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Perfiles trombolíticos de los activadores de plasminógeno dirigidos a los coágulos. Parámetros que determinan la
P Holvoet1, M Dewerchin, J M Stassen
1Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Circulation
|March 1, 1993
Resumen
La orientación del activador plasminógeno recombinante de tipo urokinasa de cadena única (rscu-PA) con anticuerpos específicos de la fibrina mejora su potencia trombolítica. Este enfoque mejora la orientación de los coágulos sin alterar la tasa de lisis máxima o la fase de retraso, ofreciendo una estrategia prometedora para la terapia trombolítica.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Farmacología Farmacología.
- Investigación de la trombosis.
Sus antecedentes:
- Los anticuerpos monoclonales específicos de la fibrina pueden dirigirse a los activadores plasminógenos de los trombos, aumentando potencialmente la eficacia trombolítica.
- El activador de plasminógeno recombinante de tipo urokinasa de cadena única (rscu-PA) es un agente trombolítico clave.
Objetivo del estudio:
- Para determinar la cinética de unión al coágulo de los anticuerpos monoclonales específicos de la fibrina (MA-12B3 y MA-15C5).
- Evaluar la potencia trombolítica y la cinética de lisis de rscu-PA conjugado con estos anticuerpos (rscu-PA/MA-12B3 y rscu-PA/MA-15C5) en comparación con el rscu-PA no conjugado y el activador de plasminógeno de tipo tisular (rt-PA) in vivo.
Principales métodos:
- Estudios in vivo en hámsters y conejos utilizando bucles arteriovenosos extracorporales y coágulos de la arteria pulmonar.
- Evaluación de las relaciones coágulo-sangre, lisis de coágulos in vivo, potencia trombolítica, aclaramiento plasmático, tasas máximas de lisis y fases de retraso.
- Se utilizaron anticuerpos etiquetados con 125I y escaneo continuo de radioisótopos para el monitoreo.
Principales resultados:
- MA-12B3 mostró proporciones de coágulos de sangre significativamente más altas que MA-15C5 en conejos.
- Los conjugados rscu-PA/anticuerpo demostraron una lisis de coágulos in vivo relacionada con la dosis en hámsters, con una potencia trombolítica significativamente mejorada en comparación con rscu-PA y rt-PA.
- Los conjugados exhibieron un aclaramiento plasmático más lento, tasas de lisis máximas similares y fases de retraso mínimo comparables a los agentes no conjugados.
Conclusiones:
- La orientación de coágulos de rscu-PA con anticuerpos específicos de fibrina aumenta sustancialmente su potencia trombolítica, impulsada principalmente por el aclaramiento y las características de unión.
- Si bien la orientación de anticuerpos aumenta la potencia, no altera significativamente la velocidad máxima o la fase de retraso mínimo de la lisis de coágulos.
- Estos parámetros cinéticos parecen independientes del activador específico del plasminógeno y la estrategia de orientación.
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