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International Journal of Chronic... 2018Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist... (Review)
Review
Recently, two "fixed triple" single-inhaler combinations of an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) have become available for patients with COPD. This review presents the clinical evidence that led to the approval of these triple therapies, discusses the role of ICS in patients with COPD, and presents data on the relative efficacy of "fixed triple" (ICS/LAMA/LABA) therapy vs LAMA, ICS/LABA, and LAMA/LABA combinations, and summarizes studies in which ICS/LABAs were combined with LAMAs to form "open triple" combinations. Of the five main fixed triple studies completed so far, three evaluated the efficacy and safety of an extrafine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium; the other two studies evaluated fluticasone furoate, vilanterol, and umeclidinium. Overall, compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio. Furthermore, triple therapy showed a promising signal in terms of improved survival. The evidence suggests that triple therapy is the most effective treatment in moderate/severe symptomatic patients with COPD at risk of exacerbations, with marginal if any risk of side effects including pneumonia. Ongoing studies are examining the role of triple therapy in less severe symptomatic patients with COPD and asthma-COPD overlap.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Combinations; Evidence-Based Medicine; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Risk Factors; Severity of Illness Index; Treatment Outcome
PubMed: 30587953
DOI: 10.2147/COPD.S185975 -
The Annals of Pharmacotherapy Mar 2019To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS)... (Review)
Review
OBJECTIVE
To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS) nebulizer, approved for maintenance treatment of chronic obstructive pulmonary disease (COPD).
DATA SOURCES
A PubMed search was conducted (January 2000 to July 2018) using the following terms/phrases: nebulized glycopyrrolate, inhalation devices in COPD, long-acting muscarinic antagonists COPD, and COPD survey. Retrieved articles were reviewed to identify additional references.
STUDY SELECTION AND DATA EXTRACTION
Primary and review articles on GLY/eFlow CS and other treatment options for patients with COPD were selected.
DATA SYNTHESIS
Guidelines recommend the use of LAMAs, alone or in combination with long-acting β-agonists, as maintenance therapy for the majority of patients with COPD. With the range of different devices and bronchodilators now available, treatment can be tailored based on individual needs. The eFlow CS nebulizer delivers GLY rapidly over a 2- to 3-minute period and provides bronchodilation within 30 minutes, lasting 12 hours. Phase 2 dose-finding and phase 3 studies demonstrated sustained statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with GLY/eFlow CS. Relevance to Patient Care and Clinical Practice: GLY/eFlow CS provides a novel, portable, efficient, and rapid drug delivery system.
CONCLUSIONS
The recently approved GLY/eFlow CS drug-device combination provides a viable treatment option for patients with COPD, particularly those with conditions that may impair proper use of traditional handheld inhalers.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Delivery Systems; Female; Glycopyrrolate; Humans; Male; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome
PubMed: 30175596
DOI: 10.1177/1060028018798753 -
Respiratory Research Jul 2020Bronchodilators are the mainstay of pharmacological treatment in chronic obstructive pulmonary disease (COPD), and long-acting muscarinic antagonist (LAMA) monotherapy... (Review)
Review
BACKGROUND
Bronchodilators are the mainstay of pharmacological treatment in chronic obstructive pulmonary disease (COPD), and long-acting muscarinic antagonist (LAMA) monotherapy is recommended as initial treatment for Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, and D.
MAIN BODY
Tiotropium bromide was the first LAMA available for COPD in clinical practice and, because of its long duration of action, is administered once daily. Tiotropium was initially available as an inhalation powder delivered via a dry-powder inhaler (DPI). Later, tiotropium also became available as an inhalation spray delivered via a soft mist inhaler (SMI). The SMI was designed to overcome or minimize some of the issues associated with other inhaler types (eg, the need for strong inspiratory airflow with DPIs). Results of short- and long-term randomized, controlled clinical trials of tiotropium in patients with COPD indicated tiotropium was safe and significantly improved lung function, health-related quality of life, and exercise endurance, and reduced dyspnea, lung hyperinflation, exacerbations, and use of rescue medication compared with placebo or active comparators. These positive efficacy findings triggered the evaluation of tiotropium in fixed-dose combination with olodaterol (a long-acting β-agonist). In this review, we provide an overview of studies of tiotropium for the treatment of COPD, with a focus on pivotal studies.
CONCLUSION
Tiotropium is safe and efficacious as a long-term, once-daily LAMA for the maintenance treatment of COPD and for reducing COPD exacerbations. The SMI generates a low-velocity, long-duration aerosol spray with a high fine-particle fraction, which results in marked lung drug deposition. In addition, high inspiratory flow rates are not required.
Topics: Administration, Inhalation; Bronchodilator Agents; Drug Development; Forced Expiratory Volume; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide
PubMed: 32727455
DOI: 10.1186/s12931-020-01407-y -
International Journal of Chronic... 2021Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to treatment and management that aims to reduce both symptom burden and the risk of exacerbations. Recent clinical trials have investigated single-inhaler triple therapy (SITT) with a long-acting muscarinic antagonist (LAMA), long-acting β-agonist (LABA), and inhaled corticosteroid (ICS) for patients with symptomatic COPD. Here, we review evidence from randomized controlled trials showing the benefits of SITT and weigh these against the reported risk of pneumonia with ICS use. We highlight the challenges associated with cross-trial comparisons of benefit/risk, discuss blood eosinophils as a marker of ICS responsiveness, and summarize current treatment recommendations and the position of SITT in the management of COPD, including potential advantages in terms of improving patient adherence. Evidence from trials of SITT versus dual therapies in symptomatic patients with moderate to very severe airflow limitation and increased risk of exacerbations shows benefits in lung function and patient-reported outcomes. Moreover, the key benefits reported with SITT are significant reductions in exacerbations and hospitalizations, with data also suggesting reduced all-cause mortality. These benefits outweigh the ICS-class effect of higher incidence of study-reported pneumonia compared with LAMA/LABA. Important differences in trial design, baseline population characteristics, such as exacerbation history, and assessment of outcomes, have significant implications for interpreting data from cross-trial comparisons. Current understanding interprets the blood eosinophil count as a continuum that can help predict response to ICS and has utility alongside other clinical factors to aid treatment decision-making. We conclude that treatment decisions in COPD should be guided by an approach that considers benefit versus risk, with early optimization of treatment essential for maximizing long-term benefits and patient outcomes.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive
PubMed: 33688176
DOI: 10.2147/COPD.S291967 -
Therapeutic Advances in Respiratory... Feb 2011Aclidinium is a potent and selective muscarinic antagonist, which interacts rapidly with muscarinic receptors and shows subnanomolar affinity for the five human... (Review)
Review
Aclidinium is a potent and selective muscarinic antagonist, which interacts rapidly with muscarinic receptors and shows subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)); its association rate for the M(3) receptor is similar to that of ipratropium and 2.6 times faster than that of tiotropium. Aclidinium dissociates slightly faster from M(2) and M(3) receptors than tiotropium but much more slowly than ipratropium. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Aclidinium undergoes rapid hydrolysis in the plasma into two major compounds, the alcohol (LAS34823) and the carboxylic acid (LAS34850) metabolites, resulting in low and transient systemic exposure to the active drug. The two major metabolites show no significant affinity for human muscarinic receptors. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Clinical trials have provided evidence of sustained bronchodilation similar to that observed with tiotropium. Trial results have confirmed the positive safety profile of aclidinium, particularly in terms of a very low propensity to cause anticholinergic adverse events. Aclidinium is now moving to phase III clinical development for chronic obstructive pulmonary disease (COPD).
Topics: Clinical Trials as Topic; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Tropanes
PubMed: 20884687
DOI: 10.1177/1753465810381546 -
British Journal of Clinical Pharmacology Jan 2014Acetlycholine is involved in the control of airway smooth muscle constriction and in recruitment of inflammatory cells via neuronal and paracrine effects on muscarinic... (Review)
Review
Acetlycholine is involved in the control of airway smooth muscle constriction and in recruitment of inflammatory cells via neuronal and paracrine effects on muscarinic type 3 receptors. Long acting muscarinic antagonists (LAMA) are well established in guidelines for COPD but are not currently licensed for use in asthma. There are emerging data from key clinical trials to show that LAMA may confer bronchodilator effects and improved control when used in addition to inhaled corticosteroid (ICS) alone or in conjunction with long acting β-adrenoceptor agonists (LABA). Further studies in persistent asthmatic patients are required to evaluate ICS sparing effects of LAMA looking particularly at airway hyper-responsiveness and surrogate inflammatory markers, in addition to evaluation of possible synergy between LAMA and LABA when given together. Future possible development of combination inhalers comprising ICS/LAMA or ICS/LAMA/LABA will require long term studies looking at asthma control and exacerbations in both adult and paediatric patients.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Anti-Asthmatic Agents; Asthma; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Models, Neurological; Muscarinic Antagonists
PubMed: 23534447
DOI: 10.1111/bcp.12123 -
Respiratory Research Jun 2017The natural disease course of chronic obstructive pulmonary disease (COPD) is often punctuated by exacerbations: acute events of symptom worsening associated with... (Review)
Review
The natural disease course of chronic obstructive pulmonary disease (COPD) is often punctuated by exacerbations: acute events of symptom worsening associated with significant morbidity and healthcare resource utilization; reduced quality of life; and increased risk of hospitalization and death. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that patients at risk of exacerbations (GOLD Groups C and D) receive a long-acting muscarinic antagonist (LAMA) or a long-acting β-agonist (LABA)/LAMA combination, respectively, as preferred initial treatments. The latter recommendation is based on recent trial evidence demonstrating the superior efficacy of a fixed-dose LABA/LAMA over an inhaled corticosteroid (ICS)/LABA in exacerbation prevention. ICS in combination with a LABA is also indicated for prevention of exacerbations, but the use of ICS is associated with an increased risk of adverse events such as pneumonia, and offers limited benefits beyond those provided by LABA or LAMA monotherapy. In this review, we examine evidence from a number of pivotal studies of LABAs and LAMAs, administered as monotherapy or as part of dual or triple combination therapy, with a specific focus on their effect on exacerbations. We also discuss a new proposed treatment paradigm for the management of COPD that takes into account this recent evidence and adopts a more cautious approach to the use of ICS. In alignment with GOLD 2017, we suggest that ICS should be reserved for patients with concomitant asthma or in whom exacerbations persist despite treatment with LABA/LAMA.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive
PubMed: 28633665
DOI: 10.1186/s12931-017-0601-2 -
International Journal of Chronic... 2015Randomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Randomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 µg once-daily (OD) and newer agents (aclidinium 400 µg twice-daily, glycopyrronium 50 µg OD, and umeclidinium 62.5 µg OD).
METHODS
A systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George's Respiratory Questionnaire score, and rescue medication use.
RESULTS
Twenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06-125.60]; 117.20 mL [104.50-129.90]; 114.10 mL [103.10-125.20]; 136.70 mL [104.20-169.20]); 24-week trough FEV1 (128.10 mL [84.10-172.00]; 135.80 mL [123.10-148.30]; 106.40 mL [95.45-117.30]; 115.00 mL [74.51-155.30]); 24-week St George's Respiratory Questionnaire score (-4.60 [-6.76 to -2.54]; -3.14 [-3.83 to -2.45]; -2.43 [-2.92 to -1.93]; -4.69 [-7.05 to -2.31]); 24-week transitional dyspnea index score (1.00 [0.41-1.59]; 1.01 [0.79-1.22]; 0.82 [0.62-1.02]; 1.00 [0.49-1.51]); and 24-week rescue medication use (data not available; -0.41 puffs/day [-0.62 to -0.20]; -0.52 puffs/day [-0.74 to -0.30]; -0.30 puffs/day [-0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were -12.8 mL (-39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (-7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (-11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (-11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (-5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (-15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered.
CONCLUSION
The new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician's and patient's preference.
Topics: Aged; Bayes Theorem; Bronchodilator Agents; Drug Administration Schedule; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Recovery of Function; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes
PubMed: 26604738
DOI: 10.2147/COPD.S92412 -
Brain Research Bulletin Jan 2019Central cholinergic activation stimulates water intake, but also NaCl intake when the inhibitory mechanisms are blocked with injections of moxonidine (α...
Central cholinergic activation stimulates water intake, but also NaCl intake when the inhibitory mechanisms are blocked with injections of moxonidine (α adrenergic/imidazoline agonist) into the lateral parabrachial nucleus (LPBN). In the present study, we investigated the involvement of central M and M muscarinic receptors on NaCl intake induced by pilocarpine (non-selective muscarinic agonist) intraperitoneally combined with moxonidine into the LPBN or by muscimol (GABA agonist) into the LPBN. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN and in the lateral ventricle were used. Pirenzepine (M muscarinic antagonist, 1 nmol/1 μl) or methoctramine (M muscarinic antagonist, 50 nmol/1 μL) injected intracerebroventricularly (i.c.v.) reduced 0.3 M NaCl and water intake in rats treated with pilocarpine (0.1 mg/100 g of body weight) injected intraperitoneally combined with moxonidine (0.5 nmol/0.2 μL) into the LPBN. In rats treated with muscimol (0.5 nmol/0.2 μL) into the LPBN, methoctramine i.c.v. also reduced 0.3 M NaCl and water intake, however, pirenzepine produced no effect. The results suggest that M and M muscarinic receptors activate central pathways involved in the control of water and sodium intake that are under the influence of the LPBN inhibitory mechanisms.
Topics: Animals; Diamines; Drinking; Drinking Behavior; Imidazoles; Male; Muscarinic Agonists; Muscarinic Antagonists; Muscimol; Parabrachial Nucleus; Pilocarpine; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Sodium Chloride; Sodium, Dietary
PubMed: 30391542
DOI: 10.1016/j.brainresbull.2018.10.011 -
Behavioural Neurology 2013Dystonia is a chronic disorder characterised by an aberration in the control of movement. Sustained co-contraction of opposing agonist and antagonist muscles can cause... (Review)
Review
BACKGROUND
Dystonia is a chronic disorder characterised by an aberration in the control of movement. Sustained co-contraction of opposing agonist and antagonist muscles can cause repetitive and twisting movements, or abnormal postures. Cervical dystonia (CD), often referred to as spasmodic torticollis, is a type of focal dystonia involving the muscles of the neck and sometimes the shoulders.
METHODS
This systematic review collates the available evidence regarding the safety and efficacy of a range of treatments for CD, focusing on their effectiveness as shown by double-blinded, randomised controlled trials.
RESULTS
Our review suggests that botulinum toxin type A (BTA), botulinum toxin type B (BTB) and trihexyphenidyl are safe and efficacious treatments for CD. Evidence shows that botulinum toxin therapies are more reliable for symptomatic relief and have fewer adverse effects than trihexyphenidyl. When comparing BTA to BTB, both are found to have similar clinical benefits, with BTA possibly having a longer duration of action and a marginally better side effect profile. BTB is also safe and probably just as efficacious a treatment in those patients who are unresponsive or have become resistant to BTA.
DISCUSSION
The current evidence shows that the pharmacological management of CD relies on BTA and BTB, two agents with established efficacy and tolerability profiles.
Topics: Botulinum Toxins; Botulinum Toxins, Type A; Humans; Muscarinic Antagonists; Neuromuscular Agents; Torticollis; Trihexyphenidyl
PubMed: 22713419
DOI: 10.3233/BEN-2012-120270