RESUMEN
Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
Asunto(s)
Aspirina/administración & dosificación , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Adulto , Anciano , Aspirina/farmacocinética , Ciclooxigenasa 1/sangre , Inhibidores de la Ciclooxigenasa/farmacología , Método Doble Ciego , Epoprostenol/orina , Humanos , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/farmacocinética , Trombocitemia Esencial/sangre , Trombocitemia Esencial/orinaRESUMEN
No disponible
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Apnea Obstructiva del Sueño/orina , Epoprostenol/orina , Tromboxanos/orina , Biomarcadores/orina , Proyectos PilotoRESUMEN
Established "low" aspirin dosages inconsistently inhibit platelet function in dogs. Higher aspirin dosages consistently inhibit platelet function, but are associated with adverse effects. The objectives of this study were to use an escalation in dosage to determine the lowest aspirin dosage that consistently inhibited platelet function without inhibiting prostacyclin synthesis. Eight dogs were treated with five aspirin dosages: 0.5 mg/kg q24h, 1 mg/kg q24h, 2 mg/kg q24h, 4 mg/kg q24h and 10 mg/kg q12h for 7 days. Utilizing aggregometry and a whole-blood platelet function analyzer (PFA-100), platelet function was evaluated before and after treatment. Urine 11-dehydro-thromboxane-B2 (11-dTXB2 ) and 6-keto-prostaglandin-F1α (6-keto-PGF1α ), were measured. Compared to pretreatment, there were significant post-treatment decreases in the maximum aggregometry amplitude and increases in the PFA-100 closure times for all dosages expect 0.5 mg/kg q24h. There was no difference in amplitude or closure time among the 2 mg/kg q24h, 4 mg/kg q24h, and 10 mg/kg q12h dosages. Compared to pretreatment values, there was a significant decrease in urinary 11-dTXB2 -to-creatinine and 6-keto-PGF1α -to-creatinine ratios, but there was no dose-dependent decrease for either metabolite. An aspirin dosage of 2 mg/kg q24h consistently inhibits platelet function without decreasing prostacyclin synthesis significantly more than lower aspirin dosages.
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Aspirina/farmacología , Plaquetas/efectos de los fármacos , Epoprostenol/orina , Tromboxanos/orina , 6-Cetoprostaglandina F1 alfa/orina , Animales , Aspirina/administración & dosificación , Perros , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Agregación Plaquetaria/efectos de los fármacos , Pruebas de Función Plaquetaria/veterinaria , Tromboxano B2/análogos & derivados , Tromboxano B2/orinaRESUMEN
High platelet reactivity and high platelet turnover have been implicated in incomplete platelet inhibition during immediate-release acetylsalicylic acid therapy in patients with type 2 diabetes mellitus (DM). An extended-release acetylsalicylic acid (ER-ASA; Durlaza) formulation was developed to provide 24-hour antithrombotic effects with once-daily dosing. The objective of the study was to evaluate the antiplatelet effects of ER-ASA in patients with DM. In this open-label, single-center study, patients with DM (n = 40) and multiple cardiovascular risk factors received ER-ASA 162.5 mg/day for 14 ± 4 days. Multiple platelet function tests, serum and urinary thromboxane B2 metabolites, prostacyclin metabolite, and high-sensitive C-reactive protein levels were assessed at 1, 12, 16, and 24 hours post-dose. Patients with high platelet turnover and/or high platelet reactivity were treated with ER-ASA 325 mg/day for 14 ± 4 days, and laboratory analyses were repeated. All patients responded to ER-ASA 162.5 mg/day as measured by arachidonic acid-induced aggregation, and there was no loss of the platelet inhibitory effect of ER-ASA 162.5 mg/day over 24 hours post-dose (p = not significant). The antiplatelet effect was sustained over 24 hours for all platelet function measurements. Mean 1- to 24-hour serum thromboxane B2 levels were low with both doses and were lower with ER-ASA 325 mg/day compared with 162.5 mg/day therapy (p = 0.002). In conclusion, ER-ASA 162.5 mg daily dose provided sustained antiplatelet effects over 24 hours in patients with type 2 DM and multiple cardiovascular risk factors and had a favorable tolerability profile.
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Aspirina/administración & dosificación , Enfermedades Cardiovasculares/prevención & control , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedades Vasculares Periféricas/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Anciano , Aspirina/uso terapéutico , Proteína C-Reactiva/metabolismo , Enfermedad de la Arteria Coronaria/complicaciones , Preparaciones de Acción Retardada , Diabetes Mellitus Tipo 2/complicaciones , Epoprostenol/biosíntesis , Epoprostenol/orina , Femenino , Humanos , Masculino , Manometría , Volúmen Plaquetario Medio , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/complicaciones , Agregación Plaquetaria , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tromboelastografía , Tromboxano B2/análogos & derivados , Tromboxano B2/sangre , Tromboxano B2/orina , VasodilataciónRESUMEN
The balance between vascular prostacyclin (PGI2) generated mainly via cyclooxygenase-2 (COX-2) and its physiological antagonist platelet-derived thromboxane A2 (TXA2) formed by cyclooxygenase-1 (COX-1) determines cardiovascular homeostasis. In the present work, a novel bioanalytical method for simultaneous quantification of stable plasma and urinary metabolites of PGI2 (6-keto-PGF1α, 2,3-dinor-6-keto-PGF1α) and TXA2 (TXB2, 2,3-dinor-TXB2) using ultra high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC/MS/MS) was developed. The method was validated using artificial plasma and urine and linearity range, intra- and inter-day precision and accuracy, recovery of analytes, relative and absolute matrix effect and stability of analytes were determined. The use of artificial biofluids improved the method sensitivity as it eliminated the contribution of endogenous metabolites present in mice plasma and urine to validation procedure. The newly developed and validated method allowed to quantify 6-keto-PGF1α and TXB2 in mice plasma as well as 2,3-dinor-6-keto-PGF1α and 2,3-dinor-TXB2 in urine samples with high sensitivity and accuracy. The calibration range was established from 0.1 to 100ng/mL for all analytes using artificial biofluids and the recoveries were greater than 89.9%. All validated parameters met the criteria of acceptance specified in FDA and EMA guidance. This method was successfully employed for profiling of the changes in PGI2 and TXA2 generation in NO-deficient mice. This work demonstrated that NO-deficiency induced by L-NAME, evidenced by a fall in nitrite in plasma and urine, was associated with platelet activation, robust increase in TXB2 and mild increase in 6-keto-PGF1α concentration in plasma. Changes in 2,3-dinor-6-keto-PGF1α and 2,3-dinor-TXB2 concentration in urine were less evident suggesting that the measurements in plasma better reflect modest changes in PGI2/TXA2 homeostasis than measurements in urine.
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Epoprostenol/sangre , Epoprostenol/orina , Óxido Nítrico/deficiencia , Espectrometría de Masas en Tándem/métodos , Tromboxano A2/sangre , Tromboxano A2/orina , Animales , Cromatografía Líquida de Alta Presión/métodos , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)-induced inflammation. Cyclooxygenase (COX)-formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH. METHODS AND RESULTS: Twelve healthy, male participants underwent three, 6-hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex(®) (selective COX-2 inhibitor) in a double-blind, randomized, crossover study design. Pre- and post-IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre-IH blood pressure (P ≤ 0.04) and decreased pre-IH CBF (P=0.04) while neither physiological variable was affected by COX-2 inhibition (P ≥ 0.90). Post-IH, MAP was elevated (P ≤ 0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX-2 inhibition abrogated the IH-induced MAP increase (P=0.19), but resulted in lower post-IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P ≤ 0.4) and COX-1 formed thromboxane A2 concentrations (P=0.02). CONCLUSIONS: COX-2 and COX-1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX-1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01280006.
Asunto(s)
Presión Sanguínea/fisiología , Circulación Cerebrovascular/fisiología , Ciclooxigenasa 1/fisiología , Ciclooxigenasa 2/fisiología , Hipoxia/fisiopatología , Apnea Obstructiva del Sueño/fisiopatología , Adulto , Presión Sanguínea/efectos de los fármacos , Celecoxib , Circulación Cerebrovascular/efectos de los fármacos , Estudios Cruzados , Ciclooxigenasa 1/efectos de los fármacos , Ciclooxigenasa 2/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprost/orina , Dinoprostona/orina , Método Doble Ciego , Epoprostenol/orina , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Indometacina/farmacología , Masculino , Persona de Mediana Edad , Pirazoles/farmacología , Sulfonamidas/farmacología , Tromboxano A2/orinaRESUMEN
INTRODUCTION: Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. METHODS: We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. RESULTS: The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were >142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥100 mg/kg. CONCLUSIONS: ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect.
Asunto(s)
Aspirina/uso terapéutico , Trombosis de las Arterias Carótidas/tratamiento farmacológico , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa/uso terapéutico , Fibrinolíticos/uso terapéutico , Triazoles/uso terapéutico , Animales , Aspirina/efectos adversos , Aspirina/farmacología , Trombosis de las Arterias Carótidas/enzimología , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacología , Epoprostenol/metabolismo , Epoprostenol/orina , Fibrinolíticos/efectos adversos , Fibrinolíticos/farmacología , Cobayas , Humanos , Masculino , Prostaglandinas/sangre , Prostaglandinas/metabolismo , Ratas , Estómago/efectos de los fármacos , Triazoles/efectos adversos , Triazoles/farmacología , Úlcera/inducido químicamenteRESUMEN
3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia. The aim of this combined in vitro and in vivo study was to investigate the influence of the commonly used simvastatin on prostacyclin and thromboxane A2, 2 prostaglandins with different cardiovascular effects, normally in homeostatic balance in the circulatory system. Single-dose administration of simvastatin significantly decreased urinary prostacyclin excretion of healthy volunteers (P < 0.01) and increased the ratio between thromboxane A2 and prostacyclin (2-fold increase, P < 0.01), as assessed by enzyme immunoassays of the corresponding metabolites in urine. Human vascular endothelial cells, exposed to corresponding concentrations of simvastatin and assayed in the same way, reduced the release of prostacyclin about 40% (P < 0.05), altered the transcriptional expression of cyclooxygenase and prostacyclin synthase as analyzed by real-time polymerase chain reaction, and reduced the prostacyclin synthase promoter activity by 50% (P < 0.05), evaluated in a luciferase reporter system. We speculate that simvastatin shifts the balance between thromboxane A2 and prostacyclin in favor of the thromboxane pathway in vivo, and after exposure to clinically relevant concentrations in vitro. This may have pathophysiological implications by promoting a prothrombotic state in the blood vessels.
Asunto(s)
Células Endoteliales/efectos de los fármacos , Epoprostenol/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Simvastatina/farmacología , Tromboxano A2/metabolismo , Adulto , Biomarcadores/orina , Células Cultivadas , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Epoprostenol/orina , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Técnicas para Inmunoenzimas , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , Regiones Promotoras Genéticas/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Simvastatina/administración & dosificación , Tromboxano A2/orina , Transcripción Genética/efectos de los fármacos , TransfecciónRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF(1α) (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Furanos/farmacología , Antagonistas de Prostaglandina/farmacología , Prostaglandinas/biosíntesis , Pirazoles/farmacología , Sulfonamidas/farmacología , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Adolescente , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Área Bajo la Curva , Asiático , Población Negra , Inhibidores de Anhidrasa Carbónica/farmacología , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Celecoxib , Estudios Cruzados , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Método Doble Ciego , Epoprostenol/orina , Femenino , Furanos/efectos adversos , Furanos/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Prostaglandina/efectos adversos , Antagonistas de Prostaglandina/farmacocinética , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Medición de Riesgo , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Tromboxano B2/sangre , Población Blanca , Adulto JovenRESUMEN
A sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the quantitation of 6-keto PGF(1α) in human urine and plasma. Prostacyclin (PGI(2)) is a locally acting prostanoid, which mediates vasorelaxation and inhibition of platelet aggregation. 6-Keto PGF(1α) is the most-immediate metabolite of PGI(2). Samples were spiked with an internal standard (6-keto PGF(1α)-d(4)), purified by immuno-affinity chromatography and selected reaction monitoring (SRM) was performed. Analytical validation of the 6-keto PGF(1α) assay was performed in urine. This included an assessment of assay precision, recovery, stability, sensitivity and linearity. Urinary 6-keto PGF(1α) concentrations were also correlated to urinary 2,3-dinor-6-keto PGF(1α) (PGIM) concentrations using urine samples collected from 16 healthy volunteers. The mean concentration of 6-keto PGF(1α) in urine (mean ± SD) was 92 ± 51 pg/ml or 168 ± 91 pg/mg creatinine. Overall, there was a statistically significant correlation between urinary 6-keto PGF(1α) and PGIM (r(2)=0.55, p ≤ 0.001; slope=2.7; y-intercept=130). However, PGIM was approximately 3-fold more abundant than 6-keto PGF(1α) in urine. In addition, 6-keto PGF(1α) concentrations were measured in EDTA plasma samples obtained from 7 healthy donors. The mean concentration of 6-keto PGF(1α) in plasma was 1.9 ± 0.8 pg/ml (± SD).
Asunto(s)
6-Cetoprostaglandina F1 alfa/sangre , 6-Cetoprostaglandina F1 alfa/orina , Cromatografía Liquida/métodos , Epoprostenol/metabolismo , Epoprostenol/orina , Espectrometría de Masas en Tándem/métodos , Adolescente , Adulto , Calibración , Creatinina/orina , Humanos , Masculino , Persona de Mediana Edad , Estándares de Referencia , Reproducibilidad de los Resultados , Toma de Muestras de Orina/métodos , Adulto JovenRESUMEN
Renal prostacycline (PGI(2)) and oxidative stress are known to be important factors that effect the natriurezis and diuresis. 8-iso prostaglandin F(2)α± (8-isoprostane), a member of F(2)-isoprostanes, is formed from the nonenzymatic reaction of arachidonic acid and oxygen radicals in vivo and in vitro, and also it is a marker of oxidative stress in vivo. The aim of this study is to determine the role of renal PGI(2) and 8-isoprostane in a salt and nitric oxide (NO) inhibition-induced hypertension model. Rats were distributed equally among four groups (n = 6 per group). Control rats were given normal salt diet (0.32%); high-salt (HS) rats were given high salt diet (3.2%); NG-nitro-L-arginine (L-NNA) rats were given normal salt diet and 25 mg/kg L-NNA; HS+L-NNA rats were given high salt diet and 25 mg/kg L-NNA. Rats were placed in individual metabolic cages for 17 days. Systolic blood pressure (SBP) was measured at days initial, 7th and 14th .Urinary 8-isoprostane and PGI(2) levels were analyzed. Salt- loading alone did not change SBP values. The average SBP in L-NNA and HS+L-NNA groups were shown to significantly enhance compared to initial and day 7th in the same groups, respectively. The levels of 8-isoprostane in the HS+L-NNA group was significantly enhanced compared to the other groups. L-NNA or HS diet alone did not change the levels of 8-isoprostane compared to the control group. L-NNA alone did not change PGI(2) levels in urine compared to the control. PGI(2) levels in the HS, and the HS+L-NNA group was significantly higher compared to the control group. This study concluded that NOS inhibition plus salt-loading induced oxidative stress and increased renal PGI(2). Also, it is suggested that augmented oxidative stress may aggravate the hypertension. But the renal synthesis of PGI(2) is increased in order to augment the diuresis and natriuresis without the effect of blood pressure (BP).
Asunto(s)
Dinoprost/análogos & derivados , Epoprostenol/orina , Hipertensión/etiología , Óxido Nítrico/antagonistas & inhibidores , Cloruro de Sodio Dietético/efectos adversos , Animales , Dinoprost/orina , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Hipertensión/fisiopatología , Hipertensión/orina , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio Dietético/administración & dosificaciónRESUMEN
Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity.
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Inhibidores de la Ciclooxigenasa 2/farmacología , Isoxazoles/farmacología , Sepsis/metabolismo , Infecciones Estreptocócicas/metabolismo , Streptococcus agalactiae , Tromboxanos/biosíntesis , Animales , Animales Recién Nacidos , Dinoprostona/orina , Epoprostenol/metabolismo , Epoprostenol/orina , Regulación de la Expresión Génica/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Indometacina/farmacología , Inflamación/metabolismo , Inflamación/patología , Inflamación/orina , Pulmón/efectos de los fármacos , Pulmón/patología , Recuento de Plaquetas , Receptores de Prostaglandina E/metabolismo , Sepsis/patología , Sepsis/fisiopatología , Sepsis/orina , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/patología , Infecciones Estreptocócicas/orina , Porcinos , Tromboxanos/metabolismo , Tromboxanos/orinaRESUMEN
Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) increase the incidence of cardiovascular and cerebrovascular events. Complete disruption of the murine gene encoding COX-2 (Ptgs2) leads to renal developmental problems, as well as female reproductive anomalies and patent ductus arteriosus of variable penetrance in newborns, thus rendering this genetic approach difficult to compare with coxib administration. Here, we created hypomorphic Ptgs2 (COX-2(Neo/Neo)) mice in which COX-2 expression is suppressed to an extent similar to that achieved with coxibs, but not eliminated, in an attempt to circumvent these difficulties. In LPS-challenged macrophages and cytokine-stimulated endothelial cells obtained from COX-2(Neo/Neo) mice, COX-2 expression was reduced 70-90%, and these mice developed a mild renal phenotype compared with COX-2 mice possessing an active site mutation (COX-2(Y385F/Y385F)), with minimal signs of renal dysfunction as measured by FITC-inulin clearance and blood urea nitrogen. These COX-2 knockdown mice displayed an increased propensity for thrombogenesis compared with their wild-type (COX-2(+/+)) littermates observed by intravital microscopy in cremaster muscle arterioles upon ferric chloride challenge. Measurement of urinary prostanoid metabolites indicated that COX-2(Neo/Neo) mice produced 50% less prostacyclin but similar levels of PGE(2) and thromboxane compared with COX-2(+/+) mice in the absence of any blood pressure and ex vivo platelet aggregation abnormalities. COX-2(Neo/Neo) mice, therefore, provide a genetic surrogate of coxib therapy with disrupted prostacyclin biosynthesis that predisposes to induced arterial thrombosis.
Asunto(s)
Sistema Cardiovascular/enzimología , Ciclooxigenasa 2/deficiencia , Riñón/enzimología , Trombosis/enzimología , Animales , Presión Sanguínea , Nitrógeno de la Urea Sanguínea , Sistema Cardiovascular/fisiopatología , Células Cultivadas , Cloruros , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Citocinas/metabolismo , Dinoprostona/orina , Modelos Animales de Enfermedad , Células Endoteliales/enzimología , Epoprostenol/orina , Compuestos Férricos , Tasa de Filtración Glomerular , Frecuencia Cardíaca , Riñón/fisiopatología , Macrófagos Peritoneales/enzimología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Microscopía por Video , Trombosis/inducido químicamente , Trombosis/genética , Tromboxano B2/orina , Factores de TiempoRESUMEN
OBJECTIVE: To evaluate the effect of estradiol, estradiol and norethisterone acetate (NETA), raloxifene and tibolone on the prostacyclin (PGI(2))/thromboxane A2 (TxA(2)) ratio in postmenopausal women after 8 weeks of treatment. DESIGN: This was a randomized, double-blind, cross-over study. Each patient took 8-week courses of estradiol 2 mg, estradiol 2 mg + NETA 1 mg, tibolone 2.5 mg, and raloxifene 60 mg; there was an 8-week placebo wash-out between each different intervention. All volunteers took all four treatment options and were randomized to one of three possible sequences. Urine was collected and frozen at each visit. Urinary metabolites of PGI(2) and TxA(2) were then assessed at the end of the study. RESULTS: The ratio of PGI(2)/TxA(2) was significantly increased for raloxifene. No other treatments showed statistically significant changes. CONCLUSIONS: The relationship between cardiovascular risk and hormone replacement therapy remains poorly understood. Raloxifene may have additional cardioprotective effects that the other treatments did not demonstrate, and none of the treatments statistically worsened the PGI(2)/TxA(2) ratio. This ratio may be under-utilized as a marker of net effect on cardiovascular health, but more research is needed to link it to health outcomes.
Asunto(s)
Epoprostenol/metabolismo , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno/métodos , Noretindrona/análogos & derivados , Norpregnenos/administración & dosificación , Clorhidrato de Raloxifeno/administración & dosificación , Tromboxano A2/metabolismo , Enfermedades Cardiovasculares/prevención & control , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Epoprostenol/orina , Estradiol/farmacología , Femenino , Humanos , Persona de Mediana Edad , Noretindrona/administración & dosificación , Noretindrona/farmacología , Acetato de Noretindrona , Norpregnenos/farmacología , Clorhidrato de Raloxifeno/farmacología , Tromboxano A2/orinaRESUMEN
Prostaglandin I(2) (PGI(2)) protects against RSV-induced illness in mice. A variable-number tandem repeat (VNTR) polymorphism has been detected in the promoter region of the PGI(2) synthase (PGIS) gene. We sought to determine if PGI(2) concentrations or polymorphisms of the PGIS gene correlate with severity of RSV lower respiratory tract infections (LRTI) in human infants. VNTR polymorphisms were studied in 81 previously healthy children between birth and 12 months of age who were hospitalized for LRTI due to RSV and 98 healthy adult control subjects. The severity of RSV infection was quantified using a clinical scoring system, and infant urine samples were collected during the acute illness for measurement of the urinary metabolite of PGI(2). There were no significant differences in the overall distribution of alleles and genotypes between infants with RSV LRTI and the control subjects. The severity of RSV infection significantly inversely correlated with urinary PGI(2) metabolite concentrations. The urinary PGI(2) metabolite concentration correlated with the number of VNTR. The presence of a genotype with a low number VNTR repeats significantly correlated with the most severe RSV LRTI, and genotypes with the highest number of VNTR correlated with the least severe RSV LRTI. A functional polymorphism in the promoter region of the PGIS gene is associated with both significant differences in urinary PGI(2) concentrations during RSV LRTI, and severity of RSV infection in previously healthy infants.
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Sistema Enzimático del Citocromo P-450/genética , Oxidorreductasas Intramoleculares/genética , Repeticiones de Minisatélite , Regiones Promotoras Genéticas , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Infecciones del Sistema Respiratorio/patología , Infecciones del Sistema Respiratorio/virología , Adulto , Niño Hospitalizado , Epoprostenol/orina , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Análisis de Secuencia de ADN , Índice de Severidad de la EnfermedadRESUMEN
Our study aimed to determine the role of cyclooxygenase-2 in the release of prostaglandin-(PG)-I2 following mesenteric traction during abdominal surgery. In a prospective double-blind, randomized, placebo-controlled study, 40 patients electively scheduled for non-laparoscopic abdominal surgery, were pretreated with the cyclooxygenase-2 inhibitor parecoxib (n=20) or placebo (n=20). Heart rate, arterial blood pressure, oxygenation ratio and plasma concentrations of the stable PGI2-metabolite 6-keto-PGF1alpha were compared between groups before injection of parecoxib (-40 min), immediately before mesenteric traction (0 min), and 5, 10, and 30 min thereafter. In addition, plasma concentrations of valdecoxib, the active metabolite of the prodrug parecoxib, were determined. Plasma concentrations of 6-keto-PGF1alpha and heart rate increased in both groups after mesenteric traction. There were no significant differences between groups at individual times in heart rate, arterial blood pressure and plasma concentrations of 6-keto-PGF1alpha. Oxygenation ratio decreased after 10 and 30 min following mesenteric traction in the parecoxib group with a significant difference between treatment groups at 10 and 30 min. Plasma concentrations of valdecoxib revealed therapeutic values. Our data indicate that PGI2 release following mesenteric traction is mediated by cyclooxygenase-1.
Asunto(s)
Abdomen/cirugía , Ciclooxigenasa 1/metabolismo , Epoprostenol/metabolismo , Complicaciones Intraoperatorias/prevención & control , Isoxazoles/uso terapéutico , 6-Cetoprostaglandina F1 alfa/sangre , 6-Cetoprostaglandina F1 alfa/orina , Presión Sanguínea/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Método Doble Ciego , Epoprostenol/sangre , Epoprostenol/orina , Femenino , Rubor/etiología , Rubor/fisiopatología , Rubor/prevención & control , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipotensión/etiología , Hipotensión/fisiopatología , Hipotensión/prevención & control , Complicaciones Intraoperatorias/etiología , Complicaciones Intraoperatorias/fisiopatología , Isoxazoles/administración & dosificación , Isoxazoles/sangre , Laparoscopía , Masculino , Persona de Mediana Edad , Oxígeno/metabolismo , Estudios Prospectivos , Sulfonamidas/sangre , Procedimientos Quirúrgicos Operativos/efectos adversos , Procedimientos Quirúrgicos Operativos/métodos , Taquicardia/etiología , Taquicardia/fisiopatología , Taquicardia/prevención & control , Factores de Tiempo , Resultado del TratamientoRESUMEN
This randomized, double-blind, placebo-controlled study evaluated the pharmacodynamic effects of concomitant low-dose aspirin and lumiracoxib in healthy subjects. Participants received lumiracoxib 400 mg once daily (n = 14) or placebo (n = 14) for 11 days, with concomitant low-dose aspirin (75 mg once daily) from days 5 to 11. Ex vivo pharmacodynamic assessments included assays of platelet aggregation and urinary thromboxane and prostacyclin metabolite profile. Arachidonic acid-stimulated platelet aggregation was reduced from 76.3% on day 4 to 4.8% on day 11 in the placebo group and from 75.8% on day 4 to 5.1% on day 11 in the lumiracoxib group. Collagen-induced platelet aggregation was reduced from 77.5% on day 4 to 52.8% on day 11 in the placebo group and from 79.5% on day 4 to 55.9% on day 11 in the lumiracoxib group. Urinary thromboxane and prostacyclin were unaffected by lumiracoxib. In conclusion, concomitant lumiracoxib did not interfere with the cyclooxygenase-1-mediated antiplatelet effects of low-dose aspirin.
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Aspirina/farmacología , Compuestos Orgánicos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Adolescente , Adulto , Ácido Araquidónico/farmacología , Colágeno/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Diclofenaco/análogos & derivados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Epoprostenol/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Tromboxano B2/sangre , Tromboxano B2/orinaRESUMEN
BACKGROUND: The aim of this study was to investigate the prostanoid production in pregnancies at high risk for hypertensive disorders, and the effect of low-dose acetylsalicylic acid (ASA) on prostanoids. MATERIAL AND METHODS: Ninety women with a bilateral notching in uterine arteries screened by Doppler ultrasound at 12-14 gestational weeks were randomized to the ASA (0.5 mg/kg/day) or placebo group. Forty-three women in both groups were followed up throughout the pregnancy. Urine samples were taken at baseline, and at 24-26 and 32-34 weeks of gestation to determine the urinary 11-dehydrothromboxane B(2) (u-11-dehydro-TxB(2)) and 2,3-dinor-6-keto-prostaglandin F(1alpha) (u-2,3-dinor-6-keto-PGF(1alpha)), the metabolites of thromboxane A(2) and prostacyclin, respectively. RESULTS: In the pregnancies with pregnancy-induced hypertension (PIH) before 37 gestational weeks, the 2,3-dinor-6-keto-PGF(1alpha)/11-dehydro-TxB(2) ratio did not increase as much as in other pregnancies (P = 0.028). In the placebo group pregnancies with preeclampsia had significantly lower 2,3-dinor-6-keto-PGF(1alpha) (P = 0.019) at 12-14 weeks of gestation compared to other pregnancies. In the placebo group the 2,3-dinor-6-keto-PGF(1alpha)/11-dehydroTxB(2) ratio remained unchanged throughout the pregnancy, with no significant difference between pregnancies with a normal or an adverse outcome. In the ASA group the 2,3-dinor-6-keto-PGF(1alpha)/11-dehydro-TxB(2) ratio increased (P < 0.001, early vs. midpregnancy). Again, the changes were similar in pregnancies with a normal or an adverse outcome. CONCLUSION: The balance of prostacyclin and thromboxane A(2) shifted in an unfavorable direction in pregnancies complicated by PIH. ASA had a favorable effect on the prostanoids.
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6-Cetoprostaglandina F1 alfa/análogos & derivados , Aspirina/administración & dosificación , Inhibidores de la Ciclooxigenasa/administración & dosificación , Epoprostenol/metabolismo , Hipertensión Inducida en el Embarazo/tratamiento farmacológico , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Tromboxano A2/metabolismo , Tromboxano B2/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Epoprostenol/análogos & derivados , Epoprostenol/orina , Femenino , Humanos , Hipertensión Inducida en el Embarazo/orina , Estudios Longitudinales , Embarazo , Complicaciones Cardiovasculares del Embarazo/orina , Resultado del Embarazo , Embarazo de Alto Riesgo , Prostaglandinas/metabolismo , Tromboxano A2/análogos & derivados , Tromboxano A2/orina , Tromboxano B2/orinaAsunto(s)
Epoprostenol/sangre , Preeclampsia/sangre , Tromboxanos/sangre , Epoprostenol/orina , Femenino , Edad Gestacional , Humanos , Preeclampsia/orina , Embarazo , Tromboxanos/orina , GemelosRESUMEN
BACKGROUND: Meta-analyses of the prevention of major vascular events by aspirin suggest therapeutic equivalence of all dosages. However, the optimal dosage still remains problematic, and a recent trial found aspirin 160 mg/day to be more effective than 80 mg/day for secondary prevention of ischaemic stroke. OBJECTIVE: To evaluate two low dosages of aspirin in terms of pharmacokinetics and pharmacodynamics (inhibition of platelet thromboxane generation and urinary excretion of thromboxane and prostacyclin metabolites). DESIGN AND PARTICIPANTS: A randomised cross-over study was performed in 16 healthy volunteers (9 women and 7 men, 33.8 +/- 5.1 years old) given enteric-coated aspirin 80 or 160 mg/day for 7 days. METHODS: Plasma concentrations of salicylate and aspirin were measured by high-performance liquid chromatography (HPLC) after both the first and the last dose (days 1 and 7). The usual pharmacokinetic parameters were then derived. Serum thromboxane B2 (TxB2) was measured by radioimmunoassay. The urinary excretion of 11-dehydro-TxB2 and 2,3-dinor-6-keto-prostaglandin F1alpha were measured on 8-hour urine samples by immunoassay after extraction and HPLC separation, both before and after 7 days of drug administration. RESULTS: With the 160 mg dosage, but not with the 80 mg dosage, higher concentrations of aspirin were found at day 7 compared with day 1. For aspirin 80 mg/day, 24-hour area under the concentration-time curve (AUC24) was similar on days 1 and 7 (569 +/- 339 vs 605 +/- 377 microg. h/L), but increased from 904 +/- 356 microg. h/L on day 1 to 1355 +/- 883 microg. h/L on day 7 with the higher dosage. Similarly, the AUC24 for salicylate was similar on days 1 and 7 with the lower dosage, but significantly increased from day 1 to day 7 after the higher dosage. This paralleled inhibition of serum TxB2 levels (99% vs 95% average inhibition by 160 and 80 mg/day) and of urinary excretion of thromboxane metabolite (77% vs 61% average inhibition by 160 and 80 mg/day), without altering the excretion of prostacyclin metabolite. CONCLUSIONS: Inhibition of serum TxB2 generation and of thromboxane metabolite urinary excretion by the lower dosage of aspirin, although substantial, still appeared incomplete. The small but significant further increase of serum TxB2 inhibition by the higher dosage was accompanied by an even greater inhibition of urinary excretion. We suggest that in some instances this difference would translate into a greater clinical benefit with the higher aspirin dosage. Our findings may also contribute to better definition of the recent concept of 'aspirin resistance'.