(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Dyspnea

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

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

The efficacy of inhaled corticosteroids (ICS) in moderately severe COPD patients remains unclear. At the same time, the use of extrafine particles in COPD patients is a topic of ongoing research.. This study assessed the effect of ICS in steroid-naïve mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients previously using ICS when switching to an extrafine particle BDP/F formulation (Foster using Modulite technology, Chiesi Pharmaceutici, Parma, Italy).. Novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and Computational Fluid Dynamics, were used in combination with conventional pulmonary function tests and patient reported outcomes.. The study showed that the administration of extrafine BDP/F after 4-6 h led to a significant improvement in lung function parameters and hyperinflation as determined by spirometry, body plethysmography, and functional respiratory imaging. After 6 months of treatment, it was observed that, compared to baseline, the hyperinflation on lobar level at total lung capacity was significantly reduced (-1.19±7.19 %p, p=0.009). In addition, a significant improvement in SGRQ symptom score was noted in the entire patient population. Patients who improved in terms of hyperinflation also improved their MMRC dyspnea score. CFD indicated a difference in regional deposition between extrafine and non-extrafine formulations with -11% extrathoracic deposition and up to +4% lobe deposition for the extrafine formulation.. The study showed that the administration of extrafine BDP/F improved lung function parameters and hyperinflation. Patients previously treated with ICS remained stable despite the lower dose, while ICS naïve patients improved in terms of lobar hyperinflation. FRI seems to be a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry. The next step is to confirm these findings in a controlled trial.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aerosols; Aged; Aged, 80 and over; Beclomethasone; Bronchodilator Agents; Chemistry, Pharmaceutical; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Lung; Male; Middle Aged; Multidetector Computed Tomography; Particle Size; Pilot Projects; Plethysmography, Whole Body; Powders; Predictive Value of Tests; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Radiographic Image Interpretation, Computer-Assisted; Recovery of Function; Severity of Illness Index; Spirometry; Time Factors; Treatment Outcome; Vital Capacity

Chronic obstructive pulmonary disease (COPD) is a common disease characterized by airflow obstruction and lung hyperinflation leading to dyspnea and exercise capacity limitation.. The present study was designed to evaluate whether an extra-fine combination of beclomethasone and formoterol (BDP/F) was effective in reducing air trapping in COPD patients with hyperinflation. Fluticasone salmeterol (FP/S) combination treatment was the active control.. COPD patients with forced expiratory volume in one second <65% and plethysmographic functional residual capacity ≥120% of predicted were randomized to a double-blind, double-dummy, 12-week, parallel group, treatment with either BDP/F 400/24 μg/day or FP/S 500/100 μg/day. Lung volumes were measured with full body plethysmography, and dyspnea was measured with transition dyspnea index.. Eighteen patients were evaluable for intention to treat. A significant reduction in air trapping and clinically meaningful improvement in transition dyspnea index total score was detected in the BDP/F group but not in the FP/S group. Functional residual capacity, residual volume (RV) and total lung capacity significantly improved from baseline in the BDP/F group only. With regard to group comparison, a significantly greater reduction in RV was observed with BDP/F versus FP/S.. BDP/F extra-fine combination is effective in reducing air trapping and dyspnea in COPD patients with lung hyperinflation.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Beclomethasone; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Dyspnea; Ethanolamines; Exercise Test; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Formoterol Fumarate; Functional Residual Capacity; Glucocorticoids; Humans; Italy; Lung; Male; Middle Aged; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Residual Volume; Time Factors; Total Lung Capacity; Treatment Outcome

No consistent data are available regarding the effect of inhaled corticosteroids (ICS) in alpha(1)-antitrypsin-deficiency (AATD)-related COPD. Recent data report inflammatory effects of the polymers of alpha(1)-antitrypsin on the peripheral lung.. The aim of this study was to assess the effectiveness of an extra-fine ICS, hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) with a mass median aerodynamic diameter of 1.1 microm, on lung function and exercise tolerance in COPD patients with AATD when added to long-acting bronchodilators (LABAs).. After a 1-week washout, 8 steroid-naïve COPD patients with AATD (ZZ genotype), within a double-blind randomized cross-over study, were assigned to one of the following 16-week treatments: (1) HFA-BDP 400 microg b.i.d., salmeterol 50 microg b.i.d. and oxitropium bromide 200 microg t.i.d. or (2) placebo, salmeterol 50 microg b.i.d. and oxitropium bromide 200 microg t.i.d; after a 2-week washout period they received the other treatment. In weeks 1, 17, 19 and 35, patients took a spirometry assessment (breathing air and heliox) and a shuttle walking test (SWT) with dyspnea assessed by the modified Borg scale.. Significant differences in improvement were found in FEV(1), FVC, IC, distance covered and dyspnea perceived during SWT between the 2 treatments and baseline values (p < 0.05; Friedman's test). However, further analysis showed that only the LABAs + ICS condition showed significant increases in the FEV(1), FVC, IC, DeltaMEF(50%) and distance covered during SWT along with a reduction in maximum isostep exertional dyspnea (p < 0.05; Wilcoxon test). A greater distance was walked at the end of the SWT with LABA + ICS than LABAs alone (301 +/- 105 vs. 270 +/- 112 m; p < 0.05).. In AATD-related COPD patients (ZZ genotype) the addition of extra-fine ICS to LABAs decreases airway narrowing, mostly in the small airways, further reducing dynamic hyperinflation with a marked improvement in exercise tolerance and dyspnea, suggesting that a peripheral inflammatory process contributes to airflow obstruction in these patients.

Topics: Administration, Inhalation; Aged; Albuterol; alpha 1-Antitrypsin Deficiency; Beclomethasone; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Exercise Tolerance; Female; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives

Inhaled corticosteroid therapy has proven efficacy for asthmatics, but the benefit for patients with chronic obstructive pulmonary disease (COPD) is less well supported. We hypothesized that withdrawal of inhaled steroids in elderly patients with severe irreversible airway obstruction would not lead to a deterioration in respiratory function. We designed a prospective, double-blind, randomized, placebo-controlled, crossover study to follow spirometry, quality of life questionnaire, six-minute (6-min) walk test, and sputum markers of inflammation during a 6-wk placebo treatment period and a 6-wk treatment period with beclomethasone dipropionate (BDP), 336 microg/d. There were 24 men receiving BDP who entered the study; 15 completed the study. Their mean age was 66.9 +/- 1.9 yr, and mean FEV(1) was 1.61 +/- 0.1 L (47% of predicted). There was a significant decrease in the mean FEV(1 )while using the placebo inhaler (1.70 L versus 1.60 L, baseline versus placebo: 95% CI, 0.002 to 0.195; p < 0.05). There was a decrease in the mean percentage change in FEV(1) for the study subjects during the placebo treatment period as compared with the BDP treatment period (-6.28 versus 5.03%, placebo versus BDP: 95% CI, -23.38 to 0.76; p = 0.06). Six-minute walk test results and sputum analysis for cell count and differential were not significantly different during placebo and BDP treatment periods. Borg scale assessment of dyspnea after exercise was increased while using the placebo inhaler as compared with baseline, and decreased during the BDP treatment period. Chronic Respiratory Disease Questionnaire (CRQ) scores revealed no significant difference between placebo and BDP. This study has demonstrated that in elderly patients with severe irreversible airway obstruction, withdrawal of inhaled corticosteroid therapy leads to a deterioration in ventilatory function and increased exercise-induced dyspnea.

Topics: Administration, Inhalation; Adult; Aged; Airway Obstruction; Anti-Asthmatic Agents; Beclomethasone; Cross-Over Studies; Double-Blind Method; Dyspnea; Exercise Test; Forced Expiratory Volume; Humans; Lung Diseases, Obstructive; Male; Middle Aged

Twenty male outpatients with severe-but-stable chronic obstructive pulmonary disease handicapped by exertional dyspnoea (aged 69.7 +/- 5.68 yrs; forced expiratory volume in one second (FEV1) 1.02 +/- 0.18 L or 34.6 +/- 6.5% of the predicted value; forced vital capacity (FVC) 2.51 +/- 0.34 L; arterial oxygen tension (Pa,O2) 9.11 +/- 0.32 kPa (68.5 +/- 2.4 mmHg); arterial carbon dioxide tension (Pa,CO2) 5.20 +/- 0.23 kPa (39.1 +/- 1.7 mmHg)) completed a randomized double-blind crossover study to evaluate the effects of a 4-week regular treatment with inhaled beclomethasone dipropionate via nebulizers at a dosage of 2 mg twice daily. After active and placebo treatment, no peak expiratory flow rate variation in FEV1, FVC, rescue use of beta 2-agonists, exercise tolerance and dyspnoea was observed. In conclusion, a regular short-term treatment with nebulized beclomethasone dipropionate does not give any improvement in lung function or exercise capacity in severe-but-stable chronic obstructive pulmonary disease patients handicapped by exertional dyspnoea.

Topics: Administration, Inhalation; Aerosols; Aged; Beclomethasone; Cross-Over Studies; Double-Blind Method; Dyspnea; Glucocorticoids; Humans; Lung Diseases, Obstructive; Male; Physical Exertion; Respiratory Function Tests; Statistics, Nonparametric; Treatment Outcome

Endogenously released nitric oxide (NO) has been detected in the exhaled air of humans. Exhaled NO (NOexh) levels have been significantly increased in patients with inflammatory airways disorders such as asthma, and NOexh has been suggested to be a usable marker of airway inflammation. In the present study, NOexh levels were measured both in steroid-treated and untreated subjects with mild asthma, and were correlated with the degree of airway hyperresponsiveness (AHR), measured as the dose of histamine that produced a 20% decrease in FEV1 (PC20histamine). NOexh levels, which were significantly increased in steroid-naive patients (Group A1: NOexh = 21 +/- 11 ppb; n = 56) in comparison with levels in control subjects (Group B: NOexh = 10 +/- 2 ppb; n = 20; p < 0.001), correlated significantly with the PC20histamine (r = -0.65; p < 0.0001). The NOexh level was significantly lower in patients with chronic cough of other causes than bronchial asthma (Group A2: NOexh = 11 +/- 3 ppb; n = 18) when compared with the level in subjects with mild asthma (Group A1: p < 0.001). Therefore, the noninvasive measurement of NOexh allowed us to discriminate, among patients with respiratory complaints, between those with and without AHR. In asthmatic subjects treated with inhaled steroids, the NOexh levels were significantly lower (Group A3: NOexh = 13 +/- 5 ppb; n = 25) than in untreated subjects (Group A1; p < 0.01), and there was no relationship with the PC20histamine (r = -0.18, p = NS). These findings confirm that NOexh reflects AHR in patients with mild asthma who have not already been treated with inhaled steroids. Patients treated with inhaled steroids had an NOexh level comparable to levels in control subjects, although AHR could still be demonstrated.

Topics: Adrenergic beta-Agonists; Adult; Airway Obstruction; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; Chronic Disease; Cough; Dyspnea; Female; Forced Expiratory Volume; Glucocorticoids; Histamine; Humans; Male; Nitric Oxide; Respiration; Respiratory Sounds