KP-496

Aims: The aim of this study was to evaluate the effects of inhaled KP-496, a novel dual antagonist for cysteinyl leukotriene receptor 1 and thromboxane A₂ receptor, on the allergic asthmatic responses in guinea pigs. Methods: Actively sensitized animals were repeatedly exposed to antigen, and KP-496 (0.01 and 0.1%) was inhaled for 5 min before every antigen exposure. After evaluating the effects of KP-496 on asthmatic responses, such as immediate and late asthmatic response (IAR and LAR) and airway hyperresponsiveness (AHR), histopathological analyses of the lungs of asthmatic animals were made. Results: KP-496 significantly inhibited both antigen-induced LAR and AHR to acetylcholine, and slightly inhibited antigen-induced IAR. Furthermore, histopathological analyses of the lungs of the asthmatic animals demonstrated the following: (1) KP-496 suppressed infiltration of eosinophils around airway smooth muscle, (2) KP-496 suppressed airway epithelial hypertrophy, and (3) KP-496 suppressed increased mucus production in the airway. Conclusion: In addition to suppression of LAR and AHR, our findings demonstrated that KP-496 inhibits features of airway inflammation. Since these broad ameliorative effects of KP-496 on asthmatic pathology are thought to result from the inhibition of multiple chemical mediators, KP-496 will be a potent agent in the treatment of bronchial asthma.

Bronchial asthma is characterized by chronic airway inflammation. Eosinophils are involved in airway inflammation and play crucial roles in asthma. There is accumulating evidence to suggest contributions of cysteinyl leukotrienes (cysLTs) and thromboxane (TX) A(2) to the recruitment of eosinophils into lung in asthmatics. KP-496 is a novel dual antagonist for CysLT receptor type 1 and TXA(2) receptors. The aim of this study was to evaluate the anti-inflammatory effects of KP-496 on Sephadex-induced airway inflammation. Sephadex suspension was intratracheally injected into rats. Amounts of regulated on activation, normal T cell expressed and secreted (RANTES) and eotaxin, and numbers of infiltrating cells in bronchoalveolar lavage fluid were measured 24 and 48 h after Sephadex injection, respectively. KP-496 (30, 100 microg/head) was intratracheally administered to rats 1 h before and 7 h after Sephadex injection. KP-496 and prednisolone (10 mg/kg, per os) exhibited significant inhibitory effects on infiltration of total cells and eosinophils into lung. Production of RANTES was significantly inhibited by KP-496 and prednisolone. Production of eotaxin was significantly inhibited by prednisolone. KP-496 also inhibited the production of eotaxin, though this effect was not significant. These results demonstrate that KP-496 exhibited the anti-inflammatory effects by inhibiting infiltration of inflammatory cells and productions of RANTES and eotaxin.