ORIGINAL ARTICLES
Effects of selective COX‐2 inhibition on prostanoids and platelet physiology in young healthy volunteers

https://doi.org/10.1111/j.1538-7836.2007.02782.xGet rights and content
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Summary

Background: Selective inhibitors of cyclooxygenase‐2 (COX‐2) called coxibs, are effective anti‐inflammatory and analgesic drugs. Recently, these drugs were associated with an increased risk for myocardial infarction and atherothrombotic events. The hypothesis of thromboxane‐prostacyclin imbalance has been preferred to explain these unwanted effects. Methods: We studied the effects of 14 days intake of rofecoxib (25 mg q.d.), celecoxib (200 mg b.i.d.), naproxen (500 mg b.i.d.) and placebo in a randomized, blinded, placebo‐controlled study in young healthy volunteers (median age 25–30 years, each group n =10). We assessed prostanoid metabolite excretion (PGE‐M, TXB2, 6‐keto‐PGF, 11‐dehydro‐TXB2, 2,3‐dinor‐TXB2, and dinor‐6‐keto‐PGF), the expression of platelet activation markers (CD62P, PAC‐1, fibrinogen), platelet‐leukocyte formation, the endogenous thrombin potential, platelet cAMP content and plasma thrombomodulin level. Results: Naproxen suppressed biosynthesis of PGE‐M, prostacyclin metabolites and thromboxane metabolites and thrombomodulin levels. In contrast, both coxibs had an inhibitory effect only on PGE‐M, 6‐keto‐PGF, and on dinor‐6‐keto‐PGF, whereas TXB2, 2,3‐dinor‐TXB2 and 11‐dehydro‐TXB2 excretion were unaffected. None of the coxibs exerted significant effects on the expression of platelet activation markers, cAMP generation, platelet‐leukocyte formation, or on thrombomodulin plasma levels. Interestingly, platelet TXB2 release during aggregation was enhanced after coxib treatment following arachidonic acid or collagen stimulation. Conclusion: In young healthy volunteers coxibs inhibit systemic PGE2 and PGI2 synthesis. Platelet function and expression of platelet aggregation markers are not affected; however, coxibs can stimulate TXB2 release from activated platelets. Combined decrease in vasodilatory PGE2 and PGI2 together with increased TXA2 in proaggregatory conditions may contribute to coxib side effects.

Keywords

coxibs
NSAID
platelet activation
prostacyclin
thrombin generation
thromboxane

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