Reposicionamento dos antidepressivos fluoxetina e paroxetina
Ano de defesa: | 2022 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Brasil Análises Clínicas e Toxicológicas UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
Programa de Pós-Graduação: |
Não Informado pela instituição
|
Departamento: |
Não Informado pela instituição
|
País: |
Não Informado pela instituição
|
Palavras-chave em Português: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/26611 |
Resumo: | The substantial increase in multidrug resistant (MDR) bacteria makes efforts to find more effective antimicrobial therapies urgent. Drug repositioning, defined as the process of investigating new uses for drugs that have already been clinically approved, has offered a number of advantages in the face of the current lack of therapeutic innovations. As it is a faster, safer and more economical technique than the conventional development of active substances, repositioning has shown advantages. Also, synergism resulting from the combination of two or more drugs can improve drug efficacy, reduce toxicity, and provide an expanded spectrum of activity compared to monotherapeutic regimens. Thus, this study presents candidate drugs for redirection in bacterial infections and in the face of the pandemic caused by the new coronavirus (SARS-CoV-2). The present study investigated the biological activity of antidepressants belonging to the class of selective serotonin reuptake inhibitors (SSRIs) fluoxetine (FX) and paroxetine (PX). The analysis of antibacterial activity was performed in vitro using American Type Culture Collection (ATCC) standard bacterial strains and MDR clinical isolates, determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), interaction with the antibacterial ceftriaxone (CTX) using the Checkerboard method and determination of the fractional inhibitory concentration index (FICI). It was observed that, against five ATCC standard strains and 72 MDR clinical isolates collected in 2019 and 2021 in a university hospital in southern Brazil, FX presented MIC values between 4 and 256 µg/ml, while PX ranged from 1 to 256 µg /ml. CTX, on the other hand, presented MIC ≥4096 µg/ml against most strains evaluated. The association of CTX with FX/PX using the Checkerboard method caused CTX to reduce the MIC by up to 32,000 times. FICI values < 0.5 against all strains tested ratified the synergism of the combination of drugs. FX and PX were also able to promote the cleavage of double-stranded plasmid DNA through a hydrolytic mechanism at the three concentrations tested, showing greater efficiency at pH 7,4 at 37 °C. Faced with SARSCoV-2, different studies have found that antidepressant drugs belonging to the class of SSRIs were able to reduce the risk of intubation or death related to Covid-19, reduce the need for intensive medical care, in addition to inhibiting viral titers in up to 99%. This means that, after additional studies, the repositioning of this class of drugs could be a promising alternative in the treatment of patients with Covid-19, especially fluoxetine and fluvoxamine. The antimicrobial activity of several non-antibiotic drugs belonging to different pharmacological classes was also systematically evaluated, in order to present probable candidates for repositioning in infectious diseases, especially antidepressant, antihypertensive, anti-inflammatory, antineoplastic, hypoglycemic drugs, among others. We conclude that drug repositioning is currently a promising approach against bacterial infections and in the fight against Covid-19, and that the antidepressants fluoxetine and paroxetine prove to be promising alternatives that have significant antibacterial and antiviral properties. |
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Reposicionamento dos antidepressivos fluoxetina e paroxetinaRepositioning of the antidepressants fluoxetine and paroxetineReposicionamento de medicamentosAtividade antibacterianaClivagem do DNA plasmidialAntidepressivosCovid-19FluoxetinaParoxetinaDrug repositioningAntibacterial acitivityCleavage of plasmid DNAAntidepressantsFluoxetineParoxetineCNPQ::CIENCIAS DA SAUDE::FARMACIAThe substantial increase in multidrug resistant (MDR) bacteria makes efforts to find more effective antimicrobial therapies urgent. Drug repositioning, defined as the process of investigating new uses for drugs that have already been clinically approved, has offered a number of advantages in the face of the current lack of therapeutic innovations. As it is a faster, safer and more economical technique than the conventional development of active substances, repositioning has shown advantages. Also, synergism resulting from the combination of two or more drugs can improve drug efficacy, reduce toxicity, and provide an expanded spectrum of activity compared to monotherapeutic regimens. Thus, this study presents candidate drugs for redirection in bacterial infections and in the face of the pandemic caused by the new coronavirus (SARS-CoV-2). The present study investigated the biological activity of antidepressants belonging to the class of selective serotonin reuptake inhibitors (SSRIs) fluoxetine (FX) and paroxetine (PX). The analysis of antibacterial activity was performed in vitro using American Type Culture Collection (ATCC) standard bacterial strains and MDR clinical isolates, determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), interaction with the antibacterial ceftriaxone (CTX) using the Checkerboard method and determination of the fractional inhibitory concentration index (FICI). It was observed that, against five ATCC standard strains and 72 MDR clinical isolates collected in 2019 and 2021 in a university hospital in southern Brazil, FX presented MIC values between 4 and 256 µg/ml, while PX ranged from 1 to 256 µg /ml. CTX, on the other hand, presented MIC ≥4096 µg/ml against most strains evaluated. The association of CTX with FX/PX using the Checkerboard method caused CTX to reduce the MIC by up to 32,000 times. FICI values < 0.5 against all strains tested ratified the synergism of the combination of drugs. FX and PX were also able to promote the cleavage of double-stranded plasmid DNA through a hydrolytic mechanism at the three concentrations tested, showing greater efficiency at pH 7,4 at 37 °C. Faced with SARSCoV-2, different studies have found that antidepressant drugs belonging to the class of SSRIs were able to reduce the risk of intubation or death related to Covid-19, reduce the need for intensive medical care, in addition to inhibiting viral titers in up to 99%. This means that, after additional studies, the repositioning of this class of drugs could be a promising alternative in the treatment of patients with Covid-19, especially fluoxetine and fluvoxamine. The antimicrobial activity of several non-antibiotic drugs belonging to different pharmacological classes was also systematically evaluated, in order to present probable candidates for repositioning in infectious diseases, especially antidepressant, antihypertensive, anti-inflammatory, antineoplastic, hypoglycemic drugs, among others. We conclude that drug repositioning is currently a promising approach against bacterial infections and in the fight against Covid-19, and that the antidepressants fluoxetine and paroxetine prove to be promising alternatives that have significant antibacterial and antiviral properties.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESO aumento substancial das bactérias multidroga resistentes (MDR) tornam urgentes os esforços na descoberta por terapias antimicrobianas mais eficazes. O reposicionamento de medicamentos, definido como o processo de investigar novos usos para medicamentos, já foi aprovado clinicamente e tem oferecido uma série de vantagens diante da atual carência de inovações terapêuticas. Por ser uma técnica mais rápida, segura e econômica que o desenvolvimento convencional de substâncias ativas, o reposicionamento tem apresentado vantagens. Também, o sinergismo resultante da combinação de dois ou mais medicamentos pode melhorar a eficácia dos fármacos, reduzir a toxicidade e fornecer um espectro de atividade ampliado em comparação aos regimes monoterapêuticos. Assim, esse estudo apresenta fármacos candidatos ao redirecionamento em infecções bacterianas e frente à infecção ocasionada pelo novo coronavírus (SARS-CoV-2). O presente estudo investigou a atividade biológica dos antidepressivos pertencentes à classe dos inibidores seletivos da recaptação de serotonina (ISRS) fluoxetina (FX) e paroxetina (PX). A análise da atividade antibacteriana foi realizada in vitro utilizando cepas bacterianas padrão American Type Culture Collection (ATCC) e isolados clínicos MDR, determinando-se a concentração inibitória mínima (CIM), concentração bactericida mínima (CBM), interação com o antibacteriano ceftriaxona (CTX) utilizando o método Checkerboard e determinação do índice de concentração inibitória fracionada (FICI). Foi observado que, frente a cinco cepas padrão ATCC e 72 isolados clínicos MDR coletados em 2019 e 2021 em um hospital universitário no Sul do Brasil, FX apresentou valores de CIM entre 4 e 256 µg/ml, enquanto PX variou de 1 a 256 µg/ml. Já CTX apresentou CIM ≥4096 µg/ml frente a maioria das cepas avaliadas. A associação de CTX com FX/PX utilizando o método Checkerboard fez com que CTX reduzisse a CIM em cerca de até 32 mil vezes. Valores de FICI < 0,5 frente a todas as cepas testadas ratificaram o sinergismo da associação dos medicamentos. FX e PX também foram capazes de promover a clivagem do DNA plasmidial fita dupla por meio de mecanismo hidrolítico nas três concentrações testadas, apresentando maior eficiência em pH 7,4 a 37 °C. Frente a SARS-CoV-2, diferentes estudos constataram que medicamentos antidepressivos pertencentes à classe dos ISRS foram capazes de diminuir o risco de intubação ou morte relacionada à Covid-19, reduzir a necessidade de cuidados médicos intensivos, além de inibir os títulos virais em até 99%. Isso faz com que, após estudos adicionais, o reposicionamento dessa classe de medicamentos possa ser uma alternativa promissora no tratamento de pacientes com Covid-19, especialmente FX e fluvoxamina. Também foi avaliado de modo sistemático a atividade antimicrobiana de diversos fármacos não-antibióticos pertencentes a diferentes classes farmacológicas, a fim de apresentar prováveis candidatos ao reposicionamento em doenças infecciosas, destacando-se fármacos antidepressivos, anti-hipertensivos, anti-inflamatórios, antineoplásicos, hipoglicemiantes, entre outos. Concluímos que o reposicionamento de fármacos é atualmente uma abordagem promissora frente a infecções bacterianas e no combate à Covid-19, e que os antidepressivos FX e PX demonstram ser alternativas promissoras que apresentam propriedades antibacterianas significativas.Universidade Federal de Santa MariaBrasilAnálises Clínicas e ToxicológicasUFSMPrograma de Pós-Graduação em Ciências FarmacêuticasCentro de Ciências da SaúdeHorner, Rosmarihttp://lattes.cnpq.br/5907084134183708Santos, Aline Joana R. Wohlmuth Alves dosMotta, Amanda de Souza daRamos, Daniela FernandesMurari, Anelise LevayFoletto, Vitória Segabinazzi2022-10-20T18:04:49Z2022-10-20T18:04:49Z2022-08-23info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/26611porAttribution-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:UFSM2022-10-20T18:04:50Zoai:repositorio.ufsm.br:1/26611Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-10-20T18:04:50Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Reposicionamento dos antidepressivos fluoxetina e paroxetina Repositioning of the antidepressants fluoxetine and paroxetine |
title |
Reposicionamento dos antidepressivos fluoxetina e paroxetina |
spellingShingle |
Reposicionamento dos antidepressivos fluoxetina e paroxetina Foletto, Vitória Segabinazzi Reposicionamento de medicamentos Atividade antibacteriana Clivagem do DNA plasmidial Antidepressivos Covid-19 Fluoxetina Paroxetina Drug repositioning Antibacterial acitivity Cleavage of plasmid DNA Antidepressants Fluoxetine Paroxetine CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Reposicionamento dos antidepressivos fluoxetina e paroxetina |
title_full |
Reposicionamento dos antidepressivos fluoxetina e paroxetina |
title_fullStr |
Reposicionamento dos antidepressivos fluoxetina e paroxetina |
title_full_unstemmed |
Reposicionamento dos antidepressivos fluoxetina e paroxetina |
title_sort |
Reposicionamento dos antidepressivos fluoxetina e paroxetina |
author |
Foletto, Vitória Segabinazzi |
author_facet |
Foletto, Vitória Segabinazzi |
author_role |
author |
dc.contributor.none.fl_str_mv |
Horner, Rosmari http://lattes.cnpq.br/5907084134183708 Santos, Aline Joana R. Wohlmuth Alves dos Motta, Amanda de Souza da Ramos, Daniela Fernandes Murari, Anelise Levay |
dc.contributor.author.fl_str_mv |
Foletto, Vitória Segabinazzi |
dc.subject.por.fl_str_mv |
Reposicionamento de medicamentos Atividade antibacteriana Clivagem do DNA plasmidial Antidepressivos Covid-19 Fluoxetina Paroxetina Drug repositioning Antibacterial acitivity Cleavage of plasmid DNA Antidepressants Fluoxetine Paroxetine CNPQ::CIENCIAS DA SAUDE::FARMACIA |
topic |
Reposicionamento de medicamentos Atividade antibacteriana Clivagem do DNA plasmidial Antidepressivos Covid-19 Fluoxetina Paroxetina Drug repositioning Antibacterial acitivity Cleavage of plasmid DNA Antidepressants Fluoxetine Paroxetine CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
The substantial increase in multidrug resistant (MDR) bacteria makes efforts to find more effective antimicrobial therapies urgent. Drug repositioning, defined as the process of investigating new uses for drugs that have already been clinically approved, has offered a number of advantages in the face of the current lack of therapeutic innovations. As it is a faster, safer and more economical technique than the conventional development of active substances, repositioning has shown advantages. Also, synergism resulting from the combination of two or more drugs can improve drug efficacy, reduce toxicity, and provide an expanded spectrum of activity compared to monotherapeutic regimens. Thus, this study presents candidate drugs for redirection in bacterial infections and in the face of the pandemic caused by the new coronavirus (SARS-CoV-2). The present study investigated the biological activity of antidepressants belonging to the class of selective serotonin reuptake inhibitors (SSRIs) fluoxetine (FX) and paroxetine (PX). The analysis of antibacterial activity was performed in vitro using American Type Culture Collection (ATCC) standard bacterial strains and MDR clinical isolates, determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), interaction with the antibacterial ceftriaxone (CTX) using the Checkerboard method and determination of the fractional inhibitory concentration index (FICI). It was observed that, against five ATCC standard strains and 72 MDR clinical isolates collected in 2019 and 2021 in a university hospital in southern Brazil, FX presented MIC values between 4 and 256 µg/ml, while PX ranged from 1 to 256 µg /ml. CTX, on the other hand, presented MIC ≥4096 µg/ml against most strains evaluated. The association of CTX with FX/PX using the Checkerboard method caused CTX to reduce the MIC by up to 32,000 times. FICI values < 0.5 against all strains tested ratified the synergism of the combination of drugs. FX and PX were also able to promote the cleavage of double-stranded plasmid DNA through a hydrolytic mechanism at the three concentrations tested, showing greater efficiency at pH 7,4 at 37 °C. Faced with SARSCoV-2, different studies have found that antidepressant drugs belonging to the class of SSRIs were able to reduce the risk of intubation or death related to Covid-19, reduce the need for intensive medical care, in addition to inhibiting viral titers in up to 99%. This means that, after additional studies, the repositioning of this class of drugs could be a promising alternative in the treatment of patients with Covid-19, especially fluoxetine and fluvoxamine. The antimicrobial activity of several non-antibiotic drugs belonging to different pharmacological classes was also systematically evaluated, in order to present probable candidates for repositioning in infectious diseases, especially antidepressant, antihypertensive, anti-inflammatory, antineoplastic, hypoglycemic drugs, among others. We conclude that drug repositioning is currently a promising approach against bacterial infections and in the fight against Covid-19, and that the antidepressants fluoxetine and paroxetine prove to be promising alternatives that have significant antibacterial and antiviral properties. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-10-20T18:04:49Z 2022-10-20T18:04:49Z 2022-08-23 |
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/1/26611 |
url |
http://repositorio.ufsm.br/handle/1/26611 |
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 Análises Clínicas e Toxicológicas UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Análises Clínicas e Toxicológicas 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 |
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Universidade Federal de Santa Maria (UFSM) |
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UFSM |
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UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
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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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1805930204888039424 |