The effects of inhaled KP-496, a novel dual antagonist for cysteinyl leukotriene receptor and thromboxane A(2) receptor, on allergic asthmatic responses in guinea pigs.
OBJECTIVE
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 A(2) 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.


CONCLUSIONS
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.
Suda
Masahiro
M
Department of Pharmacology, Central Research Laboratories, Kaken Pharmaceutical Co., Yamashina-ku, Kyoto, Japan. suda_masahiro@kaken.co.jp
Okuda
Toshiaki
T
Ishimura
Masakazu
M
Kurokawa
Shigeo
S
Tokuoka
Shota
S
Nakamura
Tsutomu
T
Takahashi
Yoshimasa
Y
Tanaka
Hiroyuki
H
Nagai
Hiroichi
H
D000109:Acetylcholine / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy; D018077:Receptors, Leukotriene / Q000187:drug effects*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
D018927:Anti-Asthmatic Agents; D001565:Benzoates; C528276:KP-496; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013844:Thiazoles; D010047:Ovalbumin; C083169:leukotriene D4 receptor; D000109:Acetylcholine