Long-acting Muscarinic Receptor Antagonist Research Articles

Incremental long-term benefit of drug therapies for chronic obstructive pulmonary disease in quality of life but not mortality: a network meta-analysis

IntroductionThe latest evidence revealed that dupilumab, an interleukin-4 (IL-4) and interleukin-13 (IL-13) blocker, significantly reduces the exacerbation risk in patients with chronic obstructive pulmonary disease (COPD). The efficacy of dupilumab compared with conventional inhaled drugs remains incompletely determined. This study aimed to investigate the comparative efficacy of dupilumab and conventional inhaled drugs in patients with stable COPD.Material and methodsThis study retrieved randomised clinical trials (RCTs) with follow-up ≥ 48 weeks on long-acting β-agonists (LABAs), long-acting muscarinic receptor antagonists (LAMAs), inhaled corticosteroids (ICSs), and dupilumab in the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases. The information on eligible studies was extracted after the screening. The comparative efficacy of 4 drugs and their combinations in acute exacerbation and mortality was assessed using Bayesian network meta-analysis models.ResultsThis network meta-analysis identified 69 eligible RCTs on 7 classes of drug therapies after stepwise screening and included 125,331 COPD patients. Compared with placebo, the 7 drug interventions significantly reduced the risk of acute exacerbation, and the reduction degree increased with the incremental use of drug classes. ICS/LABA/LAMA/dupilumab was the most effective in decreasing exacerbation risk (OR = 0.561 [95% CI: 0.387–0.810]), followed by ICS/LABA/LAMA (OR = 0.717 [95% CI: 0.626–0.817]). The 7 drug therapies were not significantly associated with a lower risk of death compared to placebo. Nevertheless, ICS/LABA/LAMA/dupilumab is the most likely to be effective in decreasing mortality.ConclusionsThe incremental use of combinations of conventional and novel drugs contributed to the long-term benefits in acute exacerbation but not death in COPD. The optimal drug combination in terms of acute COPD exacerbation was ICS/LABA/LAMA/dupilumab.

Individual approach in the treatment of occupational chronic obstructive pulmonary disease

Introduction. Occupational COPD (PCODD) is characterized by partially irreversible airflow limitation, the phenomenon of "air traps" and the formation of emphysema, has a steadily progressive character. In the work of a practitioner, an individual approach to the patient with targeted pharmacotherapy using new combinations in the treatment of occupational COPD is important, taking into account the evaluation of the effectiveness of previous therapy.
 The study aims to evaluate the effectiveness of therapy with combined bronchodilators in PCOPD with an analysis of the dynamics of functional parameters, exercise tolerance, using additional criteria for differential diagnosis.
 Material and methods. The effectiveness of bronchodilator therapy was analyzed in 45 men, diagnosed with occupational COPD (PCODD). Additional differential diagnostics included the following informative indicators: instantaneous volumetric velocity after exhalation 75 FVC (MOS75); cough intensity according to the CAT questionnaire (1 point); ratio of forced vital capacity to forced expiratory volume in 1 minute (FVC/FEV1); 6MWT data, % predicted; 6MWT, m; overall score on the mMRС questionnaire; the severity of shortness of breath according to the CAT questionnaire (point 4); instantaneous volumetric velocity after exhalation 25 FVC (MOS25). The discriminant equation is represented by the formula: F=–9,76+0,75×a1–2,00×a2–0,19×a3+0,27×a4–0,11×a5+1,22×a6+3,62×a7+2,22×a8.
 Results. Two clinical trials were retrospectively analyzed using combined bronchodilator therapy with long-acting muscarinic receptor antagonists (LAA) and β2-agonists (LAA) in patients with PCOD. A group of patients was identified where a statistically significant improvement in clinical and functional parameters was not achieved against the background of the therapy. When to the group of occupational bronchial asthma (OBA). When conducting an individual analysis of indicators, it was found that for patients with PCOD during bronchodilator therapy, an improvement in spirometric parameters is characteristic, in particular, an increase in FEV1 and FVC; Significant reduction in symptoms of shortness of breath, cough, sputum. Whereas, the PBA group was characterized only by an improvement in the distance traveled in 6MWT.
 Conclusion. Our earlier clinical studies on the effectiveness of treatment of patients with PCOD with combined bronchodilator therapy showed the effectiveness of this therapy in 70–75% of the patients examined. An individual analysis of the clinical and functional parameters of the examined patients made it possible to identify the features of the course of occupational bronchopulmonary pathology, with the identification of individuals who need the use of a triple combination of LABA, LAAA with the addition of topical glucocorticosteroids. In this regard, all patients, as part of diagnostic measures, in addition to the standard examination, it is necessary to include 6MWT, BPG, questionnaires using mMRС and CAT questionnaires. Calculation of discriminant equations using data from spirometry, questionnaires, 6MWT and BPG will allow at the first stage of differential diagnosis to identify a group of patients for whom "triple" therapy is the means of choice.
 Ethics. The study was carried out in accordance with the ethical principles of the Declaration of Helsinki. The Clinical Study Protocol was reviewed at a meeting of the local Ethics Committee East-Siberian Institute of Medical and Ecological Research.

Cardiovascular Events with the Use of Long-Acting Muscarinic Receptor Antagonists: An Analysis of the FAERS Database 2020–2023

PurposeThis study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS).MethodsA retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio.ResultsCompared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports.ConclusionOur study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug’s safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue.

Aerosol Plumes of Inhalers Used in COPD.

The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient's inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs). High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting β2-agonists, with or without an inhaled corticosteroid. Measurements were taken in triplicate at experimental flow rates of 30, 60, and 90 l/min. Optimal flow rates were defined based on pharmacopoeial testing requirements: 30 l/min for pMDIs and SMIs, and the rate achieving a 4-kPa pressure drop against internal inhaler resistance for DPIs. Comparison of aerosol plumes was based on the experimental flow rates closest to the optimal flow rates. The Respimat SMI had the slowest plume velocity (0.99 m/s) and longest spray duration (1447 ms) compared with pMDIs (velocity: 3.65-5.09 m/s; duration: 227-270 ms) and DPIs (velocity: 1.43-4.60 m/s; duration: 60-757 ms). With increasing flow rates, SMI aerosol duration was unaffected, but velocity increased (maximum 2.63 m/s), pMDI aerosol velocity and duration were unaffected, and DPI aerosol velocity tended to increase, with a more variable impact on duration. Aerosol characteristics (velocity and duration of aerosol plume) vary by inhaler type. Plume velocity was lower and spray duration longer for the SMI compared with pMDIs and DPIs. Increasing experimental flow rate was associated with faster plume velocity for DPIs and the SMI, with no or variable impact on plume duration, whereas pMDI aerosol velocity and duration were unaffected by increasing flow rate.

Delphi Consensus on Clinical Applications of GOLD 2023 Recommendations in COPD Management: How Aligned are Recommendations with Clinical Practice?

The objective of this Delphi study was to understand and assess the level of consensus among respiratory experts on the clinical application of GOLD 2023 recommendations in management of patients with chronic obstructive pulmonary disease (COPD). The study comprised two online surveys and a participant meeting with 34 respiratory experts from 16 countries. Responses of 73 questions were recorded using a Likert scale ranging from 0 (disagreement) to 9 (agreement). The consensus threshold was 75%. Survey 1 and survey 2 had 34 and 32 participants, respectively; and 25 attended the participant meeting. Consensus was reached on survey 1: 28/42; survey 2: 18/30 close-ended questions. A consensus was reached on the clinical relevance of most updates in definitions and diagnosis of COPD. Mixed results for the treatment recommendations by GOLD were noted: 74% agreed with the recommendation to initiate treatment with dual bronchodilators for group E patients; 63% agreed for including inhaled corticosteroids (ICS)/long-acting β2 agonist(LABA)/ Long-acting muscarinic receptor antagonists (LAMA) as a treatment option for GOLD B patients. Also, consensus lacked on removing ICS + LABA as an initial therapeutic option, in countries with challenges in access to other treatment option;. 88% agreed that they use GOLD recommendations in their daily clinical practice. This Delphi study demonstrated a high level of consensus regarding key concepts of GOLD 2023 report, with most participants favoring recent updates in definitions, diagnosis, management, and prevention of COPD. More evidence on the etiotype based management and treatment options for group B and E are required which could further strengthen clinical application of the GOLD report.

Investigation of aclidinium bromide degradation by stability-indicating HPLC methods, characterization of impurities by NMR, and identification of degradation products by LC-MS

Aclidinium bromide (ACL) is a long-acting muscarinic receptor antagonist used for the long-term treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the degradation of aclidinium bromide under stress and stability testing conditions, for which we developed and validated the first stability-indicating, specific, precise, accurate, and robust assay and related substances HPLC methods. Nine of the compounds used as reference standards were synthesized and fully characterized by 1H and 13C NMR, MS, and FTIR techniques. Two of these molecules, namely ACL-dimer and ACL-desphenyl, are novel compounds and reported herein for the first time. Hydrolysis of aclidinium resulted in major degradation via the formation of ACL-desDTG and DTGA metabolites. ACL-desphenyl and phenol were observed only under oxidative conditions at very low levels (< 0.10%), while ACL-hydroxy, known as a metabolite of aclidinium and confirmed by LC/QDa and LC/Q-TOF m/z data, formed under oxidative stress-testing conditions, UV light, and daylight. The identification of two impurities formed only when aclidinium bromide was treated with hydrogen peroxide was done by LC/QDa and LC/Q-TOF studies and the novel structures were proposed as ACL-bromophenoxy and ACL-bromothiophenyl formed via bromination of the phenyl and thiophene ring on the aclidinium, respectively. The stress and photostability testing studies showed that the aclidinium bromide drug substance is not sensitive to elevated temperature (105 °C, 10 days), slightly sensitive to daylight and UV-radiation, and it showed significant degradation under all hydrolysis and oxidizing conditions. The related substances HPLC method reported herein is also capable to monitor the potential genotoxic impurity 3-bromopropoxybenzene (3-BPB), a class 2 impurity according to ICH M7, and ensures that the impurity remains below the threshold of toxicological concern (TTC) limit, making it safe for patients.

Pharmacokinetics, Mass Balance, Tissue Distribution and Metabolism of [14C]101BHG-D01, a Novel Muscarinic Receptor Antagonist, in Rats.

101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 μCi/kg). Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.

Risk Factors for Recurrent Exacerbations in the General-Practitioner-Based Swiss Chronic Obstructive Pulmonary Disease (COPD) Cohort.

Patients with chronic obstructive pulmonary disease (COPD) often suffer from acute exacerbations. Our objective was to describe recurrent exacerbations in a GP-based Swiss COPD cohort and develop a statistical model for predicting exacerbation. COPD cohort demographic and medical data were recorded for 24 months, by means of a questionnaire-based COPD cohort. The data were split into training (75%) and validation (25%) datasets. A negative binomial regression model was developed using the training dataset to predict the exacerbation rate within 1 year. An exacerbation prediction model was developed, and its overall performance was validated. A nomogram was created to facilitate the clinical use of the model. Of the 229 COPD patients analyzed, 77% of the patients did not experience exacerbation during the follow-up. The best subset in the training dataset revealed that lower forced expiratory volume, high scores on the MRC dyspnea scale, exacerbation history, and being on a combination therapy of LABA + ICS (long-acting beta-agonists + Inhaled Corticosteroids) or LAMA + LABA (Long-acting muscarinic receptor antagonists + long-acting beta-agonists) at baseline were associated with a higher rate of exacerbation. When validated, the area-under-curve (AUC) value was 0.75 for one or more exacerbations. The calibration was accurate (0.34 predicted exacerbations vs 0.28 observed exacerbations). Nomograms built from these models can assist clinicians in the decision-making process of COPD care.

Development and validation of LC-MS/MS methods for the quantification of 101BHG-D01, a novel, long-acting and selective muscarinic receptor antagonist, and its main metabolite M6 in human plasma, urine and feces: Application to a clinical study in healthy Chinese subjects

101BHG-D01 is a novel, long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD) and rhinorrhea in rhinitis. To support its clinical study, several liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the quantification of 101BHG-D01 and its main metabolite M6 in human plasma, urine and feces were developed. The plasma samples were prepared by protein precipitation, and the urine and fecal homogenate samples were pretreated by direct dilution, respectively. The chromatographic separation was performed on an Agilent InfinityLab Poroshell 120 C18 column with 0.1% formic acid and 10.0 mM ammonium acetate buffer solution in water and methanol as the mobile phase. The MS/MS analysis was performed by using multiple reaction monitoring (MRM) under a positive ion electrospray ionization mode. The methods were validated with regards to selectivity, linearity, lower limit of quantitation (LLOQ), accuracy and precision, matrix effect, extraction recovery, dilution integrity, batch size, carryover and stability. The calibration ranges were as follows: 1.00–800 pg/mL for 101BHG-D01 and 1.00–20.0 pg/mL for M6 in plasma; 0.0500–20.0 ng/mL for 101BHG-D01 and M6 in urine; 0.400–400 ng/mL for 101BHG-D01 and 0.100–100 ng/mL for M6 in feces. There was no endogenous or cross interference observed at the retention time of the analytes and internal standard in various biological matrices. Across these matrices, for the lower limit of quantitation quality control (LLOQ QC) samples, the intra- and inter-batch coefficients of variation were within 15.7%. For other QC samples, the intra- and inter-batch coefficients of variation were within 8.9%. The intra- and inter-batch accuracy deviations for all QC samples were within the range of − 6.2–12.0%. No significant matrix effect was observed from the matrices. The extraction recoveries of these methods at different concentrations were consistent and reproducible. The analytes were stable in different matrices under various storage conditions. The other bioanalytical parameters were also fully validated and met the criteria given in the FDA guidance. These methods were successfully applied to a clinical study in healthy Chinese subjects after a single dose administration of 101BHG-D01 inhalation aerosol. After inhalation, 101BHG-D01 was absorbed into plasma rapidly with the time to reach the maximum drug concentration (Tmax) of 5 min and eliminated slowly with a half-life time about 30 h. The cumulative urinary and fecal excretion rates revealed 101BHG-D01 was mainly excreted in feces, rather than urine. The pharmacokinetic results of the study drug laid a foundation for its further clinical development.

Pharmacokinetics, metabolite profiling, safety, and tolerability of inhalation aerosol of 101BHG-D01, a novel, long-acting and selective muscarinic receptor antagonist, in healthy Chinese subjects.

101BHG-D01 is a novel, long-acting, selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD). A single-site, randomized, double-blind, placebo-controlled and dose-escalation study of 101BHG-D01 inhalation aerosol was conducted to evaluate its pharmacokinetics, metabolite profiling, safety and tolerability following the single inhaled doses ranged from 20 to 900μg in healthy Chinese subjects. After inhalation, 101BHG-D01 was absorbed rapidly into plasma with the time to maximum concentration about 5min, and eliminated slowly with the terminal phase half-life about 30h. The cumulative excretion rates of 101BHG-D01 in feces and urine were about 30% and 2%, respectively, which showed the study drug was mainly excreted in feces. The maximum drug concentration and area under the plasma concentration-time curve increased with dose escalation in the range of 20-600μg, but their values increased out of proportion to the whole studied doses. The main metabolic pathways were loss of phenyl group and hydroxylation. No metabolite that presented at greater than 10 percent of total drug-related exposure was observed. 101BHG-D01 was safe and well tolerated after administration. The study results indicate that 101BHG-D01 is a good candidate for the treatment of COPD and enable further clinical development in subsequent studies in patients. Clinical Trial Registration: http://www.chinadrugtrials.org.cn; Identifier: CTR20192058.

Electrochemical sensing of aclidinium bromide with metal ion-assisted molecularly imprinted films

This study explains the fabrication of the highly sensitive electrochemical sensor based on a metal ion-assisted molecularly imprinted polymer (MIP) for the determination of aclidinium bromide (ACL) for the first time. ACL is a relatively new drug in the group of long-acting muscarinic receptor antagonists and has an important place in chronic obstructive pulmonary disease (COPD) treatment. In this work, the MIP-based electrochemical sensor was designed by photopolymerization on the glassy carbon electrode (GCE) surface. The characterization of the electrode performance was evaluated with electrochemical analyses (cyclic voltammetry and electrochemical impedance spectroscopy). In contrast, chemical and morphological analyses were studied by using Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). It was successfully applied for ACL determination in standard solution, serum sample, and capsule dosage form with high sensitivity and accuracy using differential pulse voltammetry method meanwhile utilizing the 5 mM solution of [Fe(CN)6]3−/4– as the redox probe. The LOD values for the standard solution and serum sample were found as 2.73 × 10−16 M and 1.76 × 10−16 M, respectively, in the linear range of 1 × 10−15 M and 1 × 10−14 M. Additionally, interference studies and imprinting factor calculations were performed with common interfering agents and using oxitropium bromide, ipratropium bromide, glycopyrronium bromide, and tiotropium bromide to demonstrate the selectivity of the sensor. Finally, the non-imprinted polymer (NIP)-based sensor confirmed the performance of the MIP sensor. To the best of our knowledge, this study is the first one that reports the electrochemical determination of ACL.

Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics

IntroductionLoss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. MethodsWe performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. ResultsThe average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). ConclusionLAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.

Dual bronchodilation for the treatment of COPD: From bench to bedside.

Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting β-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice-daily agent) or 24 (with a once-daily agent) hours after the last administration of bronchodilator.

The Impact of 52-Week Single Inhaler Device Triple Therapy versus Dual Therapy on the Mortality of COPD Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There are more single inhaler device triple therapy available for COPD patients now. However, the effect of long-term triple therapy fixed dose combination (FDC) on mortality remains unclear. This study aimed to evaluate the impact of one-year single inhaler device triple therapy, including long-acting β2-agonists (LABAs), long-acting muscarinic receptor antagonists (LAMAs), and inhaled corticosteroids (ICSs), with dual therapies, comprised of either LABA/LAMA or ICS/LABA, on the mortality of patients with COPD. We searched the PubMed, Cochrane library, Web of Science, Embase databases, and clinical trial registry of clinicaltrials.gov and WHO ICTRP. Randomized controlled trials (RCTs) compared single inhaler device triple and dual therapies for 52 weeks were selected for the meta-analysis. The primary endpoint was all-cause mortality. A total of 6 RCTs were selected for the meta-analysis, including 10,274 patients who received single inhaler device triple therapy (ICS/LABA/LAMA FDC) and 12,395 patients who received ICS/LABA or LABA/LAMA dual therapy. Risk of death was significantly lower in the ICS/LABA/LAMA FDC group compared to the LABA/LAMA group (RR = 0.69, 95% CI = 0.53–0.90, p = 0.007). There was no significant difference in mortality between the ICS/LABA/LAMA FDC and ICS/LABA therapy groups (RR = 0.94, 95% CI = 0.72–1.24, p = 0.66). In addition, patients receiving ICS/LABA/LAMA FDC therapy had less moderate or severe exacerbations compared with the dual therapy groups (RR = 0.76, 95% CI = 0.73–0.80, p < 0.001 for LABA/LAMA; RR = 0.84, 95% CI = 0.78–0.90, p < 0.001 for ICS/LABA). By contrast, the risk of pneumonia in the ICS/LABA/LAMA FDC group was higher than in the LABA/LAMA group (RR = 1.43, 95% CI = 1.21–1.68, p < 0.001). In conclusion, ICS/LABA/LAMA FDC therapy could help improve the clinical outcomes of patients with COPD. However, triple therapy could increase the risk of pneumonia in comparison with LABA/LAMA dual therapy.

Escalation Time to Open Triple Combination Therapy from the Initiation of LAMA versus ICS/LABA in COPD Management: Findings from Comparing the Incidence of Tiotropium and ICS/LABA in Real-World Use in South Korea (CITRUS) Study.

Background: bronchodilators are the key treatment for chronic obstructive pulmonary disease (COPD), however, inhaled corticosteroids (ICSs)/long-acting β2-agonists (LABA) are widely prescribed. We compared the escalation time to open triple combination therapy between long-acting muscarinic receptor antagonists (LAMA) and ICS/LABA in COPD management. Methods: this retrospective study included COPD patients selected from the National Health Insurance Service of South Korea from January 2005 to April 2015. The primary outcome was the escalation time to triple therapy in patients who initially received LAMA or ICS/LABA. Other outcomes included risk factors predisposing escalation to triple combination therapy. Results: a total of 2444 patients were assigned to the LAMA or ICS/LABA groups. The incidences of triple combination therapy in the LAMA and ICS/LABA groups were 81.0 and 139.8 per 1000 person-years, respectively (p < 0.001); the median times to triple therapy escalation were 281 and 207 days, respectively (p = 0.03). Treatment with ICS/LABA showed a higher risk of triple therapy escalation compared to LAMA (hazard ratio (HR), 1.601; 95% confidence interval (CI), 1.402–1.829). The associated risk factor was male sex. (HR, 1.564; 95% CI, 1.352–1.809). Conclusions: the initiation of COPD treatment with LAMA is associated with a reduced escalation time to triple therapy compared with ICS/LABA.

Pharmacotherapeutic strategy for COPD patients: focus on dual bronchodilators

For two decades, the GOLD Initiative has consistently identified the use of bronchodilators as a priority in the pharmacotherapeutic strategy for COPD. The authors of international and national clinical guidelines consider fixed combinations of long-acting beta2-agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) as “first-line” drugs in most patients with COPD. Numerous clinical studies have shown that fixed LABAs/LAMAs combinations provide optimal bronchodilation and play a paramount role in preventing exacerbations of COPD. Outperforming placebo and active controls, LABAs, LAMAs, inhaled glucocorticosteroids (ICS)/LABAs combination bronchodilators may differ in their therapeutic potential. The available evidence base currently does not allow to make an unambiguous choice in favor of one or another fixed LABAs/ LAMAs combination. With the appearance of “triple” combinations (ICS/LABAs/LAMAs) on the pharmaceutical market, the issue of their comparison with “dual” bronchodilators has become particularly acute. Currently available data suggest that the use of “triple” therapy is not considered as a starting treatment option for COPD and is appropriate only in a subgroup of patients with a higher baseline risk of exacerbations: in the presence of a history of exacerbations ≥ 1, which required prescription of systemic antibiotics and/or glucocorticosteroids, or necessitated hospitalization during the previous year. Thus, ICS-containing therapy is justified only in cases of recurrent exacerbations of moderate COPD or single episodes of severe exacerbations, despite the continued administration of LABAs/LAMAs, as well as in certain categories of patients whose inflammatory profile suggests a “response” to ICS.

Caring for the Resident with Complex Medical Needs in Assisted Living

Caring for the Resident with Complex Medical Needs in Assisted Living

Antimuscarinic Medications for Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a disease of airway obstruction.1 A major component of therapy for the management of COPD includes bronchodilators, such as muscarinic receptor antagonists, also known as anticholinergic agents.1 These medications work at the parasympathetic sites in bronchial smooth muscle via the inhibition of acetylcholine causing bronchodilation.1 Antimuscarinic drugs for COPD management include short-acting and long-acting muscarinic receptor antagonists (SAMAs and LAMAs, respectively).

Understanding Practice Patterns of COPD: A Survey of Physicians in Nepal, Sri Lanka and Malaysia.

IntroductionThere is much recent data from Nepal, Sri Lanka and Malaysia that can help us understand the practice patterns of physicians regarding the diagnosis and management of chronic obstructive pulmonary disease (COPD) in these countries. We conducted this survey to understand the practice patterns of physicians related to the diagnosis and management of COPD in these three countries.MethodsThis questionnaire-based, observational, multicentre, cross-sectional survey was carried out with 438 randomly selected physicians consulting COPD patients.ResultsIn the survey, 73.29% of the physicians consulted at least five COPD patients daily (all patients > 40 years of age). 31.14% of the COPD patients visiting their doctors were women. Among physicians, 95.12% reported that at least 70% of their patients were smokers. 34.18% of the physicians did not routinely use spirometry to diagnose COPD. Most physicians preferred a short-acting β2-agonist (SABA) (28.19%) in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group-A and long-acting muscarinic receptor antagonist plus long-acting β2-agonist/inhaled corticosteroids (LAMA + LABA/ICS) in both the GOLD Group-C (39.86%) and Group-D (72.89%) patients. A significant number (40.67%) of physicians preferred LABA/LAMA for their GOLD Group-B patients. A pressurised metered dose inhaler (pMDI) with or without spacer was the most preferred device. Only 23.67% of the physicians believed that at least 70% of their patients had good adherence (> 80%) to therapy. Up to 54.42% of the physicians prescribed inhalation therapy to every COPD patient. Also, 39.95% of the physicians evaluated their patients’ inhalation technique on every visit. Up to 52.67% of the physicians advised home nebulisation to > 10% of patients, with nebulised SABA/short-acting muscarinic receptor antagonist (SAMA) being the most preferred management choice. Most physicians offered smoking cessation advice (94.16%) and/or vaccinations (74.30%) as non-pharmacological management, whereas pulmonary rehabilitation was offered by a smaller number of physicians. Cost of therapy and poor technique were the most common reasons for non-adherence to COPD management therapy.ConclusionAwareness of spirometry can be increased to improve the diagnosis of COPD. Though physicians are following the GOLD strategy recommendations for the pharmacological and non-pharmacological management of COPD, awareness of spirometry could be increased to improve proper diagnosis. Regular device demonstration during each visit can improve the inhalation technique and can possibly increase adherence to treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-021-00153-w.

PATIENT-CENTERED COMPREHENSIVE APPROACH IN COMBINED PATHOLOGY MANAGEMENT: ASTHMA / COPD CROSS

Introduction. Bronchial asthma and chronic obstructive pulmonary disease are serious social, epidemiological and medical health problems worldwide. The purpose of the study is to determine the main risk factors of asthma / COPD cross exacerbations in order to develop patient-centred management. Materials and methods. The study included 35 patients with asthma / COPD cross, and 35 healthy individuals. To quantify their well-being, the patients were asked to complete questionnaires: Asthma Control Questionnaire, Modified Medical Research Council Breathing Scale; to determine the level of reactive and personal anxiety, we used the questionnaire of Ch. D. Spielberger – Yu.M. Hanin. The analysis of integral indicators of the function of external respiration, including the test with bronchodilators was carried out. Medical lifestyle assessment of each patient with asthma / COPD cross was conducted by using the questionnaire of A. Nosov "Formation of components of a healthy lifestyle." Bioimpedance analysis of body composition was carried out as well. On the basis of the disturbances revealed in the behaviour of patients with asthma / COPD cross, and on the observance of lifestyle modes, we elaborated improved patient-centred approach to select the most appropriate algorithm of actions and personal behaviour to each patient. Conclusions. The integrated therapeutic measures developed for the patients with asthma / COPD and burden medical history should include in addition to the standard therapy (inhaled glucocorticosteroids, long-acting β2-agonists and / or long-acting muscarinic receptor antagonists) customized rehabilitation methods (therapeutic gymnastics according to Buteyko, hardening of the body, dietary modifications, mandatory smoking cessation) that promotes the stabilization and regression of symptoms, the increase in lung functioning, physical endurance, and improves patient’s quality of life.