The pharmacodynamic effects of Risperidone on the vestibular system were assessed via dynamic computed posturography in 12 healthy subjects (6 male). Subjects were administered 2 mg, orally, of Risperidone and assessed on the NeuroCom® Balance Master© system under varying conditions. The vestibular response was deductively quantified by first assessing balance with a static force plate and eyes closed (Condition 2), and then assessed on a dynamic force plate with eyes closed (Condition 5). On average, Condition 2 scores were 24.46 points higher than Condition 5 scores (95% CI [20.973, 27.957]). A Pearson correlation between scores in Condition 2 and 5 showed a significant, moderate positive correlation (r = .487, p <.001). A trend analysis showed the effect of time, post-dose, on equilibrium score to be linear in nature (p < .001). In conclusion, some, but not all, of the subjects involved in the study experienced diminished vestibular control after administration of Risperidone; this may be due to phenotypic differences or learning effects.

The atypical antipsychotic risperidone is associated with weight gain and cardio-metabolic side effects. In light of growing evidence implicating the gut microbiome in the host’s energy regulation and in xenobiotic metabolism, it is hypothesized that risperidone-induced weight gain is mediated through alterations in the gut microbiome. The impact of chronic and short-term risperidone treatment on the gut microbiome of pediatric, psychiatric patients was examined in a cross-sectional and prospective design. Chronic treatment with risperidone was associated with a significant increase in body mass index (BMI) and a significant reduction in the ratio of Bacteroidetes to Firmicutes, as compared to naïve psychiatric controls. Predictive metagenomic analyses, indicate that gut microbiota dominating the risperidone-treated patients are enriched for pathways, such as short-chain fatty acid production, which have been implicated in weight gain. Alterations in the microbiome due to risperidone treatment were further demonstrated in wild-type female mice and shown to be a result of a reduction in host energy expenditure. Risperidone-treated mice exhibit significant weight gain and an altered gut microbiome relative to controls while maintaining normal food intake behavior and digestive efficiency, indicating that increased weight gain is due to reduced energy expenditure. Moreover, fecal transfer from risperidone-treated mice to a second cohort of naïve mice was performed via daily gastric gavage and aerobic and non-aerobic resting metabolic rates (RMR) were monitored using combined calorimetry. This transfer has no effect on aerobic RMR in recipients, but induces a significant suppression of non-aerobic RMR in mice receiving stool from risperidone-treated donors establishing a causal effect of the altered gut microbiome upon energy expenditure. Finally, daily transfer of phage, a subset of the gut microbiome, isolated from the gut of risperidone treated donors was also sufficient to cause excess weight gain in naïve recipients animals through suppression of energy expenditure. Together, these data highlight a major role for the gut microbiome for weight gain following chronic use of risperidone, and demonstrate that the mechanism depends upon suppression of energy expenditure.

Schizophrenia is a chronic and degenerative mental disease. Patients suffer from this disease for a whole life. It`s not clear the causes of schizophrenia. Correct diagnosis and treatment are essential for disease recovery, helping patients return home or community as early as possible. Up to now medicine has been the most effective treatment for schizophrenia. Antipsychotic drug has experienced the first generation and the second generation stages. The second generation antipsychotics are significantly more effective and with less side effects compared with the first generation drugs. This study focused on schizophrenia marketing strategies in Taiwan. A detailed case study of Risperdal&#x00AE; was undertaken to analyze the marketing strategies and marketing mix (product, price, place, and promotion). The study illustrated a successful implementation of marketing plans regarding antipsychotic drugs, shed light on how to launch new products and accelerate new product introductions.

Although the use of atypical antipsychotic drugs is successful in the treatment of schizophrenia, they cause complications in the long term use that is mainly weight gain. In this study, circulating levels of hypothalamic neuropeptides/hormones, which are related to appetite regulation / neuropeptide Y (NPY), alpha melanocyte stimulating hormone (&alpha / -MSH), cocaine and amphethamine regulated transcript (CART) and plus leptin in male schizophrenic patients who were treated with an atypical antipsychotic drug, risperidone, which is a serotonin antagonist, for 4 weeks was investigated. Based on the hypothesis that the risperidone treatment might alter the circulating levels of those neuropeptides through the serotonergic antagonism, it results in the weight gain. Leptin plasma levels were increased in the risperidone treated patients accompanying by weight gain vs controls and NPY, &alpha / -MSH, CART levels were decreased in the patients before the treatment but they were not changed after treatment. To determine alterations of those candidate genes mRNA expression levels, male Wistar rats were orally administered with risperidone for 4-weeks. Rat studies show that the mRNA expression and plasma levels of POMC, AgRP, and NPY were decreased but CART mRNA levels were increased while their plasma levels were decreased unexpectedly. In conclusion, the serotonergic antagonism of risperidone on POMC neurons may cause increase in appetite / and hence, increased weight gain and leptin levels, even in a short term trial.

A risperidona é um medicamento antipsicótico que quando metabolizada da origem a dois metabólitos hidroxilados quirais, a 7-hidroxirisperidona (7-RispOH) e a 9-hidroxirisperidona (9-RispOH). A 9-RispOH apresenta as mesmas propriedades farmacológicas que a risperidona e já é comercializada como fármaco, com o nome genérico de paliperidona. Estudos em humanos mostram que existem diferenças na disposição cinética dos enantiômeros da 9-RispOH, com uma maior prevalência do enantiômero (+)-9-RispOH em plasma. Dessa forma, este trabalho teve como finalidade avaliar a capacidade de algumas espécies de fungos e também de catalisadores de Jacobsen em (bio)transformar enantiosseletivamente a risperidona em seu metabólito ativo 9-RispOH. Para tanto, foi desenvolvido um método de separação para a risperidona e seus metabólitos utilizando cromatografia líquida de alta eficiência quiral. Este método foi então aplicado nos estudos de biotransformação enantiosseletivo e nos estudos de catálise assimétrica. A separação cromatográfica foi realizada empregando a coluna Chiralcel OJ-H e metanol:etanol (50:50, v/v) + 0,2% de trietilamina como fase móvel. A vazão e temperatura utilizadas foram 0,8 mL min-1 e 25oC, respectivamente. Para extração dos analitos do meio de cultura, foi empregada a microextração em fase sólida (SPME) como técnica de preparação de amostra. O processo de SPME foi realizado utilizando uma fibra C18 mergulhando diretamente a fibra na amostra por 30 minutos e dessorvendo a fibra diretamente na fase móvel por 5 minutos. A validação e estudos de biotransformação foram realizados empregando a cromatografia líquida acoplada à espectrometria de massas (LC-MS/MS). O método foi validado e todos os parâmetros encontram-se de acordo com as recomendações da literatura. O estudo de biotransformação foi realizado com diferentes espécies de fungos e somente os fungos do gênero Cunninghamella foram capazes de biotransformar a risperidona em seu metabólito ativo. O fungo Cunninghamella echinulata foi capaz de biotransformar estereosseletivamente a risperidona no seu metabólito ativo (+)-9-RispOH com excesso enantiomérico de 100% e o fungo Cunninghamella elegans foi também capaz de biotransformar estereosseletivamente a risperidona nos dois enantiômeros da 9-RispOH em diferentes proporções. Os estudos preliminares de catálise assimétrica foram realizados empregando a cromatografia líquida e detecção por UV-Vis, injetando diretamente alíquotas no sistema cromatográfico. Esses estudos mostraram que na condição de reação 1:50:50 (em número de mols, catalisador:oxidante:substrato) houve uma catálise assimétrica da risperidona que demonstrou ser enantiosseletiva para o metabólito 7-RispOH (E1). / Risperidone is an atypical antipsychotic drug. Its metabolism yields in two hydroxylated chiral metabolites, 7-hydroxyrisperidone (7-RispOH) and 9-hydroxyrisperidone (9-RispOH). The 9-RispOH metabolite presents the same pharmacologic activity of the parent drug risperidone. This led this drug to be marketed as drug under the generic name paliperidone. Studies have shown differences in the kinetic disposition of the 9-RispOH enantiomers with higher prevalence of the (+)-9-RispOH enantiomer in plasma. Thus, this work aimed to evaluate the ability of some species of fungi and Jacobsen catalysts in the enantioselective (bio)transformation of risperidone into its active chiral metabolite 9-RispOH. To accomplish that, it was developed a separation method to analyze risperidone and its metabolites by chiral high-performance liquid chromatography. This method was employed in enantioselective biotransformation studies and in asymmetric catalysis studies. The chromatographic separation was performed on a Chiralcel OJ-H column using methanol:ethanol (50:50, v/v) plus 0.2% triethylamine as the mobile phase at a flow rate of 0.8 mL min-1. The SPME process was performed by immersing directly a C18 probe fiber in the culture medium during 30 min. The analytes were desorbed from the fiber directly in the mobile phase during 5 min. The method validation and the biotransformation studies were performed by high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The method was completely validated and all parameters were in agreement with the literature recommendations. The biotransformation studies were performed employing different species of fungi and only the Cunninghamella genus was able to biotransform risperidone into its active metabolite. The Cunninghamella echinulata fungus was able to biotransform risperidone into the active metabolite, (+)-9-RispOH, resulting in 100% of enantiomeric excess. The Cunninghamella elegans fungus was also able to biotransform stereoselectively risperidone into (+)- and ()-9-RispOH enantiomers at different rates. Preliminary studies of asymmetric catalysis were performed using high-performance liquid chromatography with UV-Vis detector (HPLC-UV). The aliquots were directly injected in the chromatography system. These studies showed that the reaction with 1:50:50 (catalyst:oxidant:substrate, in number of mols, in this sequence) presented an asymmetric catalysis of risperidone and that showed to be enantioselective to 7-RispOH (E1) metabolite.

No / Antipsychotic drug-induced side effects of weight gain and sexual dysfunction have clinical significance adversely affecting both compliance and morbidity. This study evaluated the effects of haloperidol and the atypical antipsychotic risperidone (0.1¿1.0 mg/kg) on weight gain, food and water intake, the oestrous cycle and uterine weight in female hooded Lister rats. Haloperidol and risperidone treated rats displayed marked weight gain, although only risperidone induced significant increases in food consumption over the 21-day period. Neither haloperidol nor risperidone influenced water consumption. Marked disruption of the oestrous cycle was observed in risperidone- and haloperidol-treated animals (0.5 and 1.0 mg/kg), which was supported by significantly reduced uterine weights. The findings presented here suggest that the weight gain and sexual dysfunction induced by antipsychotics may be modelled in rodents. This model may offer insight into the mechanisms involved in mediation of such side effects.

Yes / Background: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and α2-adrenergic than dopaminergic D2 receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. Methods: After operant training, rats were treated acutely with D-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5 mg/kg i.p.) or sub-chronically with PCP (2 mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute D-amphetamine– and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. Results: Deficits in reversal learning induced by acute D-amphetamine were attenuated by risperidone (0.2 mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5 mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.) all showed sustained efficacy with chronic (29 d) treatment to improve subchronic PCP-induced impairments. Conclusion: These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation. / This research was supported by Schering-Plough Corporation, now Merck & Co., Inc. and Pfizer Inc.

Patients with schizophrenia are normally treated with one of several antipsychotic medications that differ from one another in the areas of the brain they affect including the dorsal striatum, a subcortical section of the forebrain, and the prefrontal cortex (PFC), located in the anterior part of the frontal lobes. Two different tests of implicit memory, the probabilistic classification learning (PCL) and the Iowa gambling task (IGT), have been shown to rely on the dorsal striatum and the PFC, respectively. Studies have previously shown that patients with schizophrenia treated with antipsychotics that affect the dorsal striatum (e.g., risperidone), have altered performance on the PCL, and those treated with antipsychotics that affect the PFC (e.g., clozapine), have altered performance on the IGT. We tested the hypothesis that patients with schizophrenia treated with olanzapine would have a poorer performance on the IGT, but not the PCL, when compared with controls. This study aimed to clarify conflicting results from prior experiments observing the effects of olanzapine on implicit memory in people with schizophrenia. We also hypothesized that performance of patients taking aripiprazole would be comparable to those taking risperidone, or an FGA; however, we were unable to recruit a sufficient amount of participants to test this hypothesis. Patients with schizophrenia, a mental disorder characterized by a breakdown in relation between thoughts, emotion, and behavior, treated with olanzapine were recruited through local psychiatric clinics or using a newspaper ad. Administration of the Brief Psychiatric Rating Scale (BPRS) and the Mini Mental State Examination (MMSE) preceded a brief questionnaire of demographic information. Participants were tested on the PCL and the IGT using a personal computer. Results revealed poorer performance on both the MMSE and BPRS for patients when compared with controls. Patients taking olanzapine were impaired in learning the PCL but not the IGT when compared with controls. Results suggest that olanzapine acts on the PFC to augment IGT performance but further studies are needed. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2013-07-23 15:09:21.55

A risperidona (RISP) é um fármaco neuroléptico que após sua administração oral é metabolizado resultando em dois metabólitos quirais, a 7-hidroxirisperidona (7- RispOH) e a 9-hidroxirisperidona (9-RispOH). A 9-RispOH é o metabólito majoritário da risperidona a qual é comercializada na forma de racemato com o nome de paliperidona. Esse projeto teve como finalidade avaliar a capacidade dos fungos endofíticos Penicillium crustosum (VR4), Chaetomium globusum (VR10), Aspergillus fumigatus (VR12), Papulaspora immersa Hotson (SS13), Nigrospora sphaerica (Sacc.) E.W. Mason (SS67) e Glomerella cingulata (VA1) e do fungo de solo Mucor rouxii em biotransformar a risperidona em seu metabólito ativo 9-RispOH enantiosseletivamente. Foi objeto de estudo também a otimização do processo de biotransformação através do emprego de diferentes meios de cultura (Czapek, Czapek Dox e Koch`s K1) para o cultivo dos fungos utilizados no estudo. O método escolhido para a separação da risperidona e seus metabólitos quirais foi a eletroforese capilar (CE). As separações eletroforéticas dos analitos foram realizadas empregando um capilar de sílica fundida de 40 cm de comprimento e 75 ?m de diâmetro interno, uma solução tampão fosfato de sódio 100 mmol L-1 pH 3,0 contendo CD-?-sulfatada 2,0% (p/v) e carboximetil-?-CD 0,5% (p/v) como seletores quirais. Todos os experimentos no CE foram realizados no modo reverso aplicando uma tensão de -10kV. As amostras foram injetadas aplicando uma pressão 0,5 psi por 8 s. O capilar e as amostras permaneceram na temperatura de 20oC. Para a extração dos analitos do meio de cultura foi utilizado a microextração em fase líquida empregando membranas cilíndricas ocas (HF-LPME). A técnica de preparação de amostra foi realizada no modo de três fases utilizando uma fibra de polipropileno impregnada com n-octanol e preenchida com uma solução de ácido clorídrico 100 mmol L-1 pH 3,0. A fibra foi mergulhada na amostra tamponada com uma solução de fosfato de potássio dibásico 500 mmol L-1 pH 12,0. O método foi validado de acordo com os parâmetros estabelecidos pela ANVISA (Agência Nacional de Vigilância Sanitária) para análise de fármacos em material biológico avaliando os seguintes parâmetros: seletividade, linearidade, precisão, exatidão, limite de quantificação e estabilidade. Todos os parâmetros avaliados ficaram dentro dos limites estabelecidos pela ANVISA. Entre os fungos avaliados, apenas o Mucor rouxii foi capaz de biotransformar a risperidona em seu metabólito ativo e quiral 9-RispOH. Nas condições empregadas a razão enantiomérica foi de 79,6%. / Risperidone (RISP) is a neuroleptic drug which after oral administration is metabolized into two chiral metabolites, 7-hydroxyrisperidone (7-RispOH) and 9- hydroxyrisperidone (9-RispOH). 9-RispOH is the major metabolite and it is commercialized under the generic name paliperidone. The objective of this project was to evaluate the capability of the endophytic fungi Penicillium crustosum (VR4), Chaetomium globusum (VR10), Aspergillus fumigatus (VR12), Papulaspora immersa Hotson (SS13), Nigrospora sphaerica (Sacc.) E.W. Mason (SS67) and Glomerella cingulata (VA1) and the soil fungus Mucor rouxii to biotransform risperidone into its chiral and active metabolite 9-RispOH, enantioselectively. In addition, it was also optimized the biotransformation process through the use of different culture medium (Czapek, Czapek Dox and Koch`s K1). The chiral analysis was performed by capillary electrophoresis (CE). The electrophoretic separation of the analytes was accomplished in a silica capillary with 40 cm of length and 75 ?m of internal diameter. The background electrolyte was a sodium phosphate 100 mmol L-1 pH 3.0 plus 2.0% (w/v) sulfated-?-CD and 0.5% (w/v) carboxymethyl-?-CD. All experiment on CE was performed in reverse mode by applying a voltage of -10 KV. The samples were injected hydrodynamically by applying a pressure of 0.5 psi for 8 s. The temperature of analysis was 20oC. For the extraction of the analytes from the culture medium it was employed the hollow fiber liquid-phase microextraction (HF-LPME). The extraction conditions were: n-octanol as organic solvent and a hydrochloridric acid solution of 100 mm L-1 pH 3.0. The pH of the sample was controlled by the addition of potassium phosphate buffer 500 mmol L-1 pH 12.0. The method was validated according to ANVISA guidelines (Agência Nacional de Vigilância Sanitária) for the analysis of drugs in biological fluids. The following parameters were evaluated: selectivity, linearity, precision, accuracy, limit of quantification and stability. All parameters were in agreement with the established limits by ANVISA. From all the evaluate fungi only Mucor rouxii was able to biotransform risperidone into its chiral and active metabolite 9-RispOH. In the conditions used in these project the enantiomeric ratio was 79.6%.

Desde 1964, o Brasil tem lançado programas de políticas públicas para melhorar o acesso da população aos medicamentos considerados essenciais. Em 1999, com a criação da Agência Nacional de Vigilância Sanitária e a introdução dos medicamentos genéricos no mercado brasileiro, o Brasil passou a ter três classes de medicamentos disponíveis no mercado farmacêutico: referência, similar e genérico. O objetivo deste estudo foi avaliar a bioequivalência e intercambialidade entre dois antipsicóticos (referência e similar) utilizados pelo Instituto de Psiquiatria do Hospital das Clínicas da Universidade de São Paulo, contendo 2 mg de risperidona. Foi desenvolvido e validado um método analítico que emprega a cromatografia líquida de alta eficiência acoplada à espectrometria de massas para a determinação da risperidona (RSP) e seu principal metabólito a 9-hidroxirisperidona (9OH-RSP) em plasma. Para se avaliar a bioequivalência entre os medicamentos foram recrutados 22 voluntários sadios, os quais participaram do estudo clínico conduzido de forma cruzada e aleatória. As coletas sanguíneas para o ensaio de bioequivalência foram realizadas em tubos heparinizados (5 mL) e os tempos de coleta foram 0 (antes da medicação); 0,25; 0,5; 1; 1,5; 3; 5; 8; 12; 24; 48; 72; 96 e 120 horas após a administração da medicação. A determinação da bioequivalência entre os dois medicamentos deu-se através da comparação dos parâmetros farmacocinéticos: concentração plasmática máxima (Cmax), tempo para atingir a concentração plasmática máxima (Tmax) e área sobre a curva de decaimento plasmático (ASCT). Os resultados obtidos foram submetidos à análise de variância (ANOVA) e foi adotado o intervalo de confiança de 90% (IC 90%). Os valores médios para Cmax, Tmax e ASCT para RSP para os medicamentos referência e teste foram 16,02 ng/mL; 1,5 h e 348,94 ng.h/mL e 12,65 ng/mL; 1,5 h e 286,03 ng.h/mL, respectivamente. Já os valores médios para Cmax, Tmax e ASCT para 9OH-RSP para os medicamentos referência e teste foram 21,00 ng/mL; 5,0 h e 821,40 ng.h/mL e 17,85 ng/mL; 5,0 h e 632,92 ng.h/mL. Os valores de IC 90% para Cmax e ASCT para RSP para os medicamentos referência e teste foram 74 a 82% e 76 a 85%, respectivamente, e os valores de IC 90% para os mesmos parâmetros para 9OH-RSP foram 83 a 87% e 75 a 78%, respectivamente. Os resultados demonstraram diferenças significativas entre os medicamentos testados, o que permite concluir que os mesmos não são bioequivalentes e, portanto, não podem ser intercambiáveis / Brazil has launched programmes of public policies aiming to improve essential medicines access for the population since 1964. It was created in 1999 the National Agency for Sanitary Vigilance, which introduced the generic medicines in the Brazilian market, which already had the reference and the pharmaceutical equivalent ones. The objective of this study was to evaluate the bioequivalence and interchangeability between two antipsychotics (reference and pharmaceutical equivalent) used by the Institute of Psychiatry, Hospital of the Universidade de São Paulo, containing 2 mg of risperidone. It was developed and validated a high-performance liquid chromatography coupled to mass spectrometry method for the determination in plasma of risperidone (RSP) and its main metabolite, 9- hydroxy-risperidone (9OH-RSP). To assess bioequivalence between the medicines it was recruited 22 healthy volunteers, which took part in a clinical cross and random studies. The blood collections were performed on heparinizades tubes (5 ml) and runtimes collections were 0 (before medication); 0.25; 0.5; 1; 1.5; 3; 5; 8; 12; 24; 48; 72; 96 and 120 hours after the administration of medication. The determination of bioequivalence between the two drugs was achieved by a comparison of the following pharmacokinetic parameters: plasma concentration (Cmax), time to achieve Cmax (Tmax), and area under the plasma concentration-time curve (AUCT). Results were subjected to analysis of variance (ANOVA), adopting a confidence interval CI 90%. The average values for Cmax, Tmax and AUCT for RSP were 16.02 ng/ml, 1.5 h and 348.94 ng.h/ml for reference medicines and 12.65 ng/ml, 1.5 h and 286.03 ng.h/ml for testing ones. The average values for Cmax, Tmax and AUCT for 9OH-RSP were 21.00 ng/ml, 5.0 h and 821.40 ng.h/ml for reference medicines and 17.85 ng/ml, 5.0 h and 632.92 ng.h/ml for testing ones. CI 90% for Cmax and AUC (RSP) were 74-82% and 76-85%, respectively. The CI 90% for the same parameters for 9OH-RSP was 83-87% for reference medicines and 75-78% for testing ones. There was significant difference between the products tested, thus one can conclude they are not bioequivalents, therefore cannot be interchanged