Publication: Biodistribución y eficacia de nuevos fosfolípidos y flavonoles frente a la leishmaniosis visceral en criceto
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2019-04-29
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Universidad Complutense de Madrid
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Abstract
En la actualidad se dispone de un arsenal terapéutico que incluye más de 25 fármacos dirigidos al tratamiento de las leishmaniosis. Sin embargo, todos presentan importantes limitaciones en términos de seguridad, eficacia y/o fallos terapéuticos asociados a una posología incorrecta o a fenómenos de resistencia, haciendo necesaria la búsqueda de alternativas para su tratamiento. En este contexto, el proyecto NMTrypI, New Medicines for Trypanosomatidic Infections (European Union’s Seventh Framework Programme for Research, Technological Development and Demonstration, nº 603240-2, 2014-2017) identificó tres nuevos compuestos de síntesis de interés por su escasa toxicidad, alta actividad anti-Leishmania (baja IC50) y elevado índice terapéutico: dos alquilfosfocolinas, denominadas NMT-A001 y NMT-A002; y el flavonol NMT-H080.Para evaluar su potencial terapéutico frente a la leishmaniosis visceral 1) se determinaron las características farmacocinéticas y la biodistribución de dichas moléculas, 2) se desarrolló un nuevo método de inoculación en criceto (Mesocriceus auratus) para el establecimiento de leishmaniosis visceral, 3) se evaluó el potencial terapéutico de las alquilfosfocolinas frente a la leishmaniosis visceral así como su dependencia de la posología establecida, y 4) se exploró la actividad anti-Leishmania in vivo del flavonol NMT-H080 y su potenciación mediante ciclodextrinas...
Nowadays more than 25 drugs for the treatment of leishmaniasis are marketed. However all of them have serious drawbacks considering safety, efficacy and therapeutic failures associated either to the emergence of resistant strains or the inadequate posology. To cope with these limitations new therapeutic alternatives are needed. In this scenario the project NMTrypI, New Medicines for Trypanosomatidic Infections (European Union’s Seventh Framework Programme for Research, Technological Development and Demonstration, nº 603240-2, 2014-2017) identified three new compounds of interest on the basis of their scarce toxicity for mammalian cells and rodents, high anti-Leishmania activity (low IC50) and high therapeutic index: two alkylphosphocholines, NMT-A001 y NMT-A002, and one flavonol, NMT-H080.To explore their potential therapeutic value against visceral leishmaniasis 1) pharmacokinetics and biodistribution of the molecules were determined, 2) a new inoculation method, retro-orbitary injection, to establish visceral infections in hamster (Mesocricetus auratus) was developed, 3) therapeutic potential of phosphocholines and its dependence on treatment schedule was tested in experimentally infected hamsters, and 4) in vivo activity of the flavonol NMT-H080 and cyclodextrins formulations was evaluated in infected hamsters...
Nowadays more than 25 drugs for the treatment of leishmaniasis are marketed. However all of them have serious drawbacks considering safety, efficacy and therapeutic failures associated either to the emergence of resistant strains or the inadequate posology. To cope with these limitations new therapeutic alternatives are needed. In this scenario the project NMTrypI, New Medicines for Trypanosomatidic Infections (European Union’s Seventh Framework Programme for Research, Technological Development and Demonstration, nº 603240-2, 2014-2017) identified three new compounds of interest on the basis of their scarce toxicity for mammalian cells and rodents, high anti-Leishmania activity (low IC50) and high therapeutic index: two alkylphosphocholines, NMT-A001 y NMT-A002, and one flavonol, NMT-H080.To explore their potential therapeutic value against visceral leishmaniasis 1) pharmacokinetics and biodistribution of the molecules were determined, 2) a new inoculation method, retro-orbitary injection, to establish visceral infections in hamster (Mesocricetus auratus) was developed, 3) therapeutic potential of phosphocholines and its dependence on treatment schedule was tested in experimentally infected hamsters, and 4) in vivo activity of the flavonol NMT-H080 and cyclodextrins formulations was evaluated in infected hamsters...
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Tesis de la Universidad Complutense de Madrid, Facultad de Veterinaria, Departamento de Sanidad Animal, leída el 17-12-2018