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1.
Medicine (Baltimore) ; 99(28): e21122, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664138

RESUMO

RATIONALE: Lithium is the first-line medication for bipolar disorder, given a narrow therapeutic window of 0.8 to 1.2 mEq/L. Change of lithium pharmacokinetics following bariatric surgery may lead to lithium toxicity, which is particularly concerned. PATIENT CONCERNS: We presented a 39-year-old man with morbid obesity and bipolar affective disorder for 20 years, who was treated with lithium. He developed serious lithium toxicity following sleeve gastrectomy and prolonged neurologic sequelae. DIAGNOSES: He suffered from persistent watery diarrhea, general weakness, and then drowsy consciousness. Lithium level was checked immediately to be 3.42 mEq/L and lithium toxicity was diagnosed. INTERVENTIONS: After 3 courses of hemodialysis, his serum lithium level subsequently declined to 0.63 mEq/L, while his consciousness returned normal. Lithium was replaced by lamotrigine. OUTCOMES: The patient was discharged thirty-five days after admission, while his serum lithium declined to 0.06 mEq/L. Neurologic sequelae were noted by muscle weakness and pain sensation in both feet. The nerve conduction test revealed sensorimotor polyneuropathy with conduction block. He was advised to keep a passive range of motion exercise. LESSONS: Although the consensus guideline remains lacking, our report reviewed cases of relevance in the literature and highlighted the awareness of the potential risk of lithium toxicity following bariatric surgery. We suggest close monitoring of the lithium levels and perhaps a dosage adjustment for the postoperative period.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Gastrectomia/efeitos adversos , Carbonato de Lítio/efeitos adversos , Obesidade Mórbida/cirurgia , Polineuropatias/induzido quimicamente , Complicações Pós-Operatórias , Adulto , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Transtorno Bipolar/complicações , Transtorno Bipolar/metabolismo , Humanos , Laparoscopia/efeitos adversos , Lítio , Carbonato de Lítio/farmacocinética , Masculino , Obesidade Mórbida/complicações
2.
Lakartidningen ; 1172020 04 21.
Artigo em Sueco | MEDLINE | ID: mdl-32315439

RESUMO

Depression is common during pregnancy, and a considerable proportion of pregnant women take antidepressants. Modern antidepressants (e.g. SSRIs) are fairly safe to use during pregnancy. Several physiological changes occur in the pregnant state, possibly affecting the pharmacokinetics of many drugs. Metabolism via CYP enzymes are important for the elimination of antidepressants. This metabolism may increase, decrease or remain constant throughout pregnancy. The activity of CYP2D6 increases drastically with pregnancy progression, causing decreasing serum concentrations of drugs metabolised via this enzyme. Examples of such drugs are paroxetine and fluoxetine. The field of pregnancy-related pharmacokinetics of antidepressants is still in its early stages. More research will be necessary in the future, to enable evidence-based clinical decisions and optimise antidepressant treatment for pregnant women.


Assuntos
Antidepressivos , Complicações na Gravidez/tratamento farmacológico , Inibidores de Captação de Serotonina , Antidepressivos/farmacocinética , Citocromo P-450 CYP2D6 , Feminino , Fluoxetina , Humanos , Paroxetina , Gravidez , Inibidores de Captação de Serotonina/farmacocinética
3.
Artigo em Inglês | MEDLINE | ID: mdl-32163901

RESUMO

In recent years, depression occurs frequently. Given the long duration of the disease and the high risk of recurrence, the treatment of depression requires long-term medication. Zhi-Zi-Hou-Po Decoction (ZZHPD) has been used in clinical treatment of depression and related diseases for many years, and the potential toxic damage caused by its long-term use has gradually emerged. Existing research methods that expose toxicity by a one-time administration of large doses cannot provide a reference for clinical safe drug use. In this study, the potential toxicity of ZZHPD in repeated administration was studied by urinary metabolomics with nondestructive sampling. Based on ultra-high performance liquid chromatography-quadruple-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS) and chemometrics, 33 differential biomarkers, such as 3-hydroxybutyric acid, indole sulfuric acid, hippuric acid and citric acid, were screened and dynamically tracked. The changes of some endogenous substances showed obvious time dependence. Further analysis of these time-dependent components in combination with network pharmacology revealed that the potential hepatotoxicity and nephrotoxicity of ZZHPD were related to the disorders of amino acid metabolism, energy metabolism, lipid metabolism, nucleotide metabolism and gut microflora metabolism pathway. This study can better grasp the occurrence and development of drug toxicity, and provide reference for rational and safe drug use and potential toxicity prevention of ZZHPD.


Assuntos
Antidepressivos/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Iridoides/farmacocinética , Animais , Antidepressivos/efeitos adversos , Antidepressivos/urina , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/efeitos adversos , Iridoides/efeitos adversos , Iridoides/urina , Masculino , Metabolômica , Ratos Sprague-Dawley , Transdução de Sinais , Espectrometria de Massas em Tandem
4.
Sci Rep ; 10(1): 1964, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029776

RESUMO

Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. To enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Portadores de Fármacos/química , Nanocápsulas/química , Trazodona/administração & dosagem , Animais , Antidepressivos/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Injeções Intraperitoneais , Lipídeos/química , Masculino , Camundongos , Tamanho da Partícula , Poliésteres/química , Solubilidade , Trazodona/farmacocinética
5.
Int J Mol Sci ; 21(4)2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32079131

RESUMO

The review collects together some recent information on the identity and pharmacological properties of magnoflorine, a quaternary aporphine alkaloid, that is widely distributed within the representatives of several botanical families like Berberidaceae, Magnoliaceae, Papaveraceae, or Menispermaceae. Several findings published in the scientific publications mention its application in the treatment of a wide spectrum of diseases including inflammatory ones, allergies, hypertension, osteoporosis, bacterial, viral and fungal infections, and some civilization diseases like cancer, obesity, diabetes, dementia, or depression. The pharmacokinetics and perspectives on its introduction to therapeutic strategies will also be discussed.


Assuntos
Aporfinas/química , Aporfinas/farmacologia , Descoberta de Drogas , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Antialérgicos/química , Antialérgicos/farmacocinética , Antialérgicos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Antidepressivos/química , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Aporfinas/farmacocinética , Metabolismo dos Carboidratos/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacocinética , Plantas/química
6.
Exp Clin Psychopharmacol ; 28(2): 202-215, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31120287

RESUMO

This work aimed to describe and characterize the GnG-PK/PD-AD study and the population of subjects diagnosed with depression and treated with fluoxetine, paroxetine, and venlafaxine recruited in the scope of this project, particularly in terms of antidepressant pharmacokinetics and clinical outcomes and relevant genetic and nongenetic individual factors. 182 subjects diagnosed with depression and treated with these drugs were clinically and therapeutically characterized and submitted to the quantification of drug/metabolite plasma concentrations and genotyping of ABCB1, CYP2C9, CYP2C19, and CYP2D6 genes. Clinical outcomes, including remission and antidepressant adverse effects, were assessed by means of the Hamilton Depression Rating Scale and Antidepressant Side-Effect Checklist, respectively. Most subjects were women (81.9%), suffered from chronic depression (73.6%) and displayed a high prevalence of comorbidities (76.9%), polytherapy (88.5%), and genetic polymorphisms/non-wild-type genotype-predicted phenotypes at the level of CYP2C9, CYP2C19, CYP2D6, and ABCB1 genes (39-78.6%). Noteworthy, most of them were under risk of presenting P-gp, CYP2C9, CYP2C19, and CYP2D6 inhibited due to drug-induced phenoconversion (64.3-98.4%) and 80.8% were at risk of occurrence of at least one antidepressant-drug interaction. Around 40% presented drug plasma concentrations outside of the recommended therapeutic range, 66.5% did not achieve remission of the depressive symptoms and 67.6% presented at least one relevant antidepressant adverse effect. Pharmacokinetics and clinical outcomes with fluoxetine, paroxetine, and venlafaxine were found to be suboptimal and highly variable between subjects. Several genetic and nongenetic factors were identified as potential sources of interindividual variability in the antidepressant outcomes, which deserve to be further investigated. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Adolescente , Adulto , Antidepressivos/farmacocinética , Estudos Transversais , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Depressão/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
J Pharmacol Exp Ther ; 372(2): 224-236, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31594792

RESUMO

Agonists at the δ opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective in models of anxiety and depression. However, some δ opioid agonists have proconvulsant properties while tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the δ opioid receptor differentially engage signaling and regulatory pathways with significant effects on behavioral outcomes. As such, interest is now growing in the development of biased agonists as a potential means to target specific signaling pathways and potentially improve the therapeutic profile of δ opioid agonists. Here, we report on PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide), a novel G protein-biased and selective δ opioid agonist. In cell-based assays, PN6047 fully engages G protein signaling but is a partial agonist in both the arrestin recruitment and internalization assays. PN6047 is effective in rodent models of chronic pain but shows no detectable analgesic tolerance following prolonged treatment. In addition, PN6047 exhibited antidepressant-like activity in the forced swim test, and importantly, the drug had no effect on chemically induced seizures. PN6047 did not exhibit reward-like properties in the conditioned place preference test or induce respiratory depression. Thus, δ opioid ligands with limited arrestin signaling such as PN6047 may be therapeutically beneficial in the treatment of chronic pain states. SIGNIFICANCE STATEMENT: PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide) is a selective, G protein-biased δ opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment, and PN6047 does not display proconvulsant activity or other opioid-mediated adverse effects. Our data suggest that δ opioid ligands with limited arrestin signaling will be beneficial in the treatment of chronic pain.


Assuntos
Analgésicos Opioides/metabolismo , Antidepressivos/química , Benzamidas/química , Benzamidas/farmacocinética , Dor Crônica/tratamento farmacológico , Proteínas de Ligação ao GTP/metabolismo , Receptores Opioides delta/metabolismo , Animais , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Arrestina/metabolismo , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Tolerância a Medicamentos , Células HEK293 , Humanos , Masculino , Camundongos , Modelos Animais , Ratos Wistar , Resultado do Tratamento
9.
Chem Biol Interact ; 315: 108851, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31614129

RESUMO

BACKGROUND: Currently, few herbal pharmacokinetic (PK) parameters have been applied successfully for therapeutic monitoring because of the complexity of consistency when there are multiple chemicals and efficacies. PURPOSE: The present study aims to evaluate the herbal PK properties by investigating the PK parameters of the 8 absorbed bioactive compounds (ABCs), which can represent its parent herbal holistic efficacy, to achieve a PK therapeutic monitoring of herbs. METHOD: First, we tested the hypothesis that the antidepressant and prokinetic effects and related anti-inflammation and anti-oxidation activity (APIO) by Fructus aurantii-Magnolia Bark (FM) formula are related to 8 compounds according to the absorbable evidence and the determined contents. Subsequently, stable and representative APIO from 8ABCs allowed us to develop a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 8 compounds following the oral administration of FM decoction (20 g/kg) in rats. RESULT: 8 compounds either including Meranzin hydrate (MH) or MH alone almost identically (8 compounds: 91.62-108.82%)or nearly(MH: 65.38-88.41%) replicated the parent formula FM in terms of efficacy for inducing APIO. CONCLUSION: This unifying strategy shows how multi-herb formulas pharmacokinetic therapeutic monitoring can be achieved by the method we established.


Assuntos
Anti-Inflamatórios/farmacocinética , Antidepressivos/farmacocinética , Antioxidantes/farmacocinética , Medicamentos de Ervas Chinesas/química , Magnolia/química , Casca de Planta/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cumarínicos/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Frutas/química , Cinética , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
10.
Int J Neuropsychopharmacol ; 23(2): 76-87, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774497

RESUMO

OBJECTIVE: Model-based meta-analysis was used to describe the time-course and dose-effect relationships of antidepressants and also simultaneously investigate the impact of various factors on drug efficacy. METHODS: This study is a reanalysis of a published network meta-analysis. Only placebo-controlled trials were included in this study. The change rate in depression rating scale scores from baseline was used as an efficacy indicator because a continuous variable is more likely to reflect subtle differences in efficacy between drugs. RESULTS: A total 230 studies containing 64 346 patients were included in the analysis. The results showed that the number of study sites (single or multi-center) and the type of setting (inpatient or noninpatient) are important factors affecting the efficacy of antidepressants. After deducting the placebo effect, the maximum pure drug efficacy value of inpatients was 18.4% higher than that of noninpatients, and maximum pure drug efficacy value of single-center trials was 10.2% higher than that of multi-central trials. Amitriptyline showed the highest drug efficacy. The remaining 18 antidepressants were comparable or had little difference. Within the approved dose range, no significant dose-response relationship was observed. However, the time-course relationship is obvious for all antidepressants. In terms of safety, with the exception of amitriptyline, the dropout rate due to adverse events of other drugs was not more than 10% higher than that of the placebo group. CONCLUSION: The number of study sites and the type of setting are significant impact factors for the efficacy of antidepressants. Except for amitriptyline, the other 18 antidepressants have little difference in efficacy and safety.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Doença Aguda , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Metanálise em Rede
11.
Drug Des Devel Ther ; 13: 4135-4144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827320

RESUMO

Purpose: To assess the pharmacokinetics and safety of pure S-ketamine (esketamine) in Chinese patients undergoing painless gastroscopy and evaluate the potential advantage of esketamine in clinical treatment compared with racemate ketamine hydrochloride injection. Patients and methods: A randomized, open-label, parallel-controlled, Phase I study was performed with 32 patients undergoing painless gastroscopy. Patients received a single dose of esketamine (0.5 mg/kg) or racemic ketamine (1 mg/kg, esketamine:R-ketamine=1:1), injected in 10 s. Blood samples were collected for pharmacokinetic analysis. The concentrations of esketamine, R-ketamine, S-norketamine, and R-norketamine were measured with a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Results: After administering a single dose of esketamine and racemate ketamine, the pharmacokinetics parameters of esketamine and S-norketamine are both similar in treatment groups. The clearance of esketamine in two groups was 18.1±3.2 and 18.4±3.4 mL/min•kg, respectively. However, in the ketamine group, esketamine has a larger clearance than R-ketamine (18.4±3.4 mL/min·kg vs 15.8±3.1 mL/min·kg, P<0.001). Further analysis showed that gender did not affect the pharmacokinetics of esketamine and racemate ketamine. Regarding the safety of esketamine and racemate ketamine, no serious adverse events were observed during treatment, and the incidences of adverse events were 75.0% (esketamine) and 87.5% (racemate ketamine). The main adverse reactions were dizziness, agitation, nausea, vomiting, headache, and fatigue. However, compared with racemic ketamine, esketamine offers a shorter recovery time (9 mins vs. 13 mins, P<0.05) and orientation recovery time (11.5 mins vs. 17 mins, P<0.05) after short anesthesia. Conclusion: Esketamine administration as a single dose of 0.5 mg/kg was generally safe and tolerated in patients undergoing painless gastroscopy. In terms of anesthesia, a relatively small dose of esketamine can be used instead of racemate ketamine for routine treatment without consideration of gender differences.


Assuntos
Antidepressivos/farmacocinética , Gastroscopia , Ketamina/farmacocinética , Adulto , Anestesia , Antidepressivos/administração & dosagem , Antidepressivos/sangue , China , Relação Dose-Resposta a Droga , Feminino , Humanos , Ketamina/administração & dosagem , Ketamina/sangue , Masculino , Estrutura Molecular , Relação Estrutura-Atividade , Adulto Jovem
12.
J Clin Psychopharmacol ; 39(6): 583-590, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688392

RESUMO

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.


Assuntos
Antidepressivos/administração & dosagem , Citocromo P-450 CYP2D6/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Nortriptilina/administração & dosagem , Testes Farmacogenômicos , Cloridrato de Venlafaxina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nortriptilina/farmacocinética , Fatores de Tempo , Cloridrato de Venlafaxina/farmacocinética
13.
Expert Opin Drug Deliv ; 16(12): 1413-1427, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31694417

RESUMO

Background: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic interventions are imperative.Research design and methods: Venlafaxine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were surface functionalized with two ligands against transferrin receptor to enhance access to brain. An in vitro blood-brain barrier model using hCMEC/D3 cell line was developed to evaluate permeability. In vivo biodistribution studies were performed using C57/bl6 mice. Particles were administered intranasal and main organs were analyzed.Results: Particles were obtained as a lyophilized powder easily to re-suspend. Internalization and permeability studies showed the following cell association sequence: TfRp-NPs>Tf-NPs>plain NPs. Permeability studies also showed that encapsulated VLF was not affected by P-gP pump efflux increasing its concentration in the basolateral side after 24 h. In vivo studies showed that 25% of plain NPs reach the brain after 30 min of one intranasal administration while less than 5% of functionalized NPs get the target.Conclusions: Plain NPs showed the highest ability to reach the brain vs. functionalized NPs after 30 min by intranasal administration. We suggest plain NPs probably travel via direct nose-to-brian route whereas functionalized NPs reach the brain by receptor-mediated endocytosis.


Assuntos
Antidepressivos , Portadores de Fármacos , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Cloridrato de Venlafaxina , Administração Intranasal , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Encéfalo/metabolismo , Linhagem Celular , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Permeabilidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Distribuição Tecidual , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacocinética
14.
J Clin Psychiatry ; 80(6)2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31774947

RESUMO

Withdrawal symptoms commonly occur during tapering and/or after discontinuation of antidepressant drugs, particularly selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Withdrawal symptomatology does not necessarily subside within a few weeks and may be associated with other manifestations of behavioral toxicity (loss of treatment efficacy, refractoriness, switch into mania/hypomania, or paradoxical reactions). The oppositional model of tolerance provides a pathophysiologic basis for understanding and managing withdrawal syndromes. Reintroducing the antidepressant that was initially used or switching from one antidepressant to another to suppress symptomatology, as suggested by current guidelines, may actually aggravate the state of behavioral toxicity and be detrimental in the long run. Alternative strategies that do not encompass continuation of antidepressant treatment are required, but there is currently lack of adequate research for guiding the clinical approach. Some tentative suggestions are provided.


Assuntos
Antidepressivos/efeitos adversos , Síndrome de Abstinência a Substâncias/diagnóstico , Síndrome de Abstinência a Substâncias/terapia , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Esquema de Medicação , Substituição de Medicamentos/efeitos adversos , Quimioterapia Combinada , Humanos , Taxa de Depuração Metabólica/fisiologia , Retratamento , Fatores de Risco , Síndrome de Abstinência a Substâncias/sangue , Síndrome de Abstinência a Substâncias/psicologia , Síndrome
15.
Ther Deliv ; 10(11): 683-696, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31744396

RESUMO

Aim: The manuscript describes the performance of nanoparticles loaded with antidepressant drug for nose-to-brain drug delivery. Materials & methods: Poly-lactic-co-glycolic acid-loaded nanoparticles of agomelatine were prepared by nanoprecipitation method using poloxamer 407 as stabilizer. The process parameters were optimized using factorial design. Results: The drug-loaded nanoparticles having low particle size (<200 nm) with narrow size distribution and required zeta potential (-22.7 mV) to avoid aggregation showed sustained release profile and were found to have higher permeability as observed from ex vivo studies when compared with plain drug suspension. Histopathology test showed that the optimized formulation was free from nasal toxicity on the goat nasal mucosa. Pharmacodynamic study showed significant reduction in immobility time in rats treated with the formulation which indicated antidepressant activity of the formulation. Conclusion: The prepared agomelatin-loaded poly-lactic-co-glycolic acid nanoparticles showed prominent antidepressant activity by nose-to-brain delivery as observed from various studies.


Assuntos
Acetamidas/administração & dosagem , Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Acetamidas/farmacocinética , Acetamidas/toxicidade , Administração Intranasal , Animais , Antidepressivos/farmacocinética , Antidepressivos/toxicidade , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Depressão/diagnóstico , Depressão/etiologia , Modelos Animais de Doenças , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Cabras , Humanos , Nanopartículas/toxicidade , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Ratos , Testes de Toxicidade
16.
Molecules ; 24(23)2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31757051

RESUMO

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.


Assuntos
Antidepressivos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Neurônios/metabolismo , Inibidores da Captação de Neurotransmissores , Transmissão Sináptica/efeitos dos fármacos , Animais , Antidepressivos/química , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Masculino , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacocinética , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar
17.
Acta Med Port ; 32(10): 671-673, 2019 Oct 01.
Artigo em Português | MEDLINE | ID: mdl-31625880

RESUMO

Manic and hypomanic states associated with antidepressant treatments are relatively common; however, when specifically considering mirtazapine, those side effects are infrequent. The authors report a clinical case regarding a manic episode with dysphoric features in a patient with no personal or family previous psychiatric history. It began two weeks after starting treatment with mirtazapine up to 30 mg/day. This episode was treated discontinuing mirtazapine and initiating olanzapine (10 mg), with symptomatic remission. Mirtazapine has a specific pharmacodynamics, blocking not only post-synaptic serotonergic receptors but also α2-presynaptic adrenergic receptors. Taking this into consideration, it was hypothesized that this case could be attributed to a noradrenergic syndrome, characterized by dysphoria, irritability, insomnia and psychomotor agitation.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Bipolar/induzido quimicamente , Mirtazapina/efeitos adversos , Psicoses Induzidas por Substâncias/etiologia , Antidepressivos/farmacocinética , Antipsicóticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mirtazapina/farmacocinética , Olanzapina/uso terapêutico
19.
Drug Des Devel Ther ; 13: 3331-3342, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571834

RESUMO

Purpose: A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation. Methods: The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs). Results: The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0-t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.


Assuntos
Antracenos/farmacocinética , Antidepressivos/farmacocinética , Flupentixol/farmacocinética , Adulto , Antracenos/administração & dosagem , Antracenos/efeitos adversos , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Área Sob a Curva , China , Estudos Cross-Over , Combinação de Medicamentos , Jejum , Feminino , Flupentixol/administração & dosagem , Flupentixol/efeitos adversos , Voluntários Saudáveis , Humanos , Masculino , Comprimidos , Equivalência Terapêutica , Adulto Jovem
20.
Bull Exp Biol Med ; 167(5): 637-640, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31625065

RESUMO

Pharmacokinetics and relative bioavailability of antidepressant GSB-106 (hexamethylendiamide bis-(N-monosuccinyl-L-seryl-L-lysine) were determined in rabbits after single oral administration of the pharmaceutical substance and tablet mass. GSB-106 concentrations in the blood plasma were determined by HPLC-mass spectrometry. Relative bioavailability of GSB-106 tablet form was 160.79±24.33%.


Assuntos
Antidepressivos/farmacocinética , Dipeptídeos/farmacocinética , Administração Oral , Animais , Antidepressivos/sangue , Área Sob a Curva , Disponibilidade Biológica , Dipeptídeos/sangue , Avaliação Pré-Clínica de Medicamentos , Masculino , Coelhos , Comprimidos
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