Background: Long acting bronchodilators are the standard of care in the management of chronic obstructive\npulmonary disease (COPD). The aim of this study was to investigate the efficacy and safety of V0162, a novel\nanticholinergic agent with bronchodilator properties, in preclinical models and in patients with COPD.\nMethods: Guinea pigs were used to evaluate the impact of V0162 on the acetylcholine or histamine-induced\nbronchoconstriction. V0162 was also investigated in an allergic asthma model on ovalbumin-sensitized guinea pig.\nFor clinical investigations, healthy volunteers were included in a dose-escalation, randomized, placebo-controlled\nphase I study to determine the maximal tolerated dose, followed by a randomized, placebo-controlled, cross-over\nphase II study in patients with COPD. V0162 was given via inhalation route. The objectives of the phase I/II study\nwere to assess the safety and efficacy of V0162, in terms of bronchodilation and reduction in hyperinflation.\nResults: Preclinical results showed that V0162 was able to prevent bronchoconstriction induced either by\nacetylcholine or histamine. V0162 reversed the bronchoconstriction and airway inflammation caused by ovalbumin\nchallenge in sensitized guinea pigs. In the healthy volunteers study, 88 subjects were enrolled: 66 received V0162\nand 22 received placebo. No particular safety concerns were raised. The maximal tolerated dose was not reached\nand the dose escalation was stopped at 2400 ?g. A total of 20 patients with COPD were then enrolled. All patients\nreceived a single-dose of V0162 1600 ?g and of placebo in two alternating periods. In COPD patients, V0162\ndemonstrated a significant increase in FEV1 compared with placebo (148 �± 137 ml vs. 36 �± 151 ml, p = 0.003).\nThis bronchodilatory effect was corroborated by a reduction in hyperinflation. There was a trend toward dyspnea\nrelief (change in visual analog scale at 22 h, ?15.1 �± 26.0 mm vs.- 5.3 �± 28.8 mm with placebo, p = 0.054). No serious\nadverse events (AEs) were reported. Most common AEs were productive and non-productive cough, dyspnea\nand pruritus.\nConclusions: V0162 improved pulmonary function and tended to improve dyspnea in patients with COPD over\nmore than 24 h. The slight plasmatic exposure observed might support the good safety profile.
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