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Leal Pinto, Sandra Milena Mantilla Ojeda, Lucía Liliana García Sánchez, Liliana Torcoroma 2020-02-07T15:36:04Z 2020-02-07T15:36:04Z 2019-12-02 https://repositorio.udes.edu.co/handle/001/4429 T 86.19 M168e 129 p La leishmaniasis es una enfermedad metaxénica cuyo vector (Lutzomyia), transmite la enfermedad al penetrar la piel del huésped mamífero e introducir los protozoos de leishmania, quienes dependiendo de la especie dan paso a un tipo de manisfestación clínica específica, con diversos grados de severidad. Aunque existen distintos tratamientos para esta infección (Pentostam®, Glucantime®, pentamidine, anfotericina B y miltefosina), aún nos enfrentamos a múltiples retos: vía de administración, efectos tóxicos hepáticos y renales, fracaso al tratamiento, resistencia farmacológica, estado inmunológico del paciente, condiciones socioeconómicas, cronicidad de las lesiones y especie del parásito. De acuerdo con lo anterior, este estudio tuvo como objetivo, caracterizar el efecto antiparasitario in vivo de un nanoconjugado de Ftalocianina de Aluminio Clorada y paramomicina (NE+FtAlCl/PM15%) activado mediante Terapia Fotodinámica (TFD), en el modelo murino de Leishmaniasis cutánea. Para esto, se realizó la estandarización del modelo de leishmaniasis cutánea en ratones BALB/c evaluado dos inoculados en dos sitios anatómicos de infección (almohadilla plantar y base de la cola). Posteriormente, se evaluó la efectividad de NE-FtAlCl/PM en dos modelos experimentales. Terapia fotodinámica fue aplicada en los grupos tratados con el fotosensibilizador usando luz LED. La efectividad clínica y parasitológica, así como toxicidad aguda relacionada con parámetros hematológicos y bioquímicos, fue evaluada. El tratamiento mostró ser inefectivo para curar lesiones cutáneas por L. (V.) braziliensis en ratones BALB/c. Sin embargo, los resultados mostraron ser similares a los obtenidos con el grupo control tratado con Glucantime (20mg/Kg/día). Adicionalmente, en el modelo con lesión cutánea ulcerada, se observó disminución del tamaño de la úlcera en los ratones tratados con NE-FtAlCl/PM+TFD. No se observaron efectos tóxicos sistémicos del tratamiento. Este estudio es el primero en evaluar la combinación de dos fármacos bioactivos contra Leishmania spp en un mismo nanovehículo. Sin embargo, los fármacos no mostraron curar las lesiones cutáneas causadas por el parásito. La optimización del esquema de tratamiento con NE-FtAlCl/PM+TFD es recomendable. Leishmaniasis is a metaxenic disease whose vector (Lutzomyia) transmits the disease by penetrating the skin of the mammalian host and introducing the protozoa of leishmania, who depending on the species give way to a specific type of clinical manifestation, with varying degrees of severity. Although there are differents treatments (Pentostam®, Glucantime®, pentamidine, amphotericin B and miltefosine), multiple challenges are still unresolved: route of administration, liver and kidney toxic effects, treatment failure, drug resistance, immunological conditions of patient, socioeconomic surroundings, chronicity of the lesions and parasite species. For this, the standardization of the cutaneous leishmaniasis model in BALB/c mice was evaluated using two inoculated in two anatomical sites of infection (plantar pad and tail base). Subsequently, the effectiveness of NE-FtAlCl / PM in two experimental models was evaluated. Photodynamic therapy was applied in the groups treated with the photosensitizer using LED light. Clinical and parasitological effectiveness, as well as acute toxicity related to hematological and biochemical parameters, was tested. The treatment was ineffective in curing skin lesions by L. (V.) braziliensis in BALB/c mice. However, the results were similar to those obtained with the control group treated with Glucantime (20mg/Kg/day). Additionally, in the model with ulcerated skin lesion, a decrease in ulcer size was observed in mice treated with NE-FtAlCl/PM + TFD. No systemic toxic effects of the treatment were observed. This study is the first to evaluate the combination of two bioactive drugs against Leishmania spp in the same nanocarrier. However, the drugs were not shown to cure the skin lesions caused by the parasite. The optimization of the treatment scheme with NE-FtAlCl / PM + TFD is recommended INTRODUCCIÓN .................................................................................................................................. 1 1.1 LEISHMANIASIS: Generalidades y epidemiología .......................................................... 3 1.1.1. Leishmania spp: ciclo de vida .......................................................................................... 5 1.1.2. Transmisión ...................................................................................................................... 9 1.1.3. Reservorios ..................................................................................................................... 11 1.1.4. Patogénesis ..................................................................................................................... 12 1.1.5. Manifestaciones clínicas................................................................................................. 15 1.1.6. Tratamientos Convencionales ........................................................................................ 21 1.1.7. Tratamientos no Convencionales ................................................................................... 32 1.1.8. Nanobiotecnología aplicada en farmacología ............................................................... 40 2. OBJETIVOS ................................................................................................................................ 43 2.1 OBJETIVO GENERAL .................................................................................................... 43 2.2 OBJETIVOS ESPECÍFICOS ........................................................................................... 43 3. MATERIALES Y MÉTODOS .................................................................................................... 44 3.1 MATERIALES ................................................................................................................. 44 3.1.1. Animales ......................................................................................................................... 44 3.1.2. Cepa de Leishmania ....................................................................................................... 44 3.1.3. Fotosensibilizador y medicamentos ................................................................................ 44 3.1.4. Preparación sistema de nanoemulsión ........................................................................... 45 3.1.5. Sistema de irradiación .................................................................................................... 45 3.2 MÉTODOS ....................................................................................................................... 46 3.2.1. Estandarización del modelo de infección ....................................................................... 46 3.2.2. Modelo animal de Leishmaniasis cutánea ...................................................................... 47 3.2.3. Consideraciones éticas ................................................................................................... 52 3.2.4. Análisis de datos ............................................................................................................. 53 4. RESULTADOS ........................................................................................................................... 54 4.1. Estandarización del modelo de infección ......................................................................... 54 4.1.1. Leishmaniasis cutánea experimental en almohadilla de pata trasera derecha .............. 54 4.1.2. Leishmaniasis cutánea experimental en base de la cola ................................................ 62 4.1.3. Evaluación de parámetros de toxicidad ......................................................................... 64 4.2. Modelo experimental de Leishmaniasis cutánea para la evaluación de la efectividad de la TFD y paramomicina ..................................................................................................................... 70 4.2.1. Modelo de LC murina en almohadilla plantar derecha: evaluación de la eficacia clínica70 4.2.2. Modelo de LC murina en almohadilla plantar derecha: evaluación de la eficacia parasitológica ........................................................................................................................... 73 4.2.3. Modelo de LC murina en almohadilla plantar derecha: evaluación de la toxicidad ..... 76 4.2.4. Modelo de LC murina en almohadilla plantar derecha: Biodistribución FtAlCl y PM . 81 4.2.5. Modelo de LC murina en base de la cola: evaluación de la eficacia clínica ................. 81 5. DISCUSIÓN ................................................................................................................................ 89 6. CONCLUSIONES ............................................................................................................................ 99 7. RECOMENDACIONES ................................................................................................................. 100 8. 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Leishmaniasis cutánea Leishmania braziliensis Terapia fotodinámica Ftalocianina de aluminio clorada Nanoemulsión In vivo Cutaneous leishmaniasis Photodynamic therapy Chlorinated aluminum phthalocyanine Nanoemulsion http://purl.org/coar/access_right/c_abf2 http://purl.org/coar/version/c_ab4af688f83e57aa Publicationopen.access