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

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Abstract

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 μ//mL) induced a time-dependent increase in the expression of Cox-2 protein (>100 fold at 24hr). 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 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.

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Authors and Affiliations

  1. Departments of Pharmacology, Biochemistry and Molecular Pharmacology, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, H9R 4P8, Pointe Claire-Dorval, Quebec, Canada

    C. Brideau, S. Kargman, S. Liu, I. W. Rodger & C. -C. Chan

  2. Department of Clinical Pharmacology, Merck & Co., 07065-0900, Rahway, NJ, USA

    A. L. Dallob & E. W. Ehrich

Authors
  1. C. Brideau
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  2. S. Kargman
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  3. S. Liu
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  4. A. L. Dallob
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  5. E. W. Ehrich
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  6. I. W. Rodger
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  7. C. -C. Chan
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accepted by G. Letts

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Brideau, C., Kargman, S., Liu, S. et al. A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. Inflamm Res 45, 68–74 (1996). https://doi.org/10.1007/BF02265118

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  • DOI: https://doi.org/10.1007/BF02265118

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