Vol. 282, Issue 2, 1094-1101, 1997

Evaluation of the Antiinflammatory Activity of a Dual Cyclooxygenase-2 Selective/5-Lipoxygenase Inhibitor, RWJ 63556, in a Canine Model of Inflammation

T. Kirchner, D. C. Argentieri, A. G. Barbone, M. Singer, M. Steber, J. Ansell, S. A. Beers, M. P. Wachter, W. Wu, E. Malloy, A. Stewart and D. M. Ritchie

The R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.

Sterile perforated polyethylene spheres (wiffle golf balls) were implanted s.c. in beagle dogs. A local inflammatory reaction was elicited within the spheres by injecting carrageenan. Changes in leukocyte count, prostaglandin E₂, thromboxane B₂ and leukotriene B₄ levels were monitored in fluid samples collected over a 24-hr period. Blood samples were also collected at various time points and analyzed for prostaglandin E₂ and leukotriene B₄ production after ex vivo calcium ionophore treatment. Effects of standard antiinflammatory agents (aspirin, indomethacin, dexamethasone, tenidap and zileuton) and newer cyclooxygenase-2 (COX-2) selective agents (nimesulide, nabumetone and SC-58125) were determined after oral administration. Ex vivo inhibition of cyclooxygenase product synthesis (prostaglandin E₂, thromboxane B₂) in whole blood was used as an indicator of activity for the constitutive COX-1 isoform, although inhibition of the synthesis of these mediators in the chamber exudate during an inflammatory process is believed to represent COX-2 inhibition. Treatment effects on leukotriene B₄ production were also determined both ex vivo in whole blood and in the fluid. All of the compounds tested, except aspirin, inhibited leukocyte infiltration into the fluid exudate. Inhibitors that exert their effects on both isozymes of cyclooxygenase attenuate production of cyclooxygenase metabolites in both the inflammatory exudate and in peripheral blood ex vivo, although COX-2 selective inhibitors only demonstrated activity in the exudate. A 5-lipoxygenase inhibitor (zileuton), a corticosteroid (dexamethasone) and a dual COX-2 selective/5-lipoxygenase inhibitor (RWJ 63556) had similar profiles in that they all inhibited cell infiltration and eicosanoid production in the fluid and also attenuated leukotriene B₄ production in both the fluid and blood.