Effects of Y-24180, a long-acting and potent antagonist to platelet-activating factor, on immediate asthmatic response in guinea pigs.
The effect of Y-24180, a potent antagonist to-platelet-activating factor (PAF), was evaluated on the antigen-induced immediate asthmatic response (IAR) in actively sensitized guinea pigs that were pretreated with an antihistaminic agent, pyrilamine. Then, the effect was compared with that of other antiasthmatic agents. In a dose-dependent manner, Y-24180 (0.01-1 mg/kg, p.o.) suppressed the IAR, and WEB 2086 (0.1-10 mg/kg, p.o.), another PAF antagonist, also suppressed IAR in the same fashion as Y-24180. In contrast, AA-2414 (1-100 mg/kg,p.o.), a thromboxane A2 (TXA2) antagonist, was effective only at the beginning of the IAR and ONO-1078 (1-100 mg/kg, p.o.), a peptide leukotriene (pLT) antagonist, was effective only in the latter period, OKY-046, a TXA2 synthetase inhibitor, showed no significant suppression of the IAR at doses up to 100 mg/kg. Thus, PAF antagonists were more effective than the other agents tested in the present model for IAR. In a subsequent test, Y-24180 (1 mg/kg, p.o.) was confirmed to enhance the suppressive effects of theophylline (10 and 30 mg/kg, p.o.), procaterol (0.1 and 1 microgram/kg, i.v.), OKY-046 (100 mg/kg, p.o.) and ONO-1078 (100 mg/kg, p.o.) on the IAR. A combination of three agents, namely Y-24180 with OKY-046 and ONO-1078, completely suppressed the IAR. The results demonstrate that Y-24180 not only suppresses the IAR, but also enhances the suppressive effect of other antiasthmatic agents. Therefore, Y-24180 would be a clinically promising drug for the treatment of bronchial asthma.
Kagoshima
M
M
Research Laboratories, Yoshitomi Pharmacentical Industries, Ltd., Fukuoka, Japan.
Tomomatsu
N
N
Iwahisa
Y
Y
Yamaguchi
S
S
Kawakami
Y
Y
Terasawa
M
M
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D001381:Azepines / Q000008:administration & dosage*; D016227:Benzoquinones / Q000008:administration & dosage; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D002867:Chromones / Q000008:administration & dosage; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000008:administration & dosage; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013806:Theophylline / Q000627:therapeutic use; D014230:Triazoles / Q000008:administration & dosage*
D018927:Anti-Asthmatic Agents; D001381:Azepines; D016227:Benzoquinones; D001993:Bronchodilator Agents; D002867:Chromones; D006538:Heptanoic Acids; D008689:Methacrylates; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; C068035:4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine; C060230:seratrodast; D013806:Theophylline; C034364:ozagrel; C047681:pranlukast