3134
Chagas disease is an anthropozoonosis caused by the protozoan Trypanosoma cruzi (T. cruzi), and it is endemic in the Americas, affecting approximately 10 million people,\ncausing nearly 10,000 deaths per year due to cardiovascular or gastrointestinal\ncomplications.\nAvailable drugs, nifurtimox and...
Guardado en:
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Universidad de Buenos Aires. Facultad de Ciencias Veterinarias
2019
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=avaposgra&cl=CL1&d=HWA_3134 https://repositoriouba.sisbi.uba.ar/gsdl/collect/avaposgra/index/assoc/HWA_3134.dir/3134.PDF |
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I28-R145-HWA_3134 |
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dspace |
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Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-145 |
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Repositorio Digital de la Universidad de Buenos Aires (UBA) |
| language |
Español |
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spa |
| topic |
Trypanosoma cruzi Enfermedad de Chagas Reposicionamiento de fármacos Cribado fenotípico Modelo in vitro Modelo in vivo Medicina traslacional Enfermedad de Chagas Tratamiento Evaluación In vitro In vivo Farmacología |
| spellingShingle |
Trypanosoma cruzi Enfermedad de Chagas Reposicionamiento de fármacos Cribado fenotípico Modelo in vitro Modelo in vivo Medicina traslacional Enfermedad de Chagas Tratamiento Evaluación In vitro In vivo Farmacología Gulin, Julián Ernesto Nicolás 3134 |
| topic_facet |
Trypanosoma cruzi Enfermedad de Chagas Reposicionamiento de fármacos Cribado fenotípico Modelo in vitro Modelo in vivo Medicina traslacional Enfermedad de Chagas Tratamiento Evaluación In vitro In vivo Farmacología |
| description |
Chagas disease is an anthropozoonosis caused by the protozoan Trypanosoma cruzi (T. cruzi), and it is endemic in the Americas, affecting approximately 10 million people,\ncausing nearly 10,000 deaths per year due to cardiovascular or gastrointestinal\ncomplications.\nAvailable drugs, nifurtimox and benznidazole, are associated with a relatively high frequency of adverse events, the most common being nausea, anorexia, headache,\ngastrointestinal discomfort and arthralgias. It is also common for the appearance of erythema and pruritus. These effects added to the prolonged duration of treatment (up to 2 months) and the perception of moderate effectiveness during the chronic phase\nare frequent causes of treatment discontinuation.\nIn this context, searching for new safe and accessible therapeutic alternatives for\nChagas disease treatment is a pending objective.\nThere is little interest by the pharmaceutical industry on research and development of drugs for Chagas disease, mainly due to the socioeconomic characteristics of the\naffected population. The repositioning or reorientation of drugs and combinatorial\ntherapy arise as alternatives to the development of new molecules and involve a\nsignificantly lower investment of resources.\nIn this work, available drugs for clinical use were selected and were evaluated by in\nvitro and in vivo methods to determine anti-T. cruzi activity of drugs candidates.\nThirty-eight drugs were evaluated in vitro on trypomastigote and amastigote stages\nwith a low-throughput screening system using the T. cruzi VD strain, previously\ncharacterized. Also, a high-throughput screening system was standardized and optimized with the Dm28c/pLacZ strain, with which other thirty-eight drugs were evaluated. From these results, five drugs (nitazoxanide, pyrimethamine, ivermectin\nvoriconazole, and miltefosine) were evaluated in a murine model of acute infection with T. cruzi.\nThe trypanocidal or trypanostatic effects of the drugs studied confirmed the anti-T. cruzi activity of the drugs available for clinical use, validating the repositioning strategy to\nidentify new candidate compounds for the treatment of Chagas disease.\n |
| author2 |
García-Bournissen, Facundo |
| author_facet |
García-Bournissen, Facundo Gulin, Julián Ernesto Nicolás |
| format |
Tesis doctoral Tesis doctoral acceptedVersion |
| author |
Gulin, Julián Ernesto Nicolás |
| author_sort |
Gulin, Julián Ernesto Nicolás |
| title |
3134 |
| title_short |
3134 |
| title_full |
3134 |
| title_fullStr |
3134 |
| title_full_unstemmed |
3134 |
| title_sort |
3134 |
| publisher |
Universidad de Buenos Aires. Facultad de Ciencias Veterinarias |
| publishDate |
2019 |
| url |
http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=avaposgra&cl=CL1&d=HWA_3134 https://repositoriouba.sisbi.uba.ar/gsdl/collect/avaposgra/index/assoc/HWA_3134.dir/3134.PDF |
| work_keys_str_mv |
AT gulinjulianernestonicolas 3134 AT gulinjulianernestonicolas evaluacioninvitroeinvivodecombinacionesdedrogasynuevasdrogasconpotencialparaeltratamientodelaenfermedaddechagas |
| _version_ |
1824356447361695744 |
| spelling |
I28-R145-HWA_31342024-08-27 3134 Chagas disease is an anthropozoonosis caused by the protozoan Trypanosoma cruzi (T. cruzi), and it is endemic in the Americas, affecting approximately 10 million people,\ncausing nearly 10,000 deaths per year due to cardiovascular or gastrointestinal\ncomplications.\nAvailable drugs, nifurtimox and benznidazole, are associated with a relatively high frequency of adverse events, the most common being nausea, anorexia, headache,\ngastrointestinal discomfort and arthralgias. It is also common for the appearance of erythema and pruritus. These effects added to the prolonged duration of treatment (up to 2 months) and the perception of moderate effectiveness during the chronic phase\nare frequent causes of treatment discontinuation.\nIn this context, searching for new safe and accessible therapeutic alternatives for\nChagas disease treatment is a pending objective.\nThere is little interest by the pharmaceutical industry on research and development of drugs for Chagas disease, mainly due to the socioeconomic characteristics of the\naffected population. The repositioning or reorientation of drugs and combinatorial\ntherapy arise as alternatives to the development of new molecules and involve a\nsignificantly lower investment of resources.\nIn this work, available drugs for clinical use were selected and were evaluated by in\nvitro and in vivo methods to determine anti-T. cruzi activity of drugs candidates.\nThirty-eight drugs were evaluated in vitro on trypomastigote and amastigote stages\nwith a low-throughput screening system using the T. cruzi VD strain, previously\ncharacterized. Also, a high-throughput screening system was standardized and optimized with the Dm28c/pLacZ strain, with which other thirty-eight drugs were evaluated. From these results, five drugs (nitazoxanide, pyrimethamine, ivermectin\nvoriconazole, and miltefosine) were evaluated in a murine model of acute infection with T. cruzi.\nThe trypanocidal or trypanostatic effects of the drugs studied confirmed the anti-T. cruzi activity of the drugs available for clinical use, validating the repositioning strategy to\nidentify new candidate compounds for the treatment of Chagas disease.\n Fil: Gulin, Julián Ernesto Nicolás. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Buenos Aires, Argentina García-Bournissen, Facundo Gulin, Julián Ernesto Nicolás 2019-04-05 La enfermedad de Chagas, endémica del continente americano, es una\nantropozoonosis causada por el protozoario Trypanosoma cruzi (T. cruzi) que afecta\naproximadamente a 10 millones de personas provocando cerca de 10.000 muertes por año debido a complicaciones cardiovasculares y/o gastrointestinales.\nLos medicamentos disponibles, nifurtimox y benznidazol, se asocian a una frecuencia\nrelativamente alta de eventos adversos, siendo los más comunes náuseas, anorexia, cefalea, molestias gastrointestinales y artralgias. También es común la aparición de\neritema y prurito. Estos efectos, sumado a la prolongada duración del tratamiento (hasta 2 meses) y a la percepción de limitada efectividad durante la fase crónica, son causas frecuentes de abandono del tratamiento. En este escenario, la búsqueda de alternativas terapéuticas seguras y accesibles para\nel tratamiento de la enfermedad de Chagas es un objetivo pendiente. Existe escaso interés por parte de la industria farmacéutica en investigación y desarrollo de\nmedicamentos para la enfermedad de Chagas, en gran medida debido a las\ncaracterísticas socioeconómicas de la población afectada. El reposicionamiento o\nreorientación de fármacos y la terapia combinatoria surgen como alternativas al\ndesarrollo de nuevas moléculas, e implican una inversión de recursos\nsignificativamente menor.\nEn este trabajo se seleccionaron fármacos disponibles para uso clínico y se desarrollaron métodos de evaluación in vitro en in vivo para determinar la actividad anti-T. cruzi de las drogas candidatas. Se evaluaron treinta y ocho fármacos sobre\nestadios tripomastigote y amastigote in vitro con un sistema de cribado de bajo\nrendimiento utilizando la cepa VD de T. cruzi, caracterizada previamente. Además, se estandarizó y optimizó un sistema de cribado de alto rendimiento con la cepa Dm28c/pLacZ, con el cual se evaluaron otras treinta y ocho drogas. A partir de estos resultados, cinco drogas (nitazoxanida, pirimetamina, ivermectina voriconazol y miltefosina) fueron evaluadas en un modelo murino de infección aguda con T. cruzi.\nLos efectos tripanocidas y/o tripanostáticos de las drogas estudiadas permiten\nconfirmar la actividad anti-T. cruzi de los fármacos disponibles para uso clínico,\nvalidando la estrategia del reposicionamiento para identificar nuevos compuestos\ncandidatos para el tratamiento de la enfermedad de Chagas.\n application/pdf Trypanosoma cruzi Enfermedad de Chagas Reposicionamiento de fármacos Cribado fenotípico Modelo in vitro Modelo in vivo Medicina traslacional spa Universidad de Buenos Aires. Facultad de Ciencias Veterinarias info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-ncnd/2.5/ar/ Enfermedad de Chagas Tratamiento Evaluación In vitro In vivo Farmacología Ciencias Veterinarias Doctor de la Universidad de Buenos Aires Evaluación in vitro e in vivo de combinaciones de drogas y nuevas drogas con potencial para el tratamiento de la enfermedad de Chagas info:eu-repo/semantics/doctoralThesis info:ar-repo/semantics/tesis doctoral info:eu-repo/semantics/acceptedVersion http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=avaposgra&cl=CL1&d=HWA_3134 https://repositoriouba.sisbi.uba.ar/gsdl/collect/avaposgra/index/assoc/HWA_3134.dir/3134.PDF |