MISOPROSTOL STIMULATES LEUKOCYTE CYCLIC ADENOSINE-3',5'-MONOPHOSPHATEPRODUCTION AND SYNERGIZES WITH COLCHICINE - NOVEL COMBINATION OF ESTABLISHED DRUGS MAY BOOST ANTIINFLAMMATORY 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, prosta glandins E (PGEs) have received particular attention as potential immu nosuppressive and/or anti-inflammatory drugs. Their clinical use, howe ver, is limited by poor oral absorption and extreme metabolic instabil ity. Misoprostol, a synthetic analog of PGE(1) that can be given orall y and that has a significantly longer biological half-life, is now use d to prevent or treat nonsteroidal anti-inflammatory drug (NSAID)-indu ced gastric injury. Because it might also exert anti-inflammatory effe cts on leukocytes, we have characterized the effects of misoprostol on cAMP production in these cells. We have found that misoprostol does s timulate cAMP production, although with somewhat less potency and maxi mal effect than PGE(1); this stimulation is synergistically increased by pretreatment of cells with colchicine; a clinically relevant dose o f colchicine is effective given sufficient pretreatment time, and pree xposure of cells to colchicine enables a clinically relevant dose of m isoprostol to stimulate cAMP generation. We conclude that colchicine a nd misoprostol represent a drug combination that might prove clinicall y useful for therapy of inflammatory disease.