Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin's cardioprotective effects.

Background-The current controversy on the potential cardioprotective effect of naproxen prompted us to evaluate the extent and duration of platelet, monocyte, and vascular cyclooxygenase (COX) inhibition by naproxen compared with low-dose aspirin. Methods and Results-We performed a crossover, open-label study of low-dose aspirin (100 mg/d) or naproxen (500 mg BID) administered to 9 healthy subjects for 6 days. The effects on thromboxane (TX) and prostacyclin biosynthesis were assessed up to 24 hours after oral dosing. Serum TXB 2 , plasma prostaglandin (PG) E 2 , and urinary 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1␣ were measured by previously validated radioimmunoassays. The administration of naproxen or aspirin caused a similar suppression of whole-blood TXB 2 production, an index of platelet COX-1 activity ex vivo, by 94Ϯ3% and 99Ϯ0.3% (meanϮSD), respectively, and of the urinary excretion of 11-dehydro-TXB 2 , an index of systemic biosynthesis of TXA 2 in vivo, by 85Ϯ8% and 78Ϯ7%, respectively, that persisted throughout the dosing interval. Naproxen, in contrast to aspirin, significantly reduced systemic prostacyclin biosynthesis by 77Ϯ19%, consistent with differential inhibition of monocyte COX-2 activity measured ex vivo. Conclusions-The regular administration of naproxen 500 mg BID can mimic the antiplatelet COX-1 effect of low-dose aspirin. Naproxen, unlike aspirin, decreased prostacyclin biosynthesis in vivo. Key Words: aspirin Ⅲ naproxen Ⅲ thromboxanes Ⅲ epoprostenol Ⅲ platelets A spirin is the only nonsteroidal antiinflammatory drug (NSAID) known to react covalently with the cyclooxygenase (COX) channel of prostaglandin (PG) G/H synthase-1 and -2 (also referred to as COX-1 and COX-2) through a selective acetylation of a single serine residue (Ser 529 in human COX-1 and Ser 516 in human COX-2) that results in the permanent loss of the COX activity of the enzyme. 1,2 The consistency in dose requirement and saturability of the effects of aspirin in acetylating platelet COX-1, inhibiting thromboxane (TX) A 2 formation, and preventing atherothrombotic complications constitutes the best evidence that the antithrombotic effect of aspirin is largely caused by the suppression of platelet TXA 2 production. 3,4 However, it is uncertain whether other NSAIDs that act as competitive, reversible inhibitors of both COX-1 and COX-2 share an aspirin-like cardioprotective effect. This question has received considerable attention after publication of the Vioxx Gastrointestinal Outcome Research (VIGOR) trial, 5 a study of approximately 8000 patients with rheumatoid arthritis randomized to receive rofecoxib 50 mg/d or naproxen 500 mg BID with a mean duration of follow-up of 9 months. The rates of myocardial infarction were 0.5% and 0.1% in the rofecoxib-and naproxen-treated groups, respectively, raising the possibility of a thrombogenic effect of rofecoxib, a cardioprotective effect of naproxen, and/or the play of chance. 6 Six of 8 recent observational studies and a metaanalysis of these studies suggest that regular use...

We compared the variability in degree and recovery from steady-state inhibition of cyclooxygenase (COX)-1 and COX-2 ex vivo and in vivo and platelet aggregation by naproxen sodium at 220 versus 440 mg b.i.d. and low-dose aspirin in healthy subjects. Six healthy subjects received consecutively naproxen sodium (220 and 440 mg b.i.d.) and aspirin (100 mg daily) for 6 days, separated by washout periods of 2 weeks. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity: 1) the measurement of serum thromboxane (TX)B 2 levels and whole-blood lipopolysaccharide-stimulated prostaglandin (PG)E 2 levels, markers of COX-1 in platelets and COX-2 in monocytes, respectively; 2) the measurement of urinary 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1␣ levels, markers of systemic TXA 2 biosynthesis (mostly COX-1-derived) and prostacyclin biosynthesis (mostly COX-2-derived), respectively. Arachidonic acid (AA)-induced platelet aggregation was also studied. The maximal inhibition of platelet COX-1 (95.9 Ϯ 5.1 and 99.2 Ϯ 0.4%) and AA-induced platelet aggregation (92 Ϯ 3.5 and 93.7 Ϯ 1.5%) obtained at 2 h after dosing with naproxen sodium at 220 and 440 mg b.i.d., respectively, was indistinguishable from aspirin, but at 12 and 24 h after dosing, we detected marked variability, which was higher with naproxen sodium at 220 mg than at 440 mg b.i.d. Assessment of the ratio of inhibition of urinary 11-dehydro-TXB 2 versus 2,3-dinor-6-keto-PGF 1␣ showed that the treatments caused a more profound inhibition of TXA 2 than prostacyclin biosynthesis in vivo throughout dosing interval. In conclusion, neither of the two naproxen doses mimed the persistent and complete inhibition of platelet COX-1 activity obtained by aspirin, but marked heterogeneity was mitigated by the higher dose of the drug.

Objective. To investigate whether low-dose naproxen sodium (220 mg twice a day) interferes with aspirin's antiplatelet effect in healthy subjects.Methods. We performed a crossover, open-label study in 9 healthy volunteers. They received for 6 days 3 different treatments separated by 14 days of washout: 1) naproxen 2 hours before aspirin, 2) aspirin 2 hours before naproxen, and 3) aspirin alone. The primary end point was the assessment of serum thromboxane B 2 (TXB 2 ) 24 hours after the administration of naproxen 2 hours before aspirin on day 6 of treatment. In 5 volunteers, the rate of recovery of TXB 2 generation (up to 72 hours after drug discontinuation) was assessed in serum and in platelet-rich plasma stimulated with arachidonic acid (AA) or collagen. Conclusion. Sequential administration of 220 mg naproxen twice a day and low-dose aspirin interferes with the irreversible inhibition of platelet cyclooxygenase 1 afforded by aspirin. The interaction was smaller when giving naproxen 2 hours after aspirin. The clinical consequences of these 2 schedules of administration of aspirin with naproxen remain to be studied in randomized clinical trials. Results. Twenty-four hoursArthritis in general and osteoarthritis in particular are increasingly becoming global problems; however, at this time, there is no known cure for osteoarthritis. Most forms of treatment therefore have dealt with the alleviation and management of chronic pain, which can affect normal functioning and quality of life of patients.

Background. The exposure of phosphatidylserine (PS) on the outer leaflet of the erythrocyte membrane may have several pathophysiological consequences, including the development of a procoagulant phenotype, a finding that seems relevant to the thrombotic risk seen in many disorders. Methods. Because PS externalization increases in erythrocytes from patients suffering from chronic uraemia, which is frequently associated with a prothrombotic state, the possible relationship between erythrocyte PS exposure, erythrocyte procoagulant activity and plasma levels of several haemostatic markers was studied in a group of haemodialysed patients. Results. Uraemic erythrocytes displayed increased procoagulant activity, which proved to be correlated directly with erythrocyte PS exposure. Pre-incubation of uraemic erythrocytes with annexin V, a protein with high affinity and specificity for PS, strongly inhibited in vitro thrombin generation induced by erythrocytes as compared with untreated red cells. Thrombin generation and activation of fibrinolysis were found to occur in uraemic patients, as substantiated by increased plasma levels of markers for thrombin generation (prothrombin fragment F1.2 and thrombinantithrombin complex) and fibrinolysis (D-dimer and plasmin-antiplasmin complex), respectively. Significant correlations between prothrombin fragment F1.2 and D-dimer suggested that hyperfibrinolysis was secondary to thrombin generation. Correlations were also found between erythrocyte PS levels and plasma levels of haemostatic markers, including prothrombin fragment F1.2 (P ¼ 0.007), thrombin-antithrombin complex (P ¼ 0.00009), plasmin-antiplasmin complex (P ¼ 0.0009) and D-dimer (P ¼ 0.005).Conclusions. Our study suggests that increased PS exposure may cause a pathological erythrocyte procoagulant phenotype, which may be a factor inducing a hypercoagulable state in uraemia.