In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist

The Japanese Journal of Pharmacology

Takaaki Obata¹  Hideki Aishita¹  Naoki Nakagawa¹  Tadamasa Kobayashi¹  Fumio Nambu¹  Tamiya Terawaki¹  Yutaka Okada¹ 

[1] Minase Research Institute, Ono Pharmaceutical Co., Ltd.

关键词: ONO-1078;    Leukotrienes (peptide) (LTC4;    LTD4 and LTE4);    Bronchoconstriction;    Vascular permeability;    FPL55712;   

DOI  :  10.1254/jjp.60.217

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(32)Cited-By(55)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 μg/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 μg/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) F2α, PGD2, 9α, 11β-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.

【 授权许可】

Unknown