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Purpose Macrolides are a recommended treatment option for severe asthma, but data for “difficult-to-treat” asthma, the asthma-COPD “overlap” syndrome, and treatment duration beyond one year are lacking. We present long-term data from community practice experience providing insights for practice and research. Methods We report data from (1) baseline (pre-treatment) chart review of antibiotic-treated asthma patients and (2) follow-up telephone interviews documenting severe exacerbations (NIH criteria), Asthma Control Test (ACT) scores, and asthma controller use at baseline and follow-up, analyzed using a “before-after” model. Results A total of 101 patients (mean age 55.6 years (Sd 16.8), 66 females) were included. None had ever taken high dose inhaled corticosteroids and 79 (78.2%) were severely uncontrolled (ACT score ≤15) before treatment. Coexisting COPD was present in 62 (61.4%) patients. Azithromycin or azithromycin plus doxycycline was primarily prescribed with a median treatment duration of 12 months and median follow-up duration of 22 months. Severe exacerbations in the month before treatment occurred in 50.5% vs 17.8% at follow-up (P, Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/0vF55ewkTVc

Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [11C]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n = 10) scanned with the α4β2* nicotinic ligand (−)-[18F]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 ± 3.4% occupancy in striatum, 43 ± 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 ± 26% vs. 69 ± 28%, p

Wen-Chien Cheng,1– 6 Biing-Ru Wu,1,3,5,6 Wei-Chih Liao,1,2,4,7 Chih-Yu Chen,1 Wei-Chun Chen,1,3– 6 Te-Chun Hsia,1,4,8 Chih-Yen Tu,1– 3 Chia-Hung Chen,1,2,7 Wu-Huei Hsu1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, China Medical University, Taichung, Taiwan; 3Department of Life Science, National Chung Hsing University, Taichung, Taiwan; 4Department of Internal Medicine, Hyperbaric Oxygen Therapy Center, China Medical University Hospital, Taichung, Taiwan; 5Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 6Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 8Department of Respiratory Therapy, China Medical University, Taichung, TaiwanCorrespondence: Chia-Hung Chen; Chih-Yu ChenDepartment of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, Taichung, TaiwanEmail hsnu758@gmail.com; cychen0808@gmail.comPurpose: Triple therapy versus dual therapy for chronic pulmonary obstructive disease (COPD) can reduce symptoms, limit the risk of acute exacerbations (AEs) as well as improve lung function. Currently, studies that feature clinically important deterioration (CID) as a composite endpoint to assess the need for treatment intensification for patients maintained on dual therapy remained to be scarce.Patients and Methods: This study is a retrospective analysis (January 2014 to January 2018) of COPD patients that presented with moderate to severe AEs during the previous year with blood eosinophil counts ≥ 100 cells/μL. The first line of therapy included a combination of inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA). Composite CID was used in assessing the response to treatment after 24 weeks of therapy.Results: This study included 110 patients, of which 49 patients reportedly experienced CID. The most common events of CID include a decline in forced expiratory volume in 1 second (FEV1) ≥  100 mL from baseline (25/49, 51%) and an increase in COPD Assessment Test (CAT) scores ≥ 2 (13/49, 26.5%); many of these patients respond to the addition of a long-acting muscarinic antagonist (LAMA). Seven patients (7/110, 6.3%) experienced moderate to severe exacerbations while undergoing treatment with ICS/LABA. Univariate and multivariate analyses have identified low baseline FEV1 (OR = 0.81, p = 0.004), high CAT score (OR = 1.89, p = 0.004), and the frequency of AE (OR = 19.86, p = 0.021) as independent predictors of CID. A baseline FEV1 of ≤ 42%, an initial CAT score ≥ 18, and AE ≥ 2 last year were considered the optimal cut-off values, which were identified via receiver operating characteristics (ROC) curve analysis.Conclusion: Triple therapy (ICS/LABAs/LAMAs) may be considered as first-line treatment in patients experiencing more than 2 times moderate to severe AEs of COPD in the previous year and who have blood eosinophil counts ≥ 100 cells/μL, reduced lung function (FEV1 ≤ 42%), and more symptoms (CAT score ≥ 18).Keywords: inhaled corticosteroid, ICS, long-acting muscarinic antagonist, LAMA, long-acting β2 agonist, LABA, triple therapy, chronic pulmonary obstructive disease, COPD, clinically important deterioration, CID

The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting βFor this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review.Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD.The early stages of COPD may represent a "window of therapeutic opportunity" during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD.

Rationale: There is uncertainty on the use of using triple therapy (inhaled corticosteroids/long-acting β-agonist/long-acting muscarinic antagonist) inhaler therapy for patients with chronic obstru...

Introduction In pediatric patients with asthma, measurements of forced expiratory volume in 1 s (FEV1) may be normal or may not correlate with symptom severity. Forced expiratory flow at 25–75% of the vital capacity (FEF25–75%) is a potentially more sensitive parameter for assessing peripheral airway function. This post hoc analysis compared FEF25–75% with FEV1 as an endpoint to assess bronchodilator responsiveness in children with asthma. Methods Change from baseline in trough FEF25–75% and trough FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat® was analyzed in four phase III trials in children (aged 6–11 years) and adolescents (aged 12–17 years) with symptomatic moderate (VivaTinA-asthma® and PensieTinA-asthma®) and mild (CanoTinA-asthma® and RubaTinA-asthma®) asthma. Data from all treatment arms were pooled and correlations between FEF25–75% and FEV1 were calculated and analyzed. Results A total of 1590 patients were included in the analysis. Tiotropium Respimat® consistently improved FEF25–75% and FEV1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF25–75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV1. Statistical assessment of the correlation of FEV1 and FEF25–75% showed moderate-to-high correlations (Pearson’s correlation coefficients 0.73–0.80). Conclusions In pediatric patients, FEF25–75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV1 and should be evaluated as an additional lung function measurement.

Bo Ding,1 Lee Kallenbach,2 Lukas Slipski,2 Alan Wilk,2 Dan O’Brien,2 Deniz Guranlioglu3 1AstraZeneca, Gothenburg, Sweden; 2Practice Fusion, San Francisco, CA, USA; 3AstraZeneca, Cambridge, UKCorrespondence: Bo DingAstraZeneca, Pepparedsleden 1, Gothenburg SE 431 83, Mölndal, SwedenTel +46 31 776 2406Email Bo.Ding@astrazeneca.comIntroduction: This retrospective, observational cohort study utilized an integrated dataset from an electronic health records system and a claims database to describe demographic and clinical characteristics, healthcare resource utilization (HCRU), and treatment patterns in COPD patients initiating long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combination (FDC) treatment in the USA.Methods: Patients were aged ≥ 40 years and had a COPD diagnosis (Practice Fusion system) and ≥ 1 prescription of LAMA/LABA FDC therapy, with an index date (first prescription) 1 May 2014– 31 December 2017. For the HCRU analysis, patients had ≥ 2 claims from the Symphony Health database within 12 months before index. All analyses of outcomes relating to demographic and clinical characteristics, HCRU, and treatment patterns were descriptive.Results: Patients initiating LAMA/LABA FDCs (n=8224) had a mean age of 67.9 years, 52.8% were female, and mean BMI was 29.2 kg/m2. The most common comorbidities were cardiovascular disease (74.3%), hypertension (64.0%), and hyperlipidemia (45.6%). In the 12 months prior to index, 53.1% of patients had used inhaled therapy: 23.4% short-acting therapy only, 16.7% short-acting and maintenance therapy, and 13.1% maintenance therapy only. Amongst users of inhaled therapies, the pMDI was the most frequently used device (64.3%, n=2812/4370). Of 7050 patients included in the HCRU analysis, 79.8% had COPD-related costs; mean cost/patient was $4174. Mean COPD-related costs per patient for moderate and severe exacerbations were $910 and $23,208, respectively. Per-patient costs included $23,032 for inpatient visits, $2358 for emergency visits, $4432 for outpatient visits, and $1989 for pharmacy claims.Conclusion: This observational study is the first to describe the real-world demographic and clinical characteristics and HCRU of patients initiating LAMA/LABA FDC treatment in the USA. Patients were generally elderly and overweight, with comorbidities of CVD, hypertension, and hyperlipidemia. Inpatient visits were the largest contributor to COPD-related costs per patient in the year prior to initiation of LAMA/LABA FDCs.Keywords: muscarinic antagonist, β2-agonist, demographic characteristics, disease characteristics, cost

Introduction Airway obstruction is usually assessed by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). This post hoc study investigated comparative responses of lung function measurements in adults and adolescents (full analysis set, N = 3873) following treatment with tiotropium Respimat®. Methods Lung function outcomes were analysed from five phase III trials in adults (≥ 18 years) with symptomatic severe, moderate and mild asthma (PrimoTinA-asthma®, MezzoTinA-asthma® and GraziaTinA-asthma®, respectively), and one phase III trial in adolescents (12–17 years) with symptomatic moderate asthma (RubaTinA-asthma®). Changes from baseline versus placebo in FEV1, FVC, PEF and FEV1/FVC ratio with tiotropium 5 µg or 2.5 µg added to at least stable inhaled corticosteroids at week 24 (week 12 in GraziaTinA-asthma) were analysed. Results All lung function measures improved in all studies with tiotropium 5 µg (mean change from baseline versus placebo), including peak FEV1 (110–185 mL), peak FVC (57–95 mL) and morning PEF (15.8–25.6 L/min). Changes in adolescents were smaller than those in adults, and were statistically significant primarily for FEV1 and PEF, but not for FVC. Conclusion Consistent improvements were seen across all lung function measures with the addition of tiotropium to other asthma treatments in adults across all severities, whereas the improvements with tiotropium in adolescents primarily impacted measures of flow rather than lung volume. This may reflect less pronounced airway remodelling and air trapping in adolescents with asthma versus adults., Plain Language Summary Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone’s breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults. Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230.

Fernando J Martinez,1 Klaus F Rabe,2 Brian J Lipworth,3 Samir Arora,4 Martin Jenkins,5 Ubaldo J Martin,6 Colin Reisner6,7 1Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 2Department of Pneumonology, LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Division of Molecular and Clinical Medicine, Scottish Centre for Respiratory Research, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK; 4Aventiv Research Inc., Columbus, OH, USA; 5Global Medicines Development, AstraZeneca, Cambridge, UK; 6Research and Development, AstraZeneca, Gaithersburg, MD, USA; 7R&D Biopharmaceuticals, AstraZeneca, Morristown, NJ, USACorrespondence: Fernando J MartinezJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th Street, Room M-522, Box 130, New York, NY 10065, USATel +1646 962 2748Email fjm2003@med.cornell.eduBackground: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.Materials and Methods: PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458). Patients received 24 weeks’ treatment with GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI twice daily. GOLD category A patients were identified based on a COPD Assessment Test score of 1), peak change from baseline in FEV1 within 2 hrs post-dose, and adverse events (AEs).Results: The pooled intent-to-treat population comprised 729 GOLD category A patients. GFF MDI significantly improved morning pre-dose trough FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p≤0.0053), and peak FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p

Aim: To compare health plan-paid costs, exacerbations and pneumonia outcomes for patients with chronic obstructive pulmonary disease (COPD) initiating combination tiotropium olodaterol (TIO + OLO) versus triple therapy (TT: long-acting muscarinic antagonist + long-acting β 2 agonists + inhaled corticosteroid). Patients & methods: COPD patients initiating TIO + OLO or TT between 1 January 2014 and 30 June 2016 were identified from a managed care Medicare database and balanced for baseline characteristics using inverse probability of treatment weighting before assessment of outcomes. Results: Annual COPD-related and all-cause costs were US$4118 (35%) and US$5384 (23%) lower for TIO + OLO versus TT (both p ≤ 0.001). TIO + OLO patients had nearly half the severe exacerbations (8.3 vs 15.5%; p = 0.014) and pneumonia was also less common (18.9 vs 30.9%; p Conclusion: TIO + OLO was associated with improved economic and COPD health outcomes versus TT.

Background: Increasing evidence has implicated the cholinergic system as a modulator of mood episodes, with possible involvement of nicotinic and/or muscarinic receptors. A number of randomized controlled trials (RCTs) have demonstrated a putative rapid antidepressant effect of the muscarinic antagonist scopolamine. Here, we review the clinical evidence regarding the three principal muscarinic-modulating agents administered in studies involving mood disorders: scopolamine, biperiden and physostigmine. We conduct a meta-analysis on RCTs where these agents were administered to participants experiencing a depressive episode. Methods: A systematic bibliographic search of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies utilizing the above agents was conducted between January 1970 and December 2020. A meta-analysis was subsequently performed on 9 studies which satisfied inclusion criteria, including 322 participants. Results: Administration of scopolamine significantly reduced depressive symptoms compared to placebo, as measured by objective mood rating scales with SMD of -0.95 (95% CI -1.49, -0.42, p = 0.0005). This effect increased to -1.13 (95% CI -1.61, -0.66, p

Background The role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD. Methodology We included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George’s Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated. Results In total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: −0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: −2.12, P < 0.0001) and bodily pain scores in the St. George’s Respiratory Questionnaire (mean difference: −7.03, P = 0.031) significantly decreased. Conclusions Switching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

Functional autoantibodies directed to the M2 muscarinic acetylcholine receptor (M2R) could affect the heart rate directly by altering cardiac M2R activity and/or indirectly by changing vagal-mediated cardiac M2R activity. We measured M2R autoantibody activity in sera from 10 subjects with postural tachycardia syndrome (POTS) and 5 healthy control subjects using a cell-based bioassay. Half of the POTS subjects demonstrated presence of elevated M2R autoantibody activity, while no significant M2R autoantibody activity was found in the healthy subjects. Serum-derived immunoglobulin G (IgG) from antibody-positive POTS patients induced a dose-dependent activation of M2R, which was blocked by the muscarinic antagonist atropine. Moreover, antibody-positive POTS IgG decreased the responsiveness to oxotremorine, an orthosteric muscarinic agonist, indicating an indirect inhibitory effect. These data suggest that M2R autoantibodies may contribute to the pathophysiology of POTS by increasing the normal vagal withdrawal during upright posture through its negative allosteric modulation of M2R activity. M2 muscarinic receptor-activating autoantibodies are present in a subgroup of patients with POTS and act as a negative allosteric modulator of the orthosteric ligand response.

Treatment of fasted mice and rats with the nonselective muscarinic antagonist, scopolamine or atropine, causes convulsions after food intake. This study evaluated the effect of fasting on the expression of M1 and M2 muscarinic receptors in the brain regions, the relationship between receptor expression and seizure stages, and the muscarinic receptor subtype which plays a role in the occurrence of convulsions. Mice were grouped as allowed to eat ad lib (fed) and deprived of food for 24h (fasted). Fasted animals developed convulsions after being treated with scopolamine (60%) or the selective M1 receptor antagonist pirenzepine (10mg/kg; 20% and 60mg/kg; 70%) and given food. Fasting increased expression of M1 receptors in the frontal cortex and M2 receptors in the hippocampus, but produced no change in the expression of both receptors in the amygdaloid complex. Food intake after fasting decreased M1 receptor expression in the frontal cortex and M1 and M2 receptor expression in the hippocampus. Seizure severity was uncorrelated with muscarinic receptor expression in the brain regions. Taken together, these findings provide evidence for the role of M1 muscarinic receptor antagonism and fasting-induced increases in M1 and M2 expression possible underlying mechanism in the occurrence of convulsions in fasted animals.

Background: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus(®)). Methods: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV(1)) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler(® )DPI. Results: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV(1), 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV(1) from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV(1) < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3—91.9) mL in trough FEV(1) and 103.5 (7.7—199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV(1) in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV(1) < 50% predicted populations. Conclusions: Revefenacin did not produce significant improvements in FEV(1) versus tiotropium in the ITT population, but increased trough FEV(1) in patients with FEV(1) < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456)

Background: A single long-acting bronchodilator, ultra-long acting muscarinic antagonist (ultra-LAMA) or ultra-long acting β2-agonist (ultra-LABA) is preferred for the initial treatment of patients with chronic obstructive pulmonary disease (COPD); however, there are few head-to-head comparative studies between the two. Here, a meta-analysis of randomized controlled trials was performed to compare the clinical efficacy between ultra-LABA and ultra-LAMA in patients with moderate-to-severe COPD. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched (to March 1, 2017) to identify all published randomized controlled trials. Results: Of the 12,906 articles found by searching the databases, we obtained data from 10,591 patients with COPD (LABA, n=5,058; LAMA, n=5,533) in seven published studies. Our results showed that COPD exacerbation were significantly lower in patients taking ultra-LAMA than those taking ultra-LABA (odds ratio =0.857, P=0.0008). However, no significant differences were observed between ultra-LAMA and ultra-LABA patients regarding improvement in trough forced expiratory volume in 1 s, the transitional dyspnea index, or St. George’s Respiratory Questionnaire score. Conclusions: This study suggests that COPD exacerbation occurred less often in patients taking an ultra-LAMA than in those taking an ultra-LABA with similar efficacy of lung function and quality of life.

Keiji Oishi,1 Tsunahiko Hirano,2 Kazuki Hamada,2 Sho Uehara,2 Ryo Suetake,2 Yoshikazu Yamaji,2 Kosuke Ito,2 Maki Asami-Noyama,2 Nobutaka Edakuni,2 Kazuto Matsunaga2 1Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan; 2Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan Purpose: The 2017 GOLD ABCD classification shifts patients from groups C–D to A–B. Group A was the most widely distributed group in several studies. It would be useful to understand the characteristics for group A patients, but little has been reported concerning these issues. Patients and methods: This was a multicenter cross-sectional study using the COPD Assessment in Practice study database from 15 primary or secondary care facilities in Japan. We investigated the clinical characteristics of group A by stratification according to a mMRC grade 0 or 1. Results: In 1,168 COPD patients, group A patients accounted for approximately half of the patients. Compared with the groups B–D, group A was younger and had a higher proportion of males, higher pulmonary function, and higher proportion of monotherapy with long-acting muscarinic antagonist or long-acting β-agonist. The prevalence of mMRC grade 1 patients was about two-thirds of group A. Compared with the mMRC 0 patients, mMRC 1 patients showed a tendency to have a higher proportion of exacerbations (P=0.054) and had a significantly lower pulmonary function. Regardless of the mMRC grade, 60% of group A patients were treated with monotherapy of long-acting muscarinic antagonist or long-acting β-agonist. Conclusion: Group A patients accounted for approximately half of the patients, and they were younger, had higher pulmonary function, and had lower pharmacotherapy intensity compared with groups B–D. By stratifying according to the mMRC grade 0 or 1 in group A patients, there were differences in the exacerbation risk and airflow limitation. Keywords: COPD, GOLD, mMRC, exacerbation

Objective: We aimed at comparing the effectiveness of long acting β-agonist+long acting muscarinic antagonist (LABA+LAMA) versus both LABA+inhaled corticosteroid (ICS) and LAMA+ICS in non- asthmatic patients with moderate to severe COPD. In addition, we aimed at assessing the changes occur in plasma concentrations of TNF-α, fibrinogen and IL-6 with the disease activity. Methods: In this pilot study, 45 non-asthmatic patients with moderate to severe COPD were randomized into three groups; group I (LABA+ICS) received Formoterol/Budesonide, group II (LAMA+ICS) received Tiotropium/Budesonide and group III (LABA+LAMA) received Formoterol/Tiotropium for twelve weeks. The patients were assessed at baseline, four and twelve weeks after therapeutic intervention through evaluating the changes occur in FEV1 % predicted, mMRC dyspnea scale and plasma concentrations of TNF-α, fibrinogen and IL-6. Results: At baseline, the study groups were statistically similar with respect to demographic data and disease characteristics. All study therapeutic options produced an improvement in FEV1 % predicted and mMRC dyspnea scale which was associated with a reduction in plasma concentrations of the inflammatory markers. The effects produced by the three therapeutic combinations on FEV1 % predicted, plasma TNF-α, IL-6 and fibrinogen concentrations were statistically similar (four weeks after treatment; p=0.358, p=0.284, p=0.155, p=0.155 respectively) and (twelve weeks after treatment: p=0.710, p=0.773, p=0.240, p=0.076 respectively). Conclusion: In non-asthmatic patients with moderate to severe COPD, the three therapeutic combinations showed similar effectiveness. Furthermore, the results of this pilot study suggest that, inflammatory markers can be used to follow the disease activity.

Introduction and Objectives Persistent airflow limitation (PAL) predicts a positive clinical response to add-on long acting muscarinic antagonist in patients with asthma taking inhaled corticosteroids and long-acting β2-receptor agonists. We conducted a post-hoc analysis of the TRIGGER study to evaluate the effect of extrafine BDP/FF/G vs BDP/FF on asthma control and the use of systemic corticosteroids for asthma exacerbations in a subset of patients with PAL. Methods TRIGGER was a phase III, randomized, parallel group trial comparing 52-week treatment with BDP/FF/G 200/6/10µg two inhalations twice daily (BID) to BDP/FF 200/6µg BID and an open-label treatment arm consisting of BDP/FF 200/6µg BID plus tiotropium (BDP/FF+Tio). PAL criteria were a post-bronchodilator FEV1≤80% of predicted normal and FEV1/FVC≤0.7; ACQ-7 response was defined as a change from baseline in ACQ-7 score ≤-0.5 unit, and asthma control days as asthma symptom-free day without using rescue medication. Results 1437 subjects were randomized and 61.2% met the PAL criteria. In this subgroup, there was a significantly higher percentage of ACQ-7 responders on BDP/FF/G compared to BDP/FF at week 26 (60.2% vs 49.4%) and week 52 (60.8% vs 51.7%). In the overall population, the difference in the percentage of ACQ-7 responders was 61.3% vs 55.9% at week 26 and 62.3% vs 58.1% at week 52, for BDP/FF/G and BDP/FF respectively. In patients with PAL, the change from baseline in the asthma control days over 52 weeks was higher in BDP/FF/G compared to BDP/FF (14.5% vs 8.8%), with a smaller difference observed in the overall population (Table 1). Patients treated with BDP/FF/G had less days of systemic corticosteroid use for asthma exacerbations compared to BDP/FF in the PAL subpopulation (34.1% reduction; RR=0.659, 95%CI (0.389–1.118) p=0.122), and in the overall population (24.4% reduction; RR=0.756, 95%CI (0.499–1.145) p=0.186), although not statistically significant. Conclusions In adult asthmatics with PAL, treatment with high ICS dose extrafine BDP/FF/G compared to BDP/FF was associated with greater odds of experiencing asthma control and a higher trend towards a decreased use of systemic corticosteroids for asthma exacerbations, compared to the overall population.

Restraint stress (RS) is an unavoidable stress model that triggers activation of the autonomic nervous system, endocrine activity, and behavioral changes in rodents. Furthermore, RS induces secretion of oxytocin into the bloodstream, indicating a possible physiological role in the stress response in this model. The presence of oxytocin receptors in vessels and heart favors this possible idea. However, the role of oxytocin secreted in RS and effects on the cardiovascular system are still unclear. The aim of this study was to analyze the influence of oxytocin on cardiovascular effects during RS sessions. Rats were subjected to pharmacological (blockade of either oxytocin, vasopressin, or muscarinic receptors) or surgical (hypophysectomy or sinoaortic denervation) approaches to study the functional role of oxytocin and its receptor during RS. Plasma levels of oxytocin and vasopressin were measured after RS. RS increased arterial pressure, heart rate, and plasma oxytocin content, but not vasopressin. Treatment with atosiban (a Gi biased agonist) inhibited restraint-evoked tachycardia without affecting blood pressure. However, this effect was no longer observed after sinoaortic denervation, homatropine (M2 muscarinic antagonist) treatment or hypophysectomy, indicating that parasympathetic activation mediated by oxytocin secreted to the periphery is responsible for blocking the increase in tachycardic responses observed in the atosiban-treated group. Corroborating this, L-368,899 (oxytocin antagonist) treatment showed an opposite effect to atosiban, increasing tachycardic responses to restraint. Thus, this provides evidence that oxytocin secreted to the periphery attenuates tachycardic responses evoked by restraint via increased parasympathetic activity, promoting cardioprotection by reducing the stress-evoked heart rate increase.

Dear Editors, We read with interest the recent network meta-analysis of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) in chronic obstructive pulmon...

Background and Objectives Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration–time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies. Methods Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22–700 μg in 935 patients (488 men, 447 women; age 41–88 years) were analyzed using nonlinear mixed-effects modeling. Results Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration–time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518. Conclusions None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease. Registration ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510 Electronic supplementary material The online version of this article (10.1007/s40262-020-00938-3) contains supplementary material, which is available to authorized users.

Chronic obstructive pulmonary disease (COPD) is a medical condition characterised by persistent respiratory symptoms and airflow limitation. For the long-term management of COPD, inhaled therapies are the main approach to maintenance treatment. In order to improve treatment efficacy and tolerability for patients with COPD, recent clinical trials have focused on the withdrawal of inhaled corticosteroids (ICSs), the use of which has been associated with adverse outcomes, including pneumonia. In this case report, a patient with Global Initiative for Chronic Obstructive Lung Disease grade 3 COPD was switched from a combined inhaled therapy of a long-acting beta-agonist (LABA) and ICS to a combination of a LABA and a long-acting muscarinic antagonist (tiotropium/olodaterol) during hospitalisation for an acute exacerbation of COPD in April 2016. He was subsequently maintained in a stable condition, and was able to live and travel independently. This case report of successful ICS withdrawal suggests that, for moderate-to-severe COPD, if it is assessed individually, dual therapy of LABA and long-acting muscarinic antagonist can be highly effective and well-tolerated. Treatment compliance and lifestyle modifications have been shown to be critical in optimising treatment outcomes.

Dear Editor, The recent studies on combination triple therapy of inhaled corticosteroid, long acting beta2 agonist and long-acting muscarinic antagonist (ICS-LABA-LAMA) in COPD have consistently demonstrated an improvement in exacerbation frequency and/or improvement of lung function...

Introduction: LAMAs reduce the severity of daily symptoms such as dyspnoea. The potential impact of LAMAs on the physical activity (PA), sedentary time (ST) and sleep of people living with COPD is unclear. Aim: To determine changes in PA, ST and sleep after starting LAMA therapy versus usual care. Methods: Patients with moderate-severe COPD were recruited and randomised to 6 weeks of LAMA or Usual Care (UC) (or PR). SenseWear-derived steps, ST (≤1.5METs), light PA (>1.5 Results: Data from 33 patients in the LAMA group and 14 in Control group (70% male, age 67±8 years, 51% GOLD II) were analysed. No changes in PA, ST or SD were observed for either group (Fig 1). LAMA group experienced no change in NDSB whilst controls increased NDSB (LAMA: 1.2±1.4 versus 1.1±1.5 NDSB and UC: 0.7±0.9 versus 1.8±1.7 NDSB; interaction p=0.018) with no other changes in sleep outcomes. Conclusion: A six-week LAMA intervention reduced the NDSB but did not change time spent in 24-hour physical behaviours or other sleep quality outcomes.

Tiotropium bromide is a long-acting muscarinic antagonist (LAMA) and is the only LAMA licensed for management for patients’ ≥6 years old with severe asthma who have experienced one or more severe asthma exacerbations in the preceding year. Recent clinical trials have demonstrated that once-daily tiotropium is safe and efficacious in 6–17 year-olds with symptomatic asthma despite treatment with inhaled corticosteroids (ICSs), with or without additional controllers. In this paper, we review the evidence of the safety and efficacy of tiotropium add-on maintenance treatment in children and adolescents with symptomatic moderate and severe asthma.

Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress., Graphical abstract Image 1, Highlights • Activation of PPG neurons triggers increases in heart rate in mice. • PPG neurons do not provide a tonic sympathetic drive to the heart. • The tachycardic effect of systemic Ex-4 is not mediated by PPG neurons. • GLP-1 receptor activation has a sympathoexcitatory effect that increases heart rate. • Local activation of GLP-1R in the spinal cord is sufficient to elicit tachycardia.

Background Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV1) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD. Methods A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV1, St. George’s Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 μg and placebo: severe and very severe airflow limitation (percent predicted FEV1 30%–1) to short-acting bronchodilators, concurrent use of long-acting β agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors. Results Revefenacin demonstrated significant improvements in FEV1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years. Conclusions Revefenacin showed significantly greater improvements in FEV1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD. Trial registration Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

BACKGROUND Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS 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. RESULTS 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

Brian J Lipworth,1 David J Collier,2 Yasuhiro Gon,3 Nanshan Zhong,4 Koichi Nishi,5 Rongchang Chen,4 Samir Arora,6 Andrea Maes,7 Shahid Siddiqui,8 Colin Reisner,7,8 Ubaldo J Martin8 1Scottish Centre for Respiratory Research, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK; 2William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 3Itabashi Hospital, Nihon University School of Medicine, Itabashi, Tokyo, Japan; 4Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Diseases, National Clinical Research Center of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa, Japan; 6Aventiv Research Inc., Columbus, OH, USA; 7Pearl – a member of the AstraZeneca group, Morristown, NJ, USA; 8AstraZeneca, Gaithersburg, MD, USA Background: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD. Methods: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6µg, glycopyrrolate (GP) MDI 18µg, formoterol fumarate (FF) MDI 9.6µg, or placebo MDI (all twice daily) for 24weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed. Results: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72mL, respectively; all P

Rationale The DYNAGITO trial investigated the effect of bronchodilation on exacerbation rate in patients with COPD. The observed rates were 0.90 per patient-year with tiotropium/olodaterol (T/O) and 0.97 per patient-year with tiotropium alone (Tio) (rate ratio 0.93; 99% confidence interval 0.85–1.02; P=0.0498). We investigated whether the effect on exacerbation rate was the same across patients with varying degrees of baseline airflow limitation. Methods DYNAGITO was a 52-week, double-blind trial in which patients with COPD were randomized (1:1) to receive T/O 5/5µg or Tio 5µg once daily, delivered via Respimat® (NCT02296138). Patients continued to take inhaled corticosteroids (ICS) if receiving them at baseline. Inclusion criteria included post-bronchodilator FEV1 Results Overall, there were 2,784 patients classed as GOLD 2, 4,039 GOLD 3 and 992 GOLD 4. Baseline COPD treatment differed by GOLD stage. More patients were receiving a long-acting muscarinic antagonist (LAMA) only or LAMA/long-acting β2-agonist (LABA) in GOLD 2 (12.6% and 13.4%) than GOLD 3 (7.5% and 12.0%) or 4 (5.6% and 8.4%), while fewer patients were receiving LAMA/LABA/ICS in GOLD 2 (32.6%) than in GOLD 3 (42.8%) or 4 (47.7%). T/O reduced the exacerbation rate compared with Tio in GOLD 2 and 3 patients, but not in GOLD 4 patients (figure 1). Conclusion The results demonstrate that improving bronchodilation with T/O reduced the exacerbation rate compared with Tio in patients with GOLD 2 and 3 COPD. The lack of effect of bronchodilators in the most severely limited patients has been reported previously (Wedzicha et al. N Engl J Med 2016;374:2222–34) and may reflect the complex contributors to airflow obstruction in very severe COPD.

An impact of acute exacerbation of COPD (AECOPD) on the course and the prognosis of chronic obstructive pulmonary disease depends on severity of the exacerbation. Moderate and severe exacerbations are considered as clinically significant events. Clinical studies investigating a role of inhalational therapy for the risk of AECOPD differed significantly in important parameters and the patients involved were not fully described in the real clinical practice. Tiotropium alone did not demonstrate any benefit over other inhalational therapies, such as inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combinations and long-acting muscarinic antagonist (LAMA)/LABA combinations, for risk reduction of moderate to severe exacerbations. A benefit of tiotropium/olodaterol combination over tiotropium for the reduction of risk of clinically significant exacerbations was first shown in DYNAGITO study; patients’ groups in this study did not differ in a rate and a spectrum of adverse events including cardiovascular events. An efficient bronchodilating therapy should be administered to all patients with COPD as it could improve dyspnea and prevent exacerbations. Further escalation of treatment in patients with frequent exacerbations of COPD should be personalized according to clinical course and causes of AECOPD.

Background: Long-acting muscarinic antagonist (LAMA) tiotropium improved lung function and reduced risks of exacerbation when added on to inhaled corticosteroids (ICS) with or without long-acting B2 agonists (LABAs) in patients with uncontrolled asthma. However, studies predicting the effectiveness of tiotropium based on patients’ clinical characteristics were limited. Methods: We conducted this retrospective study at a single medical center from July 2016 to July 2017, and used asthma control test (ACT) to evaluate the effectiveness of tiotropium add-on therapy in patients with uncontrolled asthma. The effectiveness was shown by an increase in ACT score from baseline of 3 or greater after 3 months of tiotropium add-on therapy. Results: Patients with uncontrolled asthma despite the use of low- or medium- to high-dose of ICS plus LABA (n=160) were analyzed. Among patients having good response (n=112, ACT score increased ≥3 points) to tiotropium (TGR group) and patients having poor response (n=48, ACT increased 30 were predictors of the effectiveness of tiotropium. Patients with high serum total IgE level >430 µg/L and eosinophil count >0.6×10 9 /L had a negative impact on response to tiotropium. Multivariate logistic regression analysis demonstrated that the independent factor of poor response to tiotropium was high serum IgE level >430 µg/L. Conclusions: Tiotropium add-on therapy in patients with uncontrolled asthma was effective. However, patients with serum total IgE level >430 µg/L were less likely to benefit from tiotropium.

Central cholinergic systems regulate the hypothalamic-pituitary-adrenal (HPA) axis differentially in males and females (sexual diergism). We previously investigated the role of muscarinic receptors in this regulation by administering physostigmine (PHYSO), an acetylcholinesterase inhibitor, to male and female rats pretreated with scopolamine (SCOP), a nonselective muscarinic antagonist. SCOP pretreatment enhanced adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses in both sexes; males had greater ACTH responses while females had greater CORT responses. In the present study, we further explored the role of muscarinic receptor subtypes in HPA axis regulation by administering PHYSO to male and female rats following SCOP or various doses of either the M1 or the M2 selective muscarinic receptor antagonists, pirenzepine (PIREN) or methoctramine (METHO), respectively. Blood sampling occurred before and at multiple times after PHYSO. ACTH and CORT were determined by highly specific immunoassays. PIREN + PHYSO resulted in sustained, dose-dependent increases in ACTH and CORT: ACTH responses were similar in both sexes, CORT responses were greater in females, and percent changes from baseline for both hormones were greater in males. METHO + PHYSO resulted in overall decreases in ACTH and CORT: ACTH and CORT responses were higher in females but lower than those caused by PIREN or SCOP in both sexes, and percent changes from baseline were lower in males. Area under the curve analyses further supported these sexually diergic effects. These results suggest that specific muscarinic receptor subtypes differentially influence the HPA axis in a sexually diergic manner.

Tiotropium, a muscarinic antagonist, is approved for the treatment of chronic obstructive pulmonary disease and poorly controlled asthma. Because mucus hypersecretion is characteristic of both of these diseases, and muscarinic agonists stimulate mucus secretion, we hypothesized that tiotropium would attenuate airway MUC5AC expression. We grew normal human bronchial epithelial (NHBE) cells to a goblet cell phenotype with 1 or 5 ng/mL of IL-13 and exposed these cells to 10 nM tiotropium or excipient for the full 14 days. Normally differentiated NHBE cells (without IL-13) were exposed to neutrophil elastase (NE) 1 × 10-7 or 5 × 10-7 M for 1 h. MUC5AC was measured by quantitative PCR and ELISA. Acetylcholine production by the epithelium was evaluated by quantitative PCR and by choline/acetylcholine quantification. Tiotropium had no effect on IL-13-stimulated MUC5AC, but attenuated MUC5AC stimulated by NE (p = 0.007 at 5 × 10-7 M). IL-13 increased CarAT mRNA (p

Introduction Acute exposure to organic dust (OD) in pig barns induces intense airway inflammation with neutrophilia and hyperresponsiveness. This reaction is likely associated with increased cholinergic activity. Therefore, the involvement of cholinergic mechanisms in the reaction to acute exposure of OD was investigated in mice using the long-acting muscarinic antagonist tiotropium . Methods BALB/c mice received tiotropium (2–200 ng) intranasally on day 1 of the study. On days 2–4, mice received vehicle or OD (25 μg) intranasally. Airway hyperresponsiveness to methacholine was assessed 24 h following the last OD exposure. Bronchoalveolar lavage (BAL) fluid, lung tissue and blood were collected for analyses. Results Organic dust elevated airway responsiveness to methacholine compared with controls (PBS) assessed as Newtonian resistance (1.5 ± 0.1 vs 0.9 ± 0.1 cm H2O x s/mL), tissue damping (12.4 ± 1.4 vs 8.9 ± 0.9 cm H2O∙s/mL) and tissue elastance (41.1 ± 5.3 vs 27.2 ± 2.5 cm H2 O∙s/mL). Tiotropium (200 ng) decreased the Newtonian resistance and tissue damping after exposure to PBS or OD. Organic dust exposure increased inflammatory cells in BAL fluid by almost 400%, mainly due to neutrophil influx, which was unaffected by tiotropium. Organic dust increased levels of mainly Th1 mediators. Tiotropium treatment attenuated OD-induced release of IL-2, IL-4 and IL-6. Conclusions Tiotropium decreased the OD-induced increase of specific cytokines without influencing the OD-induced increase of airway responsiveness and neutrophil infiltration into the lungs. We conclude that the cholinergic pathway contributes to the pro-inflammatory effects caused by inhalation of OD from pig barns.

Introduction Immediate early genes are widely used as neuronal cell activity markers in neuroscience. The present study investigated the relationship between their expression and abnormality in context fear conditioning. Methods The learning test (two-way active avoidance test) was conducted in male rats administered with nonselective muscarinic antagonist scopolamine or selective dopamine D1-like receptor antagonist SCH 23390 at a dose level of 2.0 or 0.1 mg/kg, respectively, for 4 days. Expression levels of Arc and Fos mRNA in the hippocampus and amygdala were also evaluated on the second day of dosing by fluorescent in situ hybridization (FISH) and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Results Scopolamine had no effect on avoidance rate, but decreased freezing in the two-way active avoidance test. SCH 23390 decreased avoidance rate and increased freezing. In FISH and RT-qPCR assays, scopolamine decreased Arc mRNA in the hippocampus and amygdala, whereas SCH 23390 increased Arc mRNA in the hippocampus. By contrast, scopolamine and SCH 23390 did not change Fos mRNA expression compared to Arc mRNA expression. Discussion The results of the learning test indicated that scopolamine or SCH 23390 respectively inhibited fear or context conditioning in rats. Furthermore, alteration of the expression of Arc mRNA but not of Fos mRNA in the hippocampus and amygdala of the brain was suggested to be a sensitive neuronal cell activity marker to detect behavioral abnormality in the two-way active avoidance test.

Small airways represent the key factor of chronic obstructive pulmonary disease (COPD) pathophysiology. The effect of different classes of bronchodilators on small airways is still poorly understood and difficult to assess. Hence the acute effects of tiotropium (18 µg) and indacaterol (150 µg) on closing volume (CV) and ventilation inhomogeneity were investigated and compared in 51 stable patients (aged 70 ± 7 yr, mean ± SD; 82% men) with moderate to very severe COPD. Patients underwent body plethysmography, arterial blood gas analysis, tidal expiratory flow limitation (EFL), dyspnea assessment, and simultaneous recording of single-breath N2 test and transpulmonary pressure-volume curve (PL-V), before and 1 h after drug administration. The effects produced by indacaterol on each variable did not differ from those caused by tiotropium, independent of the severity of disease, assessed according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) scale and the presence of EFL. Bronchodilators significantly decreased the slope of phase III and CV (−5 ± 4 and −2.5 ± 2.1%, respectively, both P < 0.001), with an increase in both slope and height of phase IV and of the anatomical dead space. Arterial oxygen pressure and saturation significantly improved (3 ± 3 mmHg and 2 ± 2%, respectively, both P < 0.001); their changes negatively correlated with those of phase III slope ( r = −0.659 and r = −0.454, respectively, both P < 0.01). The vital capacity (VC) increased substantially, but the PL-V/VC curve above CV was unaffected. In conclusion, bronchodilators reduce the heterogeneity of peripheral airway mechanical properties and the extent of their closure, with minor effects on critical closing pressure. This should lessen the risk of small-airway damage and positively affect gas exchange. NEW & NOTEWORTHY This is the first study investigating in stable chronic obstructive pulmonary disease patients the acute effects of two long-acting bronchodilators, a β-agonist and a muscarinic antagonist, on peripheral airways using simultaneous lung pressure-volume curve and single-breath N2 test. By lessening airway mechanical property heterogeneity, both drugs similarly reduced ventilation inhomogeneity and extent of small-airway closure, as indicated by the decrease of phase III slope, increased oxygen saturation, and fall of closing volume, often below expiratory reserve volume.

Background Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting β2-agonist formoterol fumarate (FF), and long-acting muscarinic antagonist glycopyrronium (G) is in development for asthma. Objective We sought to evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate and severe asthma exacerbations. Methods TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 score ≥1.5), prebronchodilator FEV1 less than 80% predicted, history of 1 or more asthma exacerbation, who had been receiving ICS/long-acting β2-agonist for at least 4 weeks before entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post hoc analyses, the annual moderate and severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season. Results In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the long-acting muscarinic antagonist component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [P = .0008]). Reductions in the other seasons ranged between 8.6% and 12.0%. Conclusions These post hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate and severe exacerbations, and confirm the overall utility of adding long-acting muscarinic antagonist to ICS/long-acting β2-agonist in the management of asthma.

We previously demonstrated that 3-iodothyronamine (T1AM), a by-product of thyroid hormone metabolism, pharmacologically administered to mice acutely stimulated learning and memory acquisition and provided hyperalgesia with a mechanism which remains to be defined. We now aimed to investigate whether the T1AM effect on memory and pain was maintained in mice pre-treated with scopolamine, a non-selective muscarinic antagonist expected to induce amnesia and, possibly, hyperalgesia. Mice were pre-treated with scopolamine and, after 20 min, injected intracerebroventricularly (i.c.v.) with T1AM (0.13, 0.4, 1.32 μg/kg). 15 min after T1AM injection, the mice learning capacity or their pain threshold were evaluated by the light/dark box and by the hot plate test (51.5 °C) respectively. Experiments in the light/dark box were repeated in mice receiving clorgyline (2.5 mg/kg, i.p.), a monoamine oxidase (MAO) inhibitor administered 10 min before scopolamine (0.3 mg/kg). Our results demonstrated that 0.3 mg/kg scopolamine induced amnesia without modifying the murine pain threshold. T1AM fully reversed scopolamine-induced amnesia and produced hyperalgesia at a dose as low as 0.13 μg/kg. The T1AM anti-amnestic effect was lost in mice pre-treated with clorgyline. We report that the removal of muscarinic signalling increases T1AM pro learning and hyperalgesic effectiveness suggesting T1AM as a potential treatment as a “pro-drug” for memory dysfunction in neurodegenerative diseases.

Background: The recent approval of several fixed-dose combination long-acting β2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) products has increased the use of dual bronchodilators in the treatment of chronic obstructive pulmonary disease (COPD). Understanding the comparative safety of this combination is important for informing treatment decisions. Objective: To compare the risk of cardiovascular and cerebrovascular (CCV) events associated with LABA/LAMA compared with a combination of LABA and inhaled corticosteroid (ICS). Methods: This was a retrospective, observational cohort study using health insurance claims data to identify COPD patients initiating LABA/LAMA or LABA/ICS. CCV outcomes included hospitalizations with a primary diagnosis for acute coronary syndrome, heart failure, cardiac dysrhythmia, stroke, or transient ischemic attack. Patients were followed until they experienced an event, discontinued treatment, initiated medication from the opposite cohort, or lost enrollment. Patients were matched 1:4 on propensity scores, and time to event was compared using Cox proportional hazards models. Results: After matching, there were 3842 patients in the LABA/LAMA cohort and 15 225 in the LABA/ICS cohort. Cardiovascular events in the LABA/LAMA cohort were lower than in the LABA/ICS: hazard ratio (HR) = 0.794; 95% CI = 0.623-0.997. No significant difference in the risk of cerebrovascular events (HR = 1.166; 95% CI = 0.653-1.959) was observed. Conclusions: Despite concerns about the CCV effects of LAMA and LABA monotherapy, the LABA/LAMA combination had similar or lower risk of these events in comparison to LABA/ICS. Further studies are recommended to confirm these findings.

Several long-acting bronchodilators have been developed and are widely used as first-line treatment in patients with stable chronic obstructive pulmonary disease (COPD). However, the initial choice of therapy is still uncertain. The aim of this study was to examine the clinical efficacy and safety of long-acting muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA) in patients with stable COPD. We searched several databases and manufacturers’ websites to identify relevant randomized clinical trials for meta-analysis. Outcomes of interest were trough forced expiratory volume in 1 s (FEV1), acute exacerbations, transitional dyspnoea index (TDI) score, St George's Respiratory Questionnaire (SGRQ) score and adverse events. Sixteen trials with a total of 22 872 patients were included in this study. Compared with LABA, LAMA were associated with a greater reduction in acute exacerbations (OR: 0.84, 95% CI: 0.74–0.94, P = 0.003) and fewer adverse events (OR: 0.92, 95% CI: 0.86–0.97, P = 0.005). There were no significant differences in trough FEV1, TDI and SGRQ scores. In patients with stable COPD, LAMA were associated with a greater reduction in acute exacerbations and fewer adverse effects compared with LABA.

Objective: To compare the available literature regarding the use of long-acting muscarinic antagonist (LAMA)/long-acting β2 agonists (LABA) and inhaled corticosteroid (ICS)/LABA combination inhaler therapy in chronic obstructive pulmonary disease (COPD) maintenance therapy management. Data Sources: A MEDLINE literature search from database inception to February 2017 was conducted using the search terms chronic obstructive pulmonary disease, adrenergic beta-agonist, muscarinic antagonist, and inhaled corticosteroid. References from extracted sources were further searched for any relevant, missed data sources. Study Selection and Data Extraction: All English-language randomized-controlled trials comparing LAMA/LABA and ICS/LABA combination inhaler therapy were evaluated. Data Synthesis: A total of 10 randomized controlled trials have reviewed the use of LAMA/LABA compared with ICS/LABA therapy for COPD maintenance therapy. Results of clinical trials that evaluated LAMA/LABA and ICS/LABA maintenance therapy demonstrated superior improvements in pulmonary function tests via spirometry and improved clinical outcomes with LAMA/LABA therapy, specifically reduction in COPD exacerbation rates. The safety of LAMA/LABA combination therapy also is favorable compared with ICS/LABA combination therapy because of the increased infection risk with ICS therapy. Conclusions: COPD is a disease state with significant morbidity and mortality in the United States and is the third leading cause of death. Long-acting inhalers are recommended for the majority of COPD severities, and combination therapy is typically utilized. LAMA/LABA combination therapy has demonstrated superior improvements in pulmonary function and reduction in COPD exacerbation rates compared with ICS/LABA. LAMA/LABA combination therapy will have a larger future role in COPD maintenance management.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and health care expenditure throughout the world. COPD guidelines recommend the use of long-acting muscarinic antagonist (LAMA) either alone or in combination with a long-acting β2 agonist (LABA). For over 10 years, tiotropium was the only LAMA that was used in the management of COPD. Over the past few years, various new drugs have been identified that act on the muscarinic receptors and β2 receptors. Umeclidinium (Umec) is a new LAMA currently approved for use in patients with COPD either as monotherapy or in combination with vilanterol (Vil). Both Umec alone and in combination with Vil delivered through a multi-dose dry powder Ellipta™ device have shown improvement in lung function, health-related quality of life and exacerbation frequency in patients with COPD. This review provides an overview of the pharmacology, pharmacodynamics and pharmacokinetics of Umec, and evaluates the clinical efficacy and safety studies in patients with COPD.

Gustavo J Rodrigo,1 David Price,2,3 Antonio Anzueto,4,5 Dave Singh,6 Pablo Altman,7 Giovanni Bader,8 Francesco Patalano,8 Robert Fogel,7 Konstantinos Kostikas8 1Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; 2Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, UK; 3Observational and Pragmatic Research Institute, Singapore; 4University of Texas Health Science Center, 5South Texas Veterans Health Care System, San Antonio, TX, USA; 6Medicines Evaluation Unit, National Institute for Health Research Respiratory and Allergy Clinical Research Facility, University Hospital of South Manchester NHS Foundation Trust, University of Manchester, Manchester, England, UK; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 8Novartis Pharma AG, Basel, Switzerland Background: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD. Methods: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks’ LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07L and 0.08L, P100mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George’s Respiratory Questionnaire scores at week 12 versus LAMA (both P

The effects of tiotropium, an inhaled long-acting muscarinic antagonist, on lung function were investigated in current smokers and nonsmokers with asthma treated with inhaled corticosteroids (ICSs) and other asthma controllers: inhaled long-acting β 2 agonists, leukotriene receptor antagonists, and/or theophylline. We conducted a double-blind, placebo-controlled study of an inhaled single dose of tiotropium in 9 asthmatics currently smoking and 9 asthmatics who have never smoked in a crossover manner. Lung function was measured before and 1, 3, and 24 h after inhalation of 18 μg of tiotropium or a placebo. The primary outcome was a change in forced expiratory volume in 1 s (FEV 1 ) from the baseline, and the secondary outcomes were changes in peak expiratory flow rate (PEFR), V ˙ 50 , and V ˙ 25 . At baseline, asthmatics with and without a smoking history had a mean FEV 1 of 2590 ml and 2220 ml and were taking a mean dose of ICSs of 1208 and 1000 μg/day, respectively. The increase from the baseline FEV 1 was 169 ml and 105 ml higher at 3 h after tiotropium than after the placebo in current smokers and nonsmokers, respectively. PEFR, V ˙ 50 , and V ˙ 25 were also significantly increased after tiotropium as compared with the placebo in both study groups. Changes in FEV 1 and PEFR tended to be greater in asthmatics currently smoking than in subjects who have never smoked, although there were no statistical differences at any time points. Tiotropium resulted in improved lung function and symptoms both in current smoker and nonsmoker asthmatics. These findings suggest that tiotropium will provide a new strategy for the treatment of bronchial asthma.

Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem; inspiration driven by a neuronal network located in the preBotzinger Complex (preBotC) and expiration driven by a neuronal network located in the paraFacial Respiratory Group (pFRG). While continuous activity of the preBotC is necessary for maintaining ventilation, the pFRG behaves as a conditional expiratory oscillator, being silent in resting conditions and becoming rhythmically active in presence of increased respiratory drive (e.g., hypoxia, hypercapnia, exercise, or through release of inhibition). Recent evidence from our laboratory suggests that expiratory activity in the principal expiratory pump muscles, the abdominals, is modulated in a state-dependent fashion, frequently occurring during periods of REM sleep. We hypothesised that acetylcholine, a neurotransmitter released in wakefulness and REM sleep by mesopontine structures, contributes to the activation of pFRG neurons and thus acts to promote the recruitment of expiratory abdominal muscle activity. We investigated the stimulatory effect of cholinergic neurotransmission on pFRG activity and recruitment of active expiration in vivo under anaesthesia. We demonstrate that local application of the acetylcholinesterase inhibitor physostigmine into the pFRG potentiated expiratory activity. Furthermore, local application of the cholinomimetic carbachol into the pFRG activated late expiratory neurons and induced long lasting rhythmic active expiration. This effect was completely abolished by pre-application of the muscarinic antagonist scopolamine, and more selective M3 antagonists 4DAMP and J104129. We conclude that cholinergic muscarinic transmission contributes to excitation of pFRG neurons and promotes both active recruitment of abdominal muscles and active expiratory flow. This article is protected by copyright. All rights reserved

Marco Contoli,1 Paolo Solidoro,2 Fabiano Di Marco,3,4 Nicola Scichilone,5 Angelo Corsico,6 Fulvio Braido,7 Pierachille Santus4,8 1Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 2Cardiovascular and Thoracic Department, Città della Salute, Turin, Italy; 3Department of Health Sciences, University of Milan, Milan, Italy; 4Respiratory Unit, San Paolo Hospital, Milan, Italy; 5Department of Internal Medicine, Section of Pulmonology (DIBIMIS), University of Palermo, Palermo, Italy; 6Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 7Allergy and Respiratory Diseases Clinic, DIMI, University of Genoa, IRCS AOU San Martino-IST, Genoa, Italy; 8Pulmonary Rehabilitation Unit, Fondazione Salvatore Maugeri, Scientific Institute of Milan-IRCCS, Milan, Italy Abstract: The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. Keywords: COPD, quality of life, daily symptoms, LAMA, aclidinium

This article contains information on the experimental design and methods on how the safety and tolerability data concerning patients with moderate to very severe chronic obstructive pulmonary disease (COPD) were obtained. This is in addition to our original research article. [1] We have also provided information on the clinical laboratory tests that were conducted.Further interpretation and discussion of the data are demonstrated in the article “Revefenacin, a Once-daily, Lung-selective, Long-acting Muscarinic Antagonist for Nebulized Therapy: Safety and Tolerability Results of a 52-week Phase 3 Trial in Moderate to Very Severe Chronic Obstructive Pulmonary Disease.” [1] Keywords: Chronic obstructive pulmonary disease, COPD, Long-acting muscarinic antagonist, Nebulization, Revefenacin