Reposicionamento dos antidepressivos fluoxetina e paroxetina

Detalhes bibliográficos
Ano de defesa: 2022
Autor(a) principal: Foletto, Vitória Segabinazzi
Orientador(a): Não Informado pela instituição
Banca de defesa: Não Informado pela instituição
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.
id UFSM_994c2c64d41c67095f8ccaaf9d07a6ab
oai_identifier_str oai:repositorio.ufsm.br:1/26611
network_acronym_str UFSM
network_name_str Manancial - Repositório Digital da UFSM
repository_id_str
spelling 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:2024-07-29T10:41:34.297890Manancial - 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
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
_version_ 1814349687995498496