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1.
Int J Pharm Compd ; 24(4): 327-336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649306

RESUMO

Extemporaneous compounding in veterinary practice sometimes represents the only possibility for treating animals in the absence of appropriate commercial formulations, especially for particular species. This method involves manipulating pharmaceutical active ingredients to a suitable dosage and formulation for administration to humans or animals. However, veterinarians and pharmacists should focus on the risk of potential incompatibilities and instability of their preparations. To help practitioners in drug compounding, we investigated the stability of oral suspensions of tramadol, fluoxetine, and doxycycline in a commercial ready-to-use vehicle (SyrSpend). A validated high-performance liquid chromatography method was developed to assay these active pharmaceutical ingredients. The oral suspensions were prepared at two concentration ranges and were stored in amber glass bottles under refrigerated conditions and at room temperature. After 90 days, the average recovery rates were between 90% and 110% for tramadol (5 mg/mL to 30 mg/mL) and doxycycline  (2 mg/mL to 10 mg/mL) without organoleptic modification. For fluoxetine, only the formulation at 2 mg/mL was stable; at higher concentrations, the uniformity of the suspension was compromised.


Assuntos
Amido , Administração Oral , Cromatografia Líquida de Alta Pressão , Doxiciclina , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Fluoxetina , Humanos , Suspensões , Tramadol
2.
Korean J Intern Med ; 35(4): 741-748, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32668512

RESUMO

Coronavirus disease 2019 (COVID-19) emerged in December 2019 in Wuhan, China; it has since caused a pandemic, with more than 10,000 confirmed cases (> 800,000 tests) in Korea as of May 2020. Real-time reverse transcription polymerase chain reaction (RT-PCR) is currently the most commonly used method for the diagnosis of COVID-19 worldwide. The Korean Society for Laboratory Medicine and Korea Centers for Disease Prevention and Control regularly update the guidelines for COVID-19 diagnosis. Emergency use authorization for some laboratory diagnostic kits has been granted, enabling the timely diagnosis and treatment of COVID-19, and the isolation of infected patients. Due to the collective efforts of the government, medical professionals, local authorities, and the public, Korea's response to the COVID-19 outbreak has been accepted widely as a model. Here, we summarize the currently available laboratory tests for COVID-19 diagnosis. Although RT-PCR tests are used widely to confirm COVID-19, antibody tests could provide information about immune responses to the virus.


Assuntos
Infecções por Coronavirus , Coronavirus , Pandemias , Pneumonia Viral , Antidepressivos , Betacoronavirus , China , Técnicas de Laboratório Clínico , Giro Denteado , Fluoxetina , Humanos , Receptores de Dopamina D1 , República da Coreia , Serotonina
3.
Medicine (Baltimore) ; 99(21): e20170, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481286

RESUMO

BACKGROUND: Numerous studies have reported that transcranial magnetic stimulation (TMS) and fluoxetine is used in the treatment of postpartum depression (PPD). Currently, no study has systematically investigated the efficacy and safety of TMS and fluoxetine for the treatment of patients with PPD. Thus, this study will assess the efficacy and safety of TMS and fluoxetine for treating PPD. METHODS: Relevant studies involving TMS and fluoxetine for the treatment of patients with PPD will be comprehensively searched from the electronic databases from inception to the February 1, 2020: Cochrane Library, EMBASE, MEDILINE, CINAHL, AMED, WANGFANG, VIP, and CNKI databases. No language and publication time restrictions will be applied. RevMan 5.3 software will be utilized for data pooling, data analysis, and risk of bias evaluation. If necessary, we will also assess reporting bias using funnel plot and Egger test. RESULTS: This study will comprehensively summarize the existing evidence to assess the efficacy and safety of TMS and fluoxetine for treating PPD. CONCLUSION: The findings of this study may help to establish a better approach to treat PPD using TMS and fluoxetine. DISSEMINATION AND ETHICS: This study will be disseminated through a peer-reviewed journal. This study does not need ethical approval as no primary patient data will be used. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040017.


Assuntos
Depressão Pós-Parto/terapia , Fluoxetina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Estimulação Magnética Transcraniana/métodos , Adulto , Terapia Combinada/métodos , Depressão Pós-Parto/epidemiologia , Feminino , Fluoxetina/administração & dosagem , Humanos , Inibidores de Captação de Serotonina/administração & dosagem , Resultado do Tratamento
5.
Environ Sci Pollut Res Int ; 27(21): 27032-27047, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388756

RESUMO

Three different synthesis methods were applied to obtain TiO2 nanoparticles: microwave-assisted hydrothermal (TiO2-MW), sonochemical (TiO2-US), and polymeric precursor (TiO2-PP). The nanoparticles thus obtained presented 93% (TiO2-MW) and 92% (TiO2-US) anatase phase, and TiO2-PP 93% rutile phase. The TiO2-US sample performed best during the Prozac® photodegradation assays because of its lipophilic surface, attributable to the C-H groups therein. Additionally, adsorption rate and photodegradation were optimized by adjusting Prozac® solution to pH ~ 8. Following Prozac® photodegradation, quantitative monitoring of its by-products (PPMA, MAEB, and TFMP) was done using HPLC. This quantitative approach led us to conclude that semiconductor photoactivity cannot be discussed solely in terms of the main compound. Lastly, it was seen that these by-products compete with each other in the degradation mechanisms and are influenced by different materials. Graphical abstract.


Assuntos
Micro-Ondas , Nanopartículas , Catálise , Fluoxetina , Titânio
6.
Sci Total Environ ; 733: 139029, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32446052

RESUMO

Disruptive effects of chemicals on lipids in aquatic species are mostly limited to obesogens and vertebrates. Recent studies reported that antidepressants, anxiolytic, antiepileptic and ß-adrenergic pharmaceuticals, with putative distinct mechanisms of action at low environmental relevant concentrations, up-regulated common neurological and lipid metabolic pathways and enhanced similarly reproduction in the crustacean Daphnia magna. Conversely CRISPR mutants for the tryptophan hydrolase enzyme gene (TRH) that lack serotonin had the opposed phenotype: the lipid metabolism down-regulated and impaired reproduction. Lipid metabolism is strongly linked to reproduction in D. magna. The aim of this study is to test if the above mentioned neuro-active chemicals disrupted common lipid groups and showed also the opposed lipidomic effects as those individuals lacking serotonin. This study used ultra-high performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOFMS) to study how neuro-active chemicals (carbamazepine, diazepam, fluoxetine and propranolol) at low (0.1 µg/L) and higher concentrations (1 µg/L) and three CRISPR TRH mutant clones disrupt the dynamics of glycerophospholipids and glycerolipids in Daphnia adults. Lipidomic analysis identified 267 individual lipids corresponding to three classes of glycerolipids, eleven of glycerophospholipids, one of sterols and one of sphingolipids, of which 132 and 125 changed according to the chemical treatments or across clones, respectively. Most pharmaceutical treatments enhanced reproduction whereas mutated clones lacking serotonin reproduced to a lesser extent. Except for carbamazepine, most of the tested pharmaceuticals increased some triacylglycerol species and decreased monoacylglycerols, lysophospholipids, sphingomyelins and cholesterol esters in exposed females. Opposed lipidomic pattern was observed in mutated clones lacking serotonin. Lipidomic data, thus, indicate a close link between reported transcriptomic and lipidomic changes, which are likely related to serotonin and other neurological signalling pathways.


Assuntos
Daphnia , Poluentes Químicos da Água/análise , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Fluoxetina , Lipídeos , Reprodução
7.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(3): 413-417, 2020 Mar 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376570

RESUMO

OBJECTIVE: To study the behavioral characteristics of memory maintenance and regression in a mouse model of combined learning and memory training with fluoxetine treatment and explore the neural basis for learning and memory in the barrel area of the brain. METHODS: Twenty-six 16-day-old C57 mice were randomized into two equal groups and were given daily intraperitoneal injection of saline (control) or fluoxetine. The mice were subjected to stimulation of the right whiskers using a multi-sensory stimulation simulator and were given simultaneously olfactory stimulation with butyl acetate. In the initial 10 days of the experiment, the mice were given corresponding drug treatment followed by whisker and olfactory stimulations on a daily basis; from day 11 to day 17, only the drugs were administered without the stimulations; on day 18, both the drugs and stimulations were administered. The daily performance of the mice was recorded and analyzed. In the field potential experiment, the left barrel cortex of the mouse brain was selected to record the frequency of field potential signals in response to whisker stimulation. RESULTS: In the behavioral test, the mice treated with fluoxetine showed greater increments of the frequency and angle of whisker deflection than the control mice (P < 0.01). Compared with the peak levels that occurred on the 10th day, the swing angle and frequency of the whisker deflection decreased on the 17th day decreased in both groups, and the reduction was more obvious in the control group (P < 0.05). During the training on the 18th day, the whisker movement of the mice increased rapidly to the peak level and showed significant differences between the two groups (P < 0.05). In the field potential experiment on the 10th and 17th day, the frequencies of field potential signal in response to whisker stimulation was significantly higher in fluoxetine group than in the control group (P < 0.05). CONCLUSIONS: Combined training of the mice results in the formation of combined memory. Fluoxetine can enhance combined learning and memory abilities and prolong such memories in mice by promoting the function of the barrel cortex cells.


Assuntos
Aprendizagem , Córtex Somatossensorial , Animais , Fluoxetina , Camundongos , Neurônios , Vibrissas
9.
Neuropsychopharmacol Hung ; 22(1): 4-15, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32329748

RESUMO

Discovery and development of the selective serotonin reuptake inhibitors mark a milestone in neuropharmacology. Drugs from this class alter the functioning of the serotonin system by the potentiation of serotonin through the negative allosteric modulation of its neuronal uptake by the human serotonin transporter. Selective serotonin reuptake inhibitors show few side effects compared to those caused by traditional antidepressants and they vary in the binding interactions formed during binding. Generally, their binding involves three specific regions of the drug structures, each participating in vital interactions, such as salt bridge formation and additional hydrophobic interactions with conserved residues in the central binding site of the target protein. Side effects, however, such as the initial lack of response to treatment, or drowsiness, nausea, and sexual dysfunction occasionally may arise. Additional binding studies, furthermore, highlighted the importance of enantioselectivity in the binding of these compounds, raising concerns about the beneficial application of racemate mixtures of some of these compounds. Therefore, additional characterisation of binding and further structural improvement of this class of drugs is necessary. The recently synthesized sertraline salts, and functional derivatives of fluoxetine and citalopram show promising results in delivering antidepressant activity as well as in effectively overcoming anorexigenic side-effects in rodent models. Hence, despite certain non-desired effects associated with selective serotonin reuptake inhibitor applications, this class of drugs is considered as first-line medication in the management of major depression, and is carrying an excellent potential for the development and refinement of the currently available and novel antidepressant therapies.


Assuntos
Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Fluoxetina/uso terapêutico , Sertralina/uso terapêutico , Humanos , Proteínas da Membrana Plasmática de Transporte de Serotonina , Inibidores de Captação de Serotonina
10.
Environ Pollut ; 263(Pt A): 114450, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32283454

RESUMO

Pharmaceutical pollution is now recognised as a major emerging agent of global change. Increasingly, pharmaceutical pollutants are documented to disrupt ecologically important physiological and behavioural traits in exposed wildlife. However, little is known about potential impacts of pharmaceutical exposure on among-individual variation in these traits, despite phenotypic diversity being critical for population resilience to environmental change. Furthermore, although wildlife commonly experience multiple stressors contemporaneously, potential interactive effects between pharmaceuticals and biological stressors-such as predation threat-remain poorly understood. To redress this, we investigated the impacts of long-term exposure to the pervasive pharmaceutical pollutant fluoxetine (Prozac®) on among-individual variation in metabolic and behavioural traits, and the combined impacts of fluoxetine exposure and predation threat on mean metabolic and behavioural traits in a freshwater fish, the guppy (Poecilia reticulata). Using a mesocosm system, guppy populations were exposed for 15 months to one of two field-realistic levels of fluoxetine (nominal concentrations: 30 and 300 ng/L) or a solvent control. Fish from these populations were then tested for metabolic rate (oxygen uptake) and behaviour (activity), both before and after experiencing one of three levels of a predation treatment: an empty tank, a non-predatory fish (Melanotaenia splendida) or a predatory fish (Leiopotherapon unicolor). Guppies from both fluoxetine treatments had ∼70% lower among-individual variation in their activity levels, compared to unexposed fish. Similarly, fluoxetine exposure at the higher dosage was associated with a significant (26%) reduction in individual-level variation in oxygen uptake relative to unexposed fish. In addition, mean baseline metabolic rate was disrupted in low-fluoxetine exposed fish, although mean metabolic and behavioural responses to predation threat were not affected. Overall, our study demonstrates that long-term exposure to a pervasive pharmaceutical pollutant alters ecologically relevant traits in fish and erodes among-individual variability, which may be detrimental to the stability of contaminated populations globally.


Assuntos
Poluentes Ambientais , Poecilia , Poluentes Químicos da Água , Animais , Variação Biológica da População , Fluoxetina
11.
Lancet Psychiatry ; 7(4): 337-343, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32199509

RESUMO

BACKGROUND: Better understanding of the heterogeneity of treatment responses could help to improve care for adolescents with depression. We analysed data from a clinical trial to assess whether specific symptom clusters responded differently to various treatments. METHODS: For this secondary analysis, we used data from the Treatment for Adolescents with Depression Study (TADS), in which 439 US adolescents aged 12-17 with a DSM-IV diagnosis of major depressive disorder and a minimum score of 45 on the Children's Depression Rating Scale-Revised (CDRS-R) were randomly assigned (1:1:1:1) to treatment with fluoxetine, cognitive behavioural therapy (CBT), fluoxetine plus CBT, or pill placebo. Our analysis focuses on the acute phase of the trial (ie, the first 12 weeks). Groups of co-occurring symptoms were established by clustering scores for each CDRS-R item at baseline with Ward's method, with Euclidean distances for hierarchical agglomerative clustering. We then used a linear mixed-effects model to investigate the relationship between symptom clusters and treatment efficacy, with the sum of symptom scores within each cluster as the dependent measure. As fixed effects, we entered cluster, time, and treatment assignment, with all two-way and three-way interactions, into the model. The random effect providing better fit was established to be a by-subject random slope for cluster based on improvement in the Schwarz-Bayesian information criterion. OUTCOMES: We identified two symptom clusters: cluster 1 comprised depressed mood, difficulty having fun, irritability, social withdrawal, sleep disturbance, impaired schoolwork, excessive fatigue, and low self-esteem, and cluster 2 comprised increased appetite, physical complaints, excessive weeping, decreased appetite, excessive guilt, morbid ideation, and suicidal ideation. For cluster 1 symptoms, CDRS-R scores were reduced by 5·8 points (95% CI 2·8-8·9) in adolescents treated with fluoxetine plus CBT, and by 4·1 points (1·1-7·1) in those treated with fluoxetine, compared with those given placebo. For cluster 2 symptoms, no significant differences in improvements in CDRS-R scores were detected between the active treatment and placebo groups. INTERPRETATION: Response to fluoxetine and CBT among adolescents with depression is heterogeneous. Clinicians should consider clinical profile when selecting therapeutic modality. The contrast in response patterns between symptom clusters could provide opportunities to improve treatment efficacy by gearing the development of new therapies towards the resolution of specific symptoms. FUNDING: Conselho Nacional de Desenvolvimento Científico e Tecnológico.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Transtorno Depressivo Maior/terapia , Fluoxetina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Teorema de Bayes , Criança , Terapia Combinada , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Estados Unidos
12.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188355, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135169

RESUMO

The human ether-à-go-go related gene (HERG) encodes the alpha subunit of Kv11.1, which is a voltage-gated K+ channel protein mainly expressed in heart and brain tissue. HERG plays critical role in cardiac repolarization, and mutations in HERG can cause long QT syndrome. More recently, evidence has emerged that HERG channels are aberrantly expressed in many kinds of cancer cells and play important roles in cancer progression. HERG could therefore be a potential biomarker for cancer and a possible molecular target for anticancer drug design. HERG affects a number of cellular processes, including cell proliferation, apoptosis, angiogenesis and migration, any of which could be affected by dysregulation of HERG. This review provides an overview of available information on HERG channel as it relates to cancer, with focus on the mechanism by which HERG influences cancer progression. Molecular docking attempts suggest two possible protein-protein interactions of HERG with the ß1-integrin receptor and the transcription factor STAT-1 as novel HERG-directed therapeutic targeting which avoids possible cardiotoxicity. The role of epigenetics in regulating HERG channel expression and activity in cancer will also be discussed. Finally, given its inherent extracellular accessibility as an ion channel, we discuss regulatory roles of this molecule in cancer physiology and therapeutic potential. Future research should be directed to explore the possibilities of therapeutic interventions targeting HERG channels while minding possible complications.


Assuntos
Carcinogênese/patologia , Canal de Potássio ERG1/metabolismo , Integrina beta1/metabolismo , Neoplasias/patologia , Fator de Transcrição STAT1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Carcinogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/química , Canal de Potássio ERG1/genética , Epigênese Genética/efeitos dos fármacos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Síndrome do QT Longo/genética , Potenciais da Membrana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação , Miócitos Cardíacos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Conformação Proteica em alfa-Hélice , Mapeamento de Interação de Proteínas , Estrutura Quaternária de Proteína , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfanilamidas/farmacologia , Sulfanilamidas/uso terapêutico
13.
Environ Sci Technol ; 54(7): 4200-4209, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32167300

RESUMO

Fluoxetine has been recognized as one of the most toxic pharmaceuticals in the aquatic environment. Since there is growing evidence that the toxic potential of fluoxetine in surface waters is markedly influenced by its own metabolism in aquatic species, this study investigated the biotransformation of fluoxetine in the zebrafish embryo - an aquatic model organism of intermediate complexity. Zebrafish embryos were exposed to 0.1, 1.0, 10, 50, and 5000 µg/L of fluoxetine from 48 to 120 h post-fertilization (hpf), and the accumulation of fluoxetine and its metabolites was analyzed over time. Additionally, depuration of fluoxetine and its metabolites from 96 to 120 hpf was investigated, and autoinhibitory effects of fluoxetine on phase I biotransformation were analyzed. Exposure to 5000 µg/L fluoxetine resulted in elevated 7-ethoxyresorufin-O-deethylase (EROD) activity of cytochrome P450 enzymes and continuous accumulation of fluoxetine and 11 fluoxetine metabolites. Embryos exposed to 10 and 50 µg/L fluoxetine were able to reduce fluoxetine accumulation from 94 to 120 hpf. During depuration, accumulation of fluoxetine and most metabolites was clearly reduced, and biotransformation shifted in favor of norfluoxetine, the primary fluoxetine metabolite in humans. Findings demonstrated that norfluoxetine is the only metabolite of fluoxetine that accumulates in zebrafish embryos at environmentally relevant exposure scenarios.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Embrião não Mamífero , Fluoxetina/análogos & derivados , Humanos
14.
Artigo em Inglês | MEDLINE | ID: mdl-32213465

RESUMO

In this study, the use of switchable hydrophilicity solvent with a simple and low-cost lab-made device for the extraction procedure in homogeneous liquid-liquid microextraction is proposed for the first time in the determination of antidepressants in human urine. The antidepressants studied consisted of fluoxetine, amitriptyline, nortriptyline, imipramine, desipramine and sertraline. The optimization of the main parameters that can influence on the extraction efficiency was performed through multivariate approaches. The analytes were separated and identified by gas chromatography coupled to mass spectrometry (GC-MS). The optimal extraction conditions consisted of using N,N-dimethylcyclohexylamine (DMCHA) as the switchable hydrophilicity solvent (SHS), 500 µL of urine sample previously diluted with ultrapure water at 1:1 ratio (v/v), 200 µL of a mixture of SHS:HCl 6 mol L-1 (1:1 v/v), 600 µL of NaOH 10 mol L-1 and 3 min of extraction time. A volume of 40 µL of diphenylamine at concentration of 500 µg L-1 (20 ng) was used as internal standard. The method developed was in-house validated, providing coefficients of determination higher than 0.995 for all analytes, limits of detection (LOD) from 0.02 to 0.88 µg L-1, limits of quantification (LOQ) from 0.05 to 2.92 µg L-1, relative recoveries of 68 to 102%, intra-day precision from 0.5 to 15.9%, inter-day precision from 4.2 to 19.3%, selectivity and robustness. The method proposed was successfully applied in five human urine samples from a Toxicological Information Center located in Porto Alegre (Brazil). The results demonstrated that the µP-SHS-HLLME approach is highly cost-effective, rapid, simple and environmentally-friendly with satisfactory analytical performance.


Assuntos
Antidepressivos/urina , Adulto , Amitriptilina/urina , Cicloexilaminas/química , Desipramina/urina , Fluoxetina/urina , Cromatografia Gasosa-Espectrometria de Massas , Química Verde , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imipramina/urina , Limite de Detecção , Microextração em Fase Líquida , Nortriptilina/urina , Sertralina/urina , Solventes/química
16.
Arch. Clin. Psychiatry (Impr.) ; 47(1): 7-12, Jan.-Feb. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1088740

RESUMO

Abstract Objectives This study aimed to explore the effect of antidepressant treatment on the HPA axis, changes in depression score, and serum levels of TNF-α in depressed infertile women. Methods In this randomized controlled trial research, 60 infertile women who had undergone in vitro fertilization (IVF) treatment with depression scores between 16-47 were divided into two groups. The intervention group with fluoxetine capsule was under treatment for two months before the embryo transfer, while the control group was given placebo. Depression score, serum levels of tumor necrosis factor alpha (TNF-α) as well as cortisol hormone levels were measured and recorded both before and after the intervention. The data were analyzed using SPSS version 21 software. Results We analyzed the data related to 55 subjects who had undergone embryo transfer. 7 subjects in the intervention group and 3 in the control group got pregnant. We observed a significant decrease in the depression score (p < 0/001) and serum levels of cortisol (p = 0/001) in the intervention group. There was a significant increase in the serum levels of TNF-α in the intervention group (p < 0/001). There was a significant difference between the two groups in the number of pregnancies (p = 0.04). However, there was no statistical difference between them with regard to the number of harvested oocytes (p = 0.174). Discussion Decrease in depression score and cortisol level, and an increase in the levels of TNF-α in the intervention group caused any changes in the number of oocytes in comparison with the control group. However, the number of pregnancies was larger in the intervention group.


Assuntos
Humanos , Feminino , Adulto , Fator de Necrose Tumoral alfa/sangue , Depressão/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Infertilidade Feminina/psicologia , Placebos/uso terapêutico , Escalas de Graduação Psiquiátrica , Psicometria/métodos , Gravidez/psicologia , Hidrocortisona/sangue , Fertilização In Vitro , Aborto Espontâneo/etiologia , Fluoxetina/uso terapêutico , Inquéritos e Questionários , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Resultado do Tratamento , Depressão/complicações , Depressão/diagnóstico , Infertilidade/etiologia
17.
Lancet Neurol ; 19(3): 214-225, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31981516

RESUMO

BACKGROUND: Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. METHODS: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. FINDINGS: Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. INTERPRETATION: The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.


Assuntos
Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Administração Oral , Adulto , Amilorida/uso terapêutico , Encéfalo , Progressão da Doença , Método Duplo-Cego , Feminino , Fluoxetina/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Riluzol/uso terapêutico , Resultado do Tratamento
18.
PLoS One ; 15(1): e0226486, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31931515

RESUMO

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.


Assuntos
Benzodiazepinas/uso terapêutico , Encéfalo/metabolismo , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Fluoxetina/uso terapêutico , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Encéfalo/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/metabolismo , Transtorno Depressivo Resistente a Tratamento/patologia , Combinação de Medicamentos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Índice de Gravidade de Doença
19.
Life Sci ; 245: 117307, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954746

RESUMO

AIM: To investigate whether a chronic 5-HT reuptake inhibitor (i.e. Fluoxetine-FLX) exposure in young adult rats overfed during suckling period would modulate interscapular brown adipose tissue (iBAT) mitochondria and browning agents in white adipose tissue (WAT). METHODS: Male Wistar rats were assigned into either a normofed group (n = 9 per group) or an overfed group (n = 3 per group) induced by litter size reduction at postnatal day 3 (PND3). Pharmacological manipulation was carried out between PND39 and PND59 and groups were assigned accordingly: Normofed + vehicle solution - NaCl 0.9% (NV group), normofed + FLX solution - 10 mg/kg b.w. (NF group), overfed + vehicle (OV group) and overfed + FLX (OF group). We evaluated mitochondrial oxygen consumption and reactive species (RS) production, oxidative stress analyses (MDA concentration, carbonyl content, REDOX state [GSH/GSSG], global oxy score) in the iBAT, gene (leptin, Ucp1, Sirt1, Pgc1α and Prdm16) and protein (UCP1) expression in the iBAT and epididymal WAT (eWAT). KEY FINDINGS: OV group increased body weight gain, Lee index and oxidative stress in the iBAT. Both FLX-treated groups showed less weight gain compared to their controls. OF group showed different leptin expression in the WAT and iBAT; increased functional UCP1 content and mitochondrial activity with less oxidative stress in the iBAT and upregulation of browning genes in eWAT (Pgc1α, Prdm16 and Ucp1). CONCLUSION: Altogether our findings indicated that FLX treatment in young adult overfed animals improved the iBAT mitochondrial function, reduced oxidative stress and induced transcriptional activation of browning agents in white adipose tissue.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Fluoxetina/farmacologia , Mitocôndrias/efeitos dos fármacos , Hipernutrição/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína Desacopladora 1/metabolismo
20.
Bull Environ Contam Toxicol ; 104(2): 180-184, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894370

RESUMO

Melano-macrophage centers (MMCs) are nodular clusters of pigmented macrophages, implicated in homeostasis and destruction and recycling of endogenous and exogenous material. They can increase in size and/or frequency under environmental stress resulting in immunohistological biomarkers of water quality. Fluoxetine (FLX), a commonly prescribed antidepressant, can cause neuroendocrine, behavioral and reproductive alterations in teleost fish. In the present study, we analyzed the effects of a 2-week 50 µg/L FLX exposure on MMCs in histological sections of spleen and head-kidney (HK) of the cichlid fish Cichlasoma dimerus. In the spleen, FLX caused an increase in the area and a decrease in the number of MMCs. An increase in the proportion of the HK occupied by MMCs was observed in FLX-exposed fish, due to an increase in their number but not their area. The deposition rate of MMCs varies according to the hemolymphopoietic organ and would be the result of a differential response to FLX on homeostatic functions (elimination of cellular debris, iron processing and immune response).


Assuntos
Antidepressivos/toxicidade , Fluoxetina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Ciclídeos/crescimento & desenvolvimento , Ciclídeos/metabolismo , Ciclídeos/fisiologia , Água Doce/química , Rim Cefálico/efeitos dos fármacos , Rim Cefálico/metabolismo , Imuno-Histoquímica , Baço/efeitos dos fármacos , Baço/metabolismo
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