RESUMO
Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI(2)) may affect angiogenesis by preventing endothelial activation and platelet release of angiogenic factors present in platelet α-granules. Thus, a profound inhibition of COX-2-dependent PGI(2) might be associated with changes in circulating markers of angiogenesis. We aimed to address this issue by performing a clinical study with celecoxib in familial adenomatous polyposis (FAP). In nine patients with FAP and healthy controls, pair-matched for gender and age, we compared systemic biosynthesis of PGI(2), thromboxane (TX) A(2), and prostaglandin (PG) E(2), assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF(1α) (PGI-M), 11-dehydro-TXB(2) (TX-M), and 11-α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), respectively. The impact of celecoxib (400 mg b.i.d. for 7 days) on prostanoid biosynthesis and 14 circulating biomarkers of angiogenesis was evaluated in FAP. Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in cocultures of a human colon adenocarcinoma cell line (HT-29) and platelets enhanced TXA(2) generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE(2) and PGI(2) biosynthesis that was associated with a significant increase in circulating levels of most proangiogenesis proteins but also the antiangiogenic tissue inhibitor of metalloproteinase 2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of fibroblast growth factor 2 and angiogenin. In conclusion, inhibition of tumor COX-2-dependent PGE(2) by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI(2), in a context of enhanced TXA(2) biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.
Assuntos
Polipose Adenomatosa do Colo/sangue , Neovascularização Fisiológica/fisiologia , Prostaglandinas/biossíntese , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Polipose Adenomatosa do Colo/tratamento farmacológico , Adulto , Animais , Celecoxib , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Epoprostenol/antagonistas & inibidores , Epoprostenol/biossíntese , Feminino , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Neovascularização Fisiológica/efeitos dos fármacos , Prostaglandinas/sangue , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/biossíntese , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
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. RESULTS: Twenty-four hours after the last dosing on day 6 in volunteers receiving aspirin alone or aspirin before naproxen, serum TXB(2) was almost completely inhibited (median [range] 99.1% [97.4-99.4%] and 99.1% [98.0-99.7%], respectively). Naproxen given before aspirin caused a slightly lower inhibition of serum TXB(2) (median [range] 98.0% [90.6-99.4%]) than aspirin alone (P = 0.0007) or aspirin before naproxen (P = 0.0045). All treatments produced a maximal inhibition of AA-induced platelet aggregation. At 24 hours, compared with baseline, collagen-induced platelet aggregation was still inhibited by aspirin alone (P = 0.0003), but not by aspirin given 2 hours before or after naproxen. Compared with administration of aspirin alone, the sequential administration of naproxen and aspirin caused a significant parallel upward shift of the regression lines describing the recovery of platelet TXB(2). 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.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Naproxeno/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/sangue , Ácido Araquidônico/farmacologia , Aspirina/efeitos adversos , Aspirina/sangue , Colágeno/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Naproxeno/efeitos adversos , Naproxeno/sangue , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/sangue , Plasma Rico em Plaquetas/efeitos dos fármacos , Valores de Referência , Tromboxano B2/sangue , Adulto JovemRESUMO
NO-donating aspirins consist of aspirin to which a NO-donating group is covalently linked via a spacer molecule. NCX 4040 and NCX 4016 are positional isomers with respect to the -CH(2)ONO(2) group (para and meta, respectively) on the benzene ring of the spacer. Because positional isomerism is critical for antitumor properties of NO-donating aspirins, we aimed to compare their anti-inflammatory effects with those of aspirin in vitro. Thus, we assessed their impacts on cyclooxygenase-2 activity (by measuring PGE(2) levels), protein expression, and cytokine generation(IL-1beta, IL-18, TNF-alpha, and IL-10) in human whole blood and isolated human monocytes stimulated with LPS. Interestingly, we found that micromolar concentrations of NCX 4040, but not NCX 4016 or aspirin, affected cyclooxygenase-2 expression and cytokine generation. We compared the effects of NCX 4040 with those of NCX 4016 or aspirin on IkappaB-alpha stabilization and proteasome activity in the LPS-stimulated human monocytic cell line THP1. Differently from aspirin and NCX 4016, NCX 4040, at a micromolar concentration range, inhibited IkappaB-alpha degradation. In fact, NCX 4040 caused concentration-dependent accumulation of IkappaB-alpha and its phosphorylated form. This effect was not reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase, thus excluding the contribution of NO-dependent cGMP generation. In contrast, IkappaB-alpha accumulation by NCX 4040 may involve an inhibitory effect on proteasome functions. Indeed, NCX 4040 inhibited 20S proteasome activity when incubated with intact cells but not in the presence of cell lysate supernatants, thus suggesting an indirect inhibitory effect. In conclusion, NCX 4040 is an inhibitor of IkappaB-alpha degradation and proteasome function, and it should be taken into consideration for the development of novel anti-inflammatory and chemopreventive agents.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/análogos & derivados , Proteínas I-kappa B/antagonistas & inibidores , Proteínas I-kappa B/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Doadores de Óxido Nítrico/farmacologia , Nitrocompostos/farmacologia , Adulto , Anti-Inflamatórios não Esteroides/química , Aspirina/química , Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/sangue , Ciclo-Oxigenase 2/sangue , Dinoprostona/biossíntese , Dinoprostona/sangue , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/fisiologia , Inibidor de NF-kappaB alfa , Doadores de Óxido Nítrico/química , Nitrocompostos/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
Following our previous research on anti-inflammatory drugs (NSAIDs), we report here the synthesis of chiral 1,5-diarylpyrroles derivatives that were characterized for their in vitro inhibitory effects toward cyclooxygenase (COX) isozymes. Analysis of enzymatic affinity and COX-2 selectivity led us to the selection of one compound (+/-)-10b that was further tested in vitro in the human whole blood (HWB) and in vivo for its anti-inflammatory activity in mice. The affinity data have been rationalized through docking simulations.
Assuntos
Álcoois/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Éteres/química , Modelos Químicos , Pirróis/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sítios de Ligação , Carragenina , Células Cultivadas , Simulação por Computador , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.
Assuntos
Acetatos/síntese química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Ciclo-Oxigenase 2/metabolismo , Pirróis/síntese química , Acetatos/química , Acetatos/farmacologia , Adulto , Animais , Carragenina , Linhagem Celular , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/sangue , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Medição da Dor , Pirróis/química , Pirróis/farmacologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Proteínas com Domínio T/sangueRESUMO
A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1ß (IL-1ß), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Doadores de Óxido Nítrico/farmacologia , Pirróis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/química , Éteres/síntese química , Éteres/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Osteoartrite/tratamento farmacológico , Pirróis/síntese química , Pirróis/química , RatosRESUMO
The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.
Assuntos
Acetatos/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Doadores de Óxido Nítrico/síntese química , Pirróis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Linhagem Celular , Constrição Patológica/induzido quimicamente , Constrição Patológica/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ésteres , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Camundongos , Modelos Moleculares , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Vasodilatadores/síntese química , Vasodilatadores/química , Vasodilatadores/farmacologiaRESUMO
Inhibitors of microsomal prostaglandin (PG) E synthase-1 (mPGES-1) are being developed for the relief of pain. Redirection of the PGH(2) substrate to other PG synthases, found both in vitro and in vivo, in mPGES-1 knockout mice, may influence their efficacy and safety. We characterized the contribution of mPGES-1 to PGH(2) metabolism in lipopolysaccharide (LPS)-stimulated isolated human monocytes and whole blood by studying the synthesis of prostanoids [PGE(2), thromboxane (TX)B(2), PGF(2alpha) and 6-keto-PGF(1alpha)] and expression of cyclooxygenase (COX)-isozymes and down-stream synthases in the presence of pharmacological inhibition by the novel mPGES-1 inhibitor AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide]. AF3442 caused a concentration-dependent inhibition of PGE(2) in human recombinant mPGES-1 with an IC(50) of 0.06microM. In LPS-stimulated monocytes, AF3442 caused a concentration-dependent reduction of PGE(2) biosynthesis with an IC(50) of 0.41microM. At 1microM, AF3442 caused maximal selective inhibitory effect of PGE(2) biosynthesis by 61+/-3.3% (mean+/-SEM, P<0.01 versus DMSO vehicle) without significantly affecting other prostanoids (i.e. TXB(2), PGF(2alpha) and 6-keto-PGF(1alpha)). In LPS-stimulated whole blood, AF3442 inhibited in a concentration-dependent fashion inducible PGE(2) biosynthesis with an IC(50) of 29microM. A statistically significant inhibition of mPGES-1 activity was detected at 10 and 100microM (38+/-14%, P<0.05, and 69+/-5%, P<0.01, respectively). Up to 100microM, the other prostanoids were not significantly affected. In conclusion, AF3442 is a selective mPGES-1 inhibitor which reduced monocyte PGE(2) generation also in the presence of plasma proteins. Pharmacological inhibition of mPGES-1 did not translate into redirection of PGH(2) metabolism towards other terminal PG synthases in monocytes. The functional relevance of this observation deserves to be investigated in vivo.
Assuntos
Benzamidas/farmacologia , Carbazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Monócitos/metabolismo , Prostaglandinas/biossíntese , Linhagem Celular Tumoral , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Epoprostenol/biossíntese , Humanos , Lipopolissacarídeos/farmacologia , Microssomos/enzimologia , Prostaglandina H2/biossíntese , Prostaglandina-E SintasesRESUMO
A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new 1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Pirróis/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Carboxílicos , Células Cultivadas , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase , Ésteres , Concentração Inibidora 50 , Macrófagos , Camundongos , Pirróis/farmacologia , Pirróis/uso terapêuticoRESUMO
A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers (6, 7, and 8) has been synthesized with the aim to assess if in the previously reported 1,5-diarylpyrrole derivatives (5) the replacement of the acetic ester moiety with an alkoxyethyl group still led to new, highly selective and potent COX-2 inhibitors. In the in vitro cell culture assay, all the compounds proved to be potent and selective COX-2 inhibitors. In the human whole blood (HWB) assay, compound 8a had a comparable COX-2 selectivity to valdecoxib, while it was more selective than celecoxib but less selective than rofecoxib. The potential anti-inflammatory and antinociceptive activities of compounds 7a, 8a, and 8d were evaluated in vivo, where they showed a very good activity against both carrageenan-induced hyperalgesia and edema in the rat paw test. In the abdominal constriction test compound 7a, 8a, and 8d were able to reduce the number of writhes in a statistically significant manner. Furthermore, the affinity data of these compounds have been rationalized through enzyme docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site by means of the software package Autodock 3.0.5, GRID 21, and MacroModel 8.5 using the complex between COX-2 and SC-558 (1b), refined at a 3 A resolution (Brookhaven Protein Data Bank entry: 6cox ).
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Éter/síntese química , Éter/farmacologia , Pirróis/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Simulação por Computador , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Edema/tratamento farmacológico , Éter/química , Éter/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
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(1alpha) 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 +/- 5.1 and 99.2 +/- 0.4%) and AA-induced platelet aggregation (92 +/- 3.5 and 93.7 +/- 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(1alpha) 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.