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This study aimed to characterize the population pharmacokinetics of sertraline in Mexican patients with psychiatric and substance use disorders. Fifty-nine patients (13 to 76 years old) treated with doses of sertraline between 12.5 and 100 mg/day were included. Plasma sertraline concentrations were determined in blood samples and five of the main substances of abuse were determined by rapid tests in urine samples. Demographic, clinical, and pharmacogenetic factors were also evaluated. Population pharmacokinetic analysis was performed using NONMEM software with first-order conditional estimation method. A one-compartment model with proportional residual error adequately described the sertraline concentrations versus time. CYP2D6*2 polymorphism and CYP2C19 phenotypes significantly influenced sertraline clearance, which had a population mean value of 66 L/h in the final model. The absorption constant and volume of distribution were fixed at 0.855 1/h and 20.2 L/kg, respectively. The model explained 11.3% of the interindividual variability in sertraline clearance. The presence of the CYP2D6*2 polymorphism caused a 23.1% decrease in sertraline clearance, whereas patients with intermediate and poor phenotype of CYP2C19 showed 19.06% and 48.26% decreases in sertraline clearance, respectively. The model was internally validated by bootstrap and visual predictive check. Finally, stochastic simulations were performed to propose dosing regimens to achieve therapeutic levels that contribute to improving treatment response.
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Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Sertralina , Transtornos Relacionados ao Uso de Substâncias , Humanos , Sertralina/farmacocinética , Sertralina/uso terapêutico , Sertralina/sangue , Masculino , Pessoa de Meia-Idade , Adulto , Feminino , Idoso , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Adolescente , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Transtornos Relacionados ao Uso de Substâncias/sangue , Adulto Jovem , Modelos Biológicos , Transtornos Mentais/tratamento farmacológico , Polimorfismo Genético , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , México , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Antidepressivos/sangueRESUMO
Fungal infections caused by Cryptococcus spp. pose a threat to health, especially in immunocompromised individuals. The available arsenal of drugs against cryptococcosis is limited, due to their toxicity and/or lack of accessibility in low-income countries, requiring more therapeutic alternatives. Selective serotonin reuptake inhibitors (SSRIs), through drug repositioning, are a promising alternative to broaden the range of new antifungals against Cryptococcus spp. This study evaluates the antifungal activity of three SSRIs, sertraline, paroxetine, and fluoxetine, against Cryptococcus spp. strains, as well as assesses their possible mechanism of action. Seven strains of Cryptococcus spp. were used. Sensitivity to SSRIs, fluconazole, and itraconazole was evaluated using the broth microdilution assay. The interactions resulting from combinations of SSRIs and azoles were investigated using the checkerboard assay. The possible action mechanism of SSRIs against Cryptococcus spp. was evaluated through flow cytometry assays. The SSRIs exhibited in vitro antifungal activity against Cryptococcus spp. strains, with minimum inhibitory concentrations ranging from 2 to 32 µg/mL, and had synergistic and additive interactions with azoles. The mechanism of action of SSRIs against Cryptococcus spp. involved damage to the mitochondrial membrane and increasing the production of reactive oxygen species, resulting in loss of cellular viability and apoptotic cell death. Fluoxetine also was able to cause significant damage to yeast DNA. These findings demonstrate the in vitro antifungal potential of SSRIs against Cryptococcus spp. strains.
Assuntos
Cryptococcus neoformans , Cryptococcus , Humanos , Antifúngicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fluoxetina/farmacologia , Fluconazol/farmacologia , Azóis , Testes de Sensibilidade MicrobianaRESUMO
Aim: Our study evaluated the activity of sertraline (SER) alone and associated with antifungal drugs in planktonic Candida spp. strains, and investigated its mechanism of action. Materials & methods: Broth microdilution method and minimum fungicidal concentration/MIC ratio were used to assess SER anticandidal activity, and the interaction with antifungals was determined by fractional inhibitory concentration index. The mechanism of action was investigated by flow cytometry and in silico tests. Results: SER inhibited Candida spp. strains at low concentrations by the fungicidal effect and showed no loss of effectiveness when combined. Its action seemed to be related to the membrane and cell wall biosynthesis inhibition. Conclusion: SER has activity against Candida spp. isolated and associated with antifungals, and acts by causing cell wall and membrane damage.
Assuntos
Antifúngicos , Candida , Antifúngicos/farmacologia , Sertralina/farmacologia , Parede Celular , Testes de Sensibilidade MicrobianaRESUMO
PURPOSE: This study aimed to evaluate the role of Translationally Controlled Tumor Protein (TCTP) in breast cancer (BC) and investigate the effects of sertraline, a serotonin selective reuptake inhibitor (SSRI), on BC cells. The objective was to assess the potential of sertraline as a therapeutic agent in BC treatment by examining its ability to inhibit TCTP expression and exert antitumor effects. MATERIAL AND METHODS: We utilized five different BC cell lines representing the molecular heterogeneity and distinct subtypes of BC, including luminal, normal-like, HER2-positive, and triple-negative BC. These subtypes play a crucial role in determining clinical treatment strategies and prognosis. RESULTS: The highest levels of TCTP were observed in triple-negative BC cell lines, known for their aggressive behavior. Sertraline treatment reduced TCTP expression in BC cell lines, significantly impacting cell viability, clonogenicity, and migration. Additionally, sertraline sensitized triple-negative BC cell lines to cytotoxic chemotherapeutic drugs (doxorubicin and cisplatin) suggesting its potential as an adjunctive therapy to enhance the chemotherapeutic response. Bioinformatic analysis of TCTP mRNA levels in TCGA BC data revealed a negative correlation between TCTP levels and patient survival, as well as between TCTP/tpt1 and Ki67. These findings contradict our data and previous studies indicating a correlation between TCTP protein levels and aggressiveness and poor prognosis in BC. CONCLUSIONS: Sertraline shows a promise as a potential therapeutic option for BC, particularly in triple-negative BC. Its ability to inhibit TCTP expression, enhance chemotherapeutic response, highlights its potential clinical utility in BC treatment, specifically in triple-negative BC subtype.
Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Sertralina/farmacologia , Sertralina/uso terapêutico , Biomarcadores Tumorais/genética , Antineoplásicos/uso terapêutico , Células MCF-7RESUMO
The dermatophyte Trichophyton rubrum is responsible for most human cutaneous infections. Its treatment is complex, mainly because there are only a few structural classes of fungal inhibitors. Therefore, new strategies addressing these problems are essential. The development of new drugs is time-consuming and expensive. The repositioning of drugs already used in medical practice has emerged as an alternative to discovering new drugs. The antidepressant sertraline (SRT) kills several important fungal pathogens. Accordingly, we investigated the inhibitory mechanism of SRT in T. rubrum to broaden the knowledge of its impact on eukaryotic microorganisms and to assess its potential for future use in dermatophytosis treatments. We performed next-generation sequencing (RNA-seq) to identify the genes responding to SRT at the transcript level. We identified that a major effect of SRT was to alter expression for genes involved in maintaining fungal cell wall and plasma membrane stability, including ergosterol biosynthetic genes. SRT also altered the expression of genes encoding enzymes related to fungal energy metabolism, cellular detoxification, and defense against oxidative stress. Our findings provide insights into a specific molecular network interaction that maintains metabolic stability and is perturbed by SRT, showing potential targets for its strategic use in dermatophytosis.
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Candida spp. infections are a serious health problem, especially in patients with risk factors. The acquisition of resistance, often associated with biofilm production, makes treatment more difficult due to the reduced effectiveness of available antifungals. Drug repurposing is a good alternative for the treatment of infections by Candida spp. biofilms. The present study evaluated the in vitro antibiofilm activity of sertraline in reducing the cell viability of forming and matured biofilms, in addition to elucidating whether effective concentrations are safe. Sertraline reduced biofilm cell viability by more than 80â% for all Candida species tested, acting at low and safe concentrations, both on mature biofilm and in preventing its formation, even the one with highest virulence. Its preventive mechanism seemed to be related to binding with ALS3. These data indicate that sertraline is a promising drug with anticandidal biofilm potential in safe doses. However, further studies are needed to elucidate the antibiofilm mechanism and possible application of pharmaceutical forms.
Assuntos
Candida , Candidíase , Humanos , Sertralina/farmacologia , Sertralina/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Biofilmes , Testes de Sensibilidade Microbiana , Candida albicansRESUMO
Despite increased prescription of sertraline during pregnancy, little is known about its action on reproductive development. Therefore, this study aimed to investigate the impact that stress, associated or not with sertraline, causes on the reproductive development of male rats. Pregnant Wistar rats were divided into 4 groups (n = 16/group): CO-received filtered water; SE-received 20 mg/kg sertraline; ST-submitted to restraint stress and received filtered water; SS-submitted to restraint stress and received sertraline. The treatment was carried out from gestational days (GDs) 13-20. The animals were euthanized on GD 20 (n = 8/group), postnatal day (PND) 45 (n = 8/group), and PND 110 (n = 8/group). The testes and epididymis were analyzed histologically, and immunohistochemistry was performed on the testes by proliferating cell nuclear antigen (PCNA) and the Wilms tumor protein (Wt1). Sperm quality was also analyzed on PND 110. The evolution of body weight, anogenital distance (AGD), and puberty installation day were also verified. Statistical analysis: 2-way ANOVA or Kruskal-Wallis test (p ≤ .05). Fetal testes presented a large number of acidophilic cells in the sertraline-exposed groups. The SS group also showed a decrease in the nuclear volume of Leydig cells. This same group showed low expression of PCNA and Wt1, decreased weight of the testes and epididymis, lower AGD, and delayed puberty installation. The adulthood groups exposed to sertraline presented alterations in sperm morphology and motility. The results demonstrated that prenatal exposure to sertraline compromises the development of the rat reproductive system.
Assuntos
Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Sertralina , Maturidade Sexual , Animais , Feminino , Masculino , Gravidez , Ratos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Antígeno Nuclear de Célula em Proliferação , Ratos Wistar , Sêmen , Sertralina/toxicidade , Maturidade Sexual/efeitos dos fármacos , Testículo/patologiaRESUMO
Abstract Objective: To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women. Data sources: Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases. Selection of studies: The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: chronic pelvic pain in women OR endometriosis, associated with MESH/ENTREE/DeCS: gabapentinoids, gabapentin, amitriptyline, antidepressant, pregabalin, anticonvulsant, sertraline, duloxetine, nortriptyline, citalopram, imipramine, venlafaxine, neuromodulation drugs, acyclic pelvic pain, serotonin, noradrenaline reuptake inhibitors, and tricyclic antidepressants, with the Boolean operator OR. Case reports and systematic reviews were excluded. Data collection: The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results. Data synthesis: A total of 218 articles were found, with 79 being excluded because they were repeated, leaving 139 articles for analysis: 90 were excluded in the analysis of the titles, 37 after reading the abstract, and 4 after reading the articles in full, and 1 could not be found, therefore, leaving 7 articles that were included in the review. Conclusion: Most of the studies analyzed have shown pain improvement with the help of neuromodulators for chronic pain. However, no improvement was found in the study with the highest statistical power. There is still not enough evidence that neuromodulatory drugs reduce the intensity of pain in women with CPP.
Resumo Objetivo: Avaliar o efeito de drogas neuromoduladoras na intensidade da dor pélvica crônica em mulheres. Fontes de dados: As buscas foram realizadas nas bases de dados PubMed, Cochrane Central, Embase, Lilacs, OpenGrey e Clinical Trials. Seleção dos estudos: As buscas foram realizadas por dois dos autores, não delimitando data de publicação ou idioma de publicação. Foram usados os seguintes descritores: chronic pelvic pain in women OR endometriosis, associated with MESH/ENTREE/DeCS: gabapentinoids, gabapentin, amitriptyline, antidepressant, pregabalin, anticonvulsant, sertraline, duloxetine, nortriptyline, citalopram, imipramine, venlafaxine, neuromodulation drugs, acyclic pelvic pain, serotonin, noradrenaline reuptake inhibitors e tricyclic antidepressants, com o operador booleano OR. Relatos de caso e revisões sistemáticas foram excluídos. Coleta de dados: Foram extraídos os seguintes dados: autor, ano de publicação, local de origem, tipo de estudo, tamanho da amostra, detalhes da intervenção, tempo de seguimento e resultados. Síntese dos dados: Foram encontrados 218 artigos, sendo 79 deles excluídos por serem repetidos, restando 139 artigos para análise, dos quais 90 foram excluídos na análise dos títulos, 37 após a leitura do resumo e 4 após a leitura dos artigos na íntegra, e 1 não foi encontrado, restando, então, 7 artigos que foram incluídos na revisão. Conclusão: A maioria dos estudos analisados mostrou melhora da dor crônica com auxílio de neuromoduladores. No entanto, nenhuma melhora foi encontrada no artigo com maior poder estatístico. Ainda não há evidências suficientes de que drogas neuromoduladoras reduzam a intensidade da dor pélvica crônica em mulheres.
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Humanos , Feminino , Comportamento , Dor Pélvica , Sertralina/uso terapêutico , Gabapentina/uso terapêuticoRESUMO
Trichophyton rubrum is responsible for several superficial human mycoses. Novel strategies aimed at controlling this pathogen are being investigated. The objective of this study was to evaluate the antifungal activity of the antidepressant sertraline (SRT), either alone or in combination with caspofungin (CASP). We calculated the minimum inhibitory concentrations of SRT and CASP against T. rubrum. Interactions between SRT and CASP were evaluated using a broth microdilution chequerboard. We assessed the differential expression of T. rubrum cultivated in the presence of SRT or combinations of SRT and CASP. We used MTT and violet crystal assays to compare the effect of SRT alone on T. rubrum biofilms with that of the synergistic combination of SRT and CASP. A human nail infection assay was performed. SRT alone, or in combination with CASP, exhibited antifungal activity against T. rubrum. SRT targets genes involved in the biosyntheses of cell wall and ergosterol. Furthermore, the metabolic activity of the T. rubrum biofilm and its biomass were affected by SRT and the combination of SRT and CASP. SRT alone, or in combination, shows potential as an approach to minimise resistance and reduce virulence.
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Candida auris is an emerging global public health threat. It is an opportunistic yeast that usually affects critically ill patients in healthcare settings and is characterized by reduced susceptibility to multiple antifungal classes. Combination therapy with antifungals and repurposed drugs is a feasible alternative to overcome this problem. The aim of this study was to examine the in vitro interactions and potential synergy of micafungin (MFG) and voriconazole (VRC) plus the antidepressant sertraline (SRT) against clinical isolates of C. auris. Conventional antifungal testing was first performed with the three drugs according to the CLSI methodology. Drug interactions were determined by the checkerboard microdilution assay using the fractional inhibitory concentration (FIC) index. Synergistic interactions were noted with the combination of MFG and SRT plus VRC with FIC values of 0.37 to 0.49 for some strains. Indifferent interactions were observed when MFG was combined with SRT with just one exception (FIC 0.53). No antagonism was observed for any combination. The combination of VRC with MCF or SRT may be relevant for treating C. auris infections.
Assuntos
Antifúngicos , Sertralina , Humanos , Voriconazol/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Micafungina/farmacologia , Sertralina/farmacologia , Candida auris , Candida , Testes de Sensibilidade MicrobianaRESUMO
Sertraline hydrochloride is a first-line antidepressant with potential antineoplastic properties because of its structural similarity with other drugs capable to inhibit the translation-controlled tumor protein (TCTP), a biomolecule involved in cell proliferation. Recent studies suggest it could be repositioned for cancer treatment. In this review, we systematically map the findings that repurpose sertraline as an antitumoral agent, including the mechanisms of action that support this hypotesis. From experimental in vivo and in vitro tumor models of thirteen different types of neoplasms, three mechanisms of action are proposed: apoptosis, autophagy, and drug synergism. The antidepressant is able to inhibit TCTP, modulate chemotherapeutical resistance and exhibit proper cytotoxicity, resulting in reduced cell counting (in vitro) and shrunken tumor masses (in vivo). A mathematical equation determined possible doses to be used in human beings, supporting that sertraline could be explored in clinical trials as a TCTP-inhibitor.
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Abstract Personalized medicine is gaining importance in pharmacotherapeutics as it allows tailoring the drug treatment to achieve the best patient response. Orodispersible film (ODF) is easy to formulate in hospitals, produces dose flexibility to suit an individual needs, particularly for patients suffer from swallowing issues or prohibited to take fluids. Sertraline Hydrochloride (SRT) was solubilized in several cosolvents, then different SRT ODFs based on five hydrophilic polymers namely; polyvinyl alcohol (PVA), hydroxylethyl cellulose (HEC), hydroxypropyl methylcellulose E5 LV (HPMC E5 LV), sodium alginate (NaAlg) and gelatin at two concentrations (2% and 4%) were developed and characterized. The outcomes were exposed to response surface analysis to obtain the desirability results to obtain the optimized formulation. Blended ODFs were developed from 4% PVA and 2% HEC in different blends and then potassium chloride (KCl) as a pore-forming agent was added to the best formulation to investigate its dissolution enhancement effect. F14 containing 4% PVA: 2% HEC 2:1 with 5% KCl showed best physicochemical properties of suitable pH (5.6), disintegration time (6 sec), good folding endurance which released 91 % SRT after 15 min. SRT ODF is an encouraging delivery system in the course of personalized medicine for the management of depression.
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Solventes , Sertralina/análise , Medicina de Precisão , Excipientes , Otimização de ProcessosRESUMO
Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1ß, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.
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Ansiedade/genética , Ansiedade/psicologia , Comportamento Animal , Depressão/genética , Depressão/psicologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/psicologia , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Crônica Progressiva/psicologia , Canal de Cátion TRPA1/genética , Animais , Antioxidantes/farmacologia , Feminino , Elevação dos Membros Posteriores , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oximas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidoresRESUMO
OBJETIVO: caracterizar a utilização de antidepressivos no manejo da depressão pós-parto. MÉTODO: empregou-se uma revisão integrativa de literatura, das bases de dados PubMed e Biblioteca Virtual em Saúde, com aplicação de descritores, visando responder a pergunta norteadora do trabalho, entre os dias 25 de fevereiro e 10 de março de 2019. Com base nos critérios de inclusão e exclusão, foram selecionados 23 artigos que, posteriormente, foram submetidos à categorização. RESULTADOS: a sertralina deve ser a droga de escolha para o tratamento farmacológico da depressão puerperal. Constatou-se também, que a utilização profilática de antidepressivos em mulheres susceptíveis é contestável e pouco se sabe sobre os possíveis efeitos colaterais. Ademais, foi encontrado que não há consenso sobre a superioridade da terapia farmacológica em detrimento às psicoterapias. CONCLUSÃO: há evidencias que fundamentam o uso de sertralina, paroxetina, duloxetina, nortriptilina e imipramina para tratar mulheres com depressão pós-parto, sendo a amamentação sempre recomendada. Ressalta-se que emerge a necessidade de estudos com amostras representativas para validar ou restringir o uso de psicofármacos na profilaxia da depressão puerperal.
OBJECTIVE: this study aimed to characterize the use of antidepressants in the management of postpartum depression. METHOD: an integrative literature review of the PubMed and Virtual Health Library databases was used, with the application of descriptors, aiming to answer the guiding question of the work, between February 25th and March 10th, 2019. Based on the inclusion and exclusion criteria, 23 articles were selected that were later submitted to categorization. RESULTS: sertraline should be the drug of choice for the pharmacological treatment of puerperal depression. It was also found that the prophylactic use of antidepressants in susceptible women is controversial and little is known about the possible side effects. In addition, it was found that there is no consensus on the superiority of pharmacological therapy to the detriment of psychotherapies. CONCLUSION: there is evidence supporting the use of sertraline, paroxetine, duloxetine, nortriptyline and imipramine to treat women with postpartum depression, and breastfeeding is always recommended. It is worth noting that the need for studies with representative samples to validate or restrict the use of psychotropic drugs in the prophylaxis of puerperal depression emerges.
OBJETIVO: el presente estudio tuvo como objetivo caracterizar la utilización de antidepresivos en el manejo de la depresión posparto. MÉTODO: revisión integradora de literatura, de las bases de datos PubMed y Biblioteca Virtual de Salud, con aplicación de descriptores, para responder a la pregunta orientadora del trabajo, entre el 25 de febrero y el 10 de marzo de 2019. Con base en los criterios de inclusión y exclusión, se seleccionaron 23 artículos que posteriormente se sometieron a categorización. RESULTADOS: la sertralina debe ser la droga elegida para el tratamiento farmacológico de la depresión puerperal. Además, se constató que la utilización profiláctica de antidepresivos en mujeres susceptibles es discutible y poco se sabe sobre los posibles efectos colaterales. Asimismo, se encontró que no hay consenso sobre la superioridad de la terapia farmacológica en detrimento de las psicoterapias. CONCLUSIÓN: hay evidencias que fundamentan el uso de sertralina, paroxetina, duloxetina, nortriptilina e imipramina para tratar a mujeres con depresión posparto, siendo la lactancia siempre recomendada. Se destaca que surge la necesidad de realizar estudios con muestras representativas para validar o restringir el uso de psicofármacos en la profilaxis de la depresión puerperal.
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Psicotrópicos , Aleitamento Materno , Paroxetina , Depressão Pós-Parto/prevenção & controle , Cloridrato de Duloxetina , AntidepressivosRESUMO
INTRODUCTION: Disruption of intestinal barrier is a key component to various diseases. Whether barrier dysfunction is the cause or effect in these situations is still unknown, although it is believed that translocation of luminal content may initiate gastrointestinal or systemic inflammatory disorders. Since trauma- or infection-driven epithelial permeability depends on Toll-like receptor (TLR) activity, inhibition of TLR signaling has been proposed as a strategy to protect intestinal barrier integrity after infection or other pathological conditions. Recently, selective serotonin recapture inhibitors including sertraline and citalopram were shown to inhibit TLR-3 activity, but the direct effects of these antidepressant drugs on the gut mucosa barrier remain largely unexplored. MATERIALS AND METHODS: To investigate this, two approaches were used: first, ex vivo studies were performed to evaluate sertraline and citalopram-driven changes in permeability in isolated intestinal tissue. Second, both compounds were tested for their preventive effects in a rat model of disrupted gut barrier, induced by a low protein (LP) diet. RESULTS: Only sertraline was able to increase transepithelial electrical resistance in the rat colon both when used in an ex vivo (0.8 µg/mL, 180 min) or in vivo (30 mg/kg p.o., 20 days) fashion. However, citalopram (20 mg/kg p.o., 20 days), but not sertraline, prevented the increase in phospho-IRF3 protein, a marker of TLR-3 activation, in LP-rat ileum. Neither antidepressant affected locomotion, anxiety-like behaviours or stress-induced defecation. CONCLUSION: Our data provides evidence to support the investigation of sertraline as therapeutic strategy to protect intestinal barrier function under life-threatening situations or chronic conditions associated with gut epithelial disruption.
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Citalopram/farmacologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , Ração Animal , Animais , Dieta , Proteínas Alimentares/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
The emergence of non-Aspergillus mold pathogens has increased notoriously in the last decades with serious health consequences. The options of treatment for these microorganisms often resistant to a wide variety of antifungals is limited. Sertraline is an antidepressant with in vitro and in vivo antifungal properties which has been recently studied as an adjuvant in the treatment of invasive infections. In this study, we evaluated the in vitro interaction of sertraline with voriconazole and amphotericin B against Lomentospora prolificans, Scedosporium spp., Fusarium spp., Paecilomyces spp., Alternaria spp. and Curvularia spp. The minimum inhibitory concentration and minimum fungicidal concentration for sertraline were in the range of 8-32 µg/mL. Sertraline showed antifungal capacity against all fungi tested and synergism in combination with amphotericin B against some strains of Lomentospora prolificans, Scedosporium apiospermum and Alternaria alternata, antagonism with voriconazole against Purpureocillium lilacinum and indifference in both combinations for most of the other strains tested. These results suggest a potential role of sertraline as an adjuvant in the treatment of some of these serious mycoses.
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Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Fungos Mitospóricos/efeitos dos fármacos , Micoses/microbiologia , Sertralina/farmacologia , Anfotericina B/farmacologia , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Voriconazol/farmacologiaRESUMO
Pediatric obsessive-compulsive disorder (OCD) is an impairing disorder frequently associated with long-term persistence. Long-term follow-up studies that investigated psychopathological trajectories after initial treatment are scarce. The present study is a 7-9-year follow-up of a randomized clinical trial (RCT) that tested the efficacy of group cognitive-behavioral therapy (CBT) and sertraline for children with OCD (n = 40), and aimed to describe long-term outcomes of pediatric OCD and identify predictors of these outcomes. Thirty-five participants who were included in the original study were recruited for follow-up evaluations. Participants underwent a comprehensive assessment of demographic and clinical characteristics comprised of the Structured Clinical Interview for DSM Disorders (SCID) and/or Kiddie-Schedule of Affective Disorders and Schizophrenia Present-Lifetime (K-SADS-PL), and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Thirty-three participants had a complete psychiatric assessment at follow-up (mean age 21 years, SD 3.2; 65% male). At follow-up, 13 (39.4%) participants had an OCD diagnosis, 10 (30.3%) had a diagnosis of any mental disorder (excluding OCD), and 10 (30.3%) did not have any diagnosis of mental disorder. In total, 23 participants (69.7%) had at least one mental disorder (including OCD). Among those without OCD (n = 20), 60.6% had a mental disorder. The following characteristics at follow-up were associated with OCD diagnosis: YBOCS total score (p < 0.001), global functioning (p = 0.008), and presence of any anxiety disorder (p = 0.027). Being treated with GCBT or sertraline during the original RCT did not predict OCD at follow-up. New treatment strategies should consider the role of psychopathological trajectories using a dynamic approach to combine or change interventions to enhance prognosis.
Assuntos
Transtorno Obsessivo-Compulsivo/psicologia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
We report the case of a 19-year-old patient, with a history of traumatic liver damage, but with a normal liver profile at her first discharge; 1 month after the event, with post-traumatic stress disorder, treatment with 25 mg of sertraline was started every day; one month later, she develops severe hepatotoxicity without a specific etiology. According to the Naranjo algorithm, it is attributed as a probable case of sertraline hepatotoxicity. Management is carried out with support measures and suspension of the medication, and the patient recovers until she is asymptomatic, currently has normal liver tests
Reportamos el caso de una paciente de 19 años, con antecedentes de daño hepático traumático, pero con un perfil hepático normal en su primer alta; después de 1 mes del evento, con trastorno de estrés postraumático se inició tratamiento con 25 mg diarios de sertralina; un mes después, desarrolla una hepatotoxicidad severa sin etiología determinada. De acuerdo con el algoritmo de Naranjo, se atribuye como caso probable de hepatotoxicidad por sertralina. El manejo se realiza con medidas de apoyo y suspensión del medicamento, y la paciente se recupera hasta que se encuentra asintomática, actualmente tiene pruebas hepáticas normales
Assuntos
Humanos , Feminino , Adulto Jovem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Sertralina/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Algoritmos , Doença Hepática Induzida por Substâncias e Drogas/terapiaRESUMO
The repositioning of approved drugs is atopic of interest for the academy and the pharmaceutical industry. The synergistic combination of these drugs can be successful in the treatment of infections caused by resistant bacteria. This study aimed to assess the in vitro synergistic antibacterial activity of sertraline and disulfiram and their interaction with ciprofloxacin and sulfamethoxazole/trimethoprim. We determined the minimum inhibitory concentration, the minimum bactericidal concentration and the fractional inhibitory concentration index. Eighteen bacterial strains were used, being nine American Type Culture Collection reference strains and nine multidrug resistant clinical isolates. Synergy was detected between sertraline and disulfiram against a strain of Staphylococcus aureusATCC 25923 and a clinical isolate of S. aureus. When associated to sulfamethoxazole/trimethoprim and ciprofloxacin, sertraline and disulfiram showed eight synergistic events, which occurred against three different standard strains and two multidrug resistant clinical isolates. When the minimum bactericidal concentration was determined, the bactericidal activity of sertraline was enhanced with disulfiram. Our results suggest that these drugs, widely used to treat depression and chronic alcoholism, have antibacterial potential individually, in association, and combined with antimicrobials, what makes their repositioning a promising therapeutic alternative for the effective treatment of infections caused by multidrug resistant bacteria.
RESUMO
Abstract Introduction: Intradialytic hypotension (IDH) is a major complication of hemodialysis, with a prevalence of about 25% during hemodialysis sessions, causing increased morbidity and mortality. Objective: To study the effects of sertraline to prevent IDH in hemodialysis patients. Methods: This was a double-blind, crossover clinical trial comparing the use of sertraline versus placebo to reduce intradialytic hypotension. Results: Sixteen patients completed the two phases of the study during a 12-week period. The IDH prevalence was 32%. A comparison between intradialytic interventions, intradialytic symptoms, and IDH episodes revealed no statistical difference in the reduction of IDH episodes (p = 0.207) between the two intervention groups. However, the risk of IDH interventions was 60% higher in the placebo group compared to the sertraline group, and the risk of IDH symptoms was 40% higher in the placebo group compared to the sertraline group. Survival analysis using Kaplan-Meier estimator supported the results of this study. Sertraline presented a number needed to treat (NNT) of 16.3 patients to prevent an episode from IDH intervention and 14.2 patients to prevent an episode from intradialytic symptoms. Conclusion: This study suggests that the use of sertraline may be beneficial to reduce the number of symptoms and ID interventions, although there was no statistically significant difference in the blood pressure levels.
Resumo Introdução: A hipotensão intradialítica (HID) é uma das principais complicações da hemodiálise, com uma prevalência de cerca de 25% durante as sessões de hemodiálise, causando aumento da morbimortalidade. Objetivo: Estudar os efeitos da sertralina na prevenção da HID em pacientes em hemodiálise. Métodos: Este foi um ensaio clínico duplo-cego, cruzado, comparando o uso de sertralina versus placebo para reduzir a hipotensão intradialítica. Resultados: Dezesseis pacientes completaram as duas fases do estudo durante um período de 12 semanas. A prevalência de HID foi de 32%. Uma comparação entre intervenções intradialíticas, sintomas intradialíticos (ID) e episódios de HID não revelou diferença estatística na redução dos episódios de HID (p = 0,207) entre os dois grupos de intervenção. No entanto, o risco de intervenções para HID foi 60% maior no grupo placebo em comparação com o grupo Sertralina, e o risco de sintomas ID foi 40% maior no grupo placebo em comparação com o grupo Sertralina. A análise de sobrevida utilizando o estimador de Kaplan-Meier corroborou os resultados deste estudo. A sertralina apresentou um número necessário para tratar (NNT) de 16,3 pacientes para prevenir um episódio de intervenção de HID e 14,2 pacientes para prevenir um episódio de sintomas intradialíticos. Conclusão: Este estudo sugere que o uso de sertralina pode ser benéfico para reduzir o número de sintomas e intervenções de HID, embora não tenha havido diferença estatisticamente significante nos níveis pressóricos.