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

Abstract

1. The aim of this study was to determine whether a synthetic inhibitor of the interleukin-1 beta 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 micrograms kg-1) potently reduced carrageenin-induced paw oedema, with an oral ED50 of approximately 25 micrograms 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 ED50s 11 micrograms kg-1 and 4 micrograms 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.

• Authors: P R Elford, R Heng, L Révész, A R MacKenzie
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 115 Issue 4 Pg. 601-6 (Jun 1995) ISSN: 0007-1188 [Print] England
• PMID: 7582478 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cysteine Proteinase Inhibitors
• Interleukin-1
• Lipopolysaccharides
• Oligopeptides
• SDZ 224015
• Cysteine Endopeptidases
• Caspase 1

Topics

• Administration, Oral
• Adrenalectomy
• Analgesia
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacology, therapeutic use)
• Caspase 1
• Cells, Cultured
• Cysteine Endopeptidases (drug effects, metabolism)
• Cysteine Proteinase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Edema (chemically induced, drug therapy)
• Enzyme-Linked Immunosorbent Assay
• Fever (drug therapy)
• Injections, Intravenous
• Injections, Subcutaneous
• Interleukin-1 (administration & dosage, toxicity)
• Lipopolysaccharides (administration & dosage, toxicity)
• Male
• Oligopeptides (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship