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...

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Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.

Aspirin affords cardioprotection through the acetylation of serine 529 in human cyclooxygenase-1 (COX-1) of anucleated platelets, inducing a permanent defect in thromboxane A 2 (TXA 2 )-dependent platelet function. However, heterogeneity of COX-1 suppression by aspirin has been detected in cardiovascular disease and may contribute to failure to prevent clinical events. The recent recognized capacity of platelets to make proteins de novo paves the way to identify new mechanisms involved in the variable response to aspirin. We found that in washed human platelets, the complete suppression of TXA 2 biosynthesis by aspirin, in vitro, recovered in response to thrombin and fibrinogen in a time-dependent fashion (at 0.5 and 24 hours, TXB 2 averaged 0.1؎0.03 and 3؎0.8 ng/mL; in the presence of arachidonic acid [10 mol/L], it was 2؎0.7 and 25؎7 ng/mL, respectively), and it was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol 3-kinase. The results that COX-1 mRNA was readily detected in resting platelets and that [ 35 S]-methionine was incorporated into COX-1 protein after stimulation strongly support the occurrence of de novo COX-1 synthesis in platelets. This process may interfere with the complete and persistent suppression of TXA 2 biosynthesis by aspirin necessary for cardioprotection.A spirin affords cardioprotection inducing a complete and permanent defect in the capacity of platelets to generate thromboxane A 2 (TXA 2 ) through the acetylation of serine 529 of cyclooxygenase-1 (COX-1). 1,2 Because of a nonlinear relationship of inhibition of platelet TXA 2 generation with inhibition of TXA 2 -mediated platelet aggregation, an excess of 95% inhibition of COX-1 activity is required to influence platelet function. 3 In fact, even tiny concentrations of TXA 2 have been shown to cause platelet activation. Thus, 10 nmol/L of the TXA 2 mimetic U46619 induces platelet adhesion and shape change, 4 and in the presence of a subthreshold concentration of collagen, U46619 (0.5 to 10 nmol/L) causes platelet aggregation. 5 Recently, Maree et al 6 showed that many patients who are treated with low-dose enteric-coated aspirin (75 mg) for secondary prevention of cardiovascular events have persistent elevated serum TXB 2 levels (Ͼ2.2 ng/mL), which translates into a more frequent occurrence of arachidonic acid (AA)-induced platelet aggregation. Reduced bioavailability of aspirin 6 and genetic variants in COX-1 7 may participate in the intersubject variable response to aspirin. The recent recognized capacity of platelets to make proteins de novo 8 paves the way to identify new mechanisms involved in aspirin failure to cause complete and persistent suppression of platelet COX-1 activity in some individuals.Thus, in the present study, we assessed, in vitro, the hypothesis that de novo synthesis of COX-1 could account for TXA 2 biosynthesis in platelets in which the activity of preformed COX-1 was blocked by pretreatment with aspirin in vitro. Materials and MethodsHealthy volunteers (nϭ9 to 22...

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Helicobacter pylori up-regulates cyclo-oxygenase-2 (COX-2) expression, which in turn is involved in tumourigenesis. Recently, a causal link between COX-2 and multidrug resistance 1 (MDR-1) gene expression, implicated in cancer chemoresistance, has been demonstrated. Thus, the expression of COX-2 and the downstream enzyme involved in PGE2 biosynthesis, microsomal PGE-synthase1 (mPGES1), was correlated with P-gp, the product of MDR-1, and the anti-apoptotic protein, Bcl-xL, in gastric biopsies from patients with H pylori infection and in patients with gastric cancer. In a retrospective analysis of endoscopic and pathology files, 40 H pylori-negative patients (Hp-), 50 H pylori-positive patients who responded to eradication therapy (Hp+R), 84 H pylori-positive patients who did not respond to eradication therapy (Hp+NR), and 30 patients with gastric cancer (18 intestinal and 12 diffuse types) were selected. COX-2, mPGES1, P-gp, and Bcl-xL were detected by immunohistochemistry. COX-2, mPGES1, P-gp, and Bcl-xL expression was undetectable in gastric mucosa from Hp- patients. By contrast, COX-2 and mPGES1 expression was detected in 42% and 44% of Hp+R patients, respectively, and in up to 66% (range 63-66%) of Hp+NR patients (p < 0.05). The expression of COX-2 and mPGES1 correlated significantly (p < 0.0001) with that of P-gp and Bcl-xL. High levels of COX-2, mPGES1, P-gp, and Bcl-xL expression were found in intestinal-type gastric cancer samples. In conclusion, H pylori-dependent induction of COX-2 and mPGES1 is associated with enhanced production of P-gp and Bcl-xL that may contribute to gastric tumourigenesis and resistance to therapy.

Supplementation with pharmacological doses of vitamin E has no detectable effects on lipid peroxidation and thromboxane biosynthesis in vivo in healthy subjects with a mild degree of oxidant stress. These findings are consistent with the hypothesis that the basal rate of lipid peroxidation is a major determinant of the response to vitamin E supplementation and have implications for the use of vitamin E in healthy subjects as well as for the design and interpretation of clinical trials of antioxidant intervention.