A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors

• DOI: 10.1007/bf02265118
• Publication Date: 2005-12-09T01:18:33Z
• Authors: C. Brideau; S. Kargman; S. Liu; A. L. Dallob; E. W. Ehrich; I. W. Rodger; C. -C. Chan
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; Arachidonic Acid; Anti-Inflammatory Agents, Non-Steroidal; Indomethacin; Dinoprostone; 3. Good health; Thromboxane B2; 03 medical and health sciences; Humans; Cyclooxygenase Inhibitors; Female

In this study, PGE2 levels in lipopolysaccharide (LPS)-challenged human whole blood and TxB2 levels following blood coagulation were measured as biochemical index for cyclooxygenase (Cox)-2 and Cox-1 activity respectively. Incubation of human mononuclear cells isolated from whole blood with LPS (100 mu g/mL) induced a time-dependent increase in the expression of Cox-2 protein (>100 fold at 24 hr). This is associated with increases in PGE2 production and free arachidonate release in the plasma. Cox-1 protein was detected in the human mononuclear cells at time zero but was not induced by either LPS or PBS. Most non-steroidal anti-inflammatory drugs (NSAIDs) are more potent at inhibiting Cox-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. Indomethacin at a single oral dose (25 mg) inhibited approximately 90% the whole blood Cox-2 and Cox-1 activities ex vivo in healthy subjects. These results support the use of this assay to assess the biochemical efficacy of selective Cox-2 inhibitors in clinical trials.