Effect of combined leukotriene D(4) and thromboxane A(2) receptor antagonist on mediator-controlled resistance in guinea pigs.
The effects of YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl )propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D(4) and thromboxane A(2) receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A(2), complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D(4) and thromboxane A(2) equally participated, ED(50) values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzo pyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1, 4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists.
Arakida
Y
Y
Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Ibaraki 305-8585, Tsukuba, Japan.
Ohga
K
K
Okada
Y
Y
Morio
H
H
Suwa
K
K
Yokota
M
M
Yamada
T
T
D000284:Administration, Oral; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000517:prevention & control; D016227:Benzoquinones / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D017999:Leukotriene E4 / Q000378:metabolism; D050356:Lipid Metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D010047:Ovalbumin / Q000276:immunology; D018077:Receptors, Leukotriene; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors
D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000941:Antigens; D016227:Benzoquinones; D002867:Chromones; D006538:Heptanoic Acids; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D017482:Receptors, Thromboxane; D013777:Tetrazoles; D013844:Thiazoles; C115704:YM 158; D007975:Leukotriene B4; D017997:Leukotriene C4; C060230:seratrodast; D013929:Thromboxane B2; D017999:Leukotriene E4; D010047:Ovalbumin; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C047681:pranlukast; D007213:Indomethacin