La inhibición selectiva de la ciclooxigenasa-2 mejora la disfunción endotelial y disminuye el estado inflamatorio en pacientes claudicantes / Selective cyclooxygenase-2 inhibition reduces endothelial dysfunction and improves inflammatory status in patients with intermittent claudication

Introducción y objetivos. En el origen de la arteriosclerosis, actúan la disfunción endotelial y un estado proinflamatorio. En esta situación, una expresión aumentada de ciclooxigenasa-2 (COX-2) produce un incremento de sustancias vasoconstrictoras y proinflamatorias. El objetivo de este estudio es conocer la contribución de la actividad de la COX-2 en la disfunción endotelial existente en la enfermedad arterial periférica (EAP). Métodos. Estudiamos la dilatación de la arteria braquial mediada por flujo (DABMF), las concentraciones de endotelina, proteína C reactiva ultrasensible (PCRus) y el perfil lipídico de 40 pacientes claudicantes. Asignamos aleatoriamente a 20 pacientes a un grupo en el que se administró el inhibidor selectivo de la COX-2 celecoxib durante 1 semana (grupo 1), y otros 20 actuaron como controles (grupo 2). Resultados. En el grupo 1, la DABMF aumentó significativamente 3 h después de la primera dosis de celecoxib (3,33% ± 4,11% frente a 6,97% ± 3,27%; p = 0,008) y tras 1 semana (3,33% ± 4,11 frente a 7,09% ± 4,4%; p = 0,001). Las concentraciones de endotelina disminuyeron significativamente en el grupo 1 (2,92 ± 1,87 frente a 1,93 ± 1,07 pg/ml; p = 0,018), así como los de PCRus (4,78 ± 2,73 frente a 2,95 ± 2,11 mg/l; p = 0,023) y colesterol de las lipoproteínas de baja densidad (106,38 ± 18,89 frente a 90,8 ± 28,58 mg/dl; p = 0,019). Ninguno de estos parámetros cambió significativamente en el grupo 2. Conclusiones. Los productos de la COX-2 contribuyen a la disfunción endotelial y el estado inflamatorio de la EAP. Los resultados de este estudio confirman la implicación de estos fenómenos en el origen de la arteriosclerosis. Esto puede suponer una nueva vía de estudio de posibles alternativas terapéuticas para los estadios incipientes de la enfermedad (AU)

Introduction and objectives. Both endothelial dysfunction and a proinflammatory state are present during the early stages of atherosclerosis. In this context, increased expression of cyclooxygenase-2 (COX-2) results in higher levels of vasoconstrictive and proinflammatory substances. The aim of this study was to investigate the influence of COX-2 activity on endothelial dysfunction associated with peripheral arterial disease (PAD). Methods. Brachial artery flow-mediated dilatation (BAFMD), endothelin and high-sensitivity C-reactive protein (hsCRP) levels, and the lipid profile were assessed in 40 patients with intermittent claudication. Of these, 20 were randomly assigned to a group in which they received the selective COX-2 inhibitor celecoxib for 1 week (Group 1), while the other 20 served as controls (Group 2). Results. In Group 1, BAFMD increased significantly both 3 hours after the first dose of celecoxib (3.33% [4.11%] vs 6.97% [3.27%]; P=.008) and 1 week after (3.33 [4.11] vs 7.09% [4.40%]; P=.001). The endothelin level decreased significantly in Group 1 (2.92 [1.87] vs 1.93 [1.07] pg/mL; P=.018), as did the levels of hsCRP (4.78 [2.73] vs 2.95 [2.11] mg/L; P=.023) and low-density lipoprotein cholesterol (106.38 [18.89] vs 90.8 [28.58] mg/dL; P=.019). In Group 2, none of these parameters changed significantly. Conclusions. COX-2 products contribute to endothelial dysfunction and an inflammatory state in PAD. This study’s findings provide evidence that these phenomena are implicated in the initiation of atherosclerosis and could prove a new means of investigating alternative approaches to the treatment of early-stage disease (AU)

Synthesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a PET imaging probe for COX-2 expression.

Synthesis of [18F]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ([18F]celecoxib), a selective COX-2 inhibitor, is achieved via a bromide to [18F]F- exchange reaction. Synthesis of the precursor for radiolabeling was achieved from 4'-methylacetophenone in four steps with 22% overall yield. Under non-radioactive conditions, fluorination was achieved using TBAF in DMSO at 135 degrees C in 80% yield. Synthesis of [18F]celecoxib was achieved using [18F]TBAF in DMSO at 135 degrees C in 10+/-2% yield (EOS) with >99% chemical and radiochemical purities. The specific activity was 120+/-40 mCi/micromol (EOB). [18F]celecoxib was found to be stable in ethanol, however, de[18F]fluorination (6.5%) was observed after 4 h in 10% ethanol-saline solution. Rodent PET studies show bone labeling indicating in vivo de[18F]fluorination of [18F]celecoxib. PET studies in baboon indicated a lower rate of de[18F]fluorination than rat and retention of radioactivity in brain regions consistent with the known distribution of COX-2. A radiolabeling method that can generate consistent high specific activity is needed for routine human use.

Contribución de la ciclooxigenasa 2 a las afecciones del hígado: inhibición de la apoptosis en las células hepáticas / No disponible

No disponible