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      Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease

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          Abstract

          Introduction

          Bronchodilators are the cornerstone of chronic obstructive pulmonary disease (COPD) therapy and long-acting muscarinic antagonists (LAMAs) as a mono or combination treatment play a pivotal role. Several LAMAs are already available on the market in different formulations, but developing a new compound with a higher M3 receptor selectivity and a lower affinity to M2 receptors to increase the therapeutic effect and minimize the adverse effects is still a goal. Moreover, new formulations could improve adherence to therapy.

          Areas Covered

          This systematic review assesses investigational long-acting muscarinic antagonist in Phase I and II clinical trials over the last decade. It offers insights on whether LAMAs and/or their new formulations in clinical development can become effective treatments for COPD in the future.

          Expert Opinion

          Research on LAMA seems to have come to a standstill, the few new molecules under study do not show distinctive characteristics compared to the previous ones. Muscarinic antagonist/β2-agonist (MABAs) appear to be the major innovation currently under investigation, and they could theoretically open new research frontiers on the effect between adrenergic and muscarinic interaction in the same cell.

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          Most cited references61

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          Adrenergic and muscarinic receptors in the human heart.

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            Reflex regulation of airway smooth muscle tone.

            Autonomic nerves in most mammalian species mediate both contractions and relaxations of airway smooth muscle. Cholinergic-parasympathetic nerves mediate contractions, whereas adrenergic-sympathetic and/or noncholinergic parasympathetic nerves mediate relaxations. Sympathetic-adrenergic innervation of human airway smooth muscle is sparse or nonexistent based on histological analyses and plays little or no role in regulating airway caliber. Rather, in humans and in many other species, postganglionic noncholinergic parasympathetic nerves provide the only relaxant innervation of airway smooth muscle. These noncholinergic nerves are anatomically and physiologically distinct from the postganglionic cholinergic parasympathetic nerves and differentially regulated by reflexes. Although bronchopulmonary vagal afferent nerves provide the primary afferent input regulating airway autonomic nerve activity, extrapulmonary afferent nerves, both vagal and nonvagal, can also reflexively regulate autonomic tone in airway smooth muscle. Reflexes result in either an enhanced activity in one or more of the autonomic efferent pathways, or a withdrawal of baseline cholinergic tone. These parallel excitatory and inhibitory afferent and efferent pathways add complexity to autonomic control of airway caliber. Dysfunction or dysregulation of these afferent and efferent nerves likely contributes to the pathogenesis of obstructive airways diseases and may account for the pulmonary symptoms associated with extrapulmonary disorders, including gastroesophageal reflux disease, cardiovascular disease, and rhinosinusitis.
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              Barriers to new drug development in respiratory disease.

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                Author and article information

                Journal
                J Exp Pharmacol
                J Exp Pharmacol
                jep
                jexpharm
                Journal of Experimental Pharmacology
                Dove
                1179-1454
                08 December 2020
                2020
                : 12
                : 559-574
                Affiliations
                [1 ]Division of Respiratory Medicine, University Hospital Tor Vergata , Rome, Italy
                [2 ]Division of Respiratory Medicine, San Filippo Neri Hospital , Rome, Italy
                [3 ]Department of Experimental Medicine, University of Rome Tor Vergata , Rome, Italy
                [4 ]Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma , Parma, Italy
                Author notes
                Correspondence: Josuel Ora Division of Respiratory Medicine, University Hospital Tor Vergata , Viale Oxford 81, Rome00133, Italy Email josuel.ora@ptvonline.it
                Author information
                http://orcid.org/0000-0003-4895-9707
                http://orcid.org/0000-0003-0456-069X
                http://orcid.org/0000-0001-7801-5040
                Article
                259330
                10.2147/JEP.S259330
                7733406
                69f24901-2db7-4594-866b-a0c56595296b
                © 2020 Ora et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 25 September 2020
                : 25 November 2020
                Page count
                Figures: 2, Tables: 4, References: 63, Pages: 16
                Funding
                Funded by: no funding;
                There is no funding to report.
                Categories
                Review

                long-acting muscarinic antagonist,maba,lama,phase i,phase ii,efficacy,safety,copd treatment,investigational drugs,chronic obstructive pulmonary disease

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