSE-induced corticosteroid insensitivity. Nortriptyline restores corticosteroid sensitivity induced by oxidative stress via direct inhibition of PI3Kδ and is a potential treatment for corticosteroid-insensitive diseases such as COPD and severe asthma.

Topics: Adrenal Cortex Hormones; Adrenergic Uptake Inhibitors; Anti-Inflammatory Agents; Budesonide; Cells, Cultured; Chromones; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Enzyme Inhibitors; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Hydrogen Peroxide; Interleukin-8; Morpholines; Nortriptyline; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Smoking; Tumor Necrosis Factor-alpha; U937 Cells

Chronic obstructive pulmonary disease (COPD) is an important risk factor for perioperative morbidity and mortality in patients undergoing cardiac surgery. Despite high clinical relevance, current guidelines lack clear recommendations on the optimal approach for patients with insufficiently treated COPD and urgent need for cardiac surgery. The aim of the present study was to analyze the efficacy of short-term pulmonary conditioning (PC) in this subset of cardiopulmonary patients.. Eighteen patients with urgent need for cardiac surgery were treated with 1 mg budenoside twice a day, 1.25 mg salbutamol four times a day and 15 mg ambroxol three times a day. On average, patients received pulmonary conditioning for 5.1 ± 2.1 days. Lung function was assessed before and after treatment.. Pulmonary conditioning improved forced expiratory volume in one second (FEV1) by 16% (P<0.001). Predicted FEV1 increased from 48.3 ± 13.6% at baseline to 55.4 ± 16.1% after treatment (P<0.001). Total resistance was reduced from 0.933 ± 0.418 kPa·s/L to 0.631 ± 0.344 kPa·s/L after PC (P=0.004). The percentage of patients in GOLD stages III-IV was reduced from 55.6% at baseline to 27.8% after treatment. After surgery, patients needed mechanical ventilation for 2 ± 3.4 days. One patient (5.6%) received a tracheostomy and four patients (22.2%) developed pneumonia; 30-day mortality was 5.6%.. Short-term treatment with budenoside, salbutamol and ambroxol significantly improved lung function parameters. If surgery can be delayed for several days, pulmonary conditioning should be considered for patients with insufficiently treated COPD.

Topics: Aged; Airway Resistance; Albuterol; Ambroxol; Bronchodilator Agents; Budesonide; Cardiac Surgical Procedures; Drug Administration Schedule; Drug Therapy, Combination; Expectorants; Female; Forced Expiratory Volume; Germany; Heart Diseases; Humans; Lung; Male; Middle Aged; Pneumonia; Preoperative Care; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Respiration, Artificial; Respiratory Function Tests; Respiratory System Agents; Time Factors; Tracheostomy; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease associated with increasing morbidity and mortality and an economic burden that stretches beyond the patient to healthcare systems. Avoiding exacerbations and subsequent hospitalizations is an important clinical aim and can avoid significant costs associated with the disease. International guidelines recommend the addition of an inhaled corticosteroid (ICS) to a long-acting β₂-adrenoceptor agonist (LABA) for patients with severe to very severe COPD and a history of exacerbations.. To evaluate retrospectively over a 3-month period, the cost effectiveness of budesonide/formoterol added to tiotropium bromide (tiotropium) compared with placebo added to tiotropium in COPD patients eligible for ICS/LABA combination therapy, based on the CLIMB study (NCT00496470).. A cost-effectiveness analysis of data from the 12-week, randomized, double-blind CLIMB study of COPD patients (n = 659; eligible for ICS/LABA; aged ≥ 40 years) comparing budesonide/formoterol (Symbicort® Turbuhaler® 320/9 μg twice daily) added to tiotropium (18 μg daily) or placebo added to tiotropium was conducted. A severe exacerbation was defined as a requirement for systemic glucocorticosteroids and/or ED visit and/or hospitalization. The effectiveness variable used for this analysis was the number of severe exacerbations avoided. Direct costs (medications, hospitalizations, ED and GP visits) were calculated by applying year 2009 unit costs from Australia ($A), Canada ($Can) and Sweden (Swedish krona [SEK]) to the study's pooled resource use. One-way sensitivity analyses for each country's mean incremental cost-effectiveness ratio and sensitivity to overall exacerbations were conducted. Bootstrapping was performed to estimate the variation around resource use, exacerbations and each country's mean incremental cost-effectiveness ratio.. The mean number of severe exacerbations per patient 3-month period was 0.11 in the budesonide/formoterol added to tiotropium arm and 0.29 in the placebo added to tiotropium arm--a 62% reduction in the rate of severe exacerbations. Treatment with budesonide/formoterol added to tiotropium costs less in Australia and Canada (-$A90 [-€58] and -$Can4.51 [-€3]) and only slightly more in Sweden (SEK444 [€43]), i.e. the savings associated with fewer exacerbations more than offset the additional budesonide/formoterol drug cost in Australia and Canada, and partially offset it in Sweden. In the Australian and Canadian perspectives, budesonide/formoterol added to tiotropium was a dominant treatment (fewer exacerbations at a lower cost) compared with placebo added to tiotropium. In Sweden, the estimated incremental cost per avoided exacerbation was SEK2502 (€244.40).. Budesonide/formoterol added to tiotropium was the dominant strategy compared with placebo added to tiotropium based on a 12-week study in COPD patients eligible for ICS/LABA combination therapy in Australia and Canada, and appears to be a cost-effective strategy in Sweden.

Topics: Australia; Budesonide; Canada; Cost-Benefit Analysis; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Health Care Costs; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Scopolamine Derivatives; Sweden; Tiotropium Bromide

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

To compare the effectiveness of budesonide/formoterol fumarate dihydrate (BFC) and fluticasone propionate/salmeterol (FSC), two combination inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) products approved for the treatment of chronic obstructive pulmonary disease (COPD) in the US with respect to cost, therapy adherence, and related healthcare utilization. The effectiveness of these two treatments has not previously been compared in a US COPD population.. A retrospective cohort study assessed COPD-related outcomes using administrative claims data among ICS/LABA-naïve patients. Patients initiating BFC were propensity matched to FSC patients. Cost and effectiveness were measured as total healthcare expenditures, exacerbation events (hospitalizations, emergency department visits, or outpatient visits associated with oral corticosteroid or antibiotic prescription fills), and treatment medication adherence. Differences in COPD symptom control were assessed via proxy measure through claims for rescue medications and outpatient encounters.. Of the 6770 patients (3385 BFC and 3385 FSC), fewer BFC patients had claims for short-acting beta agonists (SABA) (34.7% vs 39.5%; p<0.001) and ipratropium (7.8% vs 9.8%, p<0.005) than FSC patients, but no substantial differences were seen in other clinical outcomes including tiotropium or nebulized SABA claims, COPD-related outpatient visits, or exacerbation events. There were no significant differences in total COPD-related medical costs in the 6-month period after initiation of combination therapy.. This was a retrospective observational study using claims data and accuracy of COPD diagnoses could not be verified, nor was information available on severity of disease. The results and conclusions of this study are limited to the population observed and the operational definitions of the study variables.. For most outcomes of interest, BFC and FSC showed comparable real-world effectiveness.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Comorbidity; Costs and Cost Analysis; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Health Services; Humans; Male; Medication Adherence; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies

Topics: Acyclovir; Administration, Inhalation; Antiviral Agents; Blepharitis; Budesonide; Glucocorticoids; Herpesvirus 1, Human; Humans; Keratitis, Herpetic; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

Topics: Adrenal Insufficiency; Bronchiolitis Obliterans; Bronchodilator Agents; Budesonide; Child; Child, Preschool; Cushing Syndrome; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Pulmonary Disease, Chronic Obstructive; Rhinitis, Allergic, Perennial; Ritonavir

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Fractures, Bone; Glucocorticoids; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

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

To evaluate how pulmonologists view the impact that asthma and COPD has on their patients, as well as how they treat these diseases.. Survey including 227 pulmonologists participating in the VI Brazilian Asthma Conference, II Brazilian COPD Conference and II Brazilian Smoking Conference, all of which were held in 2007.. According to the answers given by the pulmonologists, COPD is a public health problem of equal or greater importance than asthma, and COPD causes various disruptions in the lives of patients and their family members. When prescribing an inhalation device, pulmonologists feel that simplicity of use is more important than is the cost. There was a slight preference for the Aeroliser and Diskus systems. The budesonide-formoterol combination was the therapeutic regimen most often cited for the continued treatment of the symptomatic asthma, whereas tiotropium bromide was the most often cited medication for the treatment of patients with COPD. Selection of the therapeutic regimen for asthma and COPD is primarily influenced by the results of therapeutic trials published in the literature.. The opinions of pulmonologists on the topics under study are in concordance with data in the specialized literature.

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Budesonide; Cross-Sectional Studies; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Nebulizers and Vaporizers; Practice Patterns, Physicians'; Pulmonary Disease, Chronic Obstructive; Pulmonary Medicine

Rhinoviruses (RVs) are responsible for the majority of acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. RVs infect the lower airways and induce the production of pro-inflammatory and remodelling-associated mediators. Budesonide (BUD) and formoterol (FORM) synergize in controlling asthma and COPD exacerbations; however, their effects on virus-induced inflammation and remodelling are less known.. We investigated whether BUD and FORM synergize in suppressing RV-induced inflammation and remodelling in the airways.. In vitro models of RV infection of BEAS-2B and primary normal human bronchial epithelial (NHBE) cells were used. We assessed the effects of individual and combined drugs administered post-infection, at a clinically relevant concentration range (10(-6)-10(-10) m), on the production of CCL5, CXCL10, CXCL8, IL-6 and the remodelling-associated VEGF and bFGF, using ELISA and RT-PCR.. BUD effectively suppressed RV-mediated induction of all mediators studied, in a concentration-dependent manner. FORM alone suppressed the production of CXCL8 and bFGF. The combination of BUD and FORM had concentration-dependent, additive or synergistic effects in the suppression of RV-induced CCL5, CXCL8 and CXCL10 in both cell types as well as VEGF in NHBE only. Combination treatment also resulted in an enhanced suppression of RV-induced IL-6, and CCL5 at the mRNA level as compared with BUD or FORM alone.. BUD and FORM suppress RV-induced chemokines and growth factors in bronchial epithelial cells in a concentration-dependent, synergistic or additive manner. These data further support the combined use of BUD and FORM in asthma and COPD and intensification of this therapy during exacerbations.

Topics: Asthma; Bronchi; Bronchodilator Agents; Budesonide; Chemokine CXCL10; Chemokines; Drug Synergism; Epithelial Cells; Ethanolamines; Fibroblast Growth Factor 2; Formoterol Fumarate; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Picornaviridae Infections; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Rhinovirus; Vascular Endothelial Growth Factor A

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

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

Topics: Bronchodilator Agents; Budesonide; Conflict of Interest; Humans; Pneumonia; Pulmonary Disease, Chronic Obstructive

Heat shock proteins assist cellular protein folding and are required for the normal activity of steroid receptors. In this study we assessed nuclear HSP90 and HSP70 proteins and mRNA levels in cells isolated from induced sputum of chronic obstructive pulmonary disease patients treated for 4 weeks with formoterol (F) or formoterol+budesonide (F/ICS).. Nuclear heat shock protein levels were assessed by Western blot and specific mRNAs were quantified in cell lysates using qRT-PCR.. Both HSP90 and HSP70 protein levels were higher in the F/ICS-treated patients in comparison with the F-treated group (by 31%, P<0.05 and 28%, P<0.05, respectively), while specific mRNAs were lowered. HSP86/HSP89 and D6S182/HSP90-BETA were repressed by about 40% (P<0.05) while HSP70-1/HSP70-1A, HSP70-1B/HSP70-2, and HSP70-HSC54/HSC70 were repressed by 47% (P<0.01), 57% (P<0.01) and 65% (P<0.01), respectively.. It is possible that increased nuclear heat shock proteins may play a role in the attenuation of the response to glucocorticoids in COPD patients.

Topics: Budesonide; Cell Nucleus; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Pulmonary Disease, Chronic Obstructive; RNA, Messenger

Immunophilin FKBP51 assists polypeptide folding, participates in glucocorticoid actions and may play a role in glucocorticoid resistance. FKBP51 is altered in patients with asthma, but its role in chronic obstructive pulmonary disease (COPD) characterized by dysregulation of several pro/antiinflammatory genes is less clear.. We assessed changes in nuclear/cytosolic FKBP51 protein using SDS-PAGE/WB and FKBP51 mRNA by qRT-PCR in cells isolated from induced sputum of stable COPD patients treated with formoterol/budesonide or formoterol/budesonide/theo?phylline for 4 wk.. Expression of FKBP51 was higher in formoterol/ budesonide/theophylline-treated patients, compared with formoterol/budesonide group in both cytosolic and nuclear fractions by about 57% and 31%, respectively (P<0.001, P<0.01). FKBP51 mRNA was only slightly, but not significantly, higher in patients on formoterol/ budesonide/theophylline.. Increased FKBP51 in COPD patients treated with formoterol/ budesonide/theophylline may be important in altering signaling from corticosteroid receptors.

Topics: Budesonide; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Sputum; Tacrolimus Binding Proteins; Theophylline

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

Identifying chronic obstructive pulmonary disease (COPD) patients at increased risk of mortality is an important component of effective disease management.. A pooled analysis of patients with severe COPD, from two well-controlled 1-year studies, was conducted using Cox regression and spline analysis to evaluate predictability of baseline demographic data and in-study variables for mortality risk, and to evaluate the effect of treatment allocation to budesonide and formoterol, versus their respective control groups, on these outcomes.. In the pooled analysis, a Cox regression model reported a higher baseline St George's Respiratory Questionnaire (SGRQ) total score as a significant predictor of mortality (hazard ratio 1.037 [95% confidence interval 1.021-1.054]; p<0.0001). The 36-item short-form health survey (SF-36) mental and physical component scores were also predictive of an increased mortality risk (p<0.05). Age, forced expiratory volume in 1 s (FEV(1)), body mass index and smoking status were not significant predictors. Spline analysis of baseline variables revealed a linear association between SGRQ total score and mortality risk over 1 year (logarithmic scale). Other baseline variables, including FEV(1), showed different bimodal patterns in the spline analysis. There was no difference in mortality in the formoterol versus the non-formoterol treatment group while budesonide-containing treatment was associated with reduced 1-year, all-cause, in-study mortality compared with non-budesonide therapy.. Health status measured by SGRQ and SF-36 may be important for predicting COPD patients at increased mortality risk, with SGRQ total score emerging as the strongest predictor compared with other baseline covariates.

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Health Status; Humans; Male; Middle Aged; Multicenter Studies as Topic; Predictive Value of Tests; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Regression Analysis; Respiratory Function Tests; Risk Factors; Surveys and Questionnaires

Topics: Administration, Inhalation; Budesonide; Canada; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Patients with chronic obstructive pulmonary disease (COPD) are often given admixtures of nebulizable drugs to minimize the time of administration in treatment regimens.. To evaluate the physicochemical compatibility and aerodynamic characteristics of formoterol fumarate 20 microg/2 mL when mixed or sequentially nebulized with budesonide inhalation suspension 0.5 mg/2 mL, ipratropium bromide 0.5 mg/2.5 mL, cromolyn sodium 20 mg/2 mL, or acetylcysteine 10% (100 mg/mL).. The admixtures were prepared in triplicate and analyzed for physicochemical compatibility at 0, 15, 30, and 60 minutes after mixing at room temperature. Physical compatibility was determined by visual examination and measurements of pH, osmolality, and turbidity. Chemical stability was evaluated using compendial or in-house-validated high-performance liquid chromatography (HPLC) assay methods. The aerodynamic characteristics of the admixtures or sequentially nebulized drugs were determined from aerosols generated from a Pari LC Plus nebulizer, using an 8-stage cascade impactor followed by HPLC analysis of the deposited drug.. The admixtures remained clear, colorless solutions with no precipitation, except for cloudiness observed in the formoterol/budesonide combination due to budesonide suspension. The pH, osmolality, and turbidity for all admixtures were within the initial values (< or = 3%), and there were no significant changes (< or = 2%) in potency of the active components throughout the 1-hour study period. Due to increased drug volume or reconcentration in the nebulizer cup, the respirable fraction/delivered dose increased significantly (p < 0.05) for the mixed or sequentially nebulized drug. However, the fine particle fraction (FPF), mass median aerodynamic diameter, and geometric standard deviation generally remained unchanged for all admixtures, with the exception of FPF for the formoterol/budesonide combination.. Our results indicate that admixtures of formoterol with budesonide, ipratropium, cromolyn, or acetylcysteine are physically and chemically compatible. However, admixing or sequential nebulization significantly increased the amount of drug delivered compared with single drug nebulization. The clinical implications of the in vitro data in patients with COPD have not been determined.

Topics: Acetylcysteine; Aerosols; Anti-Asthmatic Agents; Bronchodilator Agents; Budesonide; Chromatography, High Pressure Liquid; Cromolyn Sodium; Drug Incompatibility; Drug Stability; Ethanolamines; Expectorants; Formoterol Fumarate; Humans; Hydrogen-Ion Concentration; Ipratropium; Nebulizers and Vaporizers; Osmolar Concentration; Particle Size; Pulmonary Disease, Chronic Obstructive; Time Factors

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C(max)) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C(max) were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C(max) were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C(max) were similar and formoterol AUC and C(max) 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Asthma; Biological Availability; Budesonide; Child; Cross-Over Studies; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Formoterol Fumarate; Glucocorticoids; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Young Adult

Smoking is the principle risk factor for development of chronic obstructive pulmonary disease (COPD). Multidrug resistance-associated protein 1 (MRP1) is known to protect against toxic compounds and oxidative stress, and might play a role in protection against smoke-induced disease progression. We questioned whether MRP1-mediated transport is influenced by pulmonary drugs that are commonly prescribed in COPD.. The immortalized human bronchial epithelial cell line 16HBE14o- was used to analyze direct in vitro effects of budesonide, formoterol, ipratropium bromide and N-acetylcysteine (NAC) on MRP1-mediated transport. Carboxyfluorescein (CF) was used as a model MRP1 substrate and was measured with functional flow cytometry.. Formoterol had a minor effect, whereas budesonide concentration-dependently decreased CF transport by MRP1. Remarkably, addition of formoterol to the highest concentration of budesonide increased CF transport. Ipratropium bromide inhibited CF transport at low concentrations and tended to increase CF transport at higher levels. NAC increased CF transport by MRP1 in a concentration-dependent manner.. Our data suggest that, besides their positive effects on respiratory symptoms, budesonide, formoterol, ipratropium bromide, and NAC modulate MRP1 activity in bronchial epithelial cells. Further studies are required to assess whether stimulation of MRP1 activity is beneficial for long-term treatment of COPD.

Topics: Acetylcysteine; Biological Transport; Bronchi; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Drug Resistance, Multiple; Epithelial Cells; Ethanolamines; Expectorants; Flow Cytometry; Formoterol Fumarate; Humans; In Vitro Techniques; Ipratropium; Multidrug Resistance-Associated Proteins; Oxidative Stress; Pulmonary Disease, Chronic Obstructive

Unreported exacerbations and failure to seek medical attention may have consequences on the health of patients with chronic obstructive pulmonary disease.. This study aims to determine the incidence of reported and unreported exacerbations, to identify predictors of reporting, and to compare the impact of reported and unreported exacerbations on health status.. The study is based on a multicenter Canadian cohort of patients with chronic obstructive pulmonary disease.. Patients completed a daily diary from which exacerbations were defined as a worsening of at least one key symptom (dyspnea, sputum amount, sputum color) recorded on at least 2 consecutive days. Patients were asked to contact the study center if there was a sustained worsening of symptom. Reported exacerbations were events that led to contacting study center or health care visit. The study enrolled 421 patients. The overall incidence of diary exacerbations was 2.7 per person per year, but only 0.8 per person per year was reported. Predictors of reporting included age (HR [hazard ratio], 0.90; 95% confidence interval [CI], 0.81-0.98 per 5-yr increase), FEV(1)% predicted (HR, 0.84; 95% CI, 0.70-0.99 per 10% increase), number of symptoms at onset (HR, 1.59; 95% CI, 1.37-1.84 per additional symptom), and time of the week (HR, 0.35; 95% CI, 0.22-0.56 weekend vs. weekday). There was a clinically important decline in health status for 52% of patients with reported exacerbation and 43% with unreported exacerbations.. This study has shown that less than one-third of the exacerbations were reported. The number of symptoms at onset was the most important predictor of reporting an exacerbation, and both reported and unreported exacerbations had an impact on health status.

Topics: Administration, Inhalation; Age Distribution; Aged; Bronchodilator Agents; Budesonide; Canada; Cohort Studies; Comorbidity; Disease Progression; Ethanolamines; Female; Follow-Up Studies; Formoterol Fumarate; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Monitoring, Physiologic; Predictive Value of Tests; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Risk Assessment; Sex Distribution; Single-Blind Method; Treatment Outcome

CCAAT/enhancer-binding proteins (C/EBPs) control cell proliferation; lack of C/EBPalpha correlates with increased proliferation of bronchial smooth muscle cells (BSMCs) of asthmatic patients.. We sought to assess disease-specific expression of C/EBPalpha, beta, delta, and epsilon and the effects of budesonide (10(-8) mol/L) and formoterol (10(-8) mol/L).. Expression and function of C/EBPalpha, beta, delta, and epsilon BSMCs of control subjects (n = 9), asthmatic patients (n = 12), and patients with chronic obstructive pulmonary disease (COPD; n = 10) were determined.. The control group expressed C/EBPalpha, beta, delta, and epsilon, which were upregulated by serum (5%). Budesonide completely inhibited C/EBPalpha and beta expression; formoterol increased C/EBPalpha expression (2-fold). C/EBPdelta and epsilon expression were not affected by the drugs. The asthmatic group did not appropriately express C/EBPalpha. Basal levels of C/EBPbeta, delta, and epsilon were upregulated by serum (5%). Budesonide and formoterol increased C/EBPbeta levels (3.4-fold and 2.5-fold, respectively), leaving C/EBPalpha, delta, and epsilon levels unaffected. The COPD group normally expressed C/EBPalpha, beta, and epsilon, which were upregulated by serum treatment (5%). Basal levels of C/EBPdelta were downregulated by serum in 7 of 10 BSMC lines. Budesonide inhibited C/EBPalpha and beta expression, upregulated C/EBPdelta (3.2-fold), and had no effect on C/EBPepsilon. Formoterol upregulated C/EBPalpha expression (3-fold) but not the other C/EBPs. Protein analysis and electrophoretic mobility shift assay confirmed the disease-specific expression pattern of C/EBPalpha in asthmatic patients and C/EBPdelta in patients with COPD.. The expression and regulation of C/EBPs in BSMCs of asthmatic patients and patients with COPD seems disease specific. Budesonide and formoterol modulate C/EBP expression in a drug- and disease-specific pattern.. The data could provide a method to discriminate between asthma and COPD at an early disease stage.

Topics: Adolescent; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Asthma; Bronchi; Bronchodilator Agents; Budesonide; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Myocytes, Smooth Muscle; Pulmonary Disease, Chronic Obstructive; RNA, Messenger

Epidemiological studies have indicated that chronic obstructive pulmonary disease (COPD) may be associated with an increased incidence of ischaemic cardiac events. The current authors performed a post hoc analysis of the European Respiratory Society's study on Chronic Obstructive Pulmonary Disease (EUROSCOP); a 3-yr, placebo-controlled study of an inhaled corticosteroid budesonide 800 microg.day(-1) in smokers (mean age 52 yrs) with mild COPD. The current study evaluates whether long-term budesonide treatment attenuates the incidence of ischaemic cardiac events, including angina pectoris, myocardial infarction, coronary artery disorder and myocardial ischaemia. Among the 1,175 patients evaluated for safety, 49 (4.2%) patients experienced 60 ischaemic cardiac events. Patients treated with budesonide had a significantly lower incidence of ischaemic cardiac events (18 out of 593; 3.0%) than those receiving placebo (31 out of 582; 5.3%). The results of the present study support the hypothesis that treatment with inhaled budesonide reduces ischaemic cardiac events in patients with mild chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Female; Humans; Inhalation; Ischemia; Male; Placebos; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Smoking

Topics: Administration, Inhalation; Aged; Blood Gas Analysis; Bronchodilator Agents; Budesonide; Disease Progression; Female; Forced Expiratory Volume; Humans; Inpatients; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Spirometry; Treatment Outcome

The current study aimed to assess the impact on patient health status during an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). A total of 421 COPD patients were enrolled in a multicentre, single-arm study with a 6-month observational follow-up period. Patients received two inhalations of Symbicort 200 Turbuhaler(R) twice a day. Patients were assessed before the run-in period, at baseline and at 1, 3 and 6 months. Patients were instructed to report a change in respiratory symptoms lasting >24 h. This defined an AECOPD. In addition to the initial call, the St George's Respiratory Questionnaire (SGRQ), COPD Control Questionnaire (CCQ), Medical Research Council (MRC) dyspnoea scale and activities of daily living (ADL) were completed at 5-7 and 12-14 days. A group of 176 patients reported at least one AECOPD. Exacerbations were associated with statistically significant mean changes (worsening) in the SGRQ activity and impact domains at onset (mean +/- sd 12.1 +/- 18.1 and 14.0 +/- 15.2), during the first (9.8 +/- 19.0 and 9.4 +/- 16.6) and second weeks (3.1 +/- 15.5 and 3.3 +/- 14.7). Clinically significant deterioration in SGRQ impact scores was shown in 71% of patients following early identification, with 55 and 37% during the first and second weeks of an AECOPD, respectively. Acute exacerbation severely impacts on health status. The current study provides valuable information on the change in health status during an acute exacerbation of chronic obstructive pulmonary disease that can be utilised for future trials that evaluate therapeutic intervention.

Topics: Activities of Daily Living; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Anti-Asthmatic Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Canada; Drug Combinations; Ethanolamines; Female; Health Status; Humans; Logistic Models; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires; Treatment Outcome

Current practice guidelines for the treatment of COPD recommend the use of combined inhaled corticosteroids and long-acting bronchodilators in severe and very severe patients (GOLD stages III and IV). The aim of this study was to evaluate, through a simulation model, the economic consequences of this recommendation in Italy. We developed a cost-effectiveness analysis (CEA) on five alternative therapeutic strategies (salmeterol/fluticasone, SF; formoterol! budesonide, FB; salmeterol alone, S; fluticasone alone, F; control, C). Published data on the Italian COPD population and efficacy data from international reference trials were fitted in a disease progression model based on a Markov chain representing severity stages and death. The yearly total direct costs of treating COPD patients in Italy was estimated at approximately Euro 7 billion, with a mean cost per patient per year of around Euro 2450. Mean survival of the cohort is 11.5 years. The C and F strategies were dominated (ie, are associated with worse outcomes and higher costs) by all alternatives. SF and FB were the most effective strategies, with a slight clinical superiority of SF, but they were also marginally more expensive than S. Incremental cost-effectiveness of SF vs S was Euro 679.5 per avoided exacerbation and Euro 3.3 per symptom-free day. Compared with current practice, the recommended use of combined inhaled corticosteroids and long-acting bronchodilators for severe and very severe COPD patients has the potential for improving clinical outcomes without increasing healthcare costs.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Budgets; Computer Simulation; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Drug Therapy, Combination; Ethanolamines; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Guideline Adherence; Health Care Costs; Health Care Rationing; Humans; Italy; Markov Chains; Models, Economic; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Treatment Outcome

The dry-powder inhaler (DPI) Turbuhaler((R)) has been on the market for nearly two decades. Products containing terbutaline, formoterol, budesonide, and the combination budesonide/formoterol are widely used by patients with asthma and COPD. Most patients and physicians find Turbuhaler((R)) easy to use, and local side effects are rare. This is thought to arise from the lack of additives or only small amounts in the formulation, in addition to minimal deposition of the drug in the oropharynx and on the vocal cords during inspiration.The function of Turbuhaler((R)) has frequently been questioned. This article aims to review and clarify some key issues that have been challenged in the literature (e.g. the effectiveness of Turbuhaler((R)) in patients with more restricting conditions), to discuss the importance of lung deposition, and to explain the low in vivo variability associated with Turbuhaler((R)) and the lack of correlation with the higher in vitro variability.Turbuhaler((R)), like other DPIs, is flow dependent to some degree. However, a peak inspiratory flow (PIF) through Turbuhaler((R)) of 30 L/min gives a good clinical effect. These PIF values can be obtained by patients with conditions thought to be difficult to manage with inhalational agents, such as asthmatic children and adult patients with acute severe airway obstruction and COPD. Excellent clinical results with Turbuhaler((R)) in large controlled studies in patients with COPD and acute severe airway obstruction provide indirect evidence that medication delivered via Turbuhaler((R)) reaches the target organ.Due to the large amount of small particles and the moderate inbuilt resistance in Turbuhaler((R)), which opens up the vocal cords during inhalation, Turbuhaler((R)) is associated with a high lung deposition (25-40% of the delivered dose) compared with pressurized metered-dose inhalers (pMDIs) and other DPIs. A good correlation has been found between lung deposition and clinical efficacy. A high lung deposition always results in the best ratio between clinical efficacy and risk of unwanted systemic activity. Studies with Turbuhaler((R)) also show that the in vivo variation in lung deposition is significantly lower compared with a pMDI or, for example, the Diskus((R)) inhaler, and much lower than the in vitro dose variability seen in laboratory tests. Turbuhaler((R)) appears to be a reliable DPI which can be used with confidence by patients with airway diseases, including those with clinical c

Topics: Administration, Inhalation; Airway Obstruction; Asthma; Budesonide; Child; Humans; Lung; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive

To investigate the trend in prescribing of inhaled corticosteroids and general practitioner (GP) consultations for respiratory diseases.. A longitudinal observation study of all prescriptions, from primary care, for inhaled corticosteroids dispensed in Scotland from January 1999 to May 2002 was undertaken. The main outcome measures were the trends in prescribing of inhaled corticosteroids and GP consultations for respiratory diseases.. The prescribing of all inhaled corticosteroids has risen over the study period. The rise in prescribing of the combination product containing fluticasone and salmeterol appears not to have been at the expense of the prescribing of fluticasone alone while the prescribing of the budesonide/eformoterol combination may be at the expense of budesonide (BUD) alone. GP consultations for both asthma and chronic obstructive pulmonary disease (COPD) have declined over a similar period. The increased prescribing of inhaled corticosteroids over this period is associated with the increased use of the fluticasone/salmeterol combination rather than an increase in the use of all inhaled corticosteroids. The accompanying fall in number of consultations with GPs may be due to this increased prescribing or a move to nurse led clinics.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Asthma; Beclomethasone; Budesonide; Drug Combinations; Drug Prescriptions; Drug Utilization Review; Ethanolamines; Formoterol Fumarate; Humans; Pharmacoepidemiology; Practice Patterns, Physicians'; Pulmonary Disease, Chronic Obstructive; Scotland; Time Factors

There are no predictors known that can identify COPD patients who will respond to treatment with ICS.. We investigated 30 patients (median age 65 (range 44-83, 12 females) with mild to moderately severe COPD. All patients had post bronchodilator FEV1/forced vital capacity ratio of less than 70% and a reversibility of less than 12% and 200 ml from baseline. We wanted to determine if airway responsiveness (AHR) to histamine and mannitol could predict who would respond to a 3-month course of ICS.. At baseline, all patients had AHR to histamine, but only 7 (23%) patients to mannitol. After 3 months of treatment with ICS, there was no significant change in spirometry or the quality of life when analysing all individuals together. However, FEV1% predicted improved from 67% (IQR12) to 79% (IQR16) in mannitol positive patients; whereas it was unchanged in the mannitol negative patients. The difference in the mean change of FEV1% predicted between the two groups was 12 (IQR13.5) and this was highly significant (p=0.001). The improvement in quality of life (SGRQ 30 (IQR10.5) to 21 (IQR12; p=0.01) was only significant in the patients positive to mannitol.. We propose that AHR to mannitol could predict ICS-responsiveness in mild to moderately severe COPD patients.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Histamine; Humans; Male; Mannitol; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Spirometry; Treatment Outcome; Vital Capacity

Emphysema is one component of chronic obstructive pulmonary disease (COPD), a respiratory disease currently increasing in prevalence worldwide. The mainstay therapy adopted to treat patients with COPD is glucocorticoids; unfortunately, this treatment has limited impact on disease symptoms or underlying airway inflammation.. There is an urgent need to develop therapies that modify both the underlying inflammation, thought to be involved in disease progression, and the structural changes in the emphysematous lung.. We have characterized an elastase-driven model of experimental emphysema in the rat that demonstrates COPD-like airway inflammation and determined the impact of a clinically relevant glucocorticoid.. We observed an increase in lung neutrophils, lymphomononuclear cells, mucus production, and inflammatory cytokines. Also present were increases in average air space area, which are associated with emphysema-like changes in lung function, such as increased residual volume and decreased flow; these increases in area were maintained for up to 10 weeks. In addition, we observed that elastase-induced airway neutrophilia is steroid resistant. Interestingly, the inflammation observed after elastase administration was found to be temporally associated with a lack of nuclear factor-kappaB pathway activation. This apparent nuclear factor-kappaB-independent inflammation may explain why treatment with a glucocorticoid was ineffective in this preclinical model and could suggest parallels in the steroid-resistant human disease.. We believe that this model, in addition to its suitability for testing therapies that may modify existing emphysema, could be useful in the search for new therapies to reduce the steroid-resistant airway inflammation evident in COPD.

Topics: Algorithms; Animals; Anti-Inflammatory Agents; Budesonide; Disease Models, Animal; Disease Progression; Drug Resistance; Emphysema; Male; NF-kappa B; Pancreatic Elastase; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Signal Transduction

To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies, and placebo, in a multinational study in patients with chronic obstructive pulmonary disease (COPD), National Heart, Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III or IV. Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo.. Patients (n = 1022) were randomised to twice-daily treatment with two inhalations of budesonide/formoterol (160 microg/4.5 microg) in a single inhaler, budesonide 200 microg, formoterol 4.5 microg or placebo for 12 months. Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective. Costs were valued in Swedish kronor (SEK) [2001 values] and converted to euros (SEK 1 = euro 0.11, 25th April 2003).. This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol (euro 2518) than for budesonide (euro 3194), formoterol (euro 3653) or placebo (euro 3213). Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol, even if the decision maker is not willing to pay anything for the additional clinical effects, and that budesonide/formoterol is cost effective compared with placebo if a decision maker is willing to pay about euro 2 per day, per avoided exacerbation.. This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost than either monocomponent or placebo. Budesonide/formoterol in patients with severe COPD (GOLD stages III or IV) may be cost effective, from the healthcare provider perspective, compared with either monocomponent.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Budesonide; Cost-Benefit Analysis; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests

Beta2-agonists and glucocorticosteroids are two common treatments for COPD and they are often used in combination. Glucocorticosteroids mediate the anti-inflammatory response through the glucocorticosteroid receptors (GRs). Beta2-agonists are potent bronchodilators but they can have some anti-inflammatory properties by elevating the level of intracellular cAMP. In this study we aimed to investigate the anti-inflammatory effect of combination therapy in vitro.. Neutrophils or the bilayer of endothelial and epithelial cells were preincubated with salbutamol, budesonide or budesonide followed by salbutamol. FMLP-induced IL-8, elastase release and neutrophil migration through the bilayer was measured.. Salbutamol at concentrations of 10(-4), 10(-5) and 10(-9) M inhibited IL-8, elastase release and migration of neutrophils in an inverse bell-shaped concentration-response manner. When given after budesonide (10(-9) and 10(-8)M), the inhibitory effect on migration was additive. This additive effect was not observed for elastase and IL-8 release.. Salbutamol inhibits neutrophil migration and IL-8 and elastase release in a concentration-dependent manner. Preincubation with low concentration of budesonide enhanced the inhibition of migration achieved by low concentrations of salbutamol.

Topics: Adrenergic beta-Agonists; Albuterol; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epithelial Cells; Humans; Interleukin-8; Neutrophil Infiltration; Neutrophils; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive

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

Exacerbations of chronic obstructive pulmonary disease (COPD) can be defined symptomatically or by healthcare contacts, yet the relationship between these events is unknown. Data were collected during a 1-yr study of the budesonide/formoterol combination in COPD patients, where exacerbations, defined by increases in treatment, were compared with daily records of respiratory symptoms, rescue medication use and peak expiratory flow (PEF). The relationship between changes in these variables and the medical event was examined using different modelling approaches. Data from the first exacerbation treated with oral corticosteroids and/or antibiotics and/or hospitalisation (event based) were available in 468 patients. Patients exacerbating were significantly more breathless and more likely to report cough than healthy patients, but did not differ in baseline spirometry. Exacerbations defined by changes in individual symptoms were only weakly related to event-based exacerbations; however, defined with 63% of such events being predicted from symptom changes. Changes in rescue medication use or PEF were poor predictors of event-based exacerbations. The mean peak change in symptoms was closely related to the onset of therapy. In conclusion, event-based exacerbations are a valid way of identifying acute symptom change in a chronic obstructive pulmonary disease population. However, daily symptom monitoring is too variable using the current diary cards to make individual management decisions.

Topics: Acute Disease; Algorithms; Bronchodilator Agents; Budesonide; Cough; Dyspnea; Ethanolamines; Formoterol Fumarate; Hospitalization; Humans; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Sleep Initiation and Maintenance Disorders

To evaluate the expression of transforming growth factor beta-1(TGF-beta1) and the effects of early drugs intervention of chronic obstructive pulmonary disease(COPD) in rat model.. The COPD rat model (group B) was established by intratracheal instillation of lipopolysaccharide twice and daily exposure to cigarette smoking. Drug intervention groups received dongchongxiacao orally daily from the three days before the experiment (group C) and erythromycin by intraperitoneal injection since the third week (group D)and inhalation of budesonide since the forth week (group E). At the end of 10 weeks, all 40 rats including normal control (group A) were assessed for lung resistance (RL) and dynamic lung compliance (Cdyn). The expression of TGF-beta1 gene and protein were also observed by immunohistochemistry and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively.. The changes of pathology and pathophysiology in rat COPD model were similar to those of human COPD. There was a significant increase in the smooth muscle and collagen thickness in the airway wall of the group B in comparison with that of the group A. RL in group B was significantly higher than that in group A (P<0.01), while it was inhibited by early drugs intervention (P<0.01). Cdyn was decreased in group B as compared with that in group A, which was limited by erythromycin and budesonide intervention (P<0.01). The relative content for TGF-beta1 was significantly increased in the epithelial cells of the bronchi, endothelial cells of the pulmonary small vessel and alveolar macrophages of COPD group as compared with those of normal controls (P<0.01).The relative contents for TGF-beta1 in the epithelial of bronchi in group D and group E were significantly lower than that in group B, but not found in group C. There was no difference between group D and group E. There were statistical positive relationships between the RL and the relative content for TGF-beta1 in the bronchial epithelial cells, between the RL and the mRNA level of TGF-beta1 in the lung tissue (P<0.01 approximately 0.05).. This rat COPD model could be helpful to obtain more information about airway remodeling. TGF-beta1 may play an important role during the process of airway remodeling, and could be influenced by early drugs intervention such as budesonide and erythromycin, which may imply their potency in the treatment of COPD. But there is not same phenomenon found in dongchongxiacao group.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Budesonide; Drugs, Chinese Herbal; Erythromycin; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Anti-Inflammatory Agents; Budesonide; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Powders; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

The practice of using inhaled steroids (ICS) in chronic obstructive pulmonary disease (COPD) is common but controversial. Four large randomized controlled trials provide an objective assessment of this practice. An examination of the design of these studies is useful to explaining some of the differences between their results but may also help to appropriately integrate the findings of these studies into clinical practice. All studies agree that the early introduction of the inhaled corticosteroids (ICS) does not appear to affect the rate of decline in FEV1. Thus, the routine prescription of these agents to asymptomatic patients with well-preserved lung function is not indicated. However, more selective use of ICS in patients with moderately severe disease (FEV1 < 50% predicted) may produce clinical benefit as measured by an increase in FEV1, reduced symptoms and fewer exacerbations. The effectiveness of ICS in patients with severe disease (FEV < 800 mL, or chronic respiratory failure) has not been studied due to practical difficulties of enrolling and maintaining such patients in clinical trials. Similarly patients with evidence of chronic bronchitis and emphysema who demonstrate high degrees of reversibility (>10% predicted FEV1) are usually excluded from both COPD and asthma trials, and the effectiveness of ICS in this population is also not known. Neither responsiveness to a single dose of beta(2)-agonist nor to a 14-day trial of systemic steroids has been shown to be a reliable predictor of response to ICS. For individual patients with moderate or severe symptomatic COPD, an 8-week therapeutic trial with ICS may be needed to assess clinical benefit.

Topics: Budesonide; Forced Expiratory Volume; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Spirometry; Treatment Outcome

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

A detailed analysis has been carried out of the correlation between the signals detected by MRI in the rat lung after allergen or endotoxin challenge and parameters of inflammation determined in the broncho-alveolar lavage (BAL) fluid. MRI signals after allergen correlated highly significantly with the BAL fluid eosinophil number, eosinophil peroxidase activity and protein concentration. Similar highly significant correlations were seen when the anti-inflammatory glucocorticosteroid, budesonide, manifested against allergen. In contrast, following endotoxin challenge, mucus was the sole BAL fluid parameter that correlated significantly with the long lasting signal detected by MRI. Since edema is an integral component of pulmonary inflammation, MRI provides a noninvasive means of monitoring the course of the inflammatory response and should prove invaluable in profiling anti-inflammatory drugs in vivo. Further, the prospect of noninvasively detecting a sustained mucus hypersecretory phenotype in the lung brings an important new perspective to models of chronic obstructive pulmonary diseases.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Budesonide; Eosinophil Peroxidase; Inflammation; Lipopolysaccharides; Lung; Magnetic Resonance Imaging; Male; Mucus; Ovalbumin; Peroxidases; Pulmonary Disease, Chronic Obstructive; Pulmonary Edema; Pulmonary Eosinophilia; Rats; Rats, Inbred BN; Respiration

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: Acute Disease; Aminophylline; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Budesonide; Critical Care; Emergencies; Humans; Intensive Care Units; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Prednisolone; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Respiratory Care Units; Respiratory Insufficiency; Respiratory Therapy; Status Asthmaticus; Time Factors

Topics: Anti-Inflammatory Agents; Budesonide; Clinical Trials as Topic; Cortisone; Humans; Pulmonary Disease, Chronic Obstructive; Treatment Outcome