Effects of KP-496, a novel dual antagonist of leukotriene D(4) and thromboxane A (2) receptors on nasal blockage in guinea pig models of allergic rhinitis.
OBJECTIVE
KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis.


METHODS
Male Hartley guinea pigs were used.


METHODS
Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge.


METHODS
As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model).


RESULTS
Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges.


CONCLUSIONS
KP-496 may be clinically effective for nasal blockage in allergic rhinitis.
Department of Pharmacology, Kyoto Pharmaceutical University, Ltd., 5 Nakauchi, Misasagi, Yamashina, Kyoto 607-8414, Japan.
N
N
Mizutani
M
M
Suda
M
M
Ishimura
S
S
Kurokawa
T
T
Nabe
S
S
Kohno
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D019540:Area Under Curve; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects*; D015508:Nasal Obstruction / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D011058:Pollen / Q000276:immunology; D018077:Receptors, Leukotriene / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy* / Q000276:immunology; D012912:Sneezing / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
D001565:Benzoates; C528276:KP-496; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013844:Thiazoles; D010047:Ovalbumin; C083169:leukotriene D4 receptor