FR167653, a cytokine synthesis inhibitor, exhibits anti-inflammatory effects early in rat carrageenin-induced pleurisy but no effect later

We prepared a pharmacological profile of FR167653 (1-[7-(4-fluorophenyl)-1, 2,3,4-tetrahydro-8-(4-pyridyl) pyrazolo[5,1-c] [1,2,4]triazin-2-yl]-2-pheny lethanedion sulfate monohydrate), a cytokine synthesis inhibitor, on early (5 h after irritation) and late (14-24 h after irritation) phases of rat ca rrageenin-induced pleurisy and on mediator-induced plasma exudation, in com parison with that of dexamethasone. In the early phase, FR167653 (30 mg/kg) and dexamethasone (0.3 mg/kg) equipotently suppressed plasma exudation and leukocyte infiltration. Furthermore, both agents significantly lowered the prostanoid levels in the exudate. Expression of cyclooxygenase-2 protein o n leukocytes in the early phase of inflammation was not affected by dexamet hasone, but it was suppressed by FR167653. However, FR167653 did not signif icantly affect the leukocyte mRNA level of cyclooxygenase-2. Both agents si gnificantly suppressed the levels of both tumor necrosis factor-alpha and i nterleukin-1 beta. FR167653 had a different pharmacological profile from de xamethasone in the late phase of this model in that, unlike dexamethasone, it did not affect cyclooxygenase-2 expression in mesothelial cells, the 6-k eto-prostaglandin F-1 alpha level in the exudate or hyperplasia of mesothel ium. Furthermore, unlike dexamethasone, FR167653 did not consistently inhib it mediator-induced plasma exudation. These results suggest that FR167653 o r one of its analogs may be new candidates for therapy with a spectrum of a ctivity distinct from that of current anti-inflammatory steroids.