Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

Cambios hemodinamicos durante la administración de protamina y eliminación de sus efectos adversos por inhibición de la ciclo-oxigenasa / Hemodymamic changes during protamine administration and elimination of this adverses effect for inhibition ciclooxygenase

La hipótesis que los efectos adversos producidos al revertir la heparina por protamina puedan ser eliminados o disminuídos al suministrar Indometacina, se trató de comprobar en 16 pacientes clasificados en dos grupos. En el grupo I (placebo) n=8, fe=0.60%; 6 masculinos y 2 femeninos; a 4 de ellos se les realizó puentes aorto coronarios u al resto reemplazo de la válvula mitral. Se determinaron los efectos hemodinámicos y la diferencia arterio-venosa de oxígeno al administrar la protamina endovenosa. El grupo II (n= 8); fe= 0.47%; 5 masculinos y 3 femeninos, fueron tratados con Indometacina (50 mgs. V.O. TID); las intervenciones efectuadas fueron puentes aorto-coronarios 5, y reemplazo valvular aórtico 2, realizándose las mismas medidas que al grupo I. Cuando se administró la protamina (1,5 mgs. por total de heparina) en 5 minutos y se compararon las variables hemodinámicas de los dos grupos, no se encontraron diferencias estadísticamente significativas en los tiempos T3, T4 y T5. Al tomar en cuenta los 2 grupos se observa que la presión arterial media aumenta en el grupo I (76 ñ 8 a 82 ñ 4) y disminuyó en el grupo II (80 ñ 7 a 73 ñ 14). La presión venosa central, la presión media en arteria pulmonar, la presión capilar pulmonar y el gasto cardíaco aumentan en ambos grupos; la resistencia vascular sistémica disminuye en ambos grupos, siendo más acentuada en el grupo II (2.181 ñ 1.283 a 996 ñ 521). La resistencia vascular pulmonar comparada con su mismo grupo mostró variación estadísticamente significativa en el grupo II, con p < 0.05 en relación a su valor base T0 (166 ñ 108 a 96 ñ 51)..

Prostaglandins as inhibitors of human platelet aggregation.

The potencies of prostaglandins (PG) I2, PGD2 and PGE1 as inhibitors of human platelet aggregation induced by threshold concentrations of four aggregating agents were determined in platelet-rich plasma from normal individuals who had not ingested aspirin. The order of activity against ADP, adrenaline and collagen was always PGI2 greater than PGD2 greater than PGE1. However, PGD2 and PGE1 were almost equipotent with PGI2 when tested against arachidonic acid (AA). The threshold inhibitory effects of PGD2, PGE1 and PGI2 could be over come by increasing the concentrations of the aggregating agents AA, collagen or ADP. Adrenaline was found to be different from the other aggregating agents. It could overcome inhibition of platelet aggregation by PGD2 but could not overcome inhibition by PGI2 or PGE1. These facts support the hypothesis that platelet receptors for PGI2 and PGE1 are similar to each other and different from the receptor(s) for PGD2. PRP obtained from normal subjects after the ingestion of aspirin exhibited only one wave of aggregation in response to ADP, adrenaline or collagen, PGI2, PGD2 and PGE1 were all powerful inhibitors of this single wave of aggregation. The inhibitory activity of all three prostaglandins at threshold concentrations was overcome by increasing the concentration of ADP or collagen but not by increasing the concentration of adrenaline.