Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2

Abstract

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 2 and on systemic biosynthesis of prostacyclin in vivo . 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 2 -dependent aggregation, induced ex vivo by arachidonic acid (83 ± 11% vs. 11.9 ± 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB 2 (−95 ± 2% vs. −6.9 ± 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB 2 (−70 ± 9.9% vs. −20.3 ± 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA 2 -dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB 2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE 2 in whole blood ex vivo ) 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 1α . These data suggest that ( i ) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; ( ii ) comparable COX-2 inhibition is attained by celecoxib (100–800 mg) and ibuprofen (800 mg) after acute dosing; and ( iii ) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.

Screening for atherosclerosis in patients with rheumatoid arthritis: Comparison of two in vivo tests of vascular function

“…In particular, NSAIDs could have a significant impact on endothelial function. The nonselective NSAIDs inhibit production of both prostacyclin (a vasodilator) and thromboxane A 2 (a vasoconstrictor), whereas the cyclooxygenase-2 (COX-2)-specific inhibitors selectively inhibit prostacyclin alone (39). Fifty-six percent of the RA patients in this study were taking various selective and nonselective NSAIDs, the plasma half-lives of which range from 1.5 to 17 hours.…”

The pharmacological properties and clinical use of valdecoxib, a new cyclo‐oxygenase‐2‐selective inhibitor

“…As COX-2 is constitutively expressed in the kidney and contributes to renal haemodynamics, 52 the renal safety of COX-2 inhibition using valdecoxib has been questioned. Pooled data on renal safety obtained from osteoarthritis and rheumatoid arthritis trials have demonstrated that the incidence of common renal adverse effects (albuminuria, peripheral oedema and hypertension) following selective COX-2 inhibition with 40 mg of valdecoxib is higher (0.9%, 2.3% and 2.8%, respectively) than that for placebo (0.2%, 0.7% and 0.6%, respectively), but does not significantly exceed that for traditional NSAIDs (0.5%, 2.2% and 1.5%, respectively).…”

Rofecoxib does not compromise platelet aggregation during anesthesia and surgery

“…Inhibition of the COX-2 isoform limits the synthesis of inflammatory and algesic mediators as may be released during tissue injury and thereby provides effective analgesia. 1,5,[9][10][11][12][13][20][21][22] However, nonselective NSAIDs have not been uniformly embraced as perioperative analgesics, primarily because of potentially undesirable binding to the COX-1 isoform. Inhibition of this isoform prevents such constitutive physiologic functions as generation of thromboxane (for vasoconstriction and platelet-derived hemostasis) and maintenance of gastrointestinal mucosal integrity.…”