Pulmonary pharmacology & therapeutics
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Pulm Pharmacol Ther · Apr 2013
A soluble guanylate cyclase stimulator, BAY 41-8543, preserves right ventricular function in experimental pulmonary embolism.
Pulmonary embolism (PE) increases pulmonary vascular resistance, causing right ventricular (RV) dysfunction, and poor clinical outcome. Present studies test if the soluble guanylate cyclase stimulator BAY 41-8543 reduces pulmonary vascular resistance and protects RV function. Experimental PE was induced in anesthetized, male Sprague-Dawley rats by infusing 25 μm polystyrene microspheres (1.95 million/100 g body wt, right jugular vein) producing moderate PE. ⋯ BAY 41-8543 significantly improved all three indices of RV heart function (PSP 35 ± 3.5, +dP/dt 1129 ± 100, -dP/dt -568 ± 87). Experimental PE produced increased PVR and RV dysfunction, which were ameliorated by treatment with BAY 41-8543. Thus, there is vasodilator reserve in this model of experimental PE that can be exploited to reduce the stress upon the heart and preserve RV contractile function.
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Pulm Pharmacol Ther · Feb 2013
ReviewEmerging mediators of airway smooth muscle dysfunction in asthma.
Phenotypic changes in airway smooth muscle are integral to the pathophysiological changes that constitute asthma - namely inflammation, airway wall remodelling and bronchial hyperresponsiveness. In vitro and in vivo studies have shown that the proliferative, secretory and contractile functions of airway smooth muscle are dysfunctional in asthma. These functions can be modulated by various mediators whose levels are altered in asthma, derived from inflammatory cells or produced by airway smooth muscle itself. In this review, we describe the emerging roles of the CXC chemokines (GROs, IP-10), Th17-derived cytokines (IL-17, IL-22) and semaphorins, as well as the influence of viral infection on airway smooth muscle function, with a view to identifying new opportunities for therapeutic intervention in asthma.
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Pulm Pharmacol Ther · Dec 2012
Randomized Controlled Trial Multicenter Study28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial.
Umeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta₂ agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD. ⋯ Once-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.
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Pulm Pharmacol Ther · Dec 2012
Comparative StudyA comparison of antiasthma drugs between acute and chronic ovalbumin-challenged guinea-pig models of asthma.
Pre-clinical evaluation of asthma therapies requires animal models of chronic airways inflammation, airway hyperresponsiveness (AHR) and lung remodelling that accurately predict drug effectiveness in human asthma. However, most animal models focus on acute allergen challenges where chronic inflammation and airway remodelling are absent. Chronic allergen challenge models have been developed in mice but few studies use guinea-pigs which may be more relevant to humans. ⋯ GW274150 also inhibited the LAR, AHR and eosinophil influx in the acute model, but not, together with the remodelling, in the chronic model. In the clinical setting, inhaled corticosteroids and phosphodiesterase 4 inhibitors are relatively effective against most features of asthma whereas the iNOS inhibitor GW274150 was ineffective. Thus, while there remain certain differences between our data and clinical effectiveness of these antiasthma drugs, a chronic pulmonary inflammation guinea-pig model does appear to be a better pre-clinical predictor of potential asthma therapeutics than an acute model.
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Pulm Pharmacol Ther · Aug 2012
ReviewCommonalities between the pro-fibrotic mechanisms in COPD and IPF.
COPD and IPF are two chronic lung diseases which are characterized by a decline in lung function, resulting in significant morbidity and mortality. Both of these diseases are more commonly associated with an aging population and the duration for which the disease has been underlying is often unknown. Significant matrix deposition occurs, resulting in either non-reversible airways obstruction in the case of COPD and impaired gas exchange and parenchymal consolidation in IPF. ⋯ Moreover, in the extreme fibrotic setting of IPF, the remodelling is sometimes associated with uncontrolled wound healing responses. As wound healing is a critical aspect to maintaining tissue function and homeostasis, targeting this process directly may result in safety concerns. This review therefore describes some of the recent advances in ascertaining pathways promoting lung fibrosis that may be amenable to therapeutic intervention in both COPD and IPF.