REDUCTION OF INFLAMMATION AND PYREXIA IN THE RAT BY ORAL-ADMINISTRATION OF SDZ-224-015, AN INHIBITOR OF THE INTERLEUKIN-1-BETA CONVERTING-ENZYME

1 The aim of this study was to determine whether a synthetic inhibitor of the interleukin-lp converting enzyme (ICE) displays oral activity in models of inflammation. 2 To this end, the ICE inhibitor, SDZ 224-015, was examined in rat paw oedema, pyrexia and nociception tests. 3 SDZ 224-015 (0.3-300 mu g kg(-1)) potently reduced carrageenin-induced paw oedema, with an oral ED(50) of approximately 25 mu g kg(-1). This effect was independent of endogenous glucocorticoid, as shown by retention of activity upon adrenalectomy. 4 Pyrexia induced by lipopolysaccharide (0.1 mg kg(-1) s.c.) or by interleukin-1 beta (100 ng i.v.) was also reduced, over a similar dose-range to oedema (oral ED(50)s 11 mu g kg(-1) and 4 mu g kg(-1) respectively). 5 SDZ 224-015 (0.2-5 mg kg(-1), p.o.) displayed analgesic activity in the Randall-Selitto yeast-inflamed paw pressure test, significant at a dose of 1 mg kg(-1) p.o. 6 Thus, SDZ 224-015 has potent oral activity in several acute models for inflammation, suggesting that ICE inhibitors may constitute a novel type of anti-inflammatory agent.