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Pharmacology Research & Perspectives Jun 2018Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution...
Pharmacological properties of revefenacin (TD-4208), a novel, nebulized long-acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues.
Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pK = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM ( = 82 minutes) compared to the hM ( = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin-mediated antagonism of acetylcholine (ACh)-evoked calcium mobilization responses were reversed less rapidly at hM compared to the hM mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible ( of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM receptor and produces potent and long-lasting antagonism of mAChR-mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once-daily dosed inhaled bronchodilator in COPD patients.
Topics: Administration, Inhalation; Animals; Benzamides; Bronchi; Carbamates; Guinea Pigs; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Rats; Recombinant Proteins; Trachea
PubMed: 29736245
DOI: 10.1002/prp2.400 -
Respiratory Investigation Nov 2023Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction on spirometry and symptoms such as dyspnea on exertion and chronic cough with sputum... (Review)
Review
Management goals and stable phase management of patients with chronic obstructive pulmonary disease in the Japanese respiratory society guideline for the management of chronic obstructive pulmonary disease 2022 (6th edition).
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction on spirometry and symptoms such as dyspnea on exertion and chronic cough with sputum production, thus making it a significant healthcare issue worldwide. Japanese patients with COPD have unique characteristics compared to patients in Western countries, including older age and lower exacerbation frequency. The Japanese Respiratory Society (JRS) published the 6th edition of the COPD guideline in June 2022. This article introduces the management goals of COPD and describes its management during the stable phase, as outlined in the guideline. Management goals include improving the current status, such as the symptoms, quality of life (QOL), exercise tolerance, and physical activity, and reducing future risks through prevention of exacerbation and suppression of disease progression to prevent shortening of healthy life expectancy. Management plans should include avoidance of causative substances, assessment of disease severity, and personalized treatment plans. Pharmacotherapy using inhalation bronchodilators is a key component of the treatment of stable COPD. Bronchodilators, including short- and long-acting dilators, are commonly used to relieve symptoms and improve QOL. Inhaled corticosteroids (ICSs) are used in combination with long-acting bronchodilators, especially in patients with asthma and COPD overlap, or those experiencing frequent exacerbation of eosinophilia. Combination therapy with a long-acting muscarinic antagonist (LAMA), a long-acting beta 2 agonist (LABA), and ICS is expected to improve QOL and respiratory function and reduce mortality and exacerbation compared to the LAMA + LABA combination. Non-pharmacological therapies, including smoking cessation and pulmonary rehabilitation, should also be considered.
Topics: Humans; Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; East Asian People; Goals; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life
PubMed: 37741092
DOI: 10.1016/j.resinv.2023.08.007 -
Biological Psychiatry Jun 2013The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or... (Review)
Review
The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine's pharmacokinetic properties and an emerging literature that characterizes scopolamine's effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.
Topics: Adolescent; Adult; Antidepressive Agents; Depression; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Randomized Controlled Trials as Topic; Scopolamine; Young Adult
PubMed: 23200525
DOI: 10.1016/j.biopsych.2012.09.031 -
Revue Medicale de Liege Jan 2019The role of the anti-inflammatory and bronchodilator triple therapy, including a long acting ß2-agonist (LABA), a long-acting muscarinic antagonist (LAMA) and an...
The role of the anti-inflammatory and bronchodilator triple therapy, including a long acting ß2-agonist (LABA), a long-acting muscarinic antagonist (LAMA) and an inhaled corticosteroid (ICS), in the prevention of the exacerbations of chronic obstructive pulmonary disease (COPD) is still not clearly established, and requires comparison with dual therapy (LABA-CSI or LABA-LAMA). IMPACT is a phase 3, double-blind randomized study comparing the tritherapy (LABA-LAMA-ICS) in a single inhaler (vilanterol 25 ?g/umeclidinium 62.5 ?g/fluticasone furoate 100 ?g) with the LABA-ICS association (vilanterol 25 ?g-fluticasone furoate 100 ?g) and the combination LABA-LAMA (vilanterol 25 ?g/umeclidinium 62.5 ?g) on the reduction of the rate of exacerbation as the primary outcome, but also on the pulmonary function, the quality of life, the dyspnea and the mortality.Triple therapy by comparison with dual therapy (LABA-ICS or LABA-LAMA) improves numerous parameters such as the rate of moderate to severe exacerbations, the symptoms, the respiratory function, the quality of life, while being well tolerated. Finally, the IMPACT study gives an "evidence base" for the GOLD guidelines proposing triple therapy in symptomatic COPD patients presenting exacerbations despite dual therapy.
Topics: Androstadienes; Benzyl Alcohols; Chlorobenzenes; Clinical Trials, Phase III as Topic; Drug Combinations; Glucocorticoids; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic
PubMed: 30680975
DOI: No ID Found -
Respiratory Medicine Apr 2017Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully... (Review)
Review
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations.
METHODS
We examined data from the literature on symptom variability and control in patients with COPD, with focus on the use of inhaled bronchodilator therapy with long-acting muscarinic antagonist agents (LAMA) plus long-acting β-agonists (LABA); in particular twice-daily fixed-dose combination LAMA/LABA therapy with aclidinium/formoterol.
RESULTS
Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator.
CONCLUSIONS
The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 μg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Forced Expiratory Volume; Formoterol Fumarate; Health Status; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Treatment Outcome; Tropanes; Vital Capacity
PubMed: 28340862
DOI: 10.1016/j.rmed.2017.03.001 -
International Journal of Chronic... 2014Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. Bronchodilator... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. Bronchodilator therapy is the cornerstone in COPD treatment. Bronchodilation in COPD is mainly achieved via administration of long- and ultralong-acting β2-agonists and with long-acting muscarinic antagonists. New combinations of bronchodilators with dual-acting muscarinic antagonist and β2-agonist properties have been licensed, and others are currently being developed with the aim of achieving once-daily dosing, and therefore may improve the likelihood of treatment compliance. These combination bronchodilators include glycopyrronium bromide/indacaterol maleate, umeclidinium (UMEC) bromide/vilanterol trifenatate (VI), aclidinium bromide/formoterol and tiotropium bromide/olodaterol (Boehringer Ingelheim, Germany). This review will focus mainly on studies and clinical trials involving the novel fixed-dose combination of UMEC/VI at doses of 125/25 μg and 62.5/25 μg in patients with COPD. Data from large clinical trials involving more than 4,500 COPD patients indicate that UMEC/VI is an effective once-daily treatment in COPD with improved pulmonary function. Future studies assessing the impact of this combination on exacerbations, delay in disease progression, and health status in patients with COPD are warranted.
Topics: Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Recovery of Function; Time Factors; Treatment Outcome
PubMed: 25061288
DOI: 10.2147/COPD.S47792 -
BioMed Research International 2018Severe asthma is associated with substantial morbidity and mortality. Therapies must be maximized to gain control of a patient's severe asthma; however, avoiding... (Review)
Review
Severe asthma is associated with substantial morbidity and mortality. Therapies must be maximized to gain control of a patient's severe asthma; however, avoiding overtreatment is also important. The mainstays of asthma maintenance treatment are inhaled corticosteroids (ICS) and long-acting -agonsits (LABAs), with the option of supplementary add-on treatments. New add-on treatments for severe asthma have emerged over the past two decades, including personalized biological therapies that are guided by a patient's asthma phenotype. In addition, the long-acting muscarinic antagonist tiotropium has been recommended as an add-on treatment for severe asthma. Phase III clinical trials have shown tiotropium in combination with ICS/LABA to be efficacious in patients with severe asthma. Further analyses of clinical trial data have indicated that there is no benefit in stratifying patients by phenotype to predict tiotropium efficacy. Furthermore, health economic studies suggest tiotropium to be a cost-effective treatment in patients with severe asthma. This review will present the evidence surrounding the role of tiotropium in severe asthma and will discuss the use of tiotropium add-on therapy before personalized medicine strategies in the stepwise process of gaining asthma control.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Asthma; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Tiotropium Bromide
PubMed: 30474042
DOI: 10.1155/2018/7473690 -
Therapeutic Advances in Respiratory... 2019Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting β agonist (LAMA/LABA)... (Review)
Review
Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting β agonist (LAMA/LABA) dual-bronchodilator maintenance therapy used to relieve symptoms and reduce future risk of exacerbations in adults with chronic obstructive pulmonary disease (COPD). To date, there have been several clinical studies and post hoc analyses of AB/FF, assessing treatment outcomes in patients with moderate-to-severe COPD. These studies have looked at a range of outcomes, including lung function parameters, patient-reported symptom scores, quality-of-life measures assessing impaired health and perceived well-being, and the frequency, duration, and severity of exacerbations. In light of the major 2017 revision to the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, and the subsequent updates, we present an update on the latest evidence supporting the efficacy and safety of AB/FF. This review discusses the clinical relevance of the improvements in lung function, symptoms, quality of life, and exacerbations in patients with COPD reported in the phase III and IV trials of AB/FF. Given the current concerns over unnecessary inhaled corticosteroid (ICS) use in COPD, we also touch briefly on the use of blood eosinophils as a biomarker for identifying those patients with COPD already using LAMA/LABA therapy for whom the addition of ICS might be of benefit.
Topics: Adrenergic beta-2 Receptor Agonists; Adult; Bronchodilator Agents; Drug Combinations; Formoterol Fumarate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Tropanes
PubMed: 31096854
DOI: 10.1177/1753466619850725 -
International Journal of Chronic... 2015Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. The cornerstone of pharmacological treatment for COPD is bronchodilation.... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. The cornerstone of pharmacological treatment for COPD is bronchodilation. Inhaled glycopyrronium bromide is a long-acting muscarinic antagonist developed as a maintenance treatment for patients with COPD. Phase III trials have shown that glycopyrronium produces rapid and sustained bronchodilation with an efficacy similar to tiotropium and is well tolerated, with a low incidence of muscarinic side effects in patients with moderate to severe COPD. A combination of glycopyrronium bromide with indacaterol maleate (QVA149) has recently been approved as a once-daily maintenance therapy in adult patients with COPD. Phase III trials (the IGNITE program) with QVA149 have demonstrated significant improvements in lung function versus placebo, glycopyrronium, and tiotropium in patients with moderate to severe COPD, with no safety concerns of note. Hence QVA149 is a safe treatment option for moderate to severe COPD patients in whom long-acting muscarinic antagonist monotherapy is inadequate.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Animals; Bronchodilator Agents; Drug Combinations; Glycopyrrolate; Humans; Indans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Severity of Illness Index; Treatment Outcome
PubMed: 25609944
DOI: 10.2147/COPD.S67758 -
Clinical Pharmacology in Drug... Jan 2020Revefenacin is a novel once-daily, lung-selective, long-acting muscarinic antagonist developed as a nebulized inhalation solution for the maintenance treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
Revefenacin is a novel once-daily, lung-selective, long-acting muscarinic antagonist developed as a nebulized inhalation solution for the maintenance treatment of chronic obstructive pulmonary disease. In a randomized, 4-way crossover study, healthy subjects received a single inhaled dose of revefenacin 175 µg (therapeutic dose), revefenacin 700 µg (supratherapeutic dose), and placebo via standard jet nebulizer, and a single oral dose of moxifloxacin 400 mg (open-label) in separate treatment periods. Electrocardiograms were recorded, and pharmacokinetic samples were collected serially after dosing. The primary end point was the placebo-corrected change from baseline QT interval corrected for heart rate using Fridericia's formula, analyzed at each postdose time. Concentration-QTc modeling was also performed. Following administration of revefenacin 175 and 700 µg, placebo-corrected change from baseline QTcF (ΔΔQTcF) values were close to 0 at all times, with the largest mean ΔΔQTcF of 1.0 millisecond (95% confidence interval [CI], -1.2 to 3.1 milliseconds) 8 hours postdose and 1.0 millisecond (95%CI, -1.1 to 3.1 milliseconds) 1 hour postdose after inhalation of revefenacin 175 and 700 µg, respectively. Revefenacin did not have a clinically meaningful effect on heart rate (within ±5 beats per minute of placebo), or PR and QRS intervals (within ±3 and ±1 milliseconds of placebo, respectively). Using concentration-QTc modeling, an effect of revefenacin > 10 milliseconds can be excluded within the observed plasma concentration range of up to ≈3 ng/mL. Both doses of revefenacin were well tolerated. These results demonstrate that revefenacin does not prolong the QT interval.
Topics: Adolescent; Adult; Benzamides; Carbamates; Cross-Over Studies; Double-Blind Method; Electrocardiography; Female; Healthy Volunteers; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Muscarinic Antagonists; Young Adult
PubMed: 31468714
DOI: 10.1002/cpdd.732