Brideau C, Kargman S, Liu S, Dallob A L, Ehrich E W, Rodger I W, Chan C C
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
Inflamm Res. 1996 Feb;45(2):68-74. doi: 10.1007/BF02265118.
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.
在本研究中，分别测定了脂多糖（LPS）刺激的人全血中PGE2水平以及血液凝固后的TxB2水平，作为环氧化酶（Cox）-2和Cox-1活性的生化指标。用LPS（100μg/mL）孵育从全血中分离的人单核细胞，可诱导Cox-2蛋白表达呈时间依赖性增加（24小时时增加超过100倍）。这与血浆中PGE2生成增加和游离花生四烯酸释放增加相关。在时间零点时在人单核细胞中检测到Cox-1蛋白，但LPS或PBS均未诱导其表达。大多数非甾体抗炎药（NSAIDs）对Cox-1的抑制作用比对Cox-2更强。五种实验化合物CGP-28238、Dup-697、NS-398、SC-58125和L-745,337对Cox-2具有更高的选择性。单剂量口服吲哚美辛（25mg）在健康受试者体内可抑制约90%的全血Cox-2和Cox-1活性。这些结果支持在临床试验中使用该检测方法来评估选择性Cox-2抑制剂的生化疗效。
