A HUMAN WHOLE-BLOOD ASSAY FOR CLINICAL-EVALUATION OF BIOCHEMICAL EFFICACY OF CYCLOOXYGENASE INHIBITORS

In this study, PGE(2) levels in lipopolysaccharide (LPS)-challenged hu man whole blood and TxB(2) levels following blood coagulation were mea sured as biochemical index for cyclooxygenase (Cox)-2 and Cox-1 activi ty respectively. Incubation of human mononuclear cells isolated from w hole blood with LPS (100 mu g/mL) induced a time-dependent increase in the expression of Cox-2 protein (>100 fold at 24hr). This is associat ed with increases in PGE(2) production and free arachidonate release i n the plasma. Cox-1 protein was detected in the human mononuclear cell s at time zero but was not induced by either LPS or PBS. Most non-ster oidal antiinflammatory drugs (NSAIDs) are more potent at inhibiting Co x-1 than Cox-2. Five experimental compounds CGP-28238, Dup-697, NS-398 , SC-58125 and L-745,337, have a greater selectivity for Cox-2. Indome thacin at a single oral dose (25 mg) inhibited approximately 90% the w hole blood Cox-2 and Cox-1 activities ex vivo in healthy subjects. The se results support the use of this assay to assess the biochemical eff icacy of selective Cox-2 inhibitors in clinical trials.