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      New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol

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          Abstract

          An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β 2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV 1, is also associated with improvements in other outcome measures that are important to COPD patients.

          Most cited references13

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          Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases.

          Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.
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            A new perspective on muscarinic receptor antagonism in obstructive airways diseases.

            Acetylcholine has traditionally only been regarded as a neurotransmitter of the parasympathetic nervous system, causing bronchoconstriction and mucus secretion in asthma and COPD by muscarinic receptor activation on airway smooth muscle and mucus-producing cells. Recent studies in experimental models indicate that muscarinic receptor stimulation in the airways also induces pro-inflammatory, pro-proliferative and pro-fibrotic effects, which may involve activation of airway structural and inflammatory cells by neuronal as well as non-neuronal acetylcholine. In addition, mechanical changes caused by muscarinic agonist-induced bronchoconstriction may be involved in airway remodeling. Crosstalk between muscarinic receptors and β2-adrenoceptors on airway smooth muscle causes a reduced bronchodilator response to β2-agonists, and a similar mechanism could possibly apply to the poor inhibition of inflammatory and remodeling processes by these drugs. Collectively, these findings provide novel perspectives for muscarinic receptor antagonists in asthma and COPD, since these drugs may not only acutely affect cholinergic airways obstruction, but also have important beneficial effects on β2-agonist responsiveness, airway inflammation and remodeling. The clinical relevance of these findings is presently under investigation and starting to emerge.
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              Project PriMo: sharing principles and practices of bronchodilator therapy monitoring in COPD: a consensus initiative for optimizing therapeutic appropriateness among Italian specialists.

              Even after publication of the 2011 update of GOLD report, some fundamental questions in the management of COPD are still open and this may weaken the applicability of these guidelines in everyday clinical practice. To assess the level of consensus amongst Italian respirologists on different topics related to diagnosis, monitoring and role of bronchodilator therapy in COPD, by using the Delphi technique. A Delphi study was undertaken between July and November 2011, when two questionnaires were consecutively sent to a panel of experts to be answered anonymously. After each round, the data were aggregated at group level of question topics and structured feedback was given to the panel. A first-round questionnaire was sent to 208 pulmonologists randomly selected from different Italian regions. The 132 respondents (63% of those initially selected) were from northern (53%), central (19%) and southern (28%) Italy. A second-round questionnaire was sent to all the first-round respondents, and a response was received from 110 of them (83%). The main topics that reached the pre-defined cut off for consensus (67% or more) were: a) bronchodilator therapy with long-acting bronchodilators could be beneficial in patients with airflow limitation even in the absence of symptoms, b) in patients not fully controlled with one long-acting bronchodilator, maximizing bronchodilation (i.e. adding another bronchodilator with a different mechanism of action) is the preferable option; and c) the use of inhaled corticosteroids (ICSs) as add on therapy should be considered in severe patients with frequent exacerbations. Italian specialists agree on several aspects of the diagnosis and treatment of COPD and expert opinion could support everyday decision process in the management of COPD. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2013
                10 October 2013
                : 7
                : 1201-1208
                Affiliations
                [1 ]Department of System Medicine, University of Rome ‘Tor Vergata’, Rome, Italy
                [2 ]Department of Experimental Medicine, Second University, Naples, Italy
                Author notes
                Correspondence: Mario Cazzola Unità di Farmacologia Clinica Respiratoria, Dipartimento di Medicina dei Sistemi, Università di Roma ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, Italy, Email mario.cazzola@ 123456uniroma2.it
                Article
                dddt-7-1201
                10.2147/DDDT.S39449
                3797618
                7f153f46-487a-4db4-9fdc-f74fd106a27a
                © 2013 Cazzola et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.

                History
                Categories
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                Pharmacology & Pharmaceutical medicine
                muscarinic antagonist,dual bronchodilation,copd
                Pharmacology & Pharmaceutical medicine
                muscarinic antagonist, dual bronchodilation, copd

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