Effects of selective COX-2 inhibition on prostanoids and platelet physiology in young healthy volunteers.
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(1alpha), 11-dehydro-TXB(2), 2,3-dinor-TXB(2), and dinor-6-keto-PGF(1alpha)), 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(1alpha), and on dinor-6-keto-PGF(1alpha), 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.


CONCLUSIONS
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.
Graff
J
J
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Theodor Stern Kai 7, Frankfurt am Main, Germany.
Skarke
C
C
Klinkhardt
U
U
Watzer
B
B
Harder
S
S
Seyberth
H
H
Geisslinger
G
G
Nüsing
R M
RM
D000328:Adult; D000951:Antigens, Neoplasm / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000068579:Celecoxib; D002448:Cell Adhesion / Q000187:drug effects; D000242:Cyclic AMP / Q000097:blood; D051546:Cyclooxygenase 2 / Q000097:blood*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004311:Double-Blind Method; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009288:Naproxen / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D019007:P-Selectin / Q000097:blood; D010741:Phospholipases A / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D040201:Platelet Membrane Glycoprotein IIb / Q000097:blood; D011453:Prostaglandins / Q000097:blood* / Q000652:urine; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D012016:Reference Values; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D013450:Sulfones / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000097:blood; D013931:Thromboxanes / Q000097:blood / Q000652:urine; D013997:Time Factors
D000951:Antigens, Neoplasm; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D019007:P-Selectin; C505096:PCA-1 antigen, human; D040201:Platelet Membrane Glycoprotein IIb; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D018180:Thrombomodulin; D013931:Thromboxanes; C116926:rofecoxib; D009288:Naproxen; D005340:Fibrinogen; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D010741:Phospholipases A; D013917:Thrombin; D000068579:Celecoxib