Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224‐015, an inhibitor of the interleukin‐1β converting enzyme

• Published in: British journal of pharmacology Vol. 115; no. 4; pp. 601 - 606
• Main Authors: Elford, P.R., Heng, R., Révész, L., MacKenzie, A.R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.1995; Nature Publishing
• Subjects: Administration, Oral; Adrenalectomy; Analgesia; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; Caspase 1; Cells, Cultured; Cysteine Endopeptidases - drug effects; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - administration & dosage; Cysteine Proteinase Inhibitors - pharmacology; Cysteine Proteinase Inhibitors - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Edema - chemically induced; Edema - drug therapy; Enzyme-Linked Immunosorbent Assay; Fever; Fever - drug therapy; inflammation; Injections, Intravenous; Injections, Subcutaneous; Interleukin-1 - administration & dosage; Interleukin-1 - toxicity; interleukin‐l; interleukin‐l converting enzyme; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - toxicity; Male; Medical sciences; Neuropharmacology; oedema; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Rat; Enzyme; Cysteine endopeptidases; Rodentia; Antiinflammatory agent; Enzyme inhibitor; Vertebrata; Chemotherapy; Mammalia; Analgesic; Treatment; Interleukin 1-β converting enzyme; Animal; Antipyretic; Hydrolases; Proteinases
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb14974.x

1 The aim of this study was to determine whether a synthetic inhibitor of the interleukin‐1β 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 μg kg−1) potently reduced carrageenin‐induced paw oedema, with an oral ED50 of approximately 25 μg 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‐1β (100 ng i.v.) was also reduced, over a similar dose‐range to oedema (oral ED50S 11 μg kg−1 and 4 μg 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.