A selective inhibitor of cyclooxygenase-2 reverses endotoxin-induced pyretic responses in non-human primates.
The anti-pyretic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furano ne), was examined in conscious, un-restrained squirrel monkeys (Saimiri sciureus) using a radio telemetric system. Injection of bacterial endotoxin (lipopolysaccharide, 6 microg kg(-1), i.v.) in squirrel monkeys caused a gradual increase in core body temperature reaching a plateau of 2.07 +/- 0.17 degrees C above baseline at 2 h post-injection. Oral administration of DFU (1 mg kg(-1)) reduced, and DFU (3 mg kg(-1)) completely reversed the lipopolysaccharide-induced pyretic responses. The onset of action of DFU (about 30 min) is in good agreement with the pharmacokinetic 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-1, it is concluded that the anti-pyretic effect of DFU can be attributed predominantly to an inhibitory action on cyclooxygenase-2. Thus, lipopolysaccharide-induced pyresis in squirrel monkeys can be used as a model for evaluation of anti-pyretic activity of cyclooxygenase inhibitors.
Chan
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CC
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada. chi_chung_chan@merck.com
Panneton
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M
Taylor
A M
AM
Therien
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M
Rodger
I W
IW
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004731:Endotoxins; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy*; D005663:Furans / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012453:Saimiri; D013997:Time Factors
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D018712:Analgesics, Non-Narcotic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D005663:Furans; D007527:Isoenzymes; D008070:Lipopolysaccharides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases