Misoprostol stimulates leukocyte cyclic adenosine 3',5' monophosphate production and synergizes with colchicine: novel combination of established drugs may boost anti-inflammatory potential.
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.
Smallwood
J I
JI
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Malawista
S E
SE
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D016595:Misoprostol / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D016595:Misoprostol; D000242:Cyclic AMP; D000527:Alprostadil; D003078:Colchicine; D015056:1-Methyl-3-isobutylxanthine