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Immunopharmacological properties of a new antiallergic agent KW-4679
WS15-9 Immunopharmacological properties of a new antiallergic agent KW-4679o K. Oh~ri, H. I s h i i , H. Manabe, Y. Sasaki and S. Okumura Department of Pharmacology, Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo, Co., Ltd., Shizuoka 411, Japan. The antiallergic a c t i v i t y p r o f i l e of KW-4679 (Z-ll-(3-dimethylaminopropyliden)-6,11dihydrodibenz[b,e]oxepin-2-acetic acid) has been compared with that of ketotifen in several in vivo models of anaphylaxis. Oral administration of KW-4679 at a dose of O.Ol mg/kg or higher showed inhibitory effects on 48 hr homologous passive cutaneous anaphylaxis in rats and passive anaphylactic bronchoconstriction in guinea pigs. These inhibitory effects of KW-4679 persisted for at least 9 hrs. On PAF- and histamineinduced bronchoconstriction in guinea pigs, KW-4679 (O.Ol - lO mg/kg) caused dose-dependent inhibition. KW-4679 at a dose of 0.03 mg/kg or higher protected rats from compound 48/80-induced l e t h a l i t y . KW-4679 did not pass the blood/brain barrier at normal therapeutic dose levels and, therefore, had minimal sedative effects and no influence on the electroencephalographic a c t i v i t i e s in rats and rabbits. These results suggest that KW-4679 is a potent a n t i a l l e r g i c agent without any side effect.
WS15-10 COMPLEMENT ACTIVATION BY MAST CELLS IN VITRO N. Arizono, S. Nakao, and O. Takeoka Department of Pathology, Shiga University of Medical Science, Ohtsu, Japan In order to clarify the interaction between u n s e n s i t i z e d mast cells and serum complement, mast cells were collected from rat peritoneal cavity and incubated in vitro with fresh normal sera from humans, rats and guinea pigs. By the incubation with 20% human serum at 37°C for 15 min, most mast cells died and a substantial histamine release was observed. The toxic effect was not observed with h e r e d i t a r y C3 deficient sera or with Clq depleted sera. With adding i0 mM Mg-EGTA to the normal serum, the c y t o t o x i c i t y was eliminated. On the mast cell membrane treated with normal human serum, Clq and C3 were demonstrated. These results indicated that the classical complement pathway was activated by the coincubation with mast cells. The CH50 activity in human sera was reduced to one half after incubation with 2x10 mast cells/ml. On the other hand, neither the c y t o t o x i c i t y to mast cells, nor the reduction of CH50 was observed in rat and guinea pig sera. The results indicate that at least in rats u n s e n s i t i z e d mast cells will not trigger the complement activation.
WS15-11 EFFECT OF OKY-046, A SELECTIVE THROMBOXANE(TX)A~ SYNTHETASE INHIBITOR, ON AIRWAY H Y P E R R E S P O N S I V E N E S S MODELS OF GUINEA PIG? H. Komatsu, Y. Takehana, S. Hamano, S. Hiraku* and S. Ikeda Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., M a t s u m o t o and * Research Institute, 0no Pharmaceutical Co., Ltd., Osaka, Japan The airway h y p e r r e s p o n s i v e n e s s (AHR) is a characteristic feature of asthma. AHR was e x p e r i m e n t a l l y induced by an inhalation of plateletactivating factor (PAF), N - f o r m y l - m e t h i o n y l - l e u c y l - p h e n y l a l a n i n e (FMLP) and a stable TXAg-mimetic agent (STAg) in guinea pig anesthetized with urethane-chloral~se. The AHR was assassed by determining the provocative concentration of acetylcholine (Ach) aerosol that increased basal intraairway pressure up to i0 cm H20 (EDen) or produced a doubling of basal pulmonary resistance (ED200). PAF ~ ~g/ml) and FMLP (I00 ~g/ml)induced AHR was s i g n i f i c a n t l y suppressed by intraduodenal or oral administration of OKY-046 (I00 mg/kg) and aspirin (30 mg/kg). However, OKY-046 and aspirin did not inhibit STA2-induced AHR. The TXB~ concentration in b r o n c h o a l v e o l a r lavage fluid (BALF) of AHR a~imals markedly increased. OKY-046 significantly inhibited the increase of TXB~ in BALF. These results suggest that AHR in asthma may be closely mediated through TXA 2 .
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WS15-10 COMPLEMENT ACTIVATION BY MAST CELLS IN VITRO N. Arizono, S. Nakao, and O. Takeoka Department of Pathology, Shiga University of Medical Science, Ohtsu, Japan In order to clarify the interaction between u n s e n s i t i z e d mast cells and serum complement, mast cells were collected from rat peritoneal cavity and incubated in vitro with fresh normal sera from humans, rats and guinea pigs. By the incubation with 20% human serum at 37°C for 15 min, most mast cells died and a substantial histamine release was observed. The toxic effect was not observed with h e r e d i t a r y C3 deficient sera or with Clq depleted sera. With adding i0 mM Mg-EGTA to the normal serum, the c y t o t o x i c i t y was eliminated. On the mast cell membrane treated with normal human serum, Clq and C3 were demonstrated. These results indicated that the classical complement pathway was activated by the coincubation with mast cells. The CH50 activity in human sera was reduced to one half after incubation with 2x10 mast cells/ml. On the other hand, neither the c y t o t o x i c i t y to mast cells, nor the reduction of CH50 was observed in rat and guinea pig sera. The results indicate that at least in rats u n s e n s i t i z e d mast cells will not trigger the complement activation.
WS15-11 EFFECT OF OKY-046, A SELECTIVE THROMBOXANE(TX)A~ SYNTHETASE INHIBITOR, ON AIRWAY H Y P E R R E S P O N S I V E N E S S MODELS OF GUINEA PIG? H. Komatsu, Y. Takehana, S. Hamano, S. Hiraku* and S. Ikeda Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., M a t s u m o t o and * Research Institute, 0no Pharmaceutical Co., Ltd., Osaka, Japan The airway h y p e r r e s p o n s i v e n e s s (AHR) is a characteristic feature of asthma. AHR was e x p e r i m e n t a l l y induced by an inhalation of plateletactivating factor (PAF), N - f o r m y l - m e t h i o n y l - l e u c y l - p h e n y l a l a n i n e (FMLP) and a stable TXAg-mimetic agent (STAg) in guinea pig anesthetized with urethane-chloral~se. The AHR was assassed by determining the provocative concentration of acetylcholine (Ach) aerosol that increased basal intraairway pressure up to i0 cm H20 (EDen) or produced a doubling of basal pulmonary resistance (ED200). PAF ~ ~g/ml) and FMLP (I00 ~g/ml)induced AHR was s i g n i f i c a n t l y suppressed by intraduodenal or oral administration of OKY-046 (I00 mg/kg) and aspirin (30 mg/kg). However, OKY-046 and aspirin did not inhibit STA2-induced AHR. The TXB~ concentration in b r o n c h o a l v e o l a r lavage fluid (BALF) of AHR a~imals markedly increased. OKY-046 significantly inhibited the increase of TXB~ in BALF. These results suggest that AHR in asthma may be closely mediated through TXA 2 .
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