A SELECTIVE INHIBITOR OF CYCLOOXYGENASE-2 REVERSES ENDOTOXIN-INDUCED PYRETIC RESPONSES IN NONHUMAN-PRIMATES

The anti-pyretic effect of a selective cyclooxygenase-2 inhibitor, DFU -(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H) furanone), was exa mined in conscious, un-restrained squirrel monkeys (Saimiri sciureus) using a radio telemetric system. Injection of bacterial endotoxin (lip opolysaccharide, 6 mu g kg(-1), i.v.) in squirrel monkeys caused a gra dual increase in core body temperature reaching a plateau of 2.07 +/- 0.17 degrees C above baseline at 2 h post-injection. Oral administrati on of DFU (1 mg kg(-1)) reduced, and DFU (3 mg kg(-1)) completely reve rsed the lipopolysaccharide-induced pyretic responses. The onset of ac tion of DFU (about 30 min) is in good agreement with the pharmacokinet ic profile of this compound in squirrel monkeys. The effect of DFU is comparable to that of a conventional non-selective non-steroidal anti- inflammatory drug (NSAID), diclofenac (3 mg kg(-1)). Since the plasma levels achieved for DFU at the dose employed in the present study are below the threshold required for inhibition of cyclooxygenase-l, it is concluded that the anti-pyretic effect of DFU can be attributed predo minantly to an inhibitory action on cyclooxygenase-2. Thus, lipopolysa ccharide-induced pyresis in squirrel monkeys can be used as a model fo r evaluation of anti-pyretic activity of cyclooxygenase inhibitors.