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1.
Mol Genet Metab ; 142(4): 108516, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38941880

RESUMO

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.


Assuntos
Flavoproteínas Transferidoras de Elétrons , Deficiência Múltipla de Acil Coenzima A Desidrogenase , Humanos , Feminino , Masculino , Criança , Adulto , Pré-Escolar , Flavoproteínas Transferidoras de Elétrons/genética , Adolescente , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Queensland , Riboflavina/uso terapêutico , Adulto Jovem , Lactente , Proteínas Ferro-Enxofre/genética , Estudos de Coortes , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Recém-Nascido , Mutação , Sequenciamento Completo do Genoma
2.
Toxicol Appl Pharmacol ; 486: 116937, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38643950

RESUMO

Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used medications for the treatment of major depressive disorder. However, long-term SSRI use has been associated with weight gain and altered lipid profiles. These findings suggest that SSRIs may have negative effects on metabolism. Exposure to certain chemicals called 'obesogens' is known to promote lipid accumulation and obesity by modulating adipogenesis. Here, we investigated whether citalopram (CIT) and sertraline (SER) interfere with the process of adipogenesis, using human mesenchymal stem cells (MSCs) in a 2D and a 3D model. Assessment of intracellular lipid accumulation by fluorescence staining was used as a measure for enhanced adipogenesis. To explore possible mechanisms behind SSRIs' effects, receptor mediated activity was studied using responsive cell lines for various nuclear receptors. Furthermore, RNA sequencing was performed in the 3D model, followed by differential gene expression and pathway analysis. A dose dependent increase in lipid accumulation was observed in both models with CIT and SER. For the 3D model, the effect was seen in a range close to reported steady-state plasma concentrations (0.065-0.65 µM for SER and 0.12-0.92 µM for CIT). Pathway analysis revealed unexpected results of downregulation in adipogenesis-related pathways and upregulation in phospholipids and lysosomal pathways. This was confirmed by an observed increase in lysosomes in the 2D model. Our findings suggest lysosomal dysfunction and disrupted lipid metabolism in mature adipocytes, leading to excessive phospholipid synthesis. Moreover, important adipogenic processes are inhibited, potentially leading to dysfunctional adipocytes, which might have implications in the maintenance of a healthy metabolic balance.


Assuntos
Adipogenia , Antidepressivos , Citalopram , Metabolismo dos Lipídeos , Células-Tronco Mesenquimais , Inibidores Seletivos de Recaptação de Serotonina , Sertralina , Adipogenia/efeitos dos fármacos , Sertralina/farmacologia , Sertralina/toxicidade , Humanos , Citalopram/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Antidepressivos/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga
3.
Am J Med Genet A ; 194(8): e63610, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38517161

RESUMO

Primrose syndrome (PS) is a rare genetic disease characterized by developmental delay, intellectual disability, sensorineural hearing loss, and dysmorphic features. PS is caused by de novo pathogenic variants in the ZBTB20 gene, which encodes a transcription factor modulating neurogenesis. We describe resolution with sertraline of neurobehavioral difficulties in a 17-year-old Hispanic male with PS with de novo heterozygous c.1916G > A (p.C639Y) variant of ZBTB20. Neurobehavioral difficulties included aggression towards self and others, irritability, tearfulness, and mood liability that did not respond to behavioral interventions or aripiprazole. Treatment with sertraline, a medication indicated for psychiatric disorders including anxiety and depression, led to the resolution of neurobehavioral difficulties after 2 weeks of initiation of medication. The treatment course suggests that selective serotonin reuptake inhibitors, such as sertraline, may be a useful tool for neurobehavioral difficulties in PS over antipsychotics that are accompanied by complex side effect profiles, and suggest that anxiety is the primary cause of the neurobehavioral difficulties in this patient.


Assuntos
Deficiência Intelectual , Sertralina , Fatores de Transcrição , Humanos , Sertralina/uso terapêutico , Masculino , Adolescente , Deficiência Intelectual/genética , Deficiência Intelectual/tratamento farmacológico , Fatores de Transcrição/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/psicologia , Calcinose , Otopatias , Atrofia Muscular , Proteínas do Tecido Nervoso
4.
Br J Clin Pharmacol ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030897

RESUMO

AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

5.
Eur J Clin Pharmacol ; 80(7): 983-1016, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38558317

RESUMO

Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Fluoxetina , Inibidores Seletivos de Recaptação de Serotonina , Sertralina , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sertralina/farmacologia , Sertralina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Fluoxetina/farmacologia , Animais , Depressão/tratamento farmacológico , Escitalopram/farmacologia , Escitalopram/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
6.
BMC Psychiatry ; 24(1): 365, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750479

RESUMO

OBJECTIVES: This study aims to evaluate the safety and efficacy of escitalopram and sertraline in post-stroke depression (PSD) patients, to provide more reliable therapeutics for cardiovascular and psychiatric clinical practice. METHODS: We recruited 60 patients (aged 40-89 years old) with an ICD-10 diagnosis of PSD, who were then randomly assigned to two groups and treated with flexible doses of escitalopram (10 to 20 mg/day, n = 30) or sertraline (50 to 200 mg/day, n = 30) for consecutive 8 weeks, respectively. The 24-item Hamilton Depression Rating Scale (HAMD-24), the 14-item Hamilton Anxiety Rating Scale (HAMA-14), the Treatment Emergent Symptom Scale (TESS), the Montreal Cognitive Assessment Scale (MOCA), and the Activity of Daily Living scale (ADL) were used to assess patients before, during, and after treatment for depression, anxiety, adverse effects, cognitive function, and daily living activities. Repeated measures ANOVA, the Mann-Whitney U test, the chi-square test (χ2), or Fisher's exact test was employed to assess baseline demographics, response rate, adverse effects rate, and changes in other clinical variables. RESULTS: Significant reduction in HAMD-24 and HAMA-14 scores was evaluated at baseline, as well as 1, 3, 4, 6, and 8 weeks of drug intervention (p < 0.01). There was a significant group difference in post-treatment HAMD-24 scores (p < 0.05), but no difference was observed in HAMA-14 scores (p > 0.05). Further analysis showed a significant variance in the HAMD-24 scores between the two groups at the end of the first week (p < 0.01). The incidence of adverse effects in both patient groups was mild, but there was a statistically significant difference between the two groups (p < 0.05). The improvement in cognitive function and the recovery of daily living abilities were comparable between both groups (p > 0.05). CONCLUSION: Escitalopram and sertraline showed comparable efficacy for anxiety symptoms, cognitive function, and daily living abilities in PSD patients. In addition, escitalopram was more appropriate for alleviating depressive symptoms. To validate the conclusion, trials with a larger sample size are in demand in the future. The registration number is ChiCTR1800017373.


Assuntos
Atividades Cotidianas , Escitalopram , Sertralina , Acidente Vascular Cerebral , Humanos , Sertralina/uso terapêutico , Sertralina/efeitos adversos , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Escitalopram/uso terapêutico , Escitalopram/efeitos adversos , Depressão/tratamento farmacológico , Depressão/etiologia , Resultado do Tratamento , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Escalas de Graduação Psiquiátrica , Antidepressivos/uso terapêutico , Antidepressivos/efeitos adversos , Citalopram/uso terapêutico , Citalopram/efeitos adversos
7.
Gerontology ; 70(4): 408-417, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38228128

RESUMO

INTRODUCTION: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in the lifespan and healthspan of Caenorhabditis elegans. METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of serotonin signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. RESULTS: Sertraline extended the lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. CONCLUSION: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Longevidade/fisiologia , Sertralina/farmacologia , Sertralina/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Lipofuscina/metabolismo , Lipofuscina/farmacologia , Insulina , Fatores de Transcrição Forkhead/genética
8.
Ecotoxicol Environ Saf ; 285: 117134, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39357382

RESUMO

Among emerging contaminants, pharmaceuticals are considered one of the most pertinent substances that may threaten aquatic ecosystems. Pharmaceuticals are designed to be directed at specific metabolic- and molecular pathways. Thus, they are assumed to be still biologically active when entering the ecosystem and may result in unpremeditated impacts on non-target organisms. One of the most widely used selective serotonin reuptake inhibitors, sertraline (an antidepressant), is regularly found in aquatic environments. However, knowledge about the effects, and in particular, of sediment-associated sertraline in benthic invertebrates is limited. We examined the impacts of chronic exposure (28 d) to sediment-associated sertraline (3.3, 33, 330 µg/g dw sed.) on survival, growth and reproduction in the deposit-feeding oligochaete, Tubifex tubifex. Sertraline significantly decreased T. tubifex survival and growth. Worms exposed to high sertraline concentrations (330 µg/g) had a lower growth rate and reproduction, as indicated by a significantly lower number of cumulated cocoons. Worms exposed to an environmentally relevant concentration (3.3 µg/g) decreased growth but maintained a reproduction rate similar to that of the control. The implications are that adult worms exposed to high sertraline concentrations presumably required more energy for maintenance and detoxification, thereby reducing available energy for reproduction and growth. This represents a trade-off between survival, reproduction and growth. In contrast, T. tubifex exposed to environmentally relevant concentrations allocated more energy to reproduction by slightly increasing the number of cocoons produced and reducing growth. However, the quantity and quality of offspring may be impacted as we observed fewer juveniles in the environmentally relevant treatment than in the control. Overall, the results indicate that sediment-associated sertraline is bioavailable and negatively impacts T. tubifex survival, growth, and reproduction even at environmentally relevant concentrations.


Assuntos
Antidepressivos , Sedimentos Geológicos , Oligoquetos , Reprodução , Sertralina , Poluentes Químicos da Água , Sertralina/toxicidade , Animais , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Sedimentos Geológicos/química , Antidepressivos/toxicidade , Oligoquetos/efeitos dos fármacos , Oligoquetos/fisiologia
9.
Nord J Psychiatry ; 78(4): 353-361, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38451197

RESUMO

BACKGROUND: Research on long-term pharmacotherapy for trauma-affected refugees is scarce. The purpose of this follow-up study of a randomised trial was to investigate the effects of sertraline compared to venlafaxine in combination with psychotherapy, 6 and 18 months after end of trial. METHOD: The primary outcome was PTSD symptoms, measured by the Harvard Trauma Questionnaire (HTQ). The secondary outcomes included: Hopkins Symptom Checklist-25 (HSCL-25), somatisation items of the Symptoms Checklist-90 (SCL), pain on a visual analogue scale, well-being on the WHO-5, Sheehan Disability Scale, Hamilton Depression and Anxiety scales and Global Assessment of Functioning. Moreover, the shorter version of the Recent Life Events (IRLE) was adopted to obtain information regarding the patients' treatment and life events between the follow-up periods. RESULTS: Out of 195 patients eligible for intention-to-treat analyses during trial, 116 participated in the 6-month follow-up and 97 participated in the 18-month follow-up. The results of our intention-to-treat analyses revealed no significant long-term differences between the groups on the primary outcome assessing PTSD symptoms (HTQ). For the secondary outcomes significant differences were found at the 18-month follow-up in favour of venlafaxine assessing symptoms of anxiety, depression and somatisation (HSCL-25 and SCL), although only in intention-to-treat and not per-protocol analyses. CONCLUSIONS: No conclusions could be drawn due to conflicting results between our intention-to-treat and per-protocol analyses.


Assuntos
Psicoterapia , Refugiados , Sertralina , Transtornos de Estresse Pós-Traumáticos , Cloridrato de Venlafaxina , Humanos , Cloridrato de Venlafaxina/uso terapêutico , Cloridrato de Venlafaxina/administração & dosagem , Feminino , Adulto , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Masculino , Seguimentos , Psicoterapia/métodos , Refugiados/psicologia , Sertralina/uso terapêutico , Terapia Combinada , Pessoa de Meia-Idade , Trauma Psicológico/terapia , Trauma Psicológico/tratamento farmacológico , Resultado do Tratamento , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico
10.
Molecules ; 29(16)2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39202813

RESUMO

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. It is important to discover new therapeutic regimens for treating CRC. Depression is known to be an important complication of cancer diseases. Repurposing antidepressants into anticancer drugs and exploring the combinational efficacy of antidepressants and chemotherapy are potentially good options for developing CRC treatment regimens. In this study, sertraline, an antidepressant drug, and paclitaxel, an anticancer drug, were chosen to study their antitumor effects in the treatment of colorectal cancer, alone or in combination, and to explore their underlying mechanisms. The data showed that sertraline exerted a dose-dependent cytotoxic effect on MC38 and CT26 colorectal cancer cell lines with IC50 values of 10.53 µM and 7.47 µM, respectively. Furthermore, sertraline synergistically sensitized chemotherapeutic agent paclitaxel efficacy in CRC cells with combination index (CI) values at various concentrations consistently lower than 1. Sertraline remarkably augmented paclitaxel-induced autophagy by increasing autophagosome formation indicated by elevated LC3-II/I ratio and promoting autophagic flux by degrading autophagy cargo receptor SQSTM1/p62, which may explain the synergistically cytotoxic effect of sertraline and paclitaxel combination therapy on CRC cells. This study provides important evidence to support repurposing sertraline as an anticancer agent and suggests a novel combinational regimen for effectively treating CRC as well as in the simultaneous treatment of CRC and depression.


Assuntos
Antidepressivos , Autofagia , Neoplasias Colorretais , Sinergismo Farmacológico , Paclitaxel , Sertralina , Sertralina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Autofagia/efeitos dos fármacos , Paclitaxel/farmacologia , Humanos , Linhagem Celular Tumoral , Antidepressivos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Animais
11.
Psychother Res ; 34(1): 17-27, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36913531

RESUMO

OBJECTIVE: Changes in trauma-related beliefs and therapeutic alliance have been found to temporally precede symptom reduction; however, it is likely these processes do not act in isolation but rather in interactive ways. METHODS: The present study examined the temporal relationships between negative posttraumatic cognitions (PTCI) and therapeutic alliance (WAI) in 142 patients who were part of a randomized trial comparing prolonged exposure (PE) to sertraline for chronic PTSD. RESULTS: Using time-lagged mixed regression models, improvements in the therapeutic alliance predicted subsequent improvements in trauma-related beliefs (d = 0.59), an effect accounted for by between-patient variability (d = 0.64) compared to within-patient variability (d = .04) giving weaker support to the causal role of alliance on outcome. Belief change did not predict improvements in alliance and neither model was moderated by treatment type. CONCLUSION: Findings suggest alliance may not be an independent driver of cognition change and point to the need for additional study of the impact of patient characteristics on treatment processes.


Assuntos
Sertralina , Transtornos de Estresse Pós-Traumáticos , Humanos , Cognição , Ensaios Clínicos Controlados Aleatórios como Assunto , Sertralina/farmacologia , Sertralina/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Aliança Terapêutica , Resultado do Tratamento
12.
Med J Armed Forces India ; 80(2): 145-152, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38525466

RESUMO

Background: Smoking is common in patients of depression and is known to affect response to antidepressants. This study was undertaken to evaluate the effect of smoking on the antidepressant effect of sertraline. Method: Patients with depression were divided into smoker and nonsmoker cohorts and followed up for 8 weeks. Serum sertraline levels were estimated using the high-performance liquid chromatography system. Response to treatment was evaluated with the Hamilton Depression Rating Scale (HAM-D). Results: Serum sertraline levels did not differ between smokers and nonsmokers at 4 and 8 weeks. Nonsmokers responded better to sertraline than smokers after 8 weeks. Adverse drug reaction profile did not vary between the two groups and was not impacted by serum sertraline levels. Nonsmokers showed a greater fall in the HAM-D score than smokers. Conclusion: This study found depression among smokers to be less responsive to sertraline. This was not explained by serum sertraline levels. Treatment of depression in smokers with sertraline might require higher doses and duration, with more frequent reviews.

13.
J Virol ; 96(24): e0124522, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36468859

RESUMO

The global spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the continuously emerging new variants underscore an urgent need for effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). Here, we screened several FDA-approved amphiphilic drugs and determined that sertraline (SRT) exhibits potent antiviral activity against infection of SARS-CoV-2 pseudovirus (PsV) and authentic virus in vitro. It effectively inhibits SARS-CoV-2 spike (S)-mediated cell-cell fusion. SRT targets the early stage of viral entry. It can bind to the S1 subunit of the S protein, especially the receptor binding domain (RBD), thus blocking S-hACE2 interaction and interfering with the proteolysis process of S protein. SRT is also effective against infection with SARS-CoV-2 PsV variants, including the newly emerging Omicron. The combination of SRT and other antivirals exhibits a strong synergistic effect against infection of SARS-CoV-2 PsV. The antiviral activity of SRT is independent of serotonin transporter expression. Moreover, SRT effectively inhibits infection of SARS-CoV-2 PsV and alleviates the inflammation process and lung pathological alterations in transduced mice in vivo. Therefore, SRT shows promise as a treatment option for COVID-19. IMPORTANCE The study shows SRT is an effective entry inhibitor against infection of SARS-CoV-2, which is currently prevalent globally. SRT targets the S protein of SARS-CoV-2 and is effective against a panel of SARS-CoV-2 variants. It also could be used in combination to prevent SARS-CoV-2 infection. More importantly, with long history of clinical use and proven safety, SRT might be particularly suitable to treat infection of SARS-CoV-2 in the central nervous system and optimized for treatment in older people, pregnant women, and COVID-19 patients with heart complications, which are associated with severity and mortality of COVID-19.


Assuntos
Antivirais , COVID-19 , SARS-CoV-2 , Sertralina , Glicoproteína da Espícula de Coronavírus , Animais , Humanos , Camundongos , Antivirais/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Sertralina/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos
14.
J Transl Med ; 21(1): 432, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37403159

RESUMO

OBJECTIVE: Despite advances in pharmacology, the treatment of schizophrenia (SZ) remains a challenge due to relapse after antipsychotic discontinuation and multiple adverse effects of antipsychotics. We hypothesized that a low dose of risperidone in combination with sertraline would reduce serious adverse effects without decreasing treatment response. This study aimed to examine the efficacy, safety, and tolerability of low-dose risperidone combined with sertraline to reduce risperidone dose and serious adverse effects in first-episode and medication-naive (FEMN) SZ patients. METHODS: A total of 230 patients with FEMN SZ were randomly assigned to receive low-dose risperidone in combination with sertraline (RS group) or regular-dose risperidone (control group). The Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HAMD), and Personal and Social Performance Scale (PSP) were assessed at baseline and the end of the first, second, third, and sixth months. In addition, serum prolactin levels and extrapyramidal symptoms were measured at baseline and follow-up. RESULTS: Repeated measures ANCOVA showed significant interaction effects of treatment by time on psychotic symptoms, as well as HAMD, PSP scores, prolactin levels, and extrapyramidal symptoms (all p < 0.05). Compared with the control group, the RS group had greater decreases in PANSS total score and its subscores and HAMD score (all p < 0.01) and a greater increase in PSP total score (p < 0.01). Notably, side effects were lower in the RS group relative to the control group. Improvements in HAMD and PANSS total scores, changes in prolactin levels and gender predicted improvements in PSP from baseline to month 6. CONCLUSIONS: Our study suggests that low-dose risperidone in combination with sertraline was more effective for psychotic symptoms and psychosocial functioning, with significantly fewer adverse effects in patients with FEMN SZ. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04076371.


Assuntos
Antipsicóticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Esquizofrenia , Humanos , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Sertralina/uso terapêutico , Prolactina/uso terapêutico , Antipsicóticos/efeitos adversos , Resultado do Tratamento
15.
BMC Psychiatry ; 23(1): 686, 2023 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-37735631

RESUMO

BACKGROUND: As 40-60% of the patients with obsessive-compulsive disorder (OCD) do not adequately respond to the first-line treatment, finding an effective second-line treatment is required. Our aim was to assess the efficacy and safety of agomelatine (a selective melatonin receptor agonist and a 5-hydroxytryptamine (HT)2 C antagonist) augmentation of sertraline in the treatment of patients with moderate to severe OCD. METHODS: In this 12-week randomized, double-blinded, placebo-controlled, parallel-group clinical trial, 65 patients with moderate to severe OCD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM-5) criteria and a Yale-Brown obsessive compulsive scale (Y-BOCS) score of over 21, were included. They were assigned with sertraline (100 mg/day for the first 4 weeks and 200 mg/day for the next 8 weeks) and either agomelatine (25 mg/day) or placebo. The primary outcome was OCD symptoms measured by the Y-BOCS. RESULTS: Fifty patients (24 in agomelatine group and 26 in placebo group) completed the trial. The Y-BOCS scores in total (MD (95% CI) = 12.25 (11.00, 13.49) (P < 0.001) vs. MD (95% CI) = 12.46 (6.65, 15.74) (P < 0.001)), the obsession subscale (MD (95% CI) = 5.04 (4.19, 5.88) (P < 0.001) vs. MD (95% CI) = 5.00 (3.84, 6.16) (P = 0.0001)), and compulsion subscale (MD (95% CI) = 7.21 (6.34, 8.07) (P < 0.001) vs. MD (95% CI) = 7.460 (6.50, 8.42) (P < 0.001)) significantly decreased in both groups. Although, at the end of the trial, no significant difference was observed between the scores of the two groups in total (MD (95% CI) = 0.480 (-1.23, 2.19) (P = 0.78)), the obsession subscale (MD (95% CI) = 1.020 (-0.15, 2.19) (P = 0.38)), and the compulsion subscale (MD (95% CI) = 0.540 (-0.34, 1.42) (P = 0.54)). No major adverse effects were recorded, and the frequency of side effects was not significantly different between the groups. CONCLUSION: Agomelatine in augmentation with sertraline is safe and tolerable in patients with moderate to severe OCD. However, our study does not support its efficacy in improving OCD symptoms, compared to placebo. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials on 14/07/2020 ( www.irct.ir ; IRCT ID: IRCT20170123032145N5).


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transtorno Obsessivo-Compulsivo , Humanos , Sertralina/uso terapêutico , Irã (Geográfico) , Acetamidas/efeitos adversos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico
16.
BMC Nephrol ; 24(1): 155, 2023 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-37270517

RESUMO

INTRODUCTION: Uremic pruritus (UP) is a common and distressing symptom in end stage renal disease (ESRD) patients. Many approaches have been tested to improve UP without a clear success. We aimed to assess the effect of sertraline on UP in hemodialysis (HD) patients. METHODS: This research is a double-blinded, placebo-controlled, multicentric randomized clinical trial which included sixty patients maintained on regular HD. Patients were allocated to receive sertraline 50 mg twice daily or placebo for 8 weeks. The Visual analogue scale (VAS) and the 5-D itch scale were used to assess pruritus before and after the course of treatment. RESULTS: At study end in sertraline group, there was a significant decrease from baseline findings in the VAS score (p < 0.001), and the 5-D itch scale (p < 0.001). On the other hand, in placebo group the VAS score showed a slight non-significant decrease (p = 0.469), and the 5-D scale (p = 0.584) increased from baseline measurements. The percentage of patients with severe and very severe pruritus decreased significantly in the sertraline group in both scores [(VAS score: p = 0.004), (5-D itch score: p = 0.002)] with no significant change in the placebo group [(VAS score: p = 0.739), (5-D itch scale: p = 0.763)]. There was a significant positive relation between the VAS and 5-D itch scores and serum urea with p value of 0.002 and 0.001 respectively, and serum ferritin with p value of < 0.001 with both. CONCLUSIONS: Patients treated with sertraline had a significant improvement in pruritus as compared with those who received placebo suggesting a potential role for sertraline to treat uremic pruritus in HD patients. Larger randomized clinical trials are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05341843. First registration date: 22/04/2022.


Assuntos
Falência Renal Crônica , Sertralina , Humanos , Sertralina/uso terapêutico , Prurido/tratamento farmacológico , Prurido/etiologia , Diálise Renal/efeitos adversos , Falência Renal Crônica/terapia , Falência Renal Crônica/tratamento farmacológico , Método Duplo-Cego
17.
Pharmacology ; 108(4): 409-415, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37257430

RESUMO

Sertraline is one of the most prescribed antidepressants, but its pharmacokinetic (PK) properties are still not completely characterized. Using nonlinear mixed-effects modeling, we examined factors influencing sertraline PK variability in outpatients with major depressive disorder. Blood samples from 53 male and female adults treated with sertraline orally were collected at a steady state. Various demographic and clinical covariates were tested by stepwise regression procedure. We found that sertraline clearance is significantly influenced by serum concentrations of its main metabolite N-desmethylsertraline, whereas clearance of N-desmethylsertraline is affected by both creatinine clearance and drug daily dose. These results were confirmed by the reduction of points dispersion in goodness-of-fit plots for their predicted versus measured concentrations and with bootstrapping analyses. This finding can serve to inform sertraline dosing optimization, especially when changes in kidney function occur in treated individuals, to prevent adverse drug reactions and maximize therapeutic benefits.


Assuntos
Transtorno Depressivo Maior , Sertralina , Adulto , Humanos , Masculino , Feminino , Sertralina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Depressão/tratamento farmacológico , Antidepressivos/uso terapêutico
18.
Ecotoxicol Environ Saf ; 260: 115084, 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37267780

RESUMO

Pharmaceutically active compounds are common and increasing in the aquatic environment. Evidence suggests they have adverse effects on non-target organisms, and they are classified as emerging pollutants for a variety of aquatic organisms. To determine the effects of environmentally relevant levels of psychoactive compounds on non-target organisms, we analyzed cardiac and locomotory activity in early developmental stages of marbled crayfish Procambarus virginalis. Responses to sertraline, methamphetamine, and a mixture of citalopram, oxazepam, sertraline, tramadol, venlafaxine, and methamphetamine at a concentration of 1 µg L-1 of each compound were assessed. On day four of exposure, cardiac activity was recorded for 5 min, and on day eight, locomotory activity was recorded for 15 min. There was a significant increase (p < 0.01) in heart rate in methamphetamine-exposed and Mix-exposed juveniles compared to the unexposed control and there was significant difference (p < 0.01) in proportion of time (activity %) was observed with sertraline-exposed, whereas velocity, and distance moved did not significantly differ (p > 0.05) in exposed and control animals. These findings revealed that low concentrations of chemicals and their mixtures can modify the physiological state of aquatic animals without outward manifestations (activity, distance moved, and velocity). Aquatic animals can be impacted earlier than is visible, but effects can potentially lead to substantial changes in populations and in ecosystem processes. Additional research to investigate chemical combinations, exposure systems, and organism physiological and molecular responses may provide evidence of broad impact of environmental pharmaceuticals.


Assuntos
Metanfetamina , Poluentes Químicos da Água , Animais , Astacoidea/fisiologia , Ecossistema , Sertralina , Metanfetamina/farmacologia , Locomoção , Poluentes Químicos da Água/farmacologia
19.
Int J Mol Sci ; 24(5)2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36902108

RESUMO

We explored the antimicrobial activity of sertraline on Listeria monocytogenes and further investigated the effects of sertraline on biofilm formation and the virulence gene expression of L. monocytogenes. The minimum inhibitory concentration and minimum bactericidal concentration for sertraline against L. monocytogenes were in the range of 16-32 µg/mL and 64 µg/mL, respectively. Sertraline-dependent damage of the cell membrane and a decrease in intracellular ATP and pHin in L. monocytogenes were observed. In addition, sertraline reduced the biofilm formation efficiency of the L. monocytogenes strains. Importantly, low concentrations (0.1 µg/mL and 1 µg/mL) of sertraline significantly down-regulated the expression levels of various L. monocytogens virulence genes (prfA, actA, degU, flaA, sigB, ltrC and sufS). These results collectively suggest a role of sertraline for the control of L. monocytogenes in the food industry.


Assuntos
Anti-Infecciosos , Proteínas de Bactérias , Listeria monocytogenes , Sertralina , Fatores de Virulência , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidade , Sertralina/farmacologia , Virulência/efeitos dos fármacos , Virulência/genética , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
20.
Int J Psychiatry Clin Pract ; : 1-8, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38019131

RESUMO

BACKGROUND: This study evaluated the effect of sertraline with desvenlafaxine and sertraline with mirtazapine on HAM-D score and inflammatory markers (IL-6 and TNF-α levels) in major depressive disorder. METHODS: Patients (18-60 years) with MDD diagnosed by DSM-V criteria and HAM-D score 18 or more were included (n = 60). Group A patients (n = 30) received sertraline 50 mg/day and desvenlafaxine 50 mg/day. Group B patients (n = 30) received sertraline 50 mg/day and mirtazapine 30 mg/day. All patients were followed up for 8 weeks for the evaluation of clinical efficacy, safety, serum IL-6, and TNF-α levels. RESULTS: Our study showed a comparatively similar and statistically significant (p < 0.05) reduction in HAM-D score in both groups in the 4th and 8th week of the treatment. Both drug combinations significantly (p < 0.05) decreased serum IL-6 and TNF-α after 8 weeks of treatment. CONCLUSION: The present study suggests that the combination therapy (as treatment initiation) with sertraline and desvenlafaxine, and sertraline with mirtazapine is effective and well tolerated in MDD patients with moderate to severe depression, and their therapeutic efficacy is accompanied by decreased inflammatory markers (serum IL-6 and TNF-α).


Recent evidence indicates that combination therapy of antidepressant drugs started as treatment initiation produces superior treatment outcomes in patients of MDD with moderate to severe depression.MDD is associated with increased inflammatory markers.Combination therapy of sertraline with desvenlafaxine and sertraline with mirtazapine as treatment initiation is effective and well tolerated in MDD patients.The therapeutic efficacy of sertraline with desvenlafaxine and sertraline with mirtazapine is associated with a significant decrease in serum levels of IL-6 and TNF-α.

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