A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors
A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors
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DOI：
10.1007/bf02265118
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发表时间：
1996-02-01
影响因子：
6.7
通讯作者：
Chan, CC
中科院分区：
文献类型：
--
作者：
Brideau, C;Kargman, S;Chan, CC
本研究以脂多糖（LPS）刺激的人全血中PGE（2）水平和凝血后TxB（2）水平分别作为环氧化酶（考克斯）-2和考克斯-1活性的生化指标。从全血分离的人单核细胞与LPS（100 μ g/mL）孵育诱导考克斯-2蛋白表达的时间依赖性增加（在24小时时>100倍）。这与血浆中PGE（2）产生和游离花生四烯酸释放的增加有关。考克斯-1蛋白在人单核细胞中在时间0检测到，但未被LPS或PBS诱导。大多数非甾体类抗炎药（NSAID）对考克斯-1的抑制作用强于对考克斯-2的抑制作用。五种实验化合物CGP-28238、Dup-697、NS-398、SC-58125和L-745，337对考克斯-2具有更高的选择性。在健康受试者中，单次口服剂量（25 mg）的吲哚美辛离体抑制约90%的全血考克斯-2和考克斯-1活性。这些结果支持在临床试验中使用该测定来评估选择性考克斯-2抑制剂的生化功效。
In this study, PGE(2) levels in lipopolysaccharide (LPS)-challenged human whole blood and TxB(2) 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 24hr). This is associated with increases in PGE(2) 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 antiinflammatory 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.