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Effects of selective COX‐2 inhibition on prostanoids and platelet physiology in young healthy volunteers
Author(s) -
GRAFF J.,
SKARKE C.,
KLINKHARDT U.,
WATZER B.,
HARDER S.,
SEYBERTH H.,
GEISSLINGER G.,
NÜSING R. M.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02782.x
Subject(s) - platelet , medicine , pharmacology , physiology
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, TXB 2 , 6‐keto‐PGF 1α , 11‐dehydro‐TXB 2 , 2,3‐dinor‐TXB 2 , and dinor‐6‐keto‐PGF 1α ), 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 1α , and on dinor‐6‐keto‐PGF 1α , whereas TXB 2 , 2,3‐dinor‐TXB 2 and 11‐dehydro‐TXB 2 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 TXB 2 release during aggregation was enhanced after coxib treatment following arachidonic acid or collagen stimulation. Conclusion: In young healthy volunteers coxibs inhibit systemic PGE 2 and PGI 2 synthesis. Platelet function and expression of platelet aggregation markers are not affected; however, coxibs can stimulate TXB 2 release from activated platelets. Combined decrease in vasodilatory PGE 2 and PGI 2 together with increased TXA 2 in proaggregatory conditions may contribute to coxib side effects.