Comparison of several new 5-lipoxygenase inhibitors in a rat Arthus pleurisy model.
The 5-lipoxygenase inhibitors WY-50,295 tromethamine, A-64,077, L-663,536 and ICI-207,968 were compared in a reverse passive Arthus reaction-induced pleurisy model of eicosanoid biosynthesis in the rat. When a 1 h pretreatment schedule was employed, all four inhibitors equivalently blocked leukotriene B4 (LTB4) production with ED50 values of 2.0-2.9 mg/kg p.o. Conversely, WY-50,295 tromethamine (225 mg/kg p.o.) and L-663,536 (100 mg/kg p.o.) did not significantly alter thromboxane B2 (TxB2) levels, whereas A-64,077 (50 mg/kg p.o.) and ICI-207,968 (100 mg/kg p.o.) significantly reduced TxB2 by 50 and 72%, respectively. When 3 and 18 h pretreatment schedules were employed, WY-50,295 tromethamine demonstrated a longer duration of action than the other 5-lipoxygenase inhibitors with ED50 values of 1.7 and 6.3 mg/kg p.o., respectively. At doses of 50 and 100 mg/kg p.o., all drugs tested significantly inhibited inflammatory cell influx by 15-27%, albeit in a non-dose-related manner. However, only A-64,077 significantly lowered fluid extravasation by 35%, presumably due to inhibition of cyclooxygenase product formation. These results demonstrate that in this rat reverse passive Arthus pleurisy model, WY-50,295 tromethamine potently and selectively inhibits 5-lipoxygenase in vivo, and possesses a longer duration of action than the other 5-lipoxygenase inhibitors employed.
Berkenkopf
J W
JW
Immunopharmacology Division, Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
Weichman
B M
BM
D000818:Animals; D001183:Arthus Reaction / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D005122:Exudates and Transudates / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008297:Male; D010998:Pleurisy / Q000188:drug therapy* / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats
D015415:Biomarkers; D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4