In vivo pharmacologic profile of ONO-1078: a potent, selective and orally active peptide leukotriene (LT) antagonist.
We investigated the in vivo antagonistic activity of ONO-1078 against peptide leukotrienes (LTs) in guinea pigs. ONO-1078, when administered p.o. (0.3-3 mg/kg), caused a dose-dependent reduction of LTC4-, LTD4- and LTE4-induced bronchoconstriction, LTD4-induced airway microvascular leakage and LTD4-induced increase in cutaneous vascular permeability. When administered intravenously, ONO-1078 (3-30 micrograms/kg) inhibited these responses approximately 200-600 fold more potently than FPL55712. When guinea pigs were treated with indomethacin to examine the antagonism of ONO-1078 on the direct action against peptide LTs, intravenous (3-30 micrograms/kg) and oral (0.3-3 mg/kg) administration of ONO-1078 also inhibited LTC4- and LTD4-induced bronchoconstriction, and its activity was approximately 300-500 fold more potent than that of FPL55712. ONO-1078 (10 mg/kg, i.v.) had no inhibitory effect on bronchoconstrictions induced by histamine, acetylcholine, serotonin, arachidonic acid, LTB4, prostaglandin (PG) F2 alpha, PGD2, 9 alpha, 11 beta-PGF2, a stable thromboxane A2 mimetic agent and platelet activating factor. Furthermore, oral administration of ONO-1078 (1-10 mg/kg) inhibited slow-reacting substance of anaphylaxis mediated bronchoconstriction induced by antigen in a dose-dependent manner. These results indicate that ONO-1078 is an extremely potent, selective and orally active peptide LT antagonist and that oral administration of ONO-1078 antagonizes not only exogenously administered peptide LTs but also endogenous peptide LTs.
Nakagawa
N
N
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Obata
T
T
Kobayashi
T
T
Okada
Y
Y
Nambu
F
F
Terawaki
T
T
Aishita
H
H
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001886:Bordetella pertussis / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D017999:Leukotriene E4; D008297:Male; D013189:SRS-A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology
D000942:Antigens, Bacterial; D002867:Chromones; D020024:Leukotriene Antagonists; D013189:SRS-A; D017999:Leukotriene E4; C006312:FPL 55712; C047681:pranlukast