Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2
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- B. F. McAdam
- EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104
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- F. Catella-Lawson
- EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104
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- I. A. Mardini
- EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104
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- S. Kapoor
- EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104
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- J. A. Lawson
- EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104
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- G. A. FitzGerald
- EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104
抄録
<jats:p> Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A <jats:sub>2</jats:sub> and on systemic biosynthesis of prostacyclin <jats:italic>in vivo</jats:italic> . Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA <jats:sub>2</jats:sub> -dependent aggregation, induced <jats:italic>ex vivo</jats:italic> by arachidonic acid (83 ± 11% vs. 11.9 ± 2.2%; <jats:italic>P</jats:italic> < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB <jats:sub>2</jats:sub> (−95 ± 2% vs. −6.9 ± 4.2%; <jats:italic>P</jats:italic> < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB <jats:sub>2</jats:sub> (−70 ± 9.9% vs. −20.3 ± 5.3%; <jats:italic>P</jats:italic> < 0.05) when compared with placebo. Despite a failure to suppress TxA <jats:sub>2</jats:sub> -dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB <jats:sub>2</jats:sub> 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE <jats:sub>2</jats:sub> in whole blood <jats:italic>ex vivo</jats:italic> ) to a comparable degree (−93.3 ± 2% vs. −83 ± 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF <jats:sub>1α</jats:sub> . These data suggest that ( <jats:italic>i</jats:italic> ) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; ( <jats:italic>ii</jats:italic> ) comparable COX-2 inhibition is attained by celecoxib (100–800 mg) and ibuprofen (800 mg) after acute dosing; and ( <jats:italic>iii</jats:italic> ) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 96 (1), 272-277, 1999-01-05
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1361137046376751616
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- NII論文ID
- 80010912130
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- ISSN
- 10916490
- 00278424
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