Airway hyperresponsiveness and inflammation characterize the airways of individuals with asthma and chronic obstructive pulmonary disease (COPD). Hence, therapeutic approaches that attenuate such manifestations may offer promise in the management of these diseases. In the present study, we investigated whether a novel long-acting cholinergic antagonist, aclidinium bromide, modulates airway function and leukocyte trafficking in an Aspergillus fumigatus (Af)-induced murine model of asthma. Nebulized aclidinium (1 mg/ml) administration completely abrogated increases in methacholine-induced lung resistance in Af-exposed mice. Parallel assessment of dynamic compliance showed that aclidinium also completely restores methacholine-mediated decreases in naïve and Af-exposed mice. As evidenced by differential cell counts within bronchoalveolar lavage fluid, aclidinium also diminished (51±4%) Af-induced airway eosinophil numbers with no significant change in other immune cell types. Further assessment of cytokine and total protein levels in bronchoalveolar lavage fluid showed that aclidinium had little effect on IL-4 or IL-6 levels in either Af-exposed or naïve mice but markedly decreased total protein levels in bronchoalveolar lavage fluid. These data suggest that aclidinium, a selective muscarinic antagonist, not only acts as a bronchodilator but could also act as an anti-inflammatory agent with potential clinical benefits in the treatment of COPD and asthma.
"These data suggest that anticholinergics such as tiotropium bromide in COPD (Oenema et al., 2010; Wollin and Pieper, 2010) may offer value in IL-8-dependent airway inflammation. In addition to inhibiting AHR, other M3R antagonists such as aclidinium bromide have substantial pharmacological benefits by inhibiting airway eosinophilia in murine models of asthma (Damera et al., 2010). Whether mast cell-derived histamine stimulates IL-8 secretion in ASM remains unknown; however, b-tryptase, another mast cellderived serine protease, substantially enhances IL-8 via transcriptional and post-transcriptional mechanisms (Mullan et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: In addition to hyperresponsiveness in asthma, airway smooth muscle (ASM) also manifests an inflammatory phenotype characterized by augmented expression of mediators that enhance inflammation, contribute to tissue remodelling and augment leucocyte trafficking and activity. Our present review summarizes contemporary understanding of ASM-derived mediators and their paracrine and autocrine actions in airway diseases. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1
British Journal of Pharmacology 12/2010; 163(1):68-80. DOI:10.1111/j.1476-5381.2010.01165.x · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bronchodilators provide the mainstay of pharmacologic therapy for chronic obstructive pulmonary disease (COPD), and anticholinergic bronchodilators, in particular, appear to be the most effective. There are currently two anticholinergic agents available in the US for the treatment of COPD (ipratropium bromide and tiotropium bromide), but several others are in various stages of development. Aclidinium bromide, a novel, long-acting, anticholinergic bronchodilator, is currently in Phase III trials for the management of COPD. Available evidence suggests that aclidinium is a safe and well tolerated drug with a relatively rapid onset and a sufficient duration of action to provide once-daily dosing. This article will provide a pharmacologic profile of aclidinium bromide and review the preclinical and clinical studies evaluating its safety and efficacy in the treatment of COPD.
International Journal of COPD 09/2011; 6(1):457-66. DOI:10.2147/COPD.S15524 · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Underlying inflammation in asthma increases the activity of the cholinergic nervous system, contributing to bronchoconstriction/airway hyper-responsiveness (AHR) and mucus hypersecretion. Inhaled anticholinergics with shorter duration of action were initially used and then discontinued when other bronchodilators became available. Previous preclinical and clinical studies have demonstrated that tiotropium bromide, a long-acting anticholinergic currently approved for chronic obstructive pulmonary disease, might be an effective therapy in asthma. Aclidinium bromide is an inhaled compound in the same class as tiotropium, which is currently being investigated in chronic obstructive pulmonary disease and asthma. In the evaluated study, it was found to reduce AHR and eosinophilic airway inflammation in an acute model of asthma.
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