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...

Sulfated polysaccharides from Laminaria saccharina (new name: Saccharina latissima) brown seaweed show promising activity for the treatment of inflammation, thrombosis, and cancer; yet the molecular mechanisms underlying these properties remain poorly understood. The aim of this work was to characterize, using in vitro and in vivo strategies, the anti-inflammatory, anti-coagulant, anti-angiogenic, and anti-tumor activities of two main sulfated polysaccharide fractions obtained from L. saccharina: a) L.s.-1.0 fraction mainly consisting of O-sulfated mannoglucuronofucans and b) L.s.-1.25 fraction mainly composed of sulfated fucans. Both fractions inhibited leukocyte recruitment in a model of inflammation in rats, although L.s.-1.25 appeared to be more active than L.s.-1.0. Also, these fractions inhibited neutrophil adhesion to platelets under flow. Only fraction L.s.-1.25, but not L.s.-1.0, displayed anticoagulant activity as measured by the activated partial thromboplastin time. Investigation of these fractions in angiogenesis settings revealed that only L.s.-1.25 strongly inhibited fetal bovine serum (FBS) induced in vitro tubulogenesis. This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells. Furthermore, only parent sulfated polysaccharides from L. saccharina (L.s.-P) and its fraction L.s.-1.25 were powerful inhibitors of basic fibroblast growth factor (bFGF) induced pathways. Consistently, the L.s.-1.25 fraction as well as L.s.-P successfully interfered with fibroblast binding to human bFGF. The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels. Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice. Finally, L.s.-1.25 markedly inhibited breast cancer cell adhesion to human platelet-coated surfaces. Thus, sulfated fucans are mainly responsible for the anti-inflammatory, anticoagulant, antiangiogenic, and antitumor activities of sulfated polysaccharides from L. saccharina brown seaweed.

The association of platelet-rich plasma + hyaluronic acid has the same efficacy of platelet-rich plasma only, administered in higher volume. We may infer that hyaluronic acid works synergically and improves the activity of several molecules contained in platelet-rich plasma.

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.