Misoprostol stimulates leukocyte cyclic adenosine 3',5' monophosphate production and synergizes with colchicine: novel combination of established drugs may boost anti-inflammatory potential

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 269; no. 3; pp. 1196 - 1204
• Main Authors: SMALLWOOD, J. I, MALAWISTA, S. E
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.06.1994
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; Alprostadil - pharmacology; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Colchicine - pharmacology; Cyclic AMP - biosynthesis; Dose-Response Relationship, Drug; Drug Synergism; Humans; Leukocytes - drug effects; Leukocytes - metabolism; Medical sciences; Misoprostol - pharmacology; Pharmacology. Drug treatments; Drug combination; Enzyme; Leukocyte; Antiinflammatory agent; Phosphorus-oxygen lyases; Cyclic AMP; Prostaglandin E1; Lyases; Synergism; Adenylate cyclase; Enzymatic activity; Analog; Drug interaction; Mechanism of action; Prostaglandin derivatives
• ISSN: 0022-3565; 1521-0103

Elevation of intracellular cyclic adenosine 3',5' monophosphate (cAMP) inhibits various proinflammatory and immune responses of leukocytes. Among agents known to stimulate cAMP production in these cells, prostaglandins E (PGEs) have received particular attention as potential immunosuppressive and/or anti-inflammatory drugs. Their clinical use, however, is limited by poor oral absorption and extreme metabolic instability. Misoprostol, a synthetic analog of PGE1 that can be given orally and that has a significantly longer biological half-life, is now used to prevent or treat nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury. Because it might also exert anti-inflammatory effects on leukocytes, we have characterized the effects of misoprostol on cAMP production in these cells. We have found that misoprostol does stimulate cAMP production, although with some-what less potency and maximal effect than PGE1; this stimulation is synergistically increased by pretreatment of cells with colchicine; a clinically relevant dose of colchicine is effective given sufficient pretreatment time, and preexposure of cells to colchicine enables a clinically relevant dose of misoprostol to stimulate cAMP generation. We conclude that colchicine and misoprostol represent a drug combination that might prove clinically useful for therapy of inflammatory disease.