Aclidinium inhibits human lung fibroblast to myofibroblast transition

2011

Background Fibroblast to myofibroblast transition is believed to contribute to airway remodelling in lung diseases such as asthma and chronic obstructive pulmonary disease. This study examines the role of aclidinium, a new long-acting muscarinic antagonist, on human fibroblast to myofibroblast transition. Methods Human bronchial fibroblasts were stimulated with carbachol (10 −8 to 10 −5  M) or transforming growth factor-β1 (TGF-β1; 2 ng/ml) in the presence or absence of aclidinium (10 −9 to 10 −7  M) or different drug modulators for 48 h. Characterisation of myofibroblasts was performed by analysis of collagen type I and α-smooth muscle actin (α-SMA) mRNA and protein expression as well as α…

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effect…

2019

AZD8871 is a novel muscarinic antagonist and β2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the β2-adrenoceptor over the β1 and β3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and β2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, r…

Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways.

2010

Mucus hypersecretion and mucin MUC5AC overexpression are pathological features of chronic obstructive pulmonary disease (COPD). This study examines the inhibitory effect of aclidinium, a new long-acting muscarinic antagonist, on MUC5AC expression in human airway epithelial cells. MUC5AC mRNA (RT-PCR) and protein expression (ELISA and immunohistochemistry) were studied in human bronchial tissue and differentiated human airway epithelial cells activated with carbachol (100 μM) or cigarette smoke extract in the absence or presence of aclidinium. Carbachol increased MUC5AC mRNA and protein expression in human bronchus and cultured epithelial cells. Aclidinium inhibited the carbachol-induced MUC…

Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients

2016

Background: Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect. Methods: Human sputum and blood neutrophils were isolated from healthy individuals ( n = 37), patients with stable COPD ( n = 52) and th…

Aclidinium Partially Prevents Human Lung Fibroblast Activation In Vitro

2011

Cigarette Smoke-Induced Fibroblast Activation Is Attenuated By Aclidinium In Vitro

2011

Pharmacological preclinical characterization of LAS190792, a novel inhaled bifunctional muscarinic receptor antagonist /β 2 -adrenoceptor agonist (MA…

2017

LAS190792 is a novel muscarinic antagonist and β2-adrenoceptor agonist in development for chronic respiratory diseases. This study investigated the pharmacological profile of LAS190792 in comparison to batefenterol, tiotropium, indacaterol and olodaterol. LAS190792 is potent at the human M3 receptor (pIC50: 8.8 in binding assays). It is selective for the β2-adrenoceptor over the β1-and β3-adrenoceptor, and shows a functional potency in a similar range to batefenterol and LABA compounds (pEC50 in spontaneous tone isolated trachea: 9.6). The relaxant potency of LAS190792 in electrically stimulated tissue is similar to batefenterol, with an antimuscarinic activity in presence of propranolol sl…

Functional Profile Of Aclidinium Bromide In Isolated Human Bronchi And Left Atria

2011

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition.

2012

Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation. This in vitro study examined the effect of cigarette smoke on bronchial fibroblast-to-myofibroblast transition, and whether aclidinium bromide inhibits this process. Human bronchial fibroblasts were incubated with aclidinium bromide (10 −9 –10 −7 M) and exposed to cigarette smoke extract. Collagen type I and α-smooth muscle actin (α-SMA) expression were measured …

Aclidinium, a New Long-Acting Antimuscarinic, Inhibits Cholinergic and Cigarette Smoke-Induced Up Regulation of Mucin MUC5AC Expression in Human Airw…

2009

The In Vitro Pharmacological Profile Of LAS100977 - A Potent, Selective And Long-acting Beta-2 Receptor Agonist

2010

Additional file 1: of Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients

2016

Supplementary Table S1. Maximal percentage of inhibition of IL-8, MMP-9, CCL-5, GM-CSF and IL-1β release from neutrophils of healthy subjects and COPD patients. Neutrophils were incubated with aclidinium (Acl; 0.1nM-1 μM), fluticasone (Flut; 0.1nM-1 μM), formoterol (Form; 0.01nM-100nM) or salmeterol (Salm; 0.1nM-1 μM) in response to LPS (1 μg/ml) or cigarette smoke extract (CSE 5 %). The levels of different cytokines in the cell supernatant were determined and the maximal percent of inhibitions were calculated. Values are mean ± SD of 3 independent experiments run in triplicate. *p 

Additional file 2: of Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients

2016

Supplementary Figure E1. Effects of formoterol and salmeterol on pro-inflammatory markers. Concentration-dependent inhibition of lipopolysaccharide (LPS)-induced cytokines or MMP-9 release by formoterol (Form) and salmeterol (Salm) from peripheral blood neutrophils of healthy subjects and COPD patients. Neutrophils were preincubated with Salm (0.1nM-1 μM) or form (0.01nM-100nM) for 1 h followed by cell stimulation with LPS (1 μg/ml) for 6 h. Results are expressed as means ± SD of n = 3 (3 cell healthy and 3 cell COPD populations run in triplicate) independent experiments. Two-way ANOVA was followed by the post hoc Bonferroni test. *p