Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp.
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/18081 |
Resumo: | The genus Fusarium is characterized by hyaline filamentous fungi that cause a wide spectrum of infections predominantly in immunocompromised patients. Disseminated fusariosis results in high rates of morbidity and mortality, since it is of difficult prevention and treatment. The remarkable primary resistance to conventional antifungals of this genus requires the search for new therapeutic possibilities. A possible attempt is the combination of antifungals and chemosensitizing agents with different mechanisms of action. This study aimed to evaluate the in vitro susceptibility of Fusarium to conventional antifungal agents (amphotericin B, itraconazole, voriconazole and caspofungin); organoselenium compounds (diphenyl diselenide and ebselen), nonantifungal drugs (amiodarone, doxycycline, moxifloxacin, pentamidine, polymyxin B, tigecycline and tobramycin), and phytocompounds (cinnamaldehyde, carvacrol and thymol), through broth microdilution method (M38-A2, CLSI). The combinations between the antifungal agents and chemosensitizers were assessed through the checkerboard technique. Among the antifungals tested amphotericin B showed greater activity in vitro (0.25-8 μg/ml); followed by voriconazole (1-16 μg/ml), itraconazole (>16 μg/ml) and caspofungin (>32 μg/ml). Diphenyl diselenide (4-32 μg/ml), ebselen (2-8 μg/ml), pentamidine (4-32 μg/ml) and polymyxin B (4-16 μg/ml) also showed antifungal activity against Fusarium spp. Ebselen and diphenyl diselenide presented high rates of synergism in combination with amphotericin B (88% and 72%, respectively) or voriconazole (80% e 64%, respectively). Combinations with nonantifungal drugs have also resulted in synergism, highlighting the following associations (% of synergism): tobramycin + amphotericin B (80%) or voriconazole (76%); polymyxin B + amphotericin B (76%) or voriconazole (64%); pentamidine + amphotericin B (72%) or voriconazole (68%); amiodarone + amphotericin B (64%) or voriconazole (76%); and moxifloxacin + amphotericin B (72%) or voriconazole (60%). Furthermore, the phytocompounds thymol and carvacrol have showed potent chemosensitizer activity in association to caspofungin (96% e 88%, respectively). Among all the tested combinations, no antagonistic interactions were observed. In conclusion, the most relevant combinations deserve a future investigation in vivo experimental models, since these associations suggest new potencial candidates for combined therapy against fusariosis. |
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Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp.Synthetic and natural chemosensitizers associated with conventional antifungals against Fusarium spp.SuscetibilidadeQuimissensibilizantesAssociaçõesAntifúngicosSinergismoFusarium spp.SusceptibilityChemosensitizersAssociationsAntifungalsSynergismCNPQ::CIENCIAS DA SAUDE::FARMACIAThe genus Fusarium is characterized by hyaline filamentous fungi that cause a wide spectrum of infections predominantly in immunocompromised patients. Disseminated fusariosis results in high rates of morbidity and mortality, since it is of difficult prevention and treatment. The remarkable primary resistance to conventional antifungals of this genus requires the search for new therapeutic possibilities. A possible attempt is the combination of antifungals and chemosensitizing agents with different mechanisms of action. This study aimed to evaluate the in vitro susceptibility of Fusarium to conventional antifungal agents (amphotericin B, itraconazole, voriconazole and caspofungin); organoselenium compounds (diphenyl diselenide and ebselen), nonantifungal drugs (amiodarone, doxycycline, moxifloxacin, pentamidine, polymyxin B, tigecycline and tobramycin), and phytocompounds (cinnamaldehyde, carvacrol and thymol), through broth microdilution method (M38-A2, CLSI). The combinations between the antifungal agents and chemosensitizers were assessed through the checkerboard technique. Among the antifungals tested amphotericin B showed greater activity in vitro (0.25-8 μg/ml); followed by voriconazole (1-16 μg/ml), itraconazole (>16 μg/ml) and caspofungin (>32 μg/ml). Diphenyl diselenide (4-32 μg/ml), ebselen (2-8 μg/ml), pentamidine (4-32 μg/ml) and polymyxin B (4-16 μg/ml) also showed antifungal activity against Fusarium spp. Ebselen and diphenyl diselenide presented high rates of synergism in combination with amphotericin B (88% and 72%, respectively) or voriconazole (80% e 64%, respectively). Combinations with nonantifungal drugs have also resulted in synergism, highlighting the following associations (% of synergism): tobramycin + amphotericin B (80%) or voriconazole (76%); polymyxin B + amphotericin B (76%) or voriconazole (64%); pentamidine + amphotericin B (72%) or voriconazole (68%); amiodarone + amphotericin B (64%) or voriconazole (76%); and moxifloxacin + amphotericin B (72%) or voriconazole (60%). Furthermore, the phytocompounds thymol and carvacrol have showed potent chemosensitizer activity in association to caspofungin (96% e 88%, respectively). Among all the tested combinations, no antagonistic interactions were observed. In conclusion, the most relevant combinations deserve a future investigation in vivo experimental models, since these associations suggest new potencial candidates for combined therapy against fusariosis.Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul.O gênero Fusarium é caracterizado por fungos filamentosos hialinos que causam um amplo espectro de infecções predominantemente em pacientes imunocomprometidos. A fusariose disseminada resulta em elevados índices de morbidade e mortalidade, sendo uma infecção de difícil prevenção e tratamento. A marcante resistência primária deste gênero aos antifúngicos convencionais impõe a busca por novas possibilidades terapêuticas. Uma alternativa é a combinação entre agentes antifúngicos e quimiossensibilizantes com diferentes mecanismos de ação. Este estudo objetivou avaliar a suscetibilidade in vitro de espécies de Fusarium a antifúngicos convencionais (anfotericina B, itraconazol, voriconazol e caspofungina), compostos orgânicos de selênio (disseleneto de difenila e ebselen), fármacos não antifúngicos (amiodarona, doxiciclina, moxifloxacina, pentamidina, polimixina B, tigeciclina e tobramicina) e fitocompostos (cinamaldeído, carvacrol e timol), através do método de microdiluição em caldo (M38-A2, CLSI). As combinações entre os agentes antifúngicos e quimiossensibilizantes foram avaliadas através da técnica de checkerboard. Entre os antifúngicos testados, a anfotericina B demonstrou maior atividade in vitro (0,25-8 μg/ml); seguida pelo voriconazol (1-16 μg/ml), itraconazol (>16 μg/ml) e caspofungina (>32 μg/ml). O disseleneto de difenila (4-32 μg/ml), ebselen (2-8 μg/ml), pentamidina (4-32 μg/ml) e polimixina B (4-16 μg/ml) também demonstraram atividade antifúngica contra Fusarium spp. Ebselen e disseleneto de difenila apresentaram altas taxas de sinergismos em combinação com anfotericina B (88% e 72%, respectivamente) ou voriconazol (80% e 64%, respectivamente). As combinações com fármacos não antifúngicos também resultaram em sinergismos, destacando-se as seguintes associações (% de sinergismo): tobramicina + anfotericina B (80%) ou voriconazol (76%); polimixina B + anfotericina B (76%) ou voriconazol (64%); pentamidina + anfotericina B (72%) ou voriconazol (68%); amiodarona + anfotericina B (64%) ou voriconazol (76%); e moxifloxacina + anfotericina B (72%) ou voriconazol (60%). Além disso, os fitocompostos, timol e carvacrol demonstraram potente atividade quimiossensibilizante em associação com caspofungina (96% e 88%, respectivamente). Entre todas as combinações testadas não foram observadas interações antagônicas. Em conclusão, as combinações mais relevantes merecem uma futura investigação em modelos experimentais in vivo, pois estas associações apontam novos candidatos potenciais para a terapia combinada da fusariose.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em Ciências FarmacêuticasCentro de Ciências da SaúdeAlves, Sydney Hartzhttp://lattes.cnpq.br/0330782478769631Fuentefria, Alexandre Meneghellohttp://lattes.cnpq.br/3011308324416888Lopes, Paulo Guilherme Markushttp://lattes.cnpq.br/0280182736721337Trindade, Priscila de Arrudahttp://lattes.cnpq.br/0124362929241308Venturini, Tarcieli Pozzebon2019-08-29T20:38:52Z2019-08-29T20:38:52Z2016-03-24info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/18081porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2019-08-30T06:02:16Zoai:repositorio.ufsm.br:1/18081Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2019-08-30T06:02:16Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. Synthetic and natural chemosensitizers associated with conventional antifungals against Fusarium spp. |
title |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. |
spellingShingle |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. Venturini, Tarcieli Pozzebon Suscetibilidade Quimissensibilizantes Associações Antifúngicos Sinergismo Fusarium spp. Susceptibility Chemosensitizers Associations Antifungals Synergism CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. |
title_full |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. |
title_fullStr |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. |
title_full_unstemmed |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. |
title_sort |
Quimiossensibilizantes sintéticos e naturais associados a antifúngicos convencionais frente a Fusarium spp. |
author |
Venturini, Tarcieli Pozzebon |
author_facet |
Venturini, Tarcieli Pozzebon |
author_role |
author |
dc.contributor.none.fl_str_mv |
Alves, Sydney Hartz http://lattes.cnpq.br/0330782478769631 Fuentefria, Alexandre Meneghello http://lattes.cnpq.br/3011308324416888 Lopes, Paulo Guilherme Markus http://lattes.cnpq.br/0280182736721337 Trindade, Priscila de Arruda http://lattes.cnpq.br/0124362929241308 |
dc.contributor.author.fl_str_mv |
Venturini, Tarcieli Pozzebon |
dc.subject.por.fl_str_mv |
Suscetibilidade Quimissensibilizantes Associações Antifúngicos Sinergismo Fusarium spp. Susceptibility Chemosensitizers Associations Antifungals Synergism CNPQ::CIENCIAS DA SAUDE::FARMACIA |
topic |
Suscetibilidade Quimissensibilizantes Associações Antifúngicos Sinergismo Fusarium spp. Susceptibility Chemosensitizers Associations Antifungals Synergism CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
The genus Fusarium is characterized by hyaline filamentous fungi that cause a wide spectrum of infections predominantly in immunocompromised patients. Disseminated fusariosis results in high rates of morbidity and mortality, since it is of difficult prevention and treatment. The remarkable primary resistance to conventional antifungals of this genus requires the search for new therapeutic possibilities. A possible attempt is the combination of antifungals and chemosensitizing agents with different mechanisms of action. This study aimed to evaluate the in vitro susceptibility of Fusarium to conventional antifungal agents (amphotericin B, itraconazole, voriconazole and caspofungin); organoselenium compounds (diphenyl diselenide and ebselen), nonantifungal drugs (amiodarone, doxycycline, moxifloxacin, pentamidine, polymyxin B, tigecycline and tobramycin), and phytocompounds (cinnamaldehyde, carvacrol and thymol), through broth microdilution method (M38-A2, CLSI). The combinations between the antifungal agents and chemosensitizers were assessed through the checkerboard technique. Among the antifungals tested amphotericin B showed greater activity in vitro (0.25-8 μg/ml); followed by voriconazole (1-16 μg/ml), itraconazole (>16 μg/ml) and caspofungin (>32 μg/ml). Diphenyl diselenide (4-32 μg/ml), ebselen (2-8 μg/ml), pentamidine (4-32 μg/ml) and polymyxin B (4-16 μg/ml) also showed antifungal activity against Fusarium spp. Ebselen and diphenyl diselenide presented high rates of synergism in combination with amphotericin B (88% and 72%, respectively) or voriconazole (80% e 64%, respectively). Combinations with nonantifungal drugs have also resulted in synergism, highlighting the following associations (% of synergism): tobramycin + amphotericin B (80%) or voriconazole (76%); polymyxin B + amphotericin B (76%) or voriconazole (64%); pentamidine + amphotericin B (72%) or voriconazole (68%); amiodarone + amphotericin B (64%) or voriconazole (76%); and moxifloxacin + amphotericin B (72%) or voriconazole (60%). Furthermore, the phytocompounds thymol and carvacrol have showed potent chemosensitizer activity in association to caspofungin (96% e 88%, respectively). Among all the tested combinations, no antagonistic interactions were observed. In conclusion, the most relevant combinations deserve a future investigation in vivo experimental models, since these associations suggest new potencial candidates for combined therapy against fusariosis. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-03-24 2019-08-29T20:38:52Z 2019-08-29T20:38:52Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/18081 |
url |
http://repositorio.ufsm.br/handle/1/18081 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1805922032058105856 |