Search Results (10)

Background/Objectives: Several studies have demonstrated the positive clinical and functional impact of adding Long-Acting Muscarinic Antagonist (LAMA) to Inhaled Corticosteroids (ICS) and Long-Acting Beta-Agonists (LABA) therapy in the treatment of severe asthma. Aim and objectives: To demonstrate that treating Small Airways Disease (SAD) in severe asthma patients who are candidates for biologics can improve respiratory symptoms, lung function, and airways inflammation, potentially avoiding or delaying the use of biological therapy. Methods: Thirty-two severe asthma patients with SAD were transitioned from separate inhalers for ICS/LABA and LAMA to extrafine single-inhaler beclomethasone, formoterol, and glycopyrronium. None of these patients underwent biological therapy before the study. Follow-up evaluations were conducted at baseline (T0) and three months after initiation (T3). Assessments included clinical evaluations, spirometry, oscillometry, and inflammation markers. Results: Transitioning to single-inhaler triple therapy from T0 to T3 resulted in significant improvements in Asthma Control Test (ACT) and SAD parameters, including increased Forced Expiratory Volume in the mid-range of lung capacity and improved airway resistance and reactance measurements using impulse oscillometry. A significant reduction in airway inflammation was evidenced by lower levels of Fractional Exhaled Nitric Oxide 350 (FeNO 350) (p < 0.001 for all). Conclusions: Adopting a single-inhaler triple therapy notably enhanced clinical control and small airway function in patients with severe asthma and SAD, supporting the positive impact of target-therapy for the achievement of a stable state termed “Quiet Asthma”. Full article

This real-world study evaluated the efficacy of once-daily long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for improving lung function in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD who were treated with once-daily LABA/LAMA FDCs for 12 months were included. We evaluated their lung function improvement after 12 months of treatment with different LABA/LAMA FDCs. A total of 198 patients with COPD who were treated with once-daily LABA/LAMA FDCs were analyzed. A total of 114 patients were treated with umeclidinium/vilanterol (UMEC/VIL); 34 patients were treated with indacaterol/glycopyrronium (IND/GLY); and 50 patients were treated with tiotropium/olodaterol (TIO/OLO). The forced expiratory volume in 1 s (FEV1) was significantly increased in the patients treated with all three once-daily FDCs (55.2% to 60.9%, p = 0.012 for UMEC/VIL, 58.2% to 63.6%, p = 0.023 for IND/GLY, and 54.1% to 57.7%, p = 0.009 for TIO/OLO). The treatment of COPD patients with TIO/OLO resulted in a significant improvement in both forced vital capacity (FVC%) (71.7% to 77.9%, p = 0.009) and residual volume (RV%) (180.1% to 152.5%, p < 0.01) compared with those treated with UMEC/VIL (FVC%: 75.1% to 81.5%, p < 0.001; RV%:173.8% to 165.2%, p = 0.231) or IND/GLY (FVC%: 73.9% to 79.3%, p = 0.08; RV%:176.8% to 168.3%, p = 0.589). Patients treated with UMEC/VIL or TIO/OLO showed significant improvement in FVC. In addition, those receiving TIO/OLO also showed significant improvement in RV reduction. Full article

Glycopyrronium (GLY) is a pharmacological maintenance treatment for chronic obstructive pulmonary disease (COPD). However, its effectiveness and tolerability for COPD patients in routine clinical practice have not been well-investigated. This study aimed to assess the effectiveness of GLY on health-related quality of life and its safety in patients with COPD in a routine clinical care setting. This multi-center, prospective, six-month observational study recruited patients diagnosed with COPD and treated with GLY at three medical centers in central Taiwan. The full analysis set (n = 102) had a significant improvement in the Clinical COPD Questionnaire total (mean ± SD = −0.39 ± 0.90, p = 0.002), symptoms (mean ± SD = −0.61 ± 0.90, p < 0.001) and mental state scores (mean ± SD = −0.54 ± 1.72, p = 0.021) but not the functional state score (mean ± SD = −0.10 ± 1.15, p = 0.529). During the observational period, 58 patients (52.73%) experienced adverse events; only one adverse event (dizziness) was suspected to be related to the study drug. Three patients (2.73%) discontinued the study and GLY treatment because of an adverse event. One patient (0.91%) died during the study period because of a cerebral infarction, which was judged to be not associated with GLY treatment. In conclusion, GLY could be effective in improving the health status and is safe for patients with COPD in a real-life setting. Full article

Background: Triple fixed-dose combination (FDC) therapy is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Since no randomized controlled trials (RCTs) have directly compared the different inhaled corticosteroid/long-acting β₂-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) FDCs, we performed a meta-analysis to compare the impact of the current available ICS/LABA/LAMA FDCs in COPD. Methods: A meta-analysis was performed by connecting beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide or glycopyrrolate (BDP/FOR/GLY), budesonide (BUD)/GLY/FOR, and fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) FDCs via ICS/LABA or LABA/LAMA FDCs arms. The safety and efficacy profiles were investigated, and the Implemented Bidimensional Surface under the cumulative ranking curve analysis (IBiS) was carried out. Protocol registration: CRD42022301189. Results: Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant (p > 0.05) differences were detected across the triple FDCs with respect to the risk of exacerbation, trough forced expiratory volume in the first second (FEV₁), transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. According to IBiS score, BDP/FOR/GLY 200/12/25 µg twice daily (BID) was the FDC reporting the best combined efficacy/safety profile (area 41.41%), although FF/UMEC/VI 100/62.5/25 µg once daily (QD) showed the greatest efficacy profile (50.54%). The protection against mortality related to the dose of ICS. Conclusions: All triple FDCs are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference in the risk of CV SAEs and pneumonia. Full article

The effectiveness and safety of fixed dual long-acting bronchodilators for chronic obstructive pulmonary disease (COPD) patients have been well established; however, there is a paucity of clinical effectiveness comparison in patients with COPD treatment. The aim of the current study was to compare the effectiveness of three once-daily dual bronchodilator agents in patients with COPD. Patients with diagnosed COPD and treated with a long-acting beta-agonist (LABA) + long-acting muscarinic antagonist (LAMA) fixed-dose combination therapy (UME/VIL (umeclidinium and vilanterol inhalation powder), IND/GLY (indacaterol and glycopyrronium), and TIO/OLO (tiotropium and olodaterol)) were enrolled in this retrospective study over a period of 12 months. Effectiveness assessments were evaluated using a COPD assessment test (CAT) and lung function parameters. Besides, times for acute exacerbation were also assessed. The enrolled patients’ number was 177 in IND/GLY, 176 in UME/VIL and 183 in TIO/OLO. Lung function measurements with FEV1 had significantly improved for patients using TIO/OLO (98.7 mL) compared to those of IND/GLY (65.2 mL) and UME/VIL (64.4 mL) (p < 0.001). CAT scores were also significantly decreased in patients treated with TIO/OLO (CAT down 5.6) than those with IND/GLY (3.8) and UME/VIL (3.9) (p = 0.03). Acute exacerbation was also reduced in patients using TIO/OLO (4.9%) compared with those using IND/GLY (10.2%) and UME/VIL (11.9%) (p = 0.01). Significant improvement in pulmonary function, symptoms were demonstrated after 12 months of LABA/LAMA fixed-dose combination therapy with three different treatment options. TIO/OLO demonstrated higher therapeutic effects compared with UME/VIL or IND/GLY. Determining clinical relevance will require a well-designed randomized controlled trial. Full article

Background: Evidence suggests that triple therapy for patients with chronic obstructive pulmonary disease (COPD) is being used in a broader range of patients than recommended by guidelines, which may have health and cost implications. Objective: To explore the relationship between national health technology assessment (HTA) agency appraisals and market penetration of two fixed-dose combination (FDC) triple therapies. Study design: HTAs from Q3 2017 to Q1 2020 from 10 countries were evaluated. Intervention: Glycopyrronium bromide/formoterol fumarate/beclomethasone (Trimbow^®) and umeclidinium/vilanterol/fluticasone furoate (Trelegy™ Ellipta^®). Main outcome measure: HTA restrictions and prescribing rates (days of therapy). Results: Seven countries (70%) imposed restrictions on use including prescription only for patients stable on free-combination triple therapy or not controlled on dual therapy, requirement of a specialist prescription or therapeutic plan, prescription only for patients with severe COPD, and use as second-line therapy or later. In general, countries that have imposed restrictions on the use of FDC triple therapies have seen a lower than average uptake. Conclusion: Payer guidance on prescribing FDC triple therapy may potentially support more appropriate prescribing in line with clinical guidelines. It is important for payers to consider which restrictions would ensure the most efficient use of scarce resources. Full article

Expression of bronchodilatory β₂-adrenoceptors and bronchoconstrictive muscarinic M₃-receptors alter with airway size. In COPD, (a combination of) β₂-agonists and muscarinic M₃-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β₂-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β₂-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD. Full article

To advance the development of bronchodilators for asthma and chronic obstructive pulmonary disease (COPD), this study was designed to investigate the mechanism of functional antagonism between β₂-adrenergic and muscarinic M₂ receptors, focusing on allosteric effects and G proteins/ion channels coupling. Muscarinic receptor antagonists (tiotropium, glycopyrronium, atropine) synergistically enhanced the relaxant effects of β₂-adrenergic receptor agonists (procaterol, salbutamol, formoterol) in guinea pig trachealis. This crosstalk was inhibited by iberitoxin, a large-conductance Ca²⁺-activated K⁺ (K_Ca) channel inhibitor, whereas it was increased by verapamil, a L-type voltage-dependent Ca²⁺ (VDC) channel inhibitor; additionally, it was enhanced after tissues were incubated with pertussis or cholera toxin. This synergism converges in the G proteins (G_i, G_s)/K_Ca channel/VDC channel linkages. Muscarinic receptor antagonists competitively suppressed, whereas, β₂-adrenergic receptor agonists noncompetitively suppressed muscarinic contraction. In concentration-inhibition curves for β₂-adrenergic receptor agonists with muscarinic receptor antagonists, EC₅₀ was markedly decreased, and maximal inhibition was markedly increased. Hence, muscarinic receptor antagonists do not bind to allosteric sites on muscarinic receptors. β₂-Adrenergic receptor agonists bind to allosteric sites on these receptors; their intrinsic efficacy is attenuated by allosteric modulation (partial agonism). Muscarinic receptor antagonists enhance affinity and efficacy of β₂-adrenergic action via allosteric sites in β₂-adrenergic receptors (synergism). In conclusion, K_Ca channels and allosterism may be novel targets of bronchodilator therapy for diseases such as asthma and COPD. Full article

Long-acting muscarinic antagonists (LAMAs) and short-acting β₂-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca²⁺ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 μM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca²⁺-activated K⁺ (K_Ca) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca²⁺ sensitization mediated by PKC and Ca²⁺ dynamics mediated by K_Ca channels. PKC and K_Ca channels may be molecular targets for cross talk between β₂-adrenoceptors and muscarinic receptors. Full article

Combination therapy with anticholinergics and β2-agonists should be used in COPD patients after failure of previous monotherapy with one of these drugs. Synergistic effect of both mechanisms of bronchodilation can maximize the efficacy of separately administered drugs. The effectiveness of the combination of LABA and LAMA is already confirmed, nevertheless the question about the safety profile of this therapy is still remaining, particularly with regard to the cardiovascular system. The paper discusses the overall safety profile of the combined preparation compare to placebo as well as the active comparators, especially the cardiovascular safety of fixed-dose formulation. Based on the data it has been demonstrated, that the combination of two ultra -long-acting bronchodilators with different complementary mechanisms of action increases the effectiveness of COPD therapy without affecting the safety. Full article