DIFFERENTIAL INHIBITION OF HUMAN PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-1 AND SYNTHASE-2 BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS

We have evaluated the selectivity in vitro of various conventional non steroidal anti-inflammatory drugs (NSAIDs) and new anti-inflammatory c ompounds (NS-398, L-745,337 and SC58125) in inhibiting the cyclooxygen ase activity of platelet prostaglandin endoperoxide synthase (PGHS)-1 and monocyte PGHS-2 in a human whole blood assay. The effects of the c ompounds towards the cyclooxygenase activity of monocyte PGHS-2 induce d in response to lipopolysaccharide (LPS) was evaluated by measuring t he levels of PGE(2) produced in plasma. The effects of the same inhibi tors on platelet PGHS-1 activity were assessed by allowing 1-ml whole blood samples to clot at 37 degrees C for 1 h in the presence of the c ompounds and measuring immunoreactive TXB2 levels in serum. Under thes e experimental conditions, most compounds resulted equipotent towards the two isozymes. Differently, meloxicam, nimesulide and diclofenac we re approximately 10- to 20-fold more potent in inhibiting the cyclooxy genase acitvity of monocyte PGHS-2 than platelet PGHS-1. L-745,337, NS -398 and SC58125 achieved selective inhibition of monocyte PGHS-2 (IC5 0 PGHS-1/IC50 PGHS-2: <100) and may provide adequate tools to test the contribution of this novel pathway of arachidonate metabolism to huma n inflammatory disease and to verify tile hypothesis that the common s ide-effects of NSAIDs are due primarily to their ability to affect the activity of PGHS-1.