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Singh D.,University of Manchester | Magnussen H.,Pulmonary Research Institute at Hospital Grosshansdorf | Kirsten A.,Pulmonary Research Institute at Hospital Grosshansdorf | Mindt S.,Klinische Forschung Hamburg GmbH | And 4 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2012

This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 μg, 200 μg, 400 μg (via Genuair ®*), formoterol 12 μg (via Aerolizer ®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV 1) normalised area under the curve (AUC) 0-12 on Day 7. Secondary endpoints were: change from baseline in FEV 1 normalised AUC 12-24, FEV 1 normalised AUC 0-24 and morning pre-dose FEV 1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV 1 normalised AUC 0-12 vs placebo (p < 0.0001). FEV 1 normalised AUC 12-24, FEV 1 normalised AUC 0-24, and morning pre-dose FEV 1 were also statistically significantly greater with all aclidinium doses vs placebo (p < 0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 μg vs 100 μg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV 1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 μg and 400 μg as suitable doses for further investigation in Phase III trials. © 2012 Elsevier Ltd. Source

Buil M.A.,Almirall R and nter | Calbet M.,Almirall R and nter | Castillo M.,Almirall Barcelona Science Park Unit | Castro J.,Almirall R and nter | And 11 more authors.
European Journal of Medicinal Chemistry | Year: 2016

Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times. © 2016 Elsevier Masson SAS. All rights reserved. Source

Ramis I.,Almirall R and nter | Otal R.,Almirall R and nter | Carreno C.,Almirall R and nter | Domenech A.,Almirall R and nter | And 8 more authors.
Pharmacological Research | Year: 2015

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma. © 2015 Elsevier Ltd. All rights reserved. Source

Alba J.D.,Almirall R and nter | Otal R.,Almirall R and nter | Calama E.,Almirall R and nter | Domenech A.,Almirall R and nter | And 3 more authors.
Clinical Science | Year: 2015

RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition. © 2015 Authors. Source

Aparici M.,Almirall R and nter | Gomez-Angelats M.,Almirall R and nter | Vilella D.,Almirall R and nter | Otal R.,Almirall R and nter | And 15 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

Abediterol is a novel potent, long-acting inhaled β2- adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β2-adrenoceptor and a functional selectivity over β1-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human β2- adrenoceptor (Emax = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC50 = 1.9 ± 0.4 nM; t1/2 onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t1/2 ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t1/2 = 36 h) than salmeterol (t1/2 = 6 h) and formoterol (t1/2 = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics. Source

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