This is a bibliografic review about inmunosuppressive drugs in transpiantation. We compare diverses drugs with Ciclosporine (Sandimmun NeoralR) gold standard for this drugs at world level.
Preparaciones biológicas antilinfociticas (Muromonab CD 3, OKT3), ATGAM o globulina antitimocítica) y anticuerpos monoclonales selectivos (MAbs):
Los anticuerpos polielonales actúan contra las células inmunocompetentes y previenen o revierten los episodios de rechazo agudo. Ejemplos de Anticuerpos policlonales lo son las anticuerpos de conejo para linfocitos humanos (ALG) y los anticuerpos de caballo para timocitos humanos (8, 76, 83). Se menciona a la globulina antitimocítica, anticuerpos monoclonales CD 3 (OKT3) para prevenir o revertir el proceso de rechazo. Debido a que estos agentes interactúan con los linfocitos T se han reportado diversos efectos secundarios (8, 127, 128). Se ha establecido mejor acción por parte de timoglobulina en comparación a Atgam (Globulina timocftica antihumana), en revertir rechazo renal agudo y prevenir la recurrencia de rechazo después de trasplante renal (8, 32, 92). Comparados con el régimen de ciclosporina A, micofenolato, se encuentran menos efectos secundarios y menor sensibilización contra OKT3 (83). Los anticuerpos monoclonales selectivos (Mabs), con potencial de regular respuesta especifica inmunológica, vía receptores funcionales, reducen los efectos secundarios (51). Bloquean selectivamente la célula T activada, sin evidencia de mayor incidencia de infecciones o efectos secundarios, como enfermedad del suero, reacción de primera dosis por liberación de citokinas, trombocitopenia o neutropenia (83, 110). Los anticuerpos monoclonales selectivos (Mabs) como el basiliximab (Simulect) y el declizumab (ZenapaxgR) han disminuido significativamente los episodios de rechazo agudo 6 o 12 meses despúes del trasplante, asociado a inmunosupresión con microemulsión de ciclosporina y esteroides (22). Su disminución en la incidencia de rechazo agudo es de alrededor del 35%, sin aumento de la incidencia de infecciones u otros efectos adversos, al cabo de un año de seguimiento (19). El basiliximab es un receptor de interleukina - 2 (contra el antígeno CD 25) sobre linfocitos activados, quimérico, utilizado en inmunoprofilaxis de rechazo agudo en trasplante renal, incluso en trasplante renal en diabéticos, al asociarlo con Neoral y esteroides, reduce los episodios de rechazo (82). Su quimerización le ha brindado potencia a la inmunoprofilaxis, permitiendo un tiempo prolongado de acción, la disminución de la incidencia del síndrome de liberación de citokinas y las reacciones alérgicas (10, 60, 62, 109,111,113). Se recomienda confirmar el diagnóstico clínico de rechazo por biopsia renal (22). Se ha reducido la dosis de esteroides con el uso concomitante de basiliximab (51). Este medicamento actúa bloqueando la estimulación de linfocitos T por IL-2 (60). Su uso es al primer día y al cuarto del transplante, en dos dosis de 20 mgs en infusión, que proveen inmunosupresión por 30 a 45 días (10, 22,60, 109). No se ha demostrado mayor incidencia de infecciones por citomegalovirus con su uso, por el contrario reduciendo su incidencia y la estancia hospitalaria (66). El daclizumab (ZenapaxgR) se produce por recombinación de ADN y se une específicamente a la subunidad (p55, CD 25 o subunidad TAC) del receptor de la IL - 2, expresado en la superficie de linfocitos activados. Se compone de 90% de secuencia de anticuerpos humanos y 10% murinos. Al bloquear los receptores de IL - 2, bloquea la respuesta de linfocitos T activados. Se recomienda utilizarlo como profilaxis de rechazo de trasplante renal. Su dosis sugerida es de 5 dosis intravenosas iniciada en el pretrasplante o a las 24 horas posteriores al mismo, y darla a intervalos de 14 días es un total de 5 dosis (110).
OTROS INMUNO SUPRESORES:
Se menciona el uso de (6,
19, 64, 77,112,128):
Enalapril (Inhibidores de
angiotensina y bloqueadores de receptores de Angiotensina II)
Moléculas anti-adhesión
Antisueros
Terapia genética
Inducción de tolerancia
Péptidos
Malononitrilamidas (Cuyos
estudios indican que inhiben la generación de radicales de oxígeno
de los fagoticos mononucleares activados).
Proteasomas (Que parecen
inhibir la proliferación de células T así como eliminar
aloantígenos específicos, vía apoptosis).
ESQUEMAS DE INMUNOSUPRESION:
En los Estados Unidos, con
93 934 trasplantes renales, realizados hasta 1996 se recomienda el uso
de ciclosporina como primera elección (39). La
mayor parte de los protocolos utilizados en los centros de trasplante,
envuelven la participación de varias drogas, directamente utilizadas
para actuar a diversos sitios sobre la cascada de activación de
las células T, cada una también con efectos secundarios diversos.
Así se utilizan Ciclosporina A (CsA, azatioprina, corticosteroides,
FK - 506 (tacrolimus) y micofenolato mofetil, aprobadas por la FDA, mientras
la eficacia clínica de rapamicina (sirolimus), mizoribine, 15 -deoxispergualina
y leflunomida está aú n explotándose (114).
Los inmunosupresores se pueden clasificar según su sitio primario
de acción (62, 113, 130):
Inhibición de la
trascripción: Ciclosporina A, tacrolimus.
Inhibidores de la síntesis
de nucleótido y de replicación cromosómica: Azatioprina,
mofetil micofenolato, mizoribina, leflunomida.
Inhibidores de la señal
de transducción de crecimiento: Sirolimus, leflunomida.
Inhibidores de la diferenciación:
15 - deoxispergualina.
Anticuerpos anti - linfocíticos,
que actúan directamente sobre el receptor de antígenos de
células T (OKT 3, TIOB 9), o anticuerpos monoclonales que actúan
directamente sobre la superficie celular de antígenos, incluyendo
receptores de interleukina 2.
El paradigma prevalente
continúa siendo el mecanismo de acción de los inmunosupresores,
previniendo o inhibiendo la activación celular, la producción
de citokinas, la proliferación / inhibición (114).
EFECTOS SECUNDARIOS:
Se han mencionado como efectos
secundarios de los inmunosupresores:
Supresión medular,
especialmente con azatioprina y brequinar sódico (19,130).
Nefrotoxicidad: Se ha relacionado con Tacrolimus, Ciclosporina A, Rapamicina (14, 18, 19, 51, 85, 126, 130).
Hipertensión arterial:
Se ha relacionado con Esteroldes, Ciclosporina A y en menor grado con Tacrolimus
(18, 51, 88, 130,
137), se ha visto alteraciones en el balance de vasodilatadores
/ vasoconstrictores, fibrosis, isquemia renal, activación de endotelio
e inhibición de la calcineurina (19, 59,
79), sin embargo disminuye en pacientes con insuficiencia
renal crónica de
96% a 51 % después
del trasplante renal (40).
Síndrome hemolítico urémico: que se ha reportado al uso de ciclosporina y de tacrolimus (29, 41, 55).
Osteoporosis: Se asocia al uso de esteroides y se recomienda el uso de bisfosfonatos (4, 5, 96).
Intolerancia gastrointestinal: Incluyendo nausea, constipación, diarrea relacionadas al micofenolato y al brequinar, aunque se ha reportado prácticamente en todos los inmunosupresores (46, 51, 126).
Infecciones: Con mayor incidencia y severidad, incluyendo citomegalovirus, tuberculosis, hepatitis C y otras virosis (18, 26, 38, 46, 68, 74, 78, 107). La incidencia de infecciones por citomegalovirus se ha reportado con una alta incidencia, específicamente con azatioprina y micofenolato (19, 68), así como las infecciones micóticas (94). Igualmente se reporta infección por Parvovirus B 19 y aplasia de células rojas, con el uso de tacrolimus (131).
Malignidad: Se ha reportado Carcinoma epidermoide de piel, Sarcoma de Kaposi, linfoma no Hodgkin y otros tumores (42, 74, 124). Se ha documentado transmisión de cáncer en 43% de recipientes de órganos en pacientes con malignidad, proponiéndose el examen cuidadoso de todos los órganos, la biopsia en lesiones sospechosas y la autopsia de donadores, si es posible (90).
Intolerancia a la glucosa: Empeorando la condición vascular del receptor, relacionado con esteroides, ciclosporina, tacrolimus y rapamicina (18,31, 49,51,71, 115, 126, 139). La incidencia de aparición de diabetes con ciclosporina y tacrolimus es similar (71, 115, 126), aunque algunos estudios reportan una tasa más alta de diabetes en pacientes tratados con ciclosporina en relación a los tratados con tacrolimus (4% vrs. 19%) (49, 126 ). Se estudia la posibilidad de utilizar esquemas sin esteroides para tratar de disminuir la incidencia de diabetes (71, 115).
Cardíacos: Se ha reportado aumento de intervalo QT después de uso intravenoso de tacrolimus (128).
Hiperlipidemia: Se ha observado con ciclosporina, esteroides y sirolimus (1, 15, 93), depende del régimen utilizado y conviene ajustarlo individualmente (1, 135).
Neurotoxicidad: Se ha reportado con el uso de tacrolimus (19).
Síndrome de secuela por liberación de citokinas (10, 14, 45,60, 62, 109, 114, 119, 134), que se ha asociado a activación de radicales libres (87), apoptosis de células endoteliales (45, 122), y se ha relacionado con tacrolimus (119).
Piel: El brequinar se ha asociado a mucositis ulcerativa severa, dermatitis (124).
Transaminasas hepáticas: Se ha encontrado aumentadas en pacientes tratados con sirolimus (71) y colestasis asociada a tacrolimus (97), así como hipokalemia (116).
También existen reportes de problemas de cicatrización de herida, cambios en la personalidad, cataratas (esteroides), ictericia colestásica, pancreatitis (azatioprina), disfunción hepática, hipertricosis, tremor, disfunción hepática, convulsiones, hirsutismo, hiperplasia gingival, parestesias, ansiedad, conjuntivitis (ciclosporina) (18, 130).
DISCUSIÓN
Se ha incrementado el arsenal inmunosupresor en los últimos años, sin embargo aún no hay consenso sobre el esquema inmunosupresor ideal, debido a los efectos secundarios de los diversos medicamentos. Hay que esperar la respuesta de los anticuerpos monoclonales selectivos.
RESUMEN
Se realiza una revisión bibliográfica acerca de los inmunosupresores utilizados en trasplante. Los medicamentos utilizados para este fin son comparados con la Ciclosporina (Sandimmun NeoralR) que se presenta como el estandard de comparación de acuerdo a la experiencia mundial y conocimiento del mismo.
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