RESUMO
BACKGROUND: Extensive research has been undertaken to predict treatment response (TR) to antipsychotics. Most studies address TR to antipsychotics in general and as monotherapy, however, it is unknown whether patients might respond favourably to a combination of antipsychotics. AIMS: This study aimed to identify differential predictors for TR to monotherapy with amisulpride or olanzapine compared to a combination of antipsychotics. METHODS: Post-hoc analysis was conducted of data collected from the COMBINE-study, a double-blind, randomized, controlled trial. Demographic and disease-related measures were gathered at baseline to predict TR after eight weeks defined by the Positive and Negative Syndrome Scale. Missing values were accounted for by a random replacement procedure. Attrition effects and multicollinearity were analysed and sets of logistic regression models were calculated for different treatment groups. RESULTS: Of the 321 randomized patients, 201 completed procedures until week eight and 197 were included in the analyses. For all treatment groups, early TR after two weeks and high subjective well-being under antipsychotics at baseline were robust predictors for TR. The propensity for early side effects also indicated a higher risk of later non-response. Specific parameter estimates were rather similar between treatment groups. CONCLUSION: Early TR, drug-related subjective well-being, and early side effect propensity evolved as predictors for later TR whether to monotherapy or combination strategy. Accordingly, due to a lack of differential predictors, early and close monitoring of targeted and unwanted effects is indicated to guide respective treatment decisions.
Assuntos
Amissulprida , Antipsicóticos , Quimioterapia Combinada , Olanzapina , Esquizofrenia , Humanos , Amissulprida/administração & dosagem , Amissulprida/farmacologia , Olanzapina/administração & dosagem , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Esquizofrenia/tratamento farmacológico , Feminino , Masculino , Adulto , Método Duplo-Cego , Pessoa de Meia-Idade , Resultado do Tratamento , Doença Aguda , Adulto Jovem , Sulpirida/análogos & derivados , Sulpirida/administração & dosagem , Sulpirida/efeitos adversos , Escalas de Graduação PsiquiátricaRESUMO
Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.
Assuntos
Amissulprida , Encéfalo , Preparações de Ação Retardada , Receptores de Dopamina D2 , Equivalência Terapêutica , Amissulprida/administração & dosagem , Amissulprida/farmacocinética , Humanos , Animais , Encéfalo/metabolismo , Masculino , Receptores de Dopamina D2/metabolismo , Adulto , Desenvolvimento de Medicamentos/métodos , Modelos Biológicos , Feminino , Descoberta de DrogasAssuntos
Amissulprida , Antipsicóticos , Olanzapina , Esquizofrenia , Humanos , Olanzapina/administração & dosagem , Olanzapina/uso terapêutico , Amissulprida/administração & dosagem , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Esquizofrenia/tratamento farmacológico , Quimioterapia Combinada , Masculino , Feminino , Idade de InícioRESUMO
OBJECTIVE: To investigate the changes in mental state and serum prolactin levels in patients with schizophrenia and depression after receiving the combination therapy of amisulpride and chloroprothixol tablets. METHODS: A total of 148 schizophrenic patients with depression were randomly divided into control group (N = 73) and study group (N = 75). The control group was treated with clopidothiol, and the study group was treated with amisulpride. Symptom scores, sleep quality, adverse reactions, therapeutic effects, prolactin, and progesterone levels, HAMD, PANSS, and PSP scores were compared between the two groups. RESULTS: The symptom scores of both groups were significantly reduced, but when compared to the control group, the symptom scores of the research group were significantly reduced more significantly (P < 0.05); serum GDNF levels of both groups were significantly increased, while serum NSE, IL-1, and MBP levels were significantly reduced (P < 0.05). However, the research group altered more substantially (P < 0.05) than the control group; the overall PSQI score of the research group was lower (P < 0.05) than the control group; and the incidence of adverse responses in the control and study groups was 12.3 percent and 4.0 percent. The research group had a lower rate of adverse responses (P < 0.05) than the control group, and the effective treatment of the control and research groups was 82.2 percent and 98.7%, respectively. The research group had a lower rate of adverse reactions (P < 0.05) than the control group, while the control and research groups' successful treatment rates were 82.2 percent and 98.7%, respectively. When compared to the control group, the research group had a greater treatment efficiency (P < 0.05); blood prolactin and progesterone levels were considerably lowered in both groups, but the reductions in the research group were more evident (P < 0.05). Both groups had considerably lower HAMD and PANSS scores, and both had significantly higher PSP scores, although the difference in the research group was more evident (P < 0.05). CONCLUSION: For people with schizophrenia and depression, a combination of amisulpride and chloroprothixol pills has a considerable effect. It can help patients with their clinical symptoms and sleep quality while also lowering their serum prolactin levels, which is favorable to their illness recovery. As a result, the combined treatment of amisulpride and chloroprothixol pills deserves to be promoted and used.
Assuntos
Amissulprida/administração & dosagem , Clorprotixeno/análogos & derivados , Depressão/sangue , Depressão/tratamento farmacológico , Prolactina/sangue , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Antipsicóticos/administração & dosagem , Clorprotixeno/administração & dosagem , Biologia Computacional , Depressão/complicações , Quimioterapia Combinada , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Progesterona/sangue , Esquizofrenia/complicações , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To explain the high inter-individual variability (IIV) and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride, a population pharmacokinetic (PPK) model in Chinese patients with schizophrenia was built based on therapeutic drug monitoring (TDM) data to guide individualized therapy. PATIENTS AND METHODS: Plasma concentration data (330 measurements from 121 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCE I). The concentrations of amisulpride were detected by HPLC-MS/MS. Age, weight, sex, combination medication history and renal function status were evaluated as main covariates. The model was internally validated using goodness-of-fit, bootstrap and normalized prediction distribution error (NPDE). Recommended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model. RESULTS: A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentration in Chinese patients with schizophrenia. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. Age significantly affected the clearance of amisulpride and the final model was as follows: CL/F=1.04×(AGE/32)-0.624 (L/h). To avoid exceeding the laboratory alert level (640 ng/mL), the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg/d for patients aged 60 years, 800 mg/d for those aged 40 years and 1200 mg/d for those aged 20 years, respectively. CONCLUSION: Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions. The model can be used as a suitable tool for designing individualized therapy for Chinese patients with schizophrenia.
Assuntos
Amissulprida/administração & dosagem , Antipsicóticos/administração & dosagem , Modelos Biológicos , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Amissulprida/farmacocinética , Antipsicóticos/farmacocinética , Povo Asiático , Simulação por Computador , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Medicina de Precisão , Estudos Retrospectivos , Distribuição Tecidual , Adulto JovemRESUMO
BACKGROUND: Most studies investigating antipsychotic effectiveness report either total psychopathology or symptom cluster findings. Studies focusing on a separate symptom, such as hallucinations, a hallmark symptom in schizophrenia, are scarce.Therefore, the current study aims to compare the antihallucinatory effectiveness of 3 pharmacologically different antipsychotics: olanzapine, amisulpride, and aripiprazole. METHODS: The present study is part of the Bergen-Stavanger-Innsbruck-Trondheim study, a 12-month prospective, randomized, pragmatic antipsychotic drug trial in active-phase schizophrenia spectrum disorders. The primary outcome of the present study was change of hallucinations as measured by item P3 (hallucinatory behavior) from the Positive and Negative Syndrome Scale in the subgroup with hallucinations at baseline. Primary analyses were intention to treat. RESULTS: A total of 144 participants were included in the study, where 105 (72%) had a score of 3 or more on the Positive and Negative Syndrome Scale P3 item at baseline, indicating the presence of hallucinations (HALL subgroup).In the HALL subgroup, a significantly less reduction of hallucinations was revealed for participants using olanzapine in weeks 12, 26, 39, and 52 when compared with amisulpride and in weeks 26 and 52 when compared with aripiprazole. In subanalyses for participants never exposed to antipsychotic drugs (antipsychotic-naive) and those who had used antipsychotics before entering the study, antihallucinatory differences were revealed only in the latter group. CONCLUSIONS: A differential antihallucinatory effect of the 3 study drugs was present. The inferior effect of olanzapine seems to be driven by the subgroup of participants exposed to antipsychotic treatment before entering the study.
Assuntos
Amissulprida , Aripiprazol , Alucinações , Olanzapina , Esquizofrenia , Adulto , Amissulprida/administração & dosagem , Amissulprida/efeitos adversos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol/administração & dosagem , Aripiprazol/efeitos adversos , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/psicologia , Monitoramento de Medicamentos/métodos , Feminino , Alucinações/diagnóstico , Alucinações/tratamento farmacológico , Alucinações/etiologia , Humanos , Masculino , Olanzapina/administração & dosagem , Olanzapina/efeitos adversos , Gravidade do Paciente , Escalas de Graduação Psiquiátrica , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Resultado do TratamentoRESUMO
Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 µm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3'-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact.
Assuntos
Amissulprida/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Neurônios/efeitos dos fármacos , Olanzapina/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Fumarato de Quetiapina/farmacologia , Amissulprida/administração & dosagem , Animais , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Corantes Fluorescentes/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos , Masculino , Neurônios/química , Neurônios/metabolismo , Olanzapina/administração & dosagem , Ocitocina/análise , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Fumarato de Quetiapina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Vasopressinas/análiseRESUMO
Amisulpride intravenous (IV) injection (Barhemsys®; hereafter referred to as IV amisulpride), a selective dopamine receptor antagonist, is approved in the USA as a single IV infusion for the prevention and treatment of post-operative nausea and vomiting (PONV) in adults. Results from placebo-controlled phase III trials showed that IV amisulpride is efficacious both in the prevention of PONV (used either alone or in combination with an antiemetic of a different class) and in the treatment of PONV (irrespective of prior antiemetic prophylaxis status). When administered as a single IV infusion, amisulpride had a tolerability profile that was generally similar to that of placebo, with no significant safety concerns identified. Thus, IV amisulpride is a useful additional option in the prevention and treatment of PONV in adults, particularly for patients who have failed previous antiemetic prophylaxis and for whom effective treatment options may be limited.
Assuntos
Amissulprida/uso terapêutico , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/uso terapêutico , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Vômito/tratamento farmacológico , Amissulprida/administração & dosagem , Humanos , Injeções IntravenosasAssuntos
Amissulprida/efeitos adversos , Clozapina/efeitos adversos , Convulsões/induzido quimicamente , Gagueira/induzido quimicamente , Adulto , Amissulprida/administração & dosagem , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Clozapina/administração & dosagem , Quimioterapia Combinada , Fluoxetina/administração & dosagem , Fluoxetina/efeitos adversos , Humanos , Masculino , Esquizofrenia/tratamento farmacológicoRESUMO
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. The opioid epidemic in the USA has highlighted the need for alternative treatments for pain. Following reports on the opioid interactions of various antipsychotic medications, we speculated that the involvement of the opioid system in some of the antipsychotics' mechanism of action may suggest their potential use in the treatment of pain. Risperidone is a neuroleptic with a potent dopamine D2 and serotonin 5-HT2 receptor-blocking activity as well as a high affinity for adrenergic and histamine H1 receptors. Amisulpride is a neuroleptic which selectively blocks dopamine D2 and D3 receptors. Both had a potent antinociceptive effect on ICR mice tested with a tail flick assay. That effect on both medications was antagonized by naloxone, indicating that at least some of the antinociceptive effects were mediated by an opioid mechanism of action. Further investigation found that ß-Funaltrexamine hydrochloride (ß-FNA), naloxonazine, and nor-Binaltorphimine dihydrochloride (nor-BNI) reversed the antinociceptive effect of both risperidone and amisulpride. Naltrindole at a dose that blocked [D-Pen2,D-Pen5]enkephalin (DPDPE, δ analgesia) blocked notably amisplride effect and only partially reversed that of risperidone. Risperidone induced an antinociceptive effect, implying involvement of µ and κ-opioid and δ-opioid mechanisms. Amisulpride-induced antinociception was mediated through selective involvement of all three opioid receptor subtypes. These findings emphasize the need for clinical trials to assess the possibility of extending the spectrum of medications available for the treatment of pain.
Assuntos
Amissulprida/administração & dosagem , Analgésicos Opioides/administração & dosagem , Antipsicóticos/administração & dosagem , Medição da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Risperidona/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos ICR , Antagonistas de Entorpecentes/administração & dosagem , Dor/psicologia , Medição da Dor/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Postoperative nausea and vomiting (PONV) are significant issues in surgical patients, and additional treatment options are needed. Dopaminergic antiemetics have been popular for their efficacy, but their use has been limited by safety concerns, especially the potential for torsade de pointes arising from QT interval prolongation. Intravenous (IV) amisulpride, a dopamine D2 and D3 antagonist shown to be effective at preventing and treating PONV at doses of 5 and 10 mg, respectively, has a dose-dependent effect on QT but at 5 mg is not associated with clinically meaningful prolongation of the heart rate-corrected QT (QTc) interval. This study was designed to evaluate the QT effect of a 10-mg dose of amisulpride, alone and when simultaneously coadministered with ondansetron, an antiemetic of a different class, also known to prolong the QT interval. METHODS: In this randomized, double-blind, placebo-controlled, 3-period, crossover study, healthy male and female volunteers 18-65 years of age received IV, in a random sequence: (1) amisulpride 10 mg given twice, 2 hours apart; (2) amisulpride 10 mg and ondansetron 4 mg, given simultaneously; and (3) placebo. RESULTS: Thirty subjects were enrolled, and 29 completed all 3 treatment periods. The largest mean placebo-corrected change-from-baseline QT interval corrected for heart rate using Fridericia's formula (QTcF) (ΔΔQTcF) after the first and second amisulpride dose was 5.2 milliseconds (90% confidence interval [CI], 3.53-6.96 milliseconds) and 8.0 milliseconds (90% CI, 5.49-10.58 milliseconds), respectively. After coadministration of amisulpride and ondansetron, the largest mean ΔΔQTcF was 7.3 milliseconds (90% CI, 5.48-9.16 milliseconds). The slope of the amisulpride concentration-change-from-baseline QTcF (ΔQTcF) relationship was 0.006 ms/ng/mL (90% CI, 0.0020-0.0098). No QTc outliers (absolute QTcF value >480 milliseconds or increase from baseline >30 milliseconds) were seen in any period. CONCLUSIONS: A 10-mg dose of IV amisulpride, given alone or in combination with ondansetron, does not have a clinically significant effect on the QT interval.
Assuntos
Amissulprida/administração & dosagem , Gerenciamento Clínico , Antagonistas de Dopamina/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Náusea e Vômito Pós-Operatórios/prevenção & controle , Administração Intravenosa , Adolescente , Adulto , Idoso , Amissulprida/efeitos adversos , Estudos Cross-Over , Antagonistas de Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Síndrome do QT Longo/diagnóstico , Masculino , Pessoa de Meia-Idade , Náusea e Vômito Pós-Operatórios/diagnóstico , Resultado do Tratamento , Adulto JovemAssuntos
Amissulprida/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Náusea e Vômito Pós-Operatórios/prevenção & controle , Adulto , Amissulprida/efeitos adversos , Amissulprida/farmacologia , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Antieméticos/farmacologia , Antagonistas dos Receptores de Dopamina D2/efeitos adversos , Antagonistas dos Receptores de Dopamina D2/farmacologia , HumanosRESUMO
The observation of animal orofacial and behavioral reactions has played a fundamental role in research on reward but is seldom assessed in humans. Healthy volunteers (N = 131) received 400 mg of the dopaminergic antagonist amisulpride, 50 mg of the opioidergic antagonist naltrexone, or placebo. Subjective ratings, physical effort, and facial reactions to matched primary social (affective touch) and nonsocial (food) rewards were assessed. Both drugs resulted in lower physical effort and greater negative facial reactions during reward anticipation, especially of food rewards. Only opioidergic manipulation through naltrexone led to a reduction in positive facial reactions to liked rewards during reward consumption. Subjective ratings of wanting and liking were not modulated by either drug. Results suggest that facial reactions during anticipated and experienced pleasure rely on partly different neurochemical systems, and also that the neurochemical bases for food and touch rewards are not identical.
Studies in rats and other species have shown that two chemical messengers in the brain regulate how much an animal desires a reward, and how pleasant receiving the reward is. In this context, chemicals called opioids control both wanting and enjoying a reward, whereas a chemical called dopamine only regulates how much an animal desires it. However, since these results were obtained from research performed on animals, further studies are needed to determine if these chemicals play the same roles in the human brain. Korb et al. show that the same brain chemicals that control reward anticipation and pleasure in rats are also at work in humans. In the experiment, 131 healthy volunteers received either a drug that blocks opioid signaling in the brain, a drug that blocks dopamine signaling, or a placebo, a pill with no effect. Then, participants were given, on several occasions, either sweet milk with chocolate or a gentle caress on the forearm. Participants rated how much they wanted each of the rewards before receiving it, and how much they liked it after experiencing it. To measure their implicit wanting of the reward, participants also pressed a force-measuring device to increase their chances of receiving the reward. Additionally, small electrodes measured the movement of the volunteer's smiling or frowning muscles to detect changes in facial expressions of pleasure. Volunteers taking either drug pressed on the device less hard than the participants taking the placebo, suggesting they did not want the rewards as much, and they frowned more as they anticipated the reward, indicating less anticipatory pleasure. However, only the volunteers taking the opioid-blocking drug smiled less when they received a reward, indicating that these participants did not get as much pleasure as others out of receiving it. These differences were most pronounced when volunteers looked at or received the sweet milk with chocolate. This experiment helps to shed light on the chemicals in the human brain that are involved in reward-seeking behaviors. In the future, the results may be useful for developing better treatments for addictions.
Assuntos
Amissulprida/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Prazer/efeitos dos fármacos , Recompensa , Adulto , Emoções/efeitos dos fármacos , Feminino , Alimentos , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: Olanzapine (OLA), amisulpride (AMI), aripiprazole (ARI), and quetiapine (QUE) belong to antipsychotics, which administration represents still most reliable way for the treatment of schizophrenic and bipolar disorders. The intention of the present study was to explore whether the acute administration of a particular antipsychotic, indicated by the presence of c-Fos, will: a) stimulate neurons already activated by a long lasting homogeneous or heterogeneous stress preconditioning, indicated by the FosB/ΔFosB (ΔFosB) expression, or b) have a stimulatory effect only on a not activated, so called silent neurons. The pattern of ΔFosB and c-Fos spatial relationship was investigated in three forebrain structures, including the septal ventrolateral nucleus (seVL), the striatal dorsolateral area (stDL), and the shell of the nucleus accumbens (shell). METHODS: The rats were divided into 10 groups and exposed to two types of stressors. Half of them was exposed to a sequence of homogeneous stressor - handling (HDL) and the other half to a heterogeneous stressor (CMS) daily for 20 days. CMS consisted of five types of stressors: crowding, air-puff, wet bedding, predator stress, and forced swimming applied in an unexpected order. On the 21st day of the experiment, the rats were free of the stress exposure and on the 22nd day, both groups of animals receive a single intraperitoneal injection of vehicle (4% DMSO in saline, 0.1 ml/100 g) or OLA (5 mg/kg), AMI (20 mg/kg), ARI (10 mg/kg), and QUE (15 mg/kg). 90 min after the drugs administration the animals were transcardially perfused, brains removed, cut into 30 µm thick coronal sections, and double stained: first with ΔFosB antibody linked with Alexa488 fluorescent dye and second with c-Fos antibody linked to Alexa596 one. Quantitative evaluation of ΔFosB and c-Fos colocalizations was performed on fluorescence photomicrographs transformed into a final picture containing only yellow, green, and red colored circles. RESULTS: The data of this investigation demonstrate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell ones, in both HDL as well as CMS preconditioned rats. The levels of ΔFosB and c-Fos colocalizations varied in the individual forebrain areas studied. From the total 22 areas measured, level of c-Fos colocalization prevailed over ΔFosB in 18 ones. However, neither c-Fos nor ΔFosB reached 100% level of colocalization in any of the forebrain areas investigated. CONCLUSION: The present findings indicate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell, in both HDL and CMS preconditioned rats, whereas the parallel occurrence of free c-Fos as well as c-Fos colocalized with ΔFosB might speak out for a possible involvement of the c-Fos activated by antipsychotics applied in dual, i.e. short- and long-lasting, functions.
Assuntos
Amissulprida/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Corpo Estriado/efeitos dos fármacos , Olanzapina/farmacologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Fumarato de Quetiapina/farmacologia , Núcleos Septais/efeitos dos fármacos , Estresse Psicológico/metabolismo , Amissulprida/administração & dosagem , Animais , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Corpo Estriado/metabolismo , Masculino , Olanzapina/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fumarato de Quetiapina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Núcleos Septais/metabolismoRESUMO
OBJECTIVE: The goal of this study was to reveal the impact of four types of atypical antipsychotics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI), with different receptor-affinity profile and dissociation constant, on the activity of hypothalamic supraoptic nucleus (SON) vasopressinergic and oxytocinergic neurons. METHODS: Male Sprague Dawley rats received a single injection of vehicle (VEH) (0.1 ml/100g), AMI (20 mg/kg), OLA (5 mg/kg), QUE (15 mg/kg/) or ARI (10 mg/kg). Ninety min after treatment, the animals were fixed by transcardial perfusion, the brains removed, and cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black end product. Afterwards, the sections were exposed to vasopressin (AVP) and oxytocin (OXY) antibodies and the reaction product visualized by biotin-labeled fluorescent Alexa Fluor 568 dye. The data were evaluated from c-Fos and AVP or OXY merged sections. RESULTS: The present study shows that all four antipsychotics applied induced c-Fos expression in the SON. With respect to the stimulation efficacy of the individual antipsychotics, estimated based on the quantity of c-Fos-labeled AVP and OXY neurons, could be a preferential action assigned to QUE over moderate effect of ARI and lower effect to OLA and reduced effect of AMI (VEH < AMI < OLA < ARI < QUE). CONCLUSION: The present data for the first time provide an insight into the quantitative pattern of brain activity within the clusters of SON AVP and OXY cells in response to different atypical antipsychotics single treatment.
Assuntos
Amissulprida/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Neurônios/efeitos dos fármacos , Olanzapina/farmacologia , Ocitocina , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Fumarato de Quetiapina/farmacologia , Núcleo Supraóptico/efeitos dos fármacos , Vasopressinas , Amissulprida/administração & dosagem , Animais , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Masculino , Neurônios/metabolismo , Olanzapina/administração & dosagem , Ocitocina/metabolismo , Fumarato de Quetiapina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Núcleo Supraóptico/metabolismo , Vasopressinas/metabolismoAssuntos
Agranulocitose/induzido quimicamente , Amissulprida/administração & dosagem , Antipsicóticos , Clozapina , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Both amisulpride and olanzapine are leading treatments for schizophrenia in China. This study aimed to investigate the long-term cost-effectiveness of amisulpride and olanzapine in the treatment of schizophrenia in China. METHODS: A decision-analytic Markov model was developed to simulate the lifetime clinical and economic outcomes of schizophrenia treatment from the healthcare payer perspective. The long-term costs and QALYs were estimated. Sensitivity analyses were performed to explore the impact of variance of parameters on the results. RESULTS: Treatment with amisulpride provided an effectiveness gain of 16.59 QALYs at an average cost of USD 25,884 whereas olanzapine resulted in 16.38 QALYs at a cost of USD 34,839 over a lifetime horizon. One-way sensitivity analysis suggested that the most sensitive variable was the unit cost of olanzapine. In a probabilistic sensitivity analysis based on a Monte Carlo simulation with a lifetime horizon, the probability of amisulpride being cost-effective was 99.8% at a willingness-to-pay threshold of USD 9,322, the GDP per capita in China 2018. A scenario analysis with updated olanzapine unit cost suggested an ICER of 7,857 USD/QALY. CONCLUSIONS: Amisulpride is likely to be a cost-effective option with increased effectiveness compared with olanzapine in the treatment of schizophrenia patients in China.
Assuntos
Amissulprida/administração & dosagem , Antipsicóticos/administração & dosagem , Olanzapina/administração & dosagem , Esquizofrenia/tratamento farmacológico , Amissulprida/economia , Antipsicóticos/economia , China , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Humanos , Cadeias de Markov , Olanzapina/economia , Anos de Vida Ajustados por Qualidade de Vida , Esquizofrenia/economia , Fatores de TempoRESUMO
INTRODUCTION: The issue of postoperative nausea and vomiting (PONV) remains important in surgical practice, contributing to patient distress, slower recovery, and increased use of healthcare resources. Many surgical patients report it to be a worse problem than the pain. New antiemetics of different classes are still needed to help manage PONV effectively, especially the treatment of established PONV after the failure of common prophylactic antiemetics such as 5-HT3-antagonists and corticosteroids. Intravenous amisulpride, a drug with a long history of safe use in oral form as an antipsychotic, has recently been approved in the US (trade name: Barhemsys) as an intravenous antiemetic for the prevention and treatment of PONV. AREAS COVERED: This review article summarizes the published data on the clinical pharmacology, safety, and efficacy of intravenous amisulpride as an antiemetic, supplemented by published data on oral amisulpride, where relevant to the intravenous form. Literature was obtained via the PubMed search terms 'intravenous amisulpride' and 'amisulpride AND safety.' Both primary and secondary pharmacology are covered, along with clinical pharmacokinetics (distribution, metabolism, and excretion). The review of clinical safety and efficacy includes data from four studies in the prevention of PONV, two in the treatment of PONV and two investigating effects on the QT interval of the electrocardiogram in healthy volunteers. EXPERT OPINION: Given the importance of sufficient PONV prevention for patients and the healthcare system, the availability of intravenous amisulpride is helpful, restoring the dopamine-antagonist class as a potential mainstay in both combination prophylaxis and treatment.
Assuntos
Amissulprida/farmacologia , Antieméticos/farmacologia , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Administração Intravenosa , Amissulprida/administração & dosagem , Amissulprida/efeitos adversos , Animais , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Humanos , Náusea e Vômito Pós-Operatórios/fisiopatologiaRESUMO
BACKGROUND: Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds. AIMS: We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain. METHODS: All subjects included for this genome-wide association study (n=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use <2 weeks in the previous year and/or <6 weeks lifetime). Weight gain was defined as the increase in body mass index from before until approximately 1 month after amisulpride treatment. RESULTS: Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; ß=1.05; p=3.66 × 10-08; n=206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 (p=1.0 × 10-03) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain. CONCLUSION: Our findings suggest the involvement of rs78310016 and possibly 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.
Assuntos
Amissulprida/efeitos adversos , Antipsicóticos/efeitos adversos , Transtornos Psicóticos/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Adulto , Alelos , Amissulprida/administração & dosagem , Antipsicóticos/administração & dosagem , Estudos de Coortes , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Masculino , Polimorfismo de Nucleotídeo Único , Esquizofrenia/tratamento farmacológico , Aumento de Peso/genética , Adulto JovemRESUMO
Introduction: Current therapies of postoperative nausea and vomiting (PONV) are based on a combination of antiemetics from different pharmacological classes. Dopamine receptor antagonists are one of the cornerstones of such multimodal antiemetic approach, with droperidol being the best studied representative of this group. Droperidol's use has significantly declined after the FDA's black-box warning in 2001 due to its QT-prolonging properties. Amisulpride is a promising antiemetic agent which could fill this gap.Areas covered: In this review, the authors discuss the pharmacological profile as well as clinical safety and efficacy of intravenous amisulpride and its relevance in the management of PONV. The article is based on a Medline, ClinicalTrials.gov, and Cochrane Library search for studies on amisulpride conducted so far.Expert opinion: Promising clinical results on Barhemsys®, an intravenous formulation of amisulpride, make it a potential future drug of choice from the dopamine receptor antagonist group, replacing droperidol after its safety concerns. Amisulpride's success on the market will mostly be determined by its cost-effectiveness and it will likely find a brighter use on the US-market, where the black-box warning led to droperidol's withdrawal, while in many European countries, droperidol is still being used as an antiemetic.