The Experts below are selected from a list of 996 Experts worldwide ranked by ideXlab platform

Donald Banerji - One of the best experts on this subject based on the ideXlab platform.

  • blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment data from the flame trial
    American Journal of Respiratory and Critical Care Medicine, 2017
    Co-Authors: Nicolas Roche, Kenneth R Chapman, Francesco Patalano, Chau Thach, Robert Fogel, Donald Banerji, Claus Vogelmeier, Felix J F Herth, Petter Olsson, Jadwiga A. Wedzicha
    Abstract:

    Rationale: Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease (COPD).Objectives: We prospectively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long-acting β2-agonist combination versus a long-acting β2-agonist/long-acting muscarinic antagonist combination for exacerbation prevention.Methods: We conducted prespecified analyses of data from the FLAME (Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations) study, which compared once-daily long-acting β2-agonist/long-acting muscarinic antagonist indacaterol/Glycopyrronium 110/50 μg with twice-daily long-acting β2-agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 μg in patients with one or more exacerbations in the preceding year. Subsequent post hoc analyses were conducted to address further cutoffs and endpoints.Mea...

  • indacaterol Glycopyrronium versus salmeterol fluticasone for copd
    The New England Journal of Medicine, 2016
    Co-Authors: Jadwiga A. Wedzicha, Kenneth R Chapman, Jorgen Vestbo, Timothy R Ayers, Francesco Patalano, Chau Thach, Robert Fogel, Donald Banerji, Nicolas Roche, Claus Vogelmeier
    Abstract:

    BackgroundMost guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA–LAMA regimen in these patients is unclear. MethodsWe conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA Glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations. ResultsA total of 1680 patients were assigned to the indacaterol–Glycopyrronium group, and 1682 to the salmeterol–fluticasone group. Indacaterol–Glycopyrronium showed not onl...

  • lantern a randomized study of qva149 versus salmeterol fluticasone combination in patients with copd
    International Journal of Chronic Obstructive Pulmonary Disease, 2015
    Co-Authors: Nanshan Zhong, Francesco Patalano, Chau Thach, Changzheng Wang, Xiangdong Zhou, Nuofu Zhang, Michael Humphries, Linda Wang, Donald Banerji
    Abstract:

    Background The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms. The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/Glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.

  • pooled safety analysis of the fixed dose combination of indacaterol and Glycopyrronium qva149 its monocomponents and tiotropium versus placebo in copd patients
    Respiratory Medicine, 2014
    Co-Authors: Jadwiga A. Wedzicha, Peter Dandrea, Hungta Chen, Robert Fogel, Ronald Dahl, Roland Buhl, Agnes Annette Schuberttennigkeit, Donald Banerji
    Abstract:

    Summary Background To further assess the safety profile of the fixed-dose combination of indacaterol and Glycopyrronium (QVA149) and its monocomponents; we investigated the impact of individual patient-level factors and time by integrating the patient-level safety data from the QVA149 clinical programme with relevant information from the independent indacaterol and Glycopyrronium safety databases. Methods Data from 11,404 patients with chronic obstructive pulmonary disease (COPD) were pooled from 14 clinical studies of QVA149, indacaterol and Glycopyrronium of ≥3 month's duration with at least two of the treatment groups: QVA149 110/50 μg, Glycopyrronium 50 μg, indacaterol 150 μg, placebo or tiotropium 18 μg. Overall hazard ratio (HR) was assessed between the active treatments and placebo and in various subgroups related to severity of airways obstruction, inhaled corticosteroid use, cardiovascular risk factors, sex, age and body mass index for death, serious cases of cardio- and cerebrovascular (CCV) events, major adverse cardiovascular events (MACEs), pneumonia, COPD exacerbations requiring hospitalisation or atrial flutter/fibrillation (AF/F). Results The HR for QVA149 versus placebo showed no significant increase in the overall risk for death (HR [95% confidence interval]: 0.93 [0.34–2.54]); CCV events (0.60 [0.29–1.24]); MACE (1.04 [0.45–2.42]); pneumonia (1.10 [0.54–2.25]); COPD exacerbations (0.60 [0.40–0.91]); and AF/F (1.03 [0.49–2.18]). Similar results were observed for indacaterol, Glycopyrronium and tiotropium versus placebo for overall risk and in analysed subgroups. Conclusions There was no increase in the risk for the investigated safety endpoints for the fixed-dose combination QVA149, and it had a comparable safety profile as its monocomponents and tiotropium versus placebo.

  • dual bronchodilation with qva149 versus single bronchodilator therapy the shine study
    European Respiratory Journal, 2013
    Co-Authors: E D Bateman, Michelle Henley, Gary T Ferguson, Neil Barnes, Nicola Gallagher, Yulia Green, Donald Banerji
    Abstract:

    We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and Glycopyrronium, tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). This was a multicentre, randomised, double-blind, placebo- and active-controlled, 26-week trial. Patients (n = 2144) were randomised (2:2:2:2:1) to receive once-daily QVA149 (indacaterol 110 μg/Glycopyrronium 50 μg), indacaterol 150 μg, Glycopyrronium 50 μg, open-label tiotropium 18 μg or placebo. The primary end-point was trough forced expiratory volume in 1 s (FEV1) at week 26 for QVA149 versus its monocomponents. Secondary end-points included dyspnoea, health status, rescue medication use and safety. Trough FEV1 at week 26 was significantly improved (p<0.001) with QVA149 compared with indacaterol and Glycopyrronium (least squares mean (LSM) differences 0.07 L and 0.09 L, respectively), tiotropium and placebo (LSM differences 0.08 L and 0.20 L, respectively); these beneficial effects were sustained throughout the 26-week study. QVA149 significantly improved dyspnoea and health status versus placebo (p<0.001 and p = 0.002, respectively) and tiotropium (p = 0.007 and p = 0.009, respectively) at week 26. All treatments were well tolerated. Dual bronchodilation with once-daily QVA149 demonstrated superior and clinically meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator, with a safety and tolerability profile similar to placebo, supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist combinations for the treatment of COPD. Dual indacaterol/Glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD

Jadwiga A. Wedzicha - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of indacaterol Glycopyrronium versus salmeterol fluticasone in current and ex smokers a pooled analysis of ignite trials
    ERJ Open Research, 2021
    Co-Authors: David M.g. Halpin, Claus Vogelmeier, Karen Mezzi, Pritam Gupta, Konstantinos Kostikas, Jadwiga A. Wedzicha
    Abstract:

    Inhaled corticosteroids have proven to be less effective in asthmatic patients who smoke; however, there is limited information on the efficacy of inhaled corticosteroid-containing regimens in COPD patients who continue smoking. We evaluate the differential efficacy of once-daily indacaterol/Glycopyrronium 110/50 µg compared with twice-daily salmeterol/fluticasone 50/500 µg in current smokers and ex-smokers with COPD. A pooled analysis of data from ILLUMINATE, LANTERN and FLAME studies was conducted to assess the efficacy of indacaterol/Glycopyrronium compared with salmeterol/fluticasone in current smokers and ex-smokers with COPD. Efficacy was assessed in terms of improvements in trough forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) focal score, St George9s Respiratory Questionnaire (SGRQ) total score, reduced rescue medication use and exacerbation prevention at 26 weeks after the start of the therapy. In total, 1769 (38%) current smokers and 2848 (62%) ex-smokers were included. Patients treated with indacaterol/Glycopyrronium experienced greater improvements in trough FEV1versus salmeterol/fluticasone in both current and ex-smokers (least squares mean treatment difference, 105 mL and 78 mL, respectively). Improvements in TDI focal score, SGRQ total score and reduction in rescue medication use were also greater with indacaterol/Glycopyrronium versus salmeterol/fluticasone in current and ex-smokers. Furthermore, indacaterol/Glycopyrronium reduced all exacerbations (moderate/severe) compared with salmeterol/fluticasone, irrespective of smoking status. The difference in efficacy in favour of indacaterol/Glycopyrronium was more prominent in current smokers in most cases. Indacaterol/Glycopyrronium demonstrated greater efficacy versus salmeterol/fluticasone, and the differences were generally more prominent in current smokers suggesting smoking may reduce the effects of salmeterol/fluticasone.

  • late breaking abstract copd exacerbation benefits relative to pneumonia risk with budesonide Glycopyrronium formoterol metered dose inhaler analyses from ethos
    European Respiratory Journal, 2020
    Co-Authors: Klaus F Rabe, Jadwiga A. Wedzicha, Colin Reisner, Gary T Ferguson, Fernando J Martinez, Dave Singh, Martin Jenkins, Magnus Aurivillius, Paul Dorinsky
    Abstract:

    Background: In the Phase III, 52-week ETHOS study (NCT02465567), budesonide/Glycopyrronium/formoterol metered dose inhaler (BGF MDI) fixed-dose combination significantly reduced exacerbations vs dual therapies. However, use of inhaled corticosteroids (ICS) may also increase pneumonia risk. Objective: To quantify exacerbation benefits relative to pneumonia risk (expressed as numbers needed to treat [NNT] and numbers needed to harm [NNH], respectively) in ETHOS. Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year received BGF MDI 320/14.4/10 μg or 160/14.4/10 μg, Glycopyrronium/formoterol (GFF) MDI 14.4/10 μg or budesonide/formoterol (BFF) MDI 320/10 μg twice-daily via a single Aerosphere inhaler. Exacerbation and pneumonia rates were used to calculate NNT and NNH. Results: BGF MDI 320 µg reduced exacerbation rates vs GFF MDI (NNT=3 [95% CI 3, 5]) and vs BFF MDI (NNT=7 [95% CI 4, 18]), (mITT, N=8509). Pneumonia rates across treatments were 0.02–0.05 per patient year, and were lower for BGF MDI than BFF MDI; for BGF MDI 320 μg vs GFF MDI, NNH=58 (95% CI 29, 152; Table). Conclusions: In patients with moderate/very severe COPD, BGF MDI 320 µg reduced exacerbation risk vs both dual therapies. For the ICS component, the NNH (BGF MDI 320 μg vs GFF MDI) suggests a low pneumonia risk for BGF MDI relative to its benefits on exacerbations.

  • indacaterol Glycopyrronium versus tiotropium or Glycopyrronium in long acting bronchodilator naive copd patients a pooled analysis
    Respirology, 2020
    Co-Authors: Shigeo Muro, Petter Olsson, Pritam Gupta, Konstantinos Kostikas, Hajime Yoshisue, Jadwiga A. Wedzicha
    Abstract:

    BACKGROUND AND OBJECTIVE: Indacaterol/Glycopyrronium (IND/GLY) 110/50 mug once daily (q.d.) has demonstrated greater improvements in lung function, patient-reported outcomes and lower exacerbation rates versus mono long-acting muscarinic antagonists (LAMA) in chronic obstructive pulmonary disease (COPD) patients. However, data are limited on initial treatment with IND/GLY 110/50 mug q.d. versus mono LAMA in COPD patients, not previously on maintenance treatment with long-acting bronchodilators (LABD). METHODS: A pooled analysis of ARISE, SHINE and SPARK trials was conducted to evaluate the efficacy of IND/GLY 110/50 mug q.d. versus open-label (OL) tiotropium (TIO) 18 mug q.d. and GLY 50 mug q.d. in COPD patients, not on maintenance treatment with LABD at study entry (LABD-naive). Efficacy was assessed after 24/26 weeks of treatment. RESULTS: In total, 998 LABD-naive patients were included (IND/GLY: 353; OL TIO: 328; GLY: 317). Patients treated with IND/GLY 110/50 mug q.d. experienced greater improvements in trough forced expiratory volume in 1 s (FEV1 ) versus OL TIO 18 mug q.d. (least squares mean treatment difference (Delta): 0.086 L) and GLY 50 mug q.d. (Delta: 0.080 L) after 24/26 weeks. Improvements in electronic diary (eDiary) symptom scores, transition dyspnoea index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score and rescue medication use were also greater with IND/GLY versus OL TIO and GLY. Greater proportion of patients achieved minimal clinically important difference in trough FEV1 , TDI and SGRQ with IND/GLY versus OL TIO and GLY. CONCLUSION: LABD-naive patients treated with IND/GLY 110/50 mug q.d. achieved improvements in lung function, daily symptoms, dyspnoea, health-related quality of life and rescue medication use versus those who received single LAMA.

  • indacaterol Glycopyrronium versus tiotropium or Glycopyrronium in long acting bronchodilator naive copd patients a pooled analysis
    Respirology, 2020
    Co-Authors: Shigeo Muro, Petter Olsson, Pritam Gupta, Konstantinos Kostikas, Hajime Yoshisue, Jadwiga A. Wedzicha
    Abstract:

    Background and objective Indacaterol/Glycopyrronium (IND/GLY) 110/50 μg once daily (q.d.) has demonstrated greater improvements in lung function, patient-reported outcomes and lower exacerbation rates versus mono long-acting muscarinic antagonists (LAMA) in chronic obstructive pulmonary disease (COPD) patients. However, data are limited on initial treatment with IND/GLY 110/50 μg q.d. versus mono LAMA in COPD patients, not previously on maintenance treatment with long-acting bronchodilators (LABD). Methods A pooled analysis of ARISE, SHINE and SPARK trials was conducted to evaluate the efficacy of IND/GLY 110/50 μg q.d. versus open-label (OL) tiotropium (TIO) 18 μg q.d. and GLY 50 μg q.d. in COPD patients, not on maintenance treatment with LABD at study entry (LABD-naive). Efficacy was assessed after 24/26 weeks of treatment. Results In total, 998 LABD-naive patients were included (IND/GLY: 353; OL TIO: 328; GLY: 317). Patients treated with IND/GLY 110/50 μg q.d. experienced greater improvements in trough forced expiratory volume in 1 s (FEV1 ) versus OL TIO 18 μg q.d. (least squares mean treatment difference (Δ): 0.086 L) and GLY 50 μg q.d. (Δ: 0.080 L) after 24/26 weeks. Improvements in electronic diary (eDiary) symptom scores, transition dyspnoea index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score and rescue medication use were also greater with IND/GLY versus OL TIO and GLY. Greater proportion of patients achieved minimal clinically important difference in trough FEV1 , TDI and SGRQ with IND/GLY versus OL TIO and GLY. Conclusion LABD-naive patients treated with IND/GLY 110/50 μg q.d. achieved improvements in lung function, daily symptoms, dyspnoea, health-related quality of life and rescue medication use versus those who received single LAMA.

  • blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment data from the flame trial
    American Journal of Respiratory and Critical Care Medicine, 2017
    Co-Authors: Nicolas Roche, Kenneth R Chapman, Francesco Patalano, Chau Thach, Robert Fogel, Donald Banerji, Claus Vogelmeier, Felix J F Herth, Petter Olsson, Jadwiga A. Wedzicha
    Abstract:

    Rationale: Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease (COPD).Objectives: We prospectively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long-acting β2-agonist combination versus a long-acting β2-agonist/long-acting muscarinic antagonist combination for exacerbation prevention.Methods: We conducted prespecified analyses of data from the FLAME (Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations) study, which compared once-daily long-acting β2-agonist/long-acting muscarinic antagonist indacaterol/Glycopyrronium 110/50 μg with twice-daily long-acting β2-agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 μg in patients with one or more exacerbations in the preceding year. Subsequent post hoc analyses were conducted to address further cutoffs and endpoints.Mea...

Paul Dorinsky - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy of budesonide/Glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts
    'Springer Science and Business Media LLC', 2021
    Co-Authors: Shigeo Muro, Patrick Darken, Hisatoshi Sugiura, Paul Dorinsky
    Abstract:

    Abstract Background In the Phase III KRONOS study, triple therapy with budesonide/Glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus Glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. Methods KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12–24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. Results Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS 

  • late breaking abstract copd exacerbation benefits relative to pneumonia risk with budesonide Glycopyrronium formoterol metered dose inhaler analyses from ethos
    European Respiratory Journal, 2020
    Co-Authors: Klaus F Rabe, Jadwiga A. Wedzicha, Colin Reisner, Gary T Ferguson, Fernando J Martinez, Dave Singh, Martin Jenkins, Magnus Aurivillius, Paul Dorinsky
    Abstract:

    Background: In the Phase III, 52-week ETHOS study (NCT02465567), budesonide/Glycopyrronium/formoterol metered dose inhaler (BGF MDI) fixed-dose combination significantly reduced exacerbations vs dual therapies. However, use of inhaled corticosteroids (ICS) may also increase pneumonia risk. Objective: To quantify exacerbation benefits relative to pneumonia risk (expressed as numbers needed to treat [NNT] and numbers needed to harm [NNH], respectively) in ETHOS. Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year received BGF MDI 320/14.4/10 μg or 160/14.4/10 μg, Glycopyrronium/formoterol (GFF) MDI 14.4/10 μg or budesonide/formoterol (BFF) MDI 320/10 μg twice-daily via a single Aerosphere inhaler. Exacerbation and pneumonia rates were used to calculate NNT and NNH. Results: BGF MDI 320 µg reduced exacerbation rates vs GFF MDI (NNT=3 [95% CI 3, 5]) and vs BFF MDI (NNT=7 [95% CI 4, 18]), (mITT, N=8509). Pneumonia rates across treatments were 0.02–0.05 per patient year, and were lower for BGF MDI than BFF MDI; for BGF MDI 320 μg vs GFF MDI, NNH=58 (95% CI 29, 152; Table). Conclusions: In patients with moderate/very severe COPD, BGF MDI 320 µg reduced exacerbation risk vs both dual therapies. For the ICS component, the NNH (BGF MDI 320 μg vs GFF MDI) suggests a low pneumonia risk for BGF MDI relative to its benefits on exacerbations.

  • pharmacokinetics and tolerability of budesonide Glycopyrronium formoterol fumarate dihydrate and Glycopyrronium formoterol fumarate dihydrate metered dose inhalers in healthy chinese adults a randomized double blind parallel group study
    Clinical Therapeutics, 2019
    Co-Authors: Qian Chen, Pryseley Nkouibert Assam, Michael Gillen, Kai Shen, Yun Liu, Paul Dorinsky
    Abstract:

    Abstract Purpose The objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/Glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and Glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing. Methods This Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18–45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 μg, BGF MDI 160/14.4/10 μg, or GFF MDI 14.4/10 μg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC0–12, Cmax, and Tmax. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values. Findings Ninety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC0–12 and Cmax were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC0–12, 811.8 vs 1748 h · pg/mL; Cmax, 224.3 vs 459.3 pg/mL; repeated dosing: AUC0–12, 1250 vs 2510 h · pg/mL; Cmax, 315.4 vs 626.4 pg/mL). After single and repeated dosing, Glycopyrronium AUC0–12 and Cmax were similar across all treatments (single dose: AUC0–12, 27.20–29.40 h · pg/mL; Cmax, 4.884–5.674 pg/mL; repeated dosing: AUC0–12, 69.49–77.08 h · pg/mL; Cmax, 11.30–13.12 pg/mL) and formoterol (single dose: AUC0–12, 46.49–53.58 h · pg/mL; Cmax 9.651–10.62 pg/mL; repeated dosing: AUC0–12, 81.94–85.32 h · pg/mL; Cmax, 16.13–17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%–56.3%). There were no new or unexpected findings on tolerability. Implications Overall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267 .

  • pharmacokinetics of co suspension delivery technology budesonide Glycopyrronium formoterol fumarate dihydrate bgf mdi and budesonide formoterol fumarate dihydrate bff mdi fixed dose combinations compared with an active control a phase 1 randomized si
    Clinical pharmacology in drug development, 2019
    Co-Authors: Andrea Maes, Paolo Depetrillo, Shahid Siddiqui, Colin Reisner, Paul Dorinsky
    Abstract:

    This randomized, phase 1, single-dose, crossover study (NCT02189304) compared the 12-hour pharmacokinetic (PK) and safety profiles of budesonide/Glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) 320/14.4/10 μg and budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg (both formulated using innovative co-suspension delivery technology) to an active comparator (budesonide/formoterol fumarate dihydrate dry powder inhaler [BUD/FORM DPI] 320/9-μg delivered dose) in healthy adults. The potential for PK interaction between Glycopyrronium and budesonide/formoterol within BGF MDI was assessed. Of 72 subjects randomized, 59 completed treatment. Systemic budesonide exposure (primary objective) based on area under the plasma drug concentration-time curve 0-12 hours (AUC0-12 ; % coefficient of variation) was 1598.38 (49.7), 1657.09 (50.4), and 1276.75 (70.4) pg·h/mL for BGF MDI, BFF MDI, and BUD/FORM DPI, respectively; and formoterol exposure (AUC0-12 [% coefficient of variation]) was 39.16 (45.9), 39.53 (40.5), and 23.24 (59.2) pg·h/mL, respectively. BGF MDI and BFF MDI were bioequivalent for budesonide and formoterol. All treatments were well tolerated. While systemic exposure to budesonide and formoterol was higher for BGF MDI and BFF MDI than for BUD/FORM DPI, there were no appreciable differences in the incidence of pharmacologically predictable adverse events. This, coupled with the absence of PK interactions, suggests the BGF MDI safety profile will be comparable to BUD/FORM DPI.

  • the pharmacokinetics of three doses of budesonide Glycopyrronium formoterol fumarate dihydrate metered dose inhaler compared with active controls a phase i randomized single dose crossover study in healthy adults
    Pulmonary Pharmacology & Therapeutics, 2018
    Co-Authors: Patrick Darken, Colin Reisner, Paolo Depetrillo, Earl St Rose, Paul Dorinsky
    Abstract:

    The budesonide/Glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 μg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg], 160/14.4/10 μg and 80/14.4/10 μg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 μg and 160/9 μg; not using co-suspension delivery technology) and a Glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 μg) in healthy volunteers (18-45 years of age). PK parameters included area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), AUC up to the last measurable concentration (AUC0-t), maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 μg was bioequivalent to BUD/FORM MDI 320/9 μg for budesonide for Cmax, AUC0-12 and AUC0-t (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 μg and BGF MDI 160/14.4/10 μg, and between BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg. Systemic exposure to Glycopyrronium and formoterol after BGF MDI 320/14.4/10 μg treatment was similar to GFF MDI 14.4/10 μg. The rate of adverse events was 3.7-17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 μg had a similar budesonide PK profile to BUD/FORM MDI 320/9 μg. No PK drug-drug interactions were observed when budesonide was added to Glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 μg and 160 μg in future clinical trials of BGF MDI in COPD.

Luigino Calzetta - One of the best experts on this subject based on the ideXlab platform.

  • beclomethasone dipropionate formoterol fumarate and Glycopyrronium bromide synergy of triple combination therapy on human airway smooth muscle ex vivo
    British Journal of Pharmacology, 2020
    Co-Authors: Paola Rogliani, Francesco Facciolo, Maria Gabriella Matera, Mario Cazzola, Clive P Page, Luigino Calzetta
    Abstract:

    Background and purpose Combining inhaled corticosteroids (ICSs), long-acting β2 -adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA Glycopyrronium bromide in human airways. Experimental approach Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and Glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. Key results Beclomethasone/formoterol/Glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/Glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and Gsα subunit G-protein of β2 -adrenoceptors, leading to the modulation of cyclic AMP-dependent PKA pathway. Conclusion Triple beclomethasone/formoterol/Glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.

  • impact of ics laba and laba lama fdcs on functional and clinical outcomes in copd a network meta analysis
    Pulmonary Pharmacology & Therapeutics, 2019
    Co-Authors: Luigino Calzetta, Fabiano Di Marco, Francesco Blasi, Stefano Centanni, Claudio Micheletto, Andrea Rossi, Paola Rogliani
    Abstract:

    Abstract Background Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixed-dose combinations (FDCs) and LABA/long-acting muscarinic antagonist (LAMA) FDCs are extensively used to treat chronic obstructive pulmonary disease (COPD). The aim of the present network meta-analysis was to assess the comparative efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. Methods A network meta-analysis (≥3 nodes, Bayesian method) was performed by searching for randomized clinical trials (RCTs) that compared the impact of different LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. The primary endpoints were: the change from baseline in trough forced expiratory volume in 1 s (FEV1) and the risk of exacerbation of COPD (AECOPD). The secondary endpoints were: peak FEV1, St’ George's Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI), and rescue medication use. Results Data of 17,734 COPD patients were extracted from 16 RCTs. The length of treatment ranged from 6 weeks to 52 weeks. All LABA/LAMA FDCs, except aclidinium/formoterol, produced a statistically significant improvement compared to ICS/LABAs in trough FEV1. The surface under the cumulative ranking curve (SUCRA) analysis indicated that umeclidinium/vilanterol, Glycopyrronium/indacaterol and glycopyrrolate/formoterol fumarate were the most effective FDCs in improving trough FEV1. Across the FDCs analyzed for the risk of AECOPD, Glycopyrronium/indacaterol significantly reduced the exacerbation risk compared to fluticasone propionate/salmeterol and resulted the most effective combination in the SUCRA analysis. Similar trend were also observed for the peak FEV1. No significant differences were detected across the investigated FDCs regarding SGRQ, TDI, and use of rescue medication. Conclusions The results of this meta-analysis show that LABA/LAMA combinations are consistently more effective than ICS/LABA FDCs for most of the evaluated outcomes. However, differences have also been observed between FDCs belonging to the same class. Across the investigated LABA/LAMA FDCs, Glycopyrronium/indacaterol revealed a consistent and robust efficacy profile.

  • Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD : A network meta-analysis
    'Elsevier BV', 2019
    Co-Authors: Luigino Calzetta, Francesco Blasi, Stefano Centanni, Claudio Micheletto, Mario Cazzola, F. Di Marco, A. Rossi, Paola Rogliani
    Abstract:

    Background: Inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) fixed-dose combinations (FDCs) and LABA/long-acting muscarinic antagonist (LAMA) FDCs are extensively used to treat chronic obstructive pulmonary disease (COPD). The aim of the present network meta-analysis was to assess the comparative efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. Methods: A network meta-analysis (≥3 nodes, Bayesian method) was performed by searching for randomized clinical trials (RCTs) that compared the impact of different LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. The primary endpoints were: the change from baseline in trough forced expiratory volume in 1 s (FEV1) and the risk of exacerbation of COPD (AECOPD). The secondary endpoints were: peak FEV1, St’ George's Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI), and rescue medication use. Results: Data of 17,734 COPD patients were extracted from 16 RCTs. The length of treatment ranged from 6 weeks to 52 weeks. All LABA/LAMA FDCs, except aclidinium/formoterol, produced a statistically significant improvement compared to ICS/LABAs in trough FEV1. The surface under the cumulative ranking curve (SUCRA) analysis indicated that umeclidinium/vilanterol, Glycopyrronium/indacaterol and glycopyrrolate/formoterol fumarate were the most effective FDCs in improving trough FEV1. Across the FDCs analyzed for the risk of AECOPD, Glycopyrronium/indacaterol significantly reduced the exacerbation risk compared to fluticasone propionate/salmeterol and resulted the most effective combination in the SUCRA analysis. Similar trend were also observed for the peak FEV1. No significant differences were detected across the investigated FDCs regarding SGRQ, TDI, and use of rescue medication. Conclusions: The results of this meta-analysis show that LABA/LAMA combinations are consistently more effective than ICS/LABA FDCs for most of the evaluated outcomes. However, differences have also been observed between FDCs belonging to the same class. Across the investigated LABA/LAMA FDCs, Glycopyrronium/indacaterol revealed a consistent and robust efficacy profile

  • laba lama fixed dose combinations in patients with copd a systematic review
    International Journal of Chronic Obstructive Pulmonary Disease, 2018
    Co-Authors: Paola Rogliani, Luigino Calzetta, Fulvio Braido, Enrico Clini, Girolamo Pelaia, Nicola Scichilone, Andrea Rossi, Fabiano Di Marco
    Abstract:

    Objectives The aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD. Materials and methods A systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index (TDI) scores, St George's Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated. Results In total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV1) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/Glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/Glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents. Conclusion Evidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/Glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety.

  • LABA/LAMA fixed-dose combinations in patients with COPD: a systematic review
    International Journal of Chronic Obstructive Pulmonary Disease, 2018
    Co-Authors: Paola Rogliani, Luigino Calzetta, Fulvio Braido, Enrico Clini, Girolamo Pelaia, Nicola Scichilone, Andrea Rossi, Fabiano Di Marco
    Abstract:

    Objectives The aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD. Materials and methods A systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index (TDI) scores, St George's Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated. Results In total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV1) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/Glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/Glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents. Conclusion Evidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/Glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety.

Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.

  • beclomethasone dipropionate formoterol fumarate and Glycopyrronium bromide synergy of triple combination therapy on human airway smooth muscle ex vivo
    British Journal of Pharmacology, 2020
    Co-Authors: Paola Rogliani, Francesco Facciolo, Maria Gabriella Matera, Mario Cazzola, Clive P Page, Luigino Calzetta
    Abstract:

    Background and purpose Combining inhaled corticosteroids (ICSs), long-acting β2 -adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA Glycopyrronium bromide in human airways. Experimental approach Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and Glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. Key results Beclomethasone/formoterol/Glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/Glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and Gsα subunit G-protein of β2 -adrenoceptors, leading to the modulation of cyclic AMP-dependent PKA pathway. Conclusion Triple beclomethasone/formoterol/Glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.

  • pharmacological characterisation of the interaction between Glycopyrronium bromide and indacaterol fumarate in human isolated bronchi small airways and bronchial epithelial cells
    Respiratory Research, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Maria Gabriella Matera
    Abstract:

    Background Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between Glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction.

  • pharmacological characterisation of the interaction between Glycopyrronium bromide and indacaterol fumarate in human isolated bronchi small airways and bronchial epithelial cells
    Respiratory Research, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Josuel Ora, Maria Gabriella Matera
    Abstract:

    Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between Glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction. The effects of Glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach. Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P   0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase. Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium.

  • interaction between corticosteroids and muscarinic antagonists in human airways
    Pulmonary Pharmacology & Therapeutics, 2016
    Co-Authors: Mario Cazzola, Francesco Facciolo, Paola Rogliani, Luigino Calzetta, Ermanno Puxeddu, Maria Gabriella Matera
    Abstract:

    Abstract Background To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA Glycopyrronium on the human airway smooth muscle (ASM) tone. Methods We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and Glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method. Results The acute administration of beclomethasone and Glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα – cyclic adenosine monophosphate (cAMP) – protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/Glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and Glycopyrronium was associated with an increase of cAMP concentrations. Conclusions Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.

  • pharmacological assessment of the onset of action of aclidinium and Glycopyrronium versus tiotropium in copd patients and human isolated bronchi
    European Journal of Pharmacology, 2015
    Co-Authors: Paola Rogliani, Andrea Segreti, Luigino Calzetta, Maria Gabriella Matera, Josuel Ora, Roberto Lipsi, Mario Cazzola
    Abstract:

    Preclinical studies suggested that aclidinium and Glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and Glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, Glycopyrronium 50μg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, Glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and Glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, Glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1μM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1μM: 6.4±0.5min) and tiotropium (1μM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and Glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.