Background and purpose: KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT 1 ) and thromboxane A 2 (TXA 2 ) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction. Experimental approach: Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD 4 or U46619, a stable TXA 2 mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated. Key results: KP-496 significantly inhibited LTD 4 -and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT 1 antagonist, p.o., 0.3 mg kg À1 ) or seratrodast (a TP antagonist, p.o., 3 mg kg À1 ). KP-496 (1%) and oral co-administration of montelukast (10 mg kg À1 ) and seratrodast (20 mg kg À1 ) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge. Conclusions and implications: KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT 1 antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.
In the 94th Annual Meeting of the Japanese Pharmacological Society, we reported two kinds of pulmonary inflammatory models using lipopolysaccharide (LPS), LPS inhalation model and -GalCer-LPS instillation model. In the previous report, we concluded that these LPS-induced ARI models could be useful to evaluate therapeutic efficacy of drugs used for treatment of pneumonia.In the present study we carried out further research on LPS instillation model with a pretreatment of α-garactosyl ceramid (α-GalCer), and we also examined the effect of exosome from human adipose cell. We evaluated inflammatory cell infiltration in BALF (Broncho Alveolar Lavage Fluid), BALF supernatant cytokine level and SpO2. Exosome was found to be slightly effective to improve symptomatic parameters in this model. The action of exosome changed along with the time of administration. Exosome administrated 4hr after LPS instillation decreased body weight loss, inflammatory cell infiltration, IL-6 and IL-10 levels. On the other hand, administration of exosome 24hr after LPS instillation showed advanced histopathological appearance image of the lung. The results indicate that characteristic pathophysiological change of this model was identified.
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