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