RESUMEN
To examine the role of cyclooxygenase (COX) isozymes in prostaglandin formation and oxidant stress in inflammation, we administered to volunteer subjects placebo or bolus injections of lipopolysaccharide (LPS), which caused a dose-dependent increase in temperature, heart rate, and plasma cortisol. LPS caused also dose-dependent elevations in urinary excretion of 2,3-dinor 6-keto PGF(1alpha) (PGI-M) and 11-dehydro thromboxane B(2) (Tx-M). Platelet COX-1 inhibition by chronic administration of low-dose aspirin before LPS did not alter the symptomatic and febrile responses to LPS, but the increment in urinary PGI-M and Tx-M were both partially depressed. Pretreatment with ibuprofen, a nonspecific COX inhibitor, attenuated the febrile and systemic response to LPS and inhibited prostanoid biosynthesis. Both celecoxib, a selective COX-2 inhibitor, and ibuprofen attenuated the pyrexial, but not the chronotropic, response to LPS. Experimental endotoxemia caused differential expression of the COX isozymes in monocytes and polymorphonuclear leucocytes ex vivo. LPS also increased urinary iPF(2alpha)-III, iPF(2alpha)-VI, and 8,12-iso-iPF(2alpha)-VI, isoprostane (iP) indices of lipid peroxidation, and none of the drugs blunted this response. These studies indicate that (a) although COX-2 predominates, both COX isozymes are induced and contribute to the prostaglandin response to LPS in humans; (b) COX activation contributes undetectably to lipid peroxidation induced by LPS; and (c) COX-2, but not COX-1, contributes to the constitutional response to LPS in humans.
Asunto(s)
Eicosanoides/biosíntesis , Inflamación/metabolismo , Isoenzimas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Adulto , Aspirina/farmacología , Celecoxib , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Femenino , Humanos , Ibuprofeno/farmacología , Técnicas In Vitro , Inflamación/etiología , Peroxidación de Lípido/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Proteínas de la Membrana , Estrés Oxidativo/efectos de los fármacos , Prostaglandinas/biosíntesis , Prostaglandinas/orina , Pirazoles , Sulfonamidas/farmacologíaRESUMEN
Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Epoprostenol/biosíntesis , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Sulfonamidas/farmacología , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Adulto , Celecoxib , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Dinoprostona/metabolismo , Femenino , Humanos , Ibuprofeno/farmacocinética , Ibuprofeno/farmacología , Isoenzimas/sangre , Isoenzimas/efectos de los fármacos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Monocitos/enzimología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Prostaglandina-Endoperóxido Sintasas/sangre , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Pirazoles , Sulfonamidas/farmacocinética , Tromboxano B2/análogos & derivados , Tromboxano B2/sangre , Tromboxano B2/orinaRESUMEN
OBJECTIVES: To examine the fetal effects of a novel controlled-release, low dose aspirin preparation in normal and hypertensive pregnancies. DESIGN: Random double-blind study. Participants assigned to receive conventional formulation aspirin (75 mg), controlled-release low dose aspirin (75 mg), or a matching placebo. SETTING: National Maternity Hospital, Dublin. PARTICIPANTS: Eighteen women with an uncomplicated pregnancy and 18 women with preeclampsia. MAIN OUTCOME MEASURES: Urine was analysed for metabolites of thromboxane and prostacyclin by gas chromatography, mass spectrometry. Serum thromboxane B2 was determined in maternal and cord blood. RESULTS: Both aspirin preparations reduced maternal serum thromboxane B2 by 95% and induced similar reductions in the urinary 11-dehydro-thromboxane B2, a major metabolite of thromboxane A2 in vivo. In contrast, neither preparation altered urinary 2,3-dinor-6-keto PGF1alpha, the major metabolite of prostacyclin. Despite their similar effects in the mothers, the two aspirin preparations differed in their effects on the fetus. While both suppressed cord fetal thromboxane B2, this was significantly (P < 0.005) less for the controlled-release preparation (210+/-42 ng/ml for placebo vs 109+/-22 ng/ml for controlled-release aspirin and 44+/-9 ng/ml for regular oral aspirin). CONCLUSIONS: At equivalent maternal suppression of serum thromboxane B2, a controlled aspirin release preparation results in lower fetal exposure than regular oral aspirin.
Asunto(s)
Aspirina/administración & dosificación , Inhibidores de la Ciclooxigenasa/administración & dosificación , Preeclampsia/tratamiento farmacológico , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/metabolismo , Adulto , Preparaciones de Acción Retardada , Método Doble Ciego , Eicosanoides/orina , Femenino , Sangre Fetal/química , Humanos , Embarazo , Tromboxano B2/metabolismoRESUMEN
In a series of 129 patients having coronary angioplasties in St. James's Hospital in 1989, the average age was 54.8 (30-77 years). There were 102 (79%) men and 27 (21%) females. Clinical indications were unstable angina 62, stable angina 26, post myocardial infarction 39 and asymptomatic ischaemia 2. The distribution of coronary disease was single vessel 62%, double vessel 28%, triple vessel 7% and previous coronary bypass surgery 3%. Only 10 patients had more than one vessel dilated. Primary success was achieved in 119 (92%), there were no deaths, 3 patients had abrupt closure of the vessel during angioplasty and sustained a nonfatal myocardial infarction, 1 patient required urgent bypass surgery and 2 patients had peripheral vascular complications requiring surgery. There were 6 failed angioplasties, 4 of which had chronic total occlusion. At a mean follow-up of 5.3 months, 85 patients had no symptoms, 34 had angina, 2 developed myocardial infarction and 1 died suddenly at 5 months. Repeat angiography was performed in 96 (79%) patients. At follow-up, no symptoms were present in 69% of those with single vessel disease and 70% of multivessel disease. Of those who had more than one vessel dilated in multivessel disease, 80% were asymptomatic (P = NS). There were 11 patients with initial total occlusion at presentation, 4 had failed angioplasties, 5 recurrent angina of which 4 reoccluded and 1 restenosed and only 2 were asymptomatic and without restenosis. Angioplasty was performed with primary success (92%) and follow up results (70% asymptomatic). Those with single or multivessel disease had similar clinical outcome, favouring the use of target vessel angioplasty. Long term results following angioplasty of chronic total occlusions were poor and suggests the need for additional treatment.