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1.
Proc Natl Acad Sci U S A ; 116(51): 25968-25973, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31776253

RESUMO

Evidence shows that the neurotransmitter dopamine mediates the rewarding effects of nicotine and other drugs of abuse, while nondopaminergic neural substrates mediate the negative motivational effects. ß2* nicotinic acetylcholine receptors (nAChR) are necessary and sufficient for the experience of both nicotine reward and aversion in an intra-VTA (ventral tegmental area) self-administration paradigm. We selectively reexpressed ß2* nAChRs in VTA dopamine or VTA γ-amino-butyric acid (GABA) neurons in ß2-/- mice to double-dissociate the aversive and rewarding conditioned responses to nicotine in nondependent mice, revealing that ß2* nAChRs on VTA dopamine neurons mediate nicotine's conditioned aversive effects, while ß2* nAChRs on VTA GABA neurons mediate the conditioned rewarding effects in place-conditioning paradigms. These results stand in contrast to a purely dopaminergic reward theory, leading to a better understanding of the neurobiology of nicotine motivation and possibly to improved therapeutic treatments for smoking cessation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Dopamina/farmacologia , Nicotina/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Agonistas de Dopamina , Flupentixol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Motivação/efeitos dos fármacos , Recompensa
2.
Zhonghua Yi Xue Za Zhi ; 99(41): 3266-3272, 2019 Nov 05.
Artigo em Chinês | MEDLINE | ID: mdl-31694124

RESUMO

Objective: To observe the difference of brain activity in patients with diarrhea-type irritable bowel syndrome (IBS-D) treated with pinaverium bromide (PB) combined with flupentixol-melitracen (FM), and to explore the mechanism of efficacy of combined with anxiolytic/antidepressant drugs in IBS-D patients at the central level, using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-eight patients with IBS-D, including 28 males, 20 females, mean age 22-48 (33±7) years, were selected from the Affiliated Hospital of Hangzhou Normal University from October 2015 to October 2018.All patients with IBS-D underwent rs-fMRI scans before and after receiving either PB (basic treatment group, n=16), PB combined with FM (combination therapy group, n=16), or no medication (no treatment group, n=16). Rs-fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared using One-way ANOVA analysis and post analysis.Partial correlation and mediation analyses were performed on ReHo values and the improvement of symptoms scores (gastrointestinal symptom rating scale(GSRS) and hospital anxiety/depression scale (HAD)) in the two medicated groups. Results: No significant differences in ReHo values were observed among the three groups before treatment. Compared with patients on no-medication, patients receiving either PB or PB-FM showed decreased ReHo in the striatum, insular lobe, medial prefrontal cortex (MPFC) and subcallosal gyrus, and increased ReHo in the occipital cortex. In particular, the combined treatment group showed more extensive decreased ReHo in the left thalamus and left temporal pole, and increased in the left precuneus. Compared with the basic treatment group, the combined treatment group showed decreased ReHo in the right putamen, right insula, right MPFC and subcallosal gyrus, and increased ReHo in the left precuneus. In addition, the combined treatment group demonstrated a positive correlation between ReHo values in the left thalamus and the improvement of HAD score (r=0.653, P=0.011) , and a negative correlation between ReHo values in left precuneus and the improvement of GSRS and HAD score (r=-0.771, P=0.001; r=-0.716, P=0.004). ReHo values in the left precuneus were observed to mediate between gastrointestinal symptoms and anxiety-depressive symptoms in the combined treatment group. Conclusions: The efficacy of PB combined with FM is superior to PB alone in the treatment of IBS. In addition to more extensive changes in pain-related brain areas, IBS-D patients treated with anxiolytic/antidepressant also show changes in default network and brain areas related to emotional regulation, and are associated with improvement in gastrointestinal symptoms, anxiety and depression.


Assuntos
Diarreia/tratamento farmacológico , Flupentixol/uso terapêutico , Síndrome do Intestino Irritável , Imagem por Ressonância Magnética , Morfolinas/uso terapêutico , Adulto , Encéfalo , Mapeamento Encefálico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
J Clin Psychopharmacol ; 39(6): 550-560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688449

RESUMO

BACKGROUND: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). METHODS: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. RESULTS: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. CONCLUSIONS: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.


Assuntos
Antipsicóticos/sangue , Aripiprazol/sangue , Antagonistas dos Receptores de Dopamina D2/sangue , Flupentixol/sangue , Haloperidol/sangue , Olanzapina/sangue , Satisfação Pessoal , Qualidade de Vida , Receptores de Dopamina D2/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Esquizofrenia/sangue , Fatores Sexuais
4.
Medicine (Baltimore) ; 98(41): e17501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593119

RESUMO

BACKGROUND: Traditional treatment of functional dyspepsia (FD) is unsatisfactory in a subgroup of patients with FD, and the potential role of antidepressant medications also has not been definitely clarified. To provide more evidence for future optimal practice recommendations, we reviewed a 1-year clinical database of antidepressant agents applied in outpatients with FD. METHODS: Clinical presentations, treatment course, and outcomes were determined by chart review of patients referring to the functional gastrointestinal disorders specialist clinic. One hundred thirty patients with FD were included for further analysis. RESULTS: Patients were treated with different antidepressant drugs according to individual symptoms. The most commonly used drugs were flupenthixol melitracen and fluoxetine. Improvement and complete remission occurred in 93.8% and 54.6% of patients, respectively. There was a trend toward superior outcome for citalopram compared to sulpiride and mirtazapine in overall analysis. Meanwhile, regimens containing fluoxetine had significant increased remission rate compared to any other antidepressant regimens in postprandial distress syndrome subgroup analysis. Furthermore, older patients were more likely to achieve remission. However, sex and symptom duration were not associated with symptom remission. Finally, 11.5% of patients experienced adverse events. CONCLUSIONS: This retrospective cohort study indicated that small dose antidepressant therapy, especially citalopram and fluoxetine, is an effective and well tolerated treatment option for refractory FD.


Assuntos
Antracenos/uso terapêutico , Dispepsia/tratamento farmacológico , Fluoxetina/uso terapêutico , Flupentixol/uso terapêutico , Antracenos/efeitos adversos , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , China/epidemiologia , Citalopram/uso terapêutico , Combinação de Medicamentos , Dispepsia/diagnóstico , Feminino , Fluoxetina/efeitos adversos , Flupentixol/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mirtazapina/uso terapêutico , Período Pós-Prandial , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
5.
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
6.
Metab Brain Dis ; 34(6): 1679-1687, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31422510

RESUMO

First-episode psychosis (FEP) patients are more sensitive to neuroleptic side-effects such as hyperprolactinemia. We examined the prolactin levels of previously minimally treated patients with first episode schizophrenia over their first year of treatment with flupenthixol decanoate and the relationship between prolactin levels, gender and clinical features of schizophrenia. Prolactin levels were assessed at three monthly intervals in 126 patients with first-episode schizophrenia in a single-site study conducted over 12 months during treatment with flupenthixol decanoate according to a fixed protocol. The mean prolactin level for the total sample was 11.91 ng/ml (standard deviation [SD]15.52) at baseline. Women had higher levels of prolactin than men at month 3, 6 and 12, reaching statistical significance at month 12 (p = 0.02). At 12 months more women than men had hyperprolactinemia (defined as more than 20 ng/ml for males, and as more than 25 ng/ml for females (p = 0.007). Using a mixed effect model, there was a significant association between prolactin change scores over 12 months and gender (p = 0.025) as well as Positive and Negative Syndrome Scale (PANSS) total scores (p = 0.001). In addition female gender (p = 0.04) and age (p = 0.02) correlated with the risk of hyperprolactinemia as categorical variable. In this study treatment with flupenthixol decanoate was associated with relatively low levels of hyperprolactinemia, likely owing to flupenthixol's relatively atypical mode of action, as well as to the low doses used in our study. We found an inverse correlation between total PANSS scores and prolactin levels, which could support the suggested theory of prolactin having antipsychotic properties. Our study confirms the importance of gender on the prolactin raising effects of antipsychotic treatment.


Assuntos
Flupentixol/análogos & derivados , Hiperprolactinemia/induzido quimicamente , Propafenona/sangue , Esquizofrenia/tratamento farmacológico , Tranquilizantes/uso terapêutico , Adolescente , Adulto , Fatores Etários , Feminino , Flupentixol/efeitos adversos , Flupentixol/uso terapêutico , Humanos , Masculino , Esquizofrenia/sangue , Fatores Sexuais , Tranquilizantes/efeitos adversos , Resultado do Tratamento , Adulto Jovem
7.
PLoS Genet ; 15(8): e1008331, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412019

RESUMO

Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.


Assuntos
Ecdisterona/metabolismo , Proteínas de Insetos/metabolismo , Mariposas/fisiologia , Receptores Dopaminérgicos/metabolismo , Animais , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Flupentixol/farmacologia , Técnicas de Silenciamento de Genes , Proteínas de Insetos/genética , Larva/efeitos dos fármacos , Larva/fisiologia , Muda/efeitos dos fármacos , Muda/fisiologia , Mariposas/efeitos dos fármacos , Interferência de RNA , Receptores Dopaminérgicos/genética , Células Sf9
8.
Int J Biol Sci ; 15(7): 1523-1532, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337981

RESUMO

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is hyperactivated in lung cancer and regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. Thus PI3K is considered a promising target for therapy. To date, PI3K inhibitors have not been approved for lung cancer. Recent studies showed that the antipsychotic agent flupentixol induced apoptosis of lung cancer cell, however the anti-tumor mechanism of flupentixol remains unclear. Methods: (1) The idock software simulated the molecular docking between the PI3Kα protein and flupentixol. (2) Inhibition of PI3Kα by the flupentixol was examined by in vitro kinase assays. (3) The cytotoxicity of flupentixol on the NSCLC cell lines was tested by MTT assays. (4) We treated A549 and H661 cells with flupentixol and then measured the percentage of apoptotic cells by the Annexin V/PI analysis. (5) We investigated the effect of flupentixol on the expression of critical PI3K/AKT signaling pathway proteins, further analyzed on the cleavage of PARP and caspase-3 by Western blotting. (6) BALB/C nude mice were subcutaneously injected with A549 cells to evaluate the effect of flupentixol on the growth of lung carcinoma. Results: Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3Kα. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kα kinase activity. Flupentixol exhibited cytotoxicity in lung cancer cell lines A549 and H661 in a dose- and time-dependent manner. Furthermore, flupentixol more strongly inhibited the phosphorylation of AKT (T308 and S473) and the expression of its downstream target gene Bcl-2 than two known PI3K inhibitors (BYL719 and BKM120). Flupentixol induced apoptosis as measured by PARP and caspase-3 cleavage. Finally, flupentixol significantly suppressed A549 xenograft growth in BALB/C nude mice. Conclusions: Flupentixol could be docked to the PI3Kα protein and specifically inhibit the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. As an old drug, flupentixol is a new PI3K inhibitor that may be used for the treatment of lung cancers.


Assuntos
Antineoplásicos/farmacologia , Antipsicóticos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Flupentixol/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Software
9.
Psychopharmacology (Berl) ; 236(11): 3081-3092, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300829

RESUMO

RATIONALE: The licensed dose range for the long-acting injectable antipsychotic flupentixol decanoate (Depixol®) in the treatment of schizophrenia is very broad. This provides little useful direction to prescribers and may ultimately result in patients receiving unnecessarily high doses. OBJECTIVES: We aimed to estimate the effect of dose of flupentixol decanoate on relapse rates in schizophrenia and on tolerability by expanding on an earlier review and including non-RCT and German-language studies, as well as using pharmacokinetic and pharmacodynamic data to offer guidance on dosing. METHODS: A literature review using EMBASE, Medline, PsycINFO and PubMed was conducted. Treatment success rates at 6 months were extracted or extrapolated from the studies and plotted against dose to estimate a dose-response curve. RESULTS: Data from 16 studies (n = 514) allowed estimation of a dose-response curve which rises steeply between the chosen placebo anchor (25% success rate) and 10 mg every 2 weeks before reaching a maximum between 20 and 40 mg every 2 weeks (80-95% success rates). Extrapyramidal side effects (EPSEs) were frequently seen (12-71% of participants) in that dose range. Two -weekly injections seem to provide the highest trough plasma concentration per dose administered and the lowest peak-to-trough concentration ratio. Plasma concentration varied up to 5-fold among individuals receiving the same dose. CONCLUSIONS: The optimal dose of flupentixol decanoate is likely to be between 20 mg and 40 mg every 2 weeks although higher doses may be required in some individuals owing to variation in drug handling. Doses of flupentixol should be individually established in the range of 10 to 40 mg every 2 weeks according to response and tolerability.


Assuntos
Antagonistas de Dopamina/administração & dosagem , Flupentixol/análogos & derivados , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adulto , Antipsicóticos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Flupentixol/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Resultado do Tratamento
10.
Cochrane Database Syst Rev ; 3: CD011847, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30888709

RESUMO

BACKGROUND: Electroconvulsive therapy (ECT) involves the induction of a seizure by the administration of an electrical stimulus via electrodes usually placed bilaterally on the scalp and was introduced as a treatment for schizophrenia in 1938. However, ECT is a controversial treatment with concerns about long-term side effects such a memory loss. Therefore, it is important to determine its clinical efficacy and safety for people with schizophrenia who are not responding to their treatment. OBJECTIVES: Our primary objective was to assess the effects (benefits and harms) of ECT for people with treatment-resistant schizophrenia.Our secondary objectives were to determine whether ECT produces a differential response in people: who are treated with unilateral compared to bilateral ECT; who have had a long (more than 12 sessions) or a short course of ECT; who are given continuation or maintenance ECT; who are diagnosed with well-defined treatment-resistant schizophrenia as opposed to less rigorously defined treatment-resistant schizophrenia (who would be expected to have a greater affective component to their illness). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including clinical trial registries on 9 September 2015 and 4 August 2017. There were no limitations on language, date, document type, or publication status for the inclusion of records in the register. We also inspected references of all the included records to identify further relevant studies. SELECTION CRITERIA: Randomised controlled trials investigating the effects of ECT in people with treatment-resistant schizophrenia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. For binary outcomes, we calculated the risk ratio (RR) and its 95% confidence intervals (CIs), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between the groups and its 95% CIs. We employed the fixed-effect model for all analyses. We assessed risk of bias for the included studies and created 'Summary of findings' tables using the GRADE framework. MAIN RESULTS: We included 15 studies involving 1285 participants (1264 completers with an average age of 18 to 46 years) with treatment-resistant schizophrenia. We rated most studies (14/15, 93.3%) as at high risk of bias due to issues related to the blinding of participants and personnel. Our main outcomes of interest were: (i) clinically important response to treatment; (ii) clinically important change in cognitive functioning; (iii) leaving the study early; (iv) clinically important change in general mental state; (v) clinically important change in general functioning; (vi) number hospitalised; and (vii) death. No trial reported data on death.The included trials reported useable data for four comparisons: ECT plus standard care compared with sham-ECT added to standard care; ECT plus standard care compared with antipsychotic added to standard care; ECT plus standard care compared with standard care; and ECT alone compared with antipsychotic alone.For the comparison ECT plus standard care versus sham-ECT plus standard care, only average endpoint BPRS (Brief Psychiatric Rating Scale) scores from one study were available for mental state; no clear difference between groups was observed (short term; MD 3.60, 95% CI -3.69 to 10.89; participants = 25; studies = 1; very low-quality evidence). One study reported data for service use, measured as number readmitted; there was a clear difference favouring the ECT group (short term; RR 0.29, 95% CI 0.10 to 0.85; participants = 25; studies = 1; low-quality evidence).When ECT plus standard care was compared with antipsychotics (clozapine) plus standard care, data from one study showed no clear difference for clinically important response to treatment (medium term; RR 1.23, 95% CI 0.95 to 1.58; participants = 162; studies = 1; low-quality evidence). Clinically important change in mental state data were not available, but average endpoint BPRS scores were reported. A positive effect for the ECT group was found (short-term BPRS; MD -5.20, 95% CI -7.93 to -2.47; participants = 162; studies = 1; very low-quality evidence).When ECT plus standard care was compared with standard care, more participants in the ECT group had a clinically important response (medium term; RR 2.06, 95% CI 1.75 to 2.42; participants = 819; studies = 9; moderate-quality evidence). Data on clinically important change in cognitive functioning were not available, but data for memory deterioration were reported. Results showed that adding ECT to standard care may increase the risk of memory deterioration (short term; RR 27.00, 95% CI 1.67 to 437.68; participants = 72; studies = 1; very low-quality evidence). There were no clear differences between groups in satisfaction and acceptability of treatment, measured as leaving the study early (medium term; RR 1.18, 95% CI 0.38 to 3.63; participants = 354; studies = 3; very low-quality evidence). Only average endpoint scale scores were available for mental state (BPRS) and general functioning (Global Assessment of Functioning). There were clear differences in scores, favouring ECT group for mental state (medium term; MD -11.18, 95% CI -12.61 to -9.76; participants = 345; studies = 2; low-quality evidence) and general functioning (medium term; MD 10.66, 95% CI 6.98 to 14.34; participants = 97; studies = 2; very low-quality evidence).For the comparison ECT alone versus antipsychotics (flupenthixol) alone, only average endpoint scale scores were available for mental state and general functioning. Mental state scores were similar between groups (medium-term BPRS; MD -0.93, 95% CI -6.95 to 5.09; participants = 30; studies = 1; very low-quality evidence); general functioning scores were also similar between groups (medium-term Global Assessment of Functioning; MD -0.66, 95% CI -3.60 to 2.28; participants = 30; studies = 1; very low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence indicates that relative to standard care, ECT has a positive effect on medium-term clinical response for people with treatment-resistant schizophrenia. However, there is no clear and convincing advantage or disadvantage for adding ECT to standard care for other outcomes. The available evidence was also too weak to indicate whether adding ECT to standard care is superior or inferior to adding sham-ECT or other antipsychotics to standard care, and there was insufficient evidence to support or refute the use of ECT alone. More good-quality evidence is needed before firm conclusions can be made.


Assuntos
Eletroconvulsoterapia/efeitos adversos , Transtornos da Memória/etiologia , Esquizofrenia/terapia , Adulto , Antipsicóticos/uso terapêutico , Escalas de Graduação Psiquiátrica Breve , Eletroconvulsoterapia/métodos , Feminino , Flupentixol/uso terapêutico , Humanos , Masculino , Readmissão do Paciente/estatística & dados numéricos , Piperazinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrão de Cuidado , Tiazóis/uso terapêutico , Resultado do Tratamento
12.
Medicine (Baltimore) ; 98(2): e14064, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633208

RESUMO

BACKGROUND: There are many trials on the combination of Pinaverium bromide (PB) and Flupentixol-melitracen (FM) in the treatment of diarrhea-type irritable bowel syndrome (IBS-D), but the sample sizes are small, and the research conclusions are inconsistent. Thus, a meta-analysis was performed, aiming to evaluate the efficacy and safety of this combination therapy in patients with IBS-D. METHODS: A systematic literature search was conducted in 7 databases covering the period up to July 2018 to identify randomized controlled trials (RCTs) of PB combined with FM versus PB alone for IBS-D. The primary outcome was the total symptom relief rate. The other outcomes were the adverse events rate, HAMA/SAS score, and HAMD/SDS score. The methodological quality of the RCTs was assessed independently using 6 criteria according to the Cochrane Collaboration. All data were analyzed using Review Manager 5.3. RESULTS: Fifteen RCTs with 1487 participants were identified from 2005 to 2018. Compared with PB alone, 15 RCTs showed significant effects of PB plus FM in terms of improved symptom relief in patients with IBS-D (n = 1487, OR = 5.17, 95%CI, 3.79-7.07, P < .00001). Eleven RCTs reported adverse effects in both the PB plus FM and PB groups, there was no statistically significant difference in the adverse events rate between the 2 groups (n = 1207, OR = 2.91, 95%CI, 0.91-9.28, P = 0.07). Two RCTs and 3 RCTs reported HAMA and HAMD scores respectively, and 3 RCTs reported both SAS and SDS scores. After treatment, the above scores in the PB plus FM group were significantly lower than the PB group (all P < .01). However, the trials were deemed to have a medium risk of bias. CONCLUSIONS: The efficacy of PB combined with FM is superior to PB alone in the treatment of IBS-D, and it is safe for clinical use. However, the conclusions still need to be verified by conducting more large-scale and high-quality RCTs.


Assuntos
Antracenos/uso terapêutico , Flupentixol/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Morfolinas/uso terapêutico , Antracenos/efeitos adversos , Diarreia/tratamento farmacológico , Combinação de Medicamentos , Quimioterapia Combinada , Flupentixol/efeitos adversos , Fármacos Gastrointestinais/efeitos adversos , Humanos , Morfolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
J Neurosci ; 39(9): 1744-1754, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30617206

RESUMO

The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aDLS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopamine-dependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (0, 5, 10, and 15 µg/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control.SIGNIFICANCE STATEMENT Over the course of addictive drug exposure, there is a transition in the control over drug seeking from ventral to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms, but it is unclear whether this is causally involved in the development of compulsive drug seeking. We tested the hypothesis that individual differences in the reliance of alcohol seeking on aDLS dopamine predicts and underlies the emergence of compulsive alcohol seeking. We identified individual differences in the reliance of well established alcohol seeking, but not taking behavior, on aDLS mechanisms and also showed that this predicted the subsequent development of compulsive alcohol-seeking behavior. Thus, those individuals in whom alcohol seeking depended on aDLS mechanisms were vulnerable subsequently to display compulsivity.


Assuntos
Alcoolismo/fisiopatologia , Comportamento Compulsivo/fisiopatologia , Corpo Estriado/fisiopatologia , Comportamento de Procura de Droga , Alcoolismo/metabolismo , Animais , Comportamento Compulsivo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Flupentixol/farmacologia , Masculino , Ratos , Recompensa
14.
MAGMA ; 32(1): 51-61, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30515642

RESUMO

OBJECTIVE: This study examines the influence of the environmental factor temperature on the 19F NMR characteristics of fluorinated compounds in phantom studies and in tissue. MATERIALS AND METHODS: 19F MR mapping and MR spectroscopy techniques were used to characterize the 19F NMR characteristics of perfluoro-crown ether (PFCE), isoflurane, teriflunomide, and flupentixol. T1 and T2 mapping were performed, while temperature in the samples was changed (T = 20-60 °C) and monitored using fiber optic measurements. In tissue, T1 of PFCE nanoparticles was determined at physiological temperatures and compared with the T1-measured at room temperature. RESULTS: Studies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, T1 and T2. T1 of PFCE nanoparticles was higher at physiological body temperatures compared to room temperature. DISCUSSION: The impact of temperature on the 19F NMR parameters of fluorinated compounds demonstrated in this study not only opens a trajectory toward 19F MR-based thermometry, but also indicates the need for adapting MR sequence parameters according to environmental changes such as temperature. This will be an absolute requirement for detecting fluorinated compounds by 19F MR techniques in vivo.


Assuntos
Imagem por Ressonância Magnética de Flúor-19/instrumentação , Flúor/química , Termometria/instrumentação , Animais , Crotonatos/química , Éteres de Coroa/química , Feminino , Tecnologia de Fibra Óptica , Imagem por Ressonância Magnética de Flúor-19/métodos , Flupentixol/química , Hipertermia Induzida , Processamento de Imagem Assistida por Computador , Isoflurano , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Imagens de Fantasmas , Preparações Farmacêuticas/química , Marcadores de Spin , Temperatura , Termometria/métodos , Toluidinas/química
16.
Luminescence ; 33(6): 1026-1032, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29927539

RESUMO

One of the most commonly used drugs in treatment of schizophrenia is flupentixol dihydrochloride, therefore it is important to develop a simple, low cost and sensitive spectrofluorimetric method for the estimation of flupentixol dihydrochloride. The yellow fluorescent product that is generated from the nucleophilic substitution reaction of the free lone pair of the alcoholic hydroxyl group of the drug and 4-chloro-7-nitrobenzofurazan (NBD-Cl) in Mcllvaine buffer pH 7.0 was estimated at 510 nm (λex 460 nm). The variables that affect the development of the reaction product were explored and optimized. The linear range of this method was 0.5-2.5 µg ml-1 with a limit of quantitation equal to 0.29 µg ml-1 . Our method was successfully applied for the assurance of flupentixol in tablet form with average percentage recovery of 99.08 ± 1.01% without obstruction from the basic excipients exhibits. Furthermore, our strategy was extended to study the content uniformity testing of flupentixol in Fluaxnol® tablets.


Assuntos
Benzoxazóis/química , Corantes Fluorescentes/química , Flupentixol/análise , Ácido Clorídrico/análise , Estrutura Molecular , Espectrometria de Fluorescência
18.
Artigo em Chinês | MEDLINE | ID: mdl-29771077

RESUMO

Objective:To investigate the efficacy of flupentixol melitracen on different stages of sudden deafness patients with anxiety and depression.Method:Totally one hundred and sixty-three sudden deafness patients with anxiety and depression were randomly divided into two groups: experimental group(81 cases) and control group (82 cases). All patients were given routine treatment for 2 weeks. The experimental group was given oral flupentixol melitracen (1 tablet/day)for a period of 3 months. The hearing, tinnitus effect and vertigo treatment course were observed and compared. Curing rate of tinnitus at 2 weeks, 3 months and 6 months after treatment, self-rating anxiety scale (SAS) and depressive state scale (self-rating depression scale, SDS) score were collected and compared.Result:Total efficiency of hearing and tinnitus of experimental group(86.42%,84.21%)were higher than that of the control group(67.07%,61.29%);the vertigo cured the average treatment time of experimental group days was less than that of the control groupdays,all the differences were statistically significant.After treatment,the average hearing threshold value of the two groups of patients were lower than that before treatment,the low frequency descent type, high-frequency descent type,flat down type and total deafness type thresholds of the experimental group were lower than of the control group,all the differences were statistically significant.The tinnitus cure rate of experiment group were higher than the control group at 3months and 6 months after treatment,the differences were statistically significant;and after 3months and 6 months treatment tinnitus cure rate higher of the experimental group than that of after 2 weeks the treatment,the difference was statistically significant.After 2 weeks,3 months and 6 months treatment,the SAS and SDS scores of two groups were lower than that before treatment.The SAS and SDS scores of the experimental group decreased after 2 weeks,3 months and 6 months treatment, and the difference was statistically significant at different time points,the SAS,SDS scores of experimental group after treatment were lower than the control group at the same time,the differences were statistically significant.Conclusion:For the sudden deafness patients with anxiety and depression , the combination of flupentixol melitracen on the basis of conventional therapy can improve the clinical efficacy, the patient's mental status and long-term therapeutic effect of tinnitus..


Assuntos
Ansiedade/complicações , Depressão/complicações , Antagonistas de Dopamina/uso terapêutico , Flupentixol/uso terapêutico , Perda Auditiva Súbita/tratamento farmacológico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Transtorno Depressivo , Perda Auditiva Súbita/complicações , Humanos , Zumbido
19.
Psychiatry Res ; 262: 141-148, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29448178

RESUMO

Antipsychotics remain the most effective, and wide used option for ameliorating the symptoms of schizophrenia. However, inter-individual differences in treatment outcome are vast and suggest a role for genetic and environmental factors in affording favourable outcomes. A notable epigenetic relationship which has gained considerable traction in recent literature is the way in which the severity of childhood trauma can modify associations seen between genetic variation and antipsychotic treatment response. A potential mechanism of action which may facilitate this relationship is synaptic plasticity. This study investigated the role of variants in matrix metallopeptidase 9 (MMP9), a gene involved in synaptic plasticity, with treatment outcome considering the severity of childhood trauma as an interacting variable. The cohort comprised South African first episode schizophrenia patients treated with a single injectable antipsychotic, flupenthixol decanoate, monitored over 12 months. Relationships between novel and previously described variants, and haplotypes, with antipsychotic treatment response were found to be modified when considering childhood trauma as an interacting variable. This study provides the first evidence for the involvement of polymorphisms within MMP9 and the severity of childhood trauma in antipsychotic treatment response, and warrants further investigation into the role gene-environment interactions may play in the betterment of antipsychotic treatment strategies.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Antipsicóticos/uso terapêutico , Flupentixol/análogos & derivados , Interação Gene-Ambiente , Metaloproteinase 9 da Matriz/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adolescente , Adulto , Feminino , Flupentixol/uso terapêutico , Haplótipos , Humanos , Masculino , Polimorfismo Genético , Resultado do Tratamento , Adulto Jovem
20.
Int Ophthalmol ; 38(4): 1769-1773, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28676993

RESUMO

AIM: To report the first case report of an association between flupentixol and crystalline retinopathy. STUDY DESIGN: Observational, Case report. CASE REPORT: We report a case of crystalline retinopathy in a 36-year-old female who was suffering from depression and being treated with tablet flupentixol in a cumulative dose of 4380 mg over two years. Fundus examination of both eyes showed multiple, discrete, yellowish white refractile intraretinal deposits over the macula and peripapillary region, located in the inner retina as shown by OCT. CONCLUSION: We propose regular retinal evaluation in patients with chronic flupentixol intake and larger studies to establish causal relationship between flupentixol and crystalline retinopathy.


Assuntos
Antipsicóticos/efeitos adversos , Cristalinas/metabolismo , Flupentixol/efeitos adversos , Doenças Retinianas/induzido quimicamente , Feminino , Humanos , Doenças Retinianas/patologia , Transtornos da Visão/induzido quimicamente
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