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1.
Environ Sci Pollut Res Int ; 26(25): 26293-26303, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286368

RESUMO

Since behavior is the connection between the internal physiological processes of an animal and its interaction with the environment, a complete behavioral repertoire is crucial for fish survival and fitness, at both the individual and population levels. Thus, unintended exposure of non-target organisms to antipsychotic residues in the environment can impact their normal behavior, and some of these behavioral changes can be seen during the entire life of the animal and passed to subsequent generations. Although there are some reports related to transgenerational toxicology, little is known of the long-term consequences of exposure to pharmaceutical compounds such as risperidone. Here, we show that zebrafish exposed to risperidone (RISP) during embryonic and larval stages presented impaired anti-predatory behavior during adulthood, characterizing a persistent effect. We also show that some of these behavioral changes are present in the following generation, characterizing a transgenerational effect. This suggests that even short exposures to environmentally relevant concentrations, at essential stages of development, can persist throughout the whole life of the zebrafish, including its offspring. From an environmental perspective, our results suggested possible risks and long-term consequences associated with drug residues in water, which can affect aquatic life and endanger species that depend on appropriate behavioral responses for survival.


Assuntos
Risperidona/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Comportamento Animal/efeitos dos fármacos , Ecotoxicologia/métodos , Embrião não Mamífero/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Masculino , Comportamento Predatório/efeitos dos fármacos , Peixe-Zebra/embriologia , Peixe-Zebra/fisiologia
2.
ACS Chem Neurosci ; 9(9): 2274-2285, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-29701957

RESUMO

Selective activation of the M1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M1 ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M1 PAM, VU0486846. VU0486846 possesses only weak agonist activity in M1-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [3H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M1 PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M1 PAM activity (EC50 > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.


Assuntos
Cognição/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Morfolinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Pirazóis/farmacologia , Regulação Alostérica , Animais , Antipsicóticos/toxicidade , Células CHO , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Cricetulus , Medo , Camundongos , Morfolinas/toxicidade , Pirazóis/toxicidade , Ratos , Risperidona/toxicidade , Convulsões/induzido quimicamente
3.
Pharmacol Rep ; 70(5): 1023-1031, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32002949

RESUMO

BACKGROUND: Preclinical and clinical studies have suggested a beneficial effect of combination treatment with atypical antipsychotic drugs and antidepressants (ADs) in schizophrenia and in drug-resistant depression. METHODS: In the present study, we investigated the effect of chronic administration of risperidone and ADs (escitalopram or mirtazapine), given separately or jointly on the extracellular levels of dopamine (DA) and serotonin (5-HT) in the rat frontal cortex. The animals were administered risperidone (0.2 mg/kg) and escitalopram (5 mg/kg) or mirtazapine (10 mg/kg) repeatedly for 14 days. The release of monoamines in the rat frontal cortex was evaluated using a microdialysis, and DA and 5-HT levels were assayed by HPLC. We also measured the locomotor activity, catalepsy and recognition memory in these rats. RESULTS: Chronic risperidone treatment (0.2 mg/kg) increased the extracellular levels of DA and 5-HT. Co-treatment with risperidone and escitalopram (5 mg/kg) or mirtazapine (10 mg/kg) more efficiently increased the release of 5-HT but not DA in the rat frontal cortex, as compared to drugs given alone. Moreover, risperidone, escitalopram and mirtazapine given alone or in combination significantly decreased the locomotor activity and only mirtazapine increased the catalepsy evoked by risperidone. Combined treatment with risperidone and ADs impaired recognition memory in these rats. CONCLUSIONS: The obtained results suggest that chronic co-administration of risperidone and escitalopram or mirtazapine more efficiently increased 5-HT release in the rat frontal cortex as compared to drugs given alone and suggest that this effect may be of importance to the pharmacotherapy of schizophrenia and drug-resistant depression.


Assuntos
Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Citalopram/administração & dosagem , Dopamina/farmacologia , Lobo Frontal/efeitos dos fármacos , Mirtazapina/administração & dosagem , Risperidona/administração & dosagem , Serotonina/farmacologia , Animais , Antidepressivos/toxicidade , Antipsicóticos/toxicidade , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Citalopram/toxicidade , Esquema de Medicação , Interações Medicamentosas , Lobo Frontal/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Mirtazapina/toxicidade , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Risperidona/toxicidade , Fatores de Tempo
4.
Bone ; 103: 168-176, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28689816

RESUMO

Atypical antipsychotic (AA) drugs, including risperidone (RIS), are used to treat schizophrenia, bipolar disorder, and autism, and are prescribed off-label for other mental health issues. AA drugs are associated with severe metabolic side effects of obesity and type 2 diabetes. Cross-sectional and longitudinal data also show that risperidone causes bone loss and increases fracture risk in both men and women. There are several potential mechanisms of bone loss from RIS. One is hypogonadism due to hyperprolactinemia from dopamine receptor antagonism. However, many patients have normal prolactin levels; moreover we demonstrated that bone loss from RIS in mice can be blocked by inhibition of ß-adrenergic receptor activation with propranolol, suggesting the sympathetic nervous system (SNS) plays a pathological role. Further, when, we treated ovariectomized (OVX) and sham operated mice daily for 8weeks with RIS or vehicle we demonstrated that RIS causes significant trabecular bone loss in both sham operated and OVX mice. RIS directly suppressed osteoblast number in both sham and OVX mice, but increased osteoclast number and surface in OVX mice alone, potentially accounting for the augmented bone loss. Thus, hypogonadism alone cannot explain RIS induced bone loss. In the current study, we show that dopamine and RIS are present in the bone marrow compartment and that RIS can exert its effects directly on bone cells via dopamine receptors. Our findings of both direct and indirect effects of AA drugs on bone are relevant for current and future clinical and translational studies investigating the mechanism of skeletal changes from AA drugs.


Assuntos
Antipsicóticos/toxicidade , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/metabolismo , Dopamina/metabolismo , Risperidona/toxicidade , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Transdução de Sinais/fisiologia
5.
Toxicol In Vitro ; 44: 190-195, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28712880

RESUMO

This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (IC50s). The effects of APs (IC50s and 1µM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P<0.0001, <0.0001 and <0.01, respectively). All APs at IC50s significantly (P<0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5mM) or quercetin (50mM)) showed each antioxidant to significantly inhibit the effects of APs at their IC50s on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity.


Assuntos
Antipsicóticos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Células Tecais/efeitos dos fármacos , Animais , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Clorpromazina/toxicidade , Clozapina/toxicidade , Feminino , Glutationa/metabolismo , Haloperidol/toxicidade , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Risperidona/toxicidade , Células Tecais/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-28062214

RESUMO

Clinical studies indicate that about one-third of pregnant women with psychotic symptoms are exposed to either typical or atypical antipsychotic drugs (APDs). Reports on prenatal subject/model are lacking hence, the present study was undertaken to investigate the effect of prenatal exposure to risperidone (RIS) on the fetal hippocampus, and their related functional changes in young rat offspring. In this study, pregnant Wistar rats were exposed to equivalent therapeutic doses of RIS at 0.8mg/kg, 1.0mg/kg, and 2.0mg/kg BW from gestation days (GD) 6 to 20. On GD 21, about half of the pregnant subjects of each group were euthanized, their fetuses were collected, fetal brains dissected, and processed for neurohistopathological evaluation. Remaining pregnant dams were allowed to deliver naturally and reared up to 8weeks of age for neurobehavioral study under selected paradigms of cognition. Our results indicate that there was a significant decrease in the thickness of fetal hippocampus with the disturbed cytoarchitectural pattern, and volume of striatum and choroid plexus was also reduced. Furthermore, RIS treated young rat offspring displayed memory impairment on different mazes of learning and memory. The current study concludes that maternal exposure to clinically relevant doses of RIS may induce neurostructural changes in developing hippocampus and striatum, and cognitive sequelae in young offspring, respectively. Therefore, caution must be taken before prescribing this drug to pregnant subjects, especially during the sensitive phase of brain development. Hence, clinical correlation of animal data is urgently warranted.


Assuntos
Antipsicóticos/toxicidade , Disfunção Cognitiva/etiologia , Hipocampo/patologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Risperidona/toxicidade , Análise de Variância , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipocampo/embriologia , Hipocampo/ultraestrutura , Aprendizagem em Labirinto/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Gravidez , Ratos , Ratos Wistar , Fatores de Tempo
7.
Naunyn Schmiedebergs Arch Pharmacol ; 389(10): 1073-80, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27405774

RESUMO

In several case reports, proarrhythmic effects of antipsychotic drugs have been reported. The aim of the present study was to investigate if application of risperidone or quetiapine has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In 24 isolated rabbit hearts, risperidone (5 and 10 µM, n = 12) or quetiapine (5 and 10 µM, n = 12) was infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of risperidone as compared with baseline (5 µM: +29 ms, 10 µM: +35 ms, p < 0.01) accompanied by an increase of action potential duration. Administration of risperidone also significantly increased spatial dispersion of repolarization (5 µM: +16 ms, 4 µM: +19 ms; p < 0.05) as well as temporal dispersion of repolarization. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 8 of 12 hearts and polymorphic ventricular tachycardia resembling torsade de pointes in 6 of 12 hearts (10 µM, 49 episodes). The results were compared with hearts treated with quetiapine (5 and 10 µM). Quetiapine led to an increase in QT interval (5 µM: +10 ms; 10 µM: +28 ms; p < 0.05) and a similar increase of APD90. However, treatment with quetiapine did not result in significant alterations of spatial and temporal dispersion of repolarization. No ventricular arrhythmias were observed in this group. In the present study, quetiapine demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, risperidone led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization.


Assuntos
Antipsicóticos/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Fumarato de Quetiapina/toxicidade , Risperidona/toxicidade , Taquicardia Ventricular/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Animais , Bloqueio Atrioventricular/fisiopatologia , Bradicardia/fisiopatologia , Estimulação Cardíaca Artificial , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Preparação de Coração Isolado , Potássio/metabolismo , Coelhos , Medição de Risco , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/metabolismo , Torsades de Pointes/fisiopatologia
8.
Toxicol Mech Methods ; 26(7): 520-528, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27387968

RESUMO

The hepatotoxic effects of the antipsychotic agent, risperidone (RIS) were investigated for better understanding the pathogenesis of RIS in liver toxicity in vivo and in in vitro. Isolated rat hepatocytes were obtained by collagenase perfusion technique and were then incubated with RIS, different antioxidants in particular coenzyme Q10 (CoQ10), N-acetyl cysteine (NAC). Our results showed that RIS could induce cytotoxicity via rising reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation. All of these effects were significantly (p < 0.05) inhibited by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Similar outcomes were obtained from the in vivo experiments. Liver function enzyme test and histopathological evaluation confirmed RIS-(6 mg/kg) induced damage. Based on these results, it is suggested that RIS-induced liver toxicity is associated with mitochondrial/lysosomal cross-talk following the initiation of oxidative stress. Thus, the use of CoQ10 and/or NAC seems to be a safe therapeutic option in this context.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Risperidona/toxicidade , Ubiquinona/análogos & derivados , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ubiquinona/farmacologia
9.
Int J Dev Neurosci ; 52: 13-23, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27184437

RESUMO

A tremendous increase has been documented in the recent past in prescribing second generation atypical antipsychotic drugs (AAPDs) to the pregnant women with psychosis, considering their reproductive and teratogenic safety. Among AAPDs, risperidone (RIS) ranked third after olanzapine (OLZ) and quetiapine (QUE) used during pregnancy, as OLZ is associated to substantial weight gain in adults and offspring. Although teratogenic safety of RIS has been established, its potential role in developmental neurotoxicity and related neurobehavioral impairments in adolescents has not been documented so far. Therefore, present study has been undertaken to elucidate the effect of prenatal exposure to risperidone (RIS) on developmental neurotoxicity and apoptotic neurodegeneration in neocortical region of fetal brain; and related functional sequelae in young rat offspring. The pregnant Wistar rats were exposed to RIS at 0.8, 1.0 and 2.0mg/kg, at equivalent therapeutic doses, orally from GD 6 to 21. Half of the pregnant rats were sacrificed and their brains were collected, weighed, and processed for neurohistopathological and apoptotic neurodegenerative evaluation. The remaining dams were allowed to deliver naturally, and their offspring were reared up to 10 weeks for neurobehavioral study. Prenatal exposure to RIS induced significant stunting of fetal body and brain weight, substantial reduction in the thickness of neocortical layers and apoptotic neurodegeneration in fetal brains, and delayed postnatal development and growth of the offspring; as well as long- lasting impact on anxiety like impaired behavioral responses on explorative mazes. Therefore, health care providers should be careful in prescribing atypical antipsychotics in general and RIS in particular, to the pregnant psychotic population.


Assuntos
Antipsicóticos/toxicidade , Apoptose/efeitos dos fármacos , Deficiências do Desenvolvimento/etiologia , Síndromes Neurotóxicas/etiologia , Efeitos Tardios da Exposição Pré-Natal , Risperidona/toxicidade , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Anexina A5/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Encéfalo/ultraestrutura , Relação Dose-Resposta a Droga , Comportamento Exploratório , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microscopia Eletrônica , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos
10.
Environ Toxicol Pharmacol ; 41: 89-94, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26667671

RESUMO

The contamination of rivers and other natural water bodies, including underground waters, is a current reality. Human occupation and some economic activities generate a wide range of contaminated effluents that reach these water resources, including psychotropic drug residues. Here we show that fluoxetine, diazepam and risperidone affected the initial development of zebrafish. All drugs increased mortality rate and heart frequency and decreased larvae length. In addition, risperidone and fluoxetine decreased egg hatching. The overall results points to a strong potential of these drugs to cause a negative impact on zebrafish initial development and, since the larvae viability was reduced, promote adverse effects at the population level. We hypothesized that eggs and larvae absorbed the drugs that exert its effects in the central nervous system. These effects on early development may have significant environmental implications.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Psicotrópicos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Diazepam/toxicidade , Feminino , Fluoxetina/toxicidade , Larva/efeitos dos fármacos , Masculino , Mortalidade , Risperidona/toxicidade , Peixe-Zebra/embriologia
11.
PLoS One ; 10(10): e0139717, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26448615

RESUMO

OBJECTIVE: The present study aimed to evaluate the efficacy and safety of adjunctive aripiprazole treatment in schizophrenia patients with risperidone-induced hyperprolactinemia. METHODS: One hundred and thirteen patients who were receiving a stable dose of risperidone were randomly assigned to either adjunctive aripiprazole treatment (10 mg/day) (aripiprazole group) or no additional treatment (control group) at a 1:1 ratio for 8 weeks. Schizophrenia symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Rating scales and safety assessments (RSESE, BARS, UKU) were performed at baseline and at weeks 4 and 8. Serum levels of prolactin were determined at baseline and at weeks 2, 4, 6 and 8. Metabolic parameters were determined at baseline and again at weeks 4 and 8. RESULTS: One hundred and thirteen patients were enrolled in this study, and 107 patients completed the study (54 in the aripiprazole group, and 53 in the control group). PANSS-total scores in the aripiprazole group decreased significantly at week 4 (P = 0.003) and week 8 (P = 0.007) compared with the control group. PANSS-negative scores in the aripiprazole group also decreased significantly at week 4 (P = 0.005) and week 8 (P< 0.001) compared with the control group. Serum levels of prolactin in the aripiprazole group decreased significantly at week 2 (P< 0.001), week 4 (P< 0.001), week 6 (P< 0.001) and week 8 (P< 0.001) compared with the control group. There were no significant differences in changes of Fasting Plasma Glucose, Total cholesterol, Triglycerides and High Density Lipoprotein within each group at week 4 and 8 execpt low density lipoproteins. There was no significant difference in the incidence of adverse reactions between the two groups. CONCLUSIONS: Adjunctive aripiprazole treatment may be beneficial in reducing serum levels of prolactin and improving negative symptoms in schizophrenia patients with risperidone-induced hyperprolactinemia. TRIAL REGISTRATION: chictr.org ChiCTR-IOR-15006278.


Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Hiperprolactinemia/induzido quimicamente , Risperidona/toxicidade , Esquizofrenia/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Glicemia/análise , Índice de Massa Corporal , Colesterol/sangue , Esquema de Medicação , Etoposídeo , Feminino , Humanos , Hiperprolactinemia/complicações , Lipoproteínas HDL/sangue , Masculino , Mitoxantrona , Prednisona , Prolactina/sangue , Escalas de Graduação Psiquiátrica , Risperidona/uso terapêutico , Esquizofrenia/complicações , Resultado do Tratamento , Triglicerídeos/sangue , Vincristina
12.
Hum Exp Toxicol ; 34(2): 205-23, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24812153

RESUMO

Long-acting injectable formulations of antipsychotics have been an important treatment option to increase the compliance of the patient with schizophrenia by monitoring drug administration and identifying medication noncompliance and to improve the long-term management of schizophrenia. Risperidone, a serotoninergic 5-HT2 and dopaminergic D2 receptor antagonist, was developed to be a long-acting sustained-release formulation for the treatment of schizophrenia. In this study, 12-week subchronic toxicity study of risperidone-loaded microspheres (RMs) in rats by intramuscular injection with an 8-week recovery phase was carried out to investigate the potential subchronic toxicity of a novel long-acting sustained-release formulation. The results indicated that the dosage of 10-90 mg/kg of RM for 2 weeks did not cause treatment-related mortality. The main drug-related findings were contributed to the dopamine D2 receptor and α1-adrenoceptor antagonism of risperidone such as elevation of serum and pituitary prolactin levels and ptosis and changes in reproductive system (uterus, ovary, vagina, mammary gland, testis, seminal vesicle, epididymis, and prostate). In addition, foreign body granuloma in muscle at injection sites caused by poly-lactide-co-glycolide was observed. At the end of the recovery phase, these changes mostly returned to normal. The results indicated that RM had a good safety profile in rats.


Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/toxicidade , Risperidona/administração & dosagem , Risperidona/toxicidade , Animais , Antipsicóticos/farmacocinética , Peso Corporal/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/toxicidade , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/toxicidade , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/patologia , Genitália Masculina/efeitos dos fármacos , Genitália Masculina/patologia , Granuloma de Corpo Estranho/induzido quimicamente , Injeções Intramusculares , Contagem de Leucócitos , Masculino , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Microesferas , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/patologia , Prolactina/sangue , Prolactina/metabolismo , Ratos Sprague-Dawley , Risperidona/farmacocinética , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/toxicidade , Testes de Toxicidade Subcrônica
13.
J Anal Toxicol ; 38(1): 57-60, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24324228

RESUMO

Postmortem femoral blood concentrations of the antipsychotic drug risperidone and the active metabolite 9-hydroxyrisperidone were determined by an achiral LC-MS/MS method in 38 cases. The cause of death was classified as unrelated to risperidone in 30 cases, in which the sum of the concentration of the drug and metabolite ranged from below the limit of quantification to 0.058 mg/kg (median 0.0098 mg/kg). This concentration range, which largely corresponds to published in vivo plasmalevels under therapy, may serve as a reference for judgment of postmortem cases involving risperidone. In one case, risperidone was judged to be a contributing factor to death, and the sum of concentrations was 0.29 mg/kg. This concentration is of the same order of magnitude as observed for plasma levels in clinical intoxication cases. For the remaining seven cases, the cause of death was unclear. The measurements observed here do not suggest that risperidone is subject to major postmortem redistribution.


Assuntos
Antipsicóticos/sangue , Autopsia/métodos , Isoxazóis/sangue , Pirimidinas/sangue , Risperidona/sangue , Cromatografia Líquida , Feminino , Artéria Femoral , Humanos , Pessoa de Meia-Idade , Palmitato de Paliperidona , Valores de Referência , Risperidona/toxicidade , Esquizofrenia/mortalidade , Espectrometria de Massas em Tandem
14.
Hum Exp Toxicol ; 33(5): 473-87, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-23925946

RESUMO

Long-acting formulations of antipsychotics are important treatment options to increase the compliance of schizophrenic patients. Risperidone, a 5-HT2 and dopaminergic D2 receptor antagonist, was developed as long-acting sustained-release microspheres with poly(lactide-co-glycolide) (PLGA) as a drug carrier for the treatment of schizophrenia. In the present study, the main objective is to determine the nonclinical safety profile of risperidone-loaded microspheres (RM) in Beagle dogs after intramuscular administration for 3 months, once in 2 weeks, followed by 8-week recovery phase. No animal death was found and no special toxicological findings were observed. The findings, such as hypoactivity, ptosis, increased heart rate, and elevated serum and pituitary prolactin levels, were observed and related to the pharmacological effects of risperidone. The changes in the reproductive system (uterus, ovary, vagina, cervix, and mammary gland) were considered secondary to the prolactin elevation, and the congestion of spleen was related to risperidone. The foreign body granulomas at injection sites might be caused by PLGA. At the end of recovery phase, the above changes mostly recovered to normal, and on administering 3 mg/kg dose level once in 2 weeks on Beagle dogs showed no observed adverse effect. Taken together, RM had exhibited the acceptable safety.


Assuntos
Antipsicóticos/toxicidade , Microesferas , Risperidona/toxicidade , Animais , Antipsicóticos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cães , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/toxicidade , Eletrocardiografia , Comportamento Alimentar/efeitos dos fármacos , Feminino , Testes Hematológicos , Injeções Intramusculares , Masculino , Risperidona/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/toxicidade
15.
J Cardiovasc Pharmacol ; 60(2): 165-71, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22561361

RESUMO

Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Bepridil/toxicidade , Sistema de Condução Cardíaco/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Piperidinas/toxicidade , Piridinas/toxicidade , Torsades de Pointes/induzido quimicamente , Testes de Toxicidade , Animais , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Técnicas In Vitro , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Bloqueadores dos Canais de Potássio/farmacologia , Medição de Risco , Risperidona/toxicidade , Fatores de Tempo , Torsades de Pointes/metabolismo , Torsades de Pointes/fisiopatologia , Testes de Toxicidade/métodos , Verapamil/toxicidade , Imagens com Corantes Sensíveis à Voltagem
16.
Toxicology ; 299(2-3): 90-8, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22595365

RESUMO

RISPERDAL(®) CONSTA(®) is a long-acting, intramuscular formulation of risperidone microspheres for the biweekly treatment of schizophrenia and other psychiatric disorders. In a 24-month carcinogenicity study male and female Wistar Hannover rats received RISPERDAL(®) CONSTA(®) by intramuscular injection at dosages of 5 or 40 mg/kg once every 2 weeks. Bone changes described as "osteodystrophy" were observed by routine microscopic examination at 40 mg/kg in the sternum of female rats after 12 months, and in the sternum and stifle joint of both male and female rats after 24 months of treatment, respectively. To investigate the etiology of these bone changes, a 12-month mechanistic study was conducted in female Wistar Hannover rats at dosages of 5, 20 and 40 mg/kg once every 2 weeks. In addition to routine parameters, this study included bone markers, hormone measurements, and peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA) bone density measurements. It revealed a treatment-related reduction in metaphyseal trabecular bone density of the femur and tibia at 20 and 40 mg/kg, which was evident in the tibia from Week 13 of treatment onwards. There was no convincing evidence for any of the modes of action known to underlie trabecular bone loss in rats including renal, nutritional, or hepatic osteodystrophy, estrogen deficiency, hyperthyroidism or glucocorticoid excess. It is hypothetized that prolonged hyperprolactinemia accompanied by an increase in parathyroid hormone-related protein (PTHrP) levels and a slight hypoestrogenic state could have caused the reduced trabecular bone density in RISPERDAL(®) CONSTA(®)-treated rats. The relevance of this finding in terms of human risk is unknown.


Assuntos
Antipsicóticos/farmacologia , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas/induzido quimicamente , Risperidona/farmacologia , Absorciometria de Fóton , Fosfatase Alcalina/sangue , Animais , Antipsicóticos/toxicidade , Doenças Ósseas/sangue , Doenças Ósseas/patologia , Calcitonina/sangue , Colágeno Tipo I/sangue , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Peptídeos/sangue , Prolactina/sangue , Distribuição Aleatória , Ratos , Ratos Wistar , Risperidona/toxicidade , Hormônios Tireóideos/sangue , Tíbia/efeitos dos fármacos , Tíbia/patologia , Tomografia Computadorizada por Raios X
17.
CNS Neurosci Ther ; 18(4): 343-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22486847

RESUMO

BACKGROUND: Stroke is the second most common cause of death and a major cause of disability worldwide. Risperidone is an atypical antipsychotic drug that may increase the risk of stroke. The present work examined whether risperidone enhances the vulnerability to stroke in hypertensive rats and the potential mechanisms underlying such action. METHODS: Experiment 1: Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHR-SPs) were treated with risperidone (0.8 and 2.4 mg/kg/d) or vehicle for 30 consecutive days. Tissue damage in response to middle cerebral artery occlusion (MCAO) was measured microscopically. The activity of superoxide dismutase, glutathione peroxidase, the levels of malondialdehyde were also determined. Experiment 2: Survival data were recorded in SHR-SPs that received daily risperidone perpetually. Experiment 3: Effect of risperidone on interleukin-6 and tumor necrosis factor-α was examined in quiescent or LPS-activated cortical microglias from WKY rats. Experiment 4: Potential damage of risperidone exposure to neurons was examined in primary neuronal culture obtained from WKY rats, SHRs, and SHR-SPs. RESULTS: Risperidone increased infarct areas upon MCAO in SHR-SPs and SHRs, but not in WKY rats. Survival time in SHR-SPs was shortened by risperidone. Apoptosis was augmented by risperidone through enhanced Bax. Risperidone also increased endothelial injury. CONCLUSIONS: Risperidone enhances the vulnerability to stroke in hypertensive rats through increasing neuronal apoptosis and endothelial injury.


Assuntos
Hipertensão/patologia , Risperidona/toxicidade , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Hipertensão/complicações , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/etiologia
18.
Pak J Pharm Sci ; 25(1): 261-6, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22186339

RESUMO

Multiple drug administration is an important aspect of clinical practice particularly in specific physiological situation such as in neonates, elderly or pregnancy, since in all such situations, possibility of unwanted effects increases due to altered body physiology. In present study, the teratogenic effects of multiple drug administration risperidone, meclizine/pyridoxine and hydralazine have been compared with the teratogenic effects of individual drugs in pregnant mice. Moreover the role of folic acid and α-tocopherol if any had also been investigated in reducing the teratogenic effects of these drugs in combinations.


Assuntos
Anormalidades Induzidas por Medicamentos/prevenção & controle , Antieméticos/toxicidade , Anti-Hipertensivos/toxicidade , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Piridoxina/uso terapêutico , Risperidona/toxicidade , alfa-Tocoferol/uso terapêutico , Animais , Antieméticos/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas , Feminino , Peso Fetal/efeitos dos fármacos , Hidralazina/administração & dosagem , Hidralazina/toxicidade , Meclizina/administração & dosagem , Meclizina/toxicidade , Camundongos , Risperidona/administração & dosagem , Natimorto
19.
Artigo em Inglês | MEDLINE | ID: mdl-21878360

RESUMO

The neurotoxicity of antipsychotic (AP) drugs seems to be linked with neurological side effects like extrapyramidal symptoms (EPS). On the other hand, neuroprotective effects can mitigate or slow the progressive degenerative structural changes in the brain leading to improved outcome of schizophrenia. First and second-generation antipsychotics may differ in their neurotoxic and neuroprotective properties. The aim of this study was to compare the neurotoxic/neuroprotective activity of haloperidol, a first-generation antipsychotic, and risperidone, a second-generation one, with paliperidone, a relatively new second-generation antipsychotic, in SK-N-SH cells. Haloperidol, risperidone and paliperidone (10, 50, 100 µM) were administered, either alone or in combination with dopamine (100 µM), to human neuroblastoma SK-N-SH. We examined the effects of the drugs on cell viability (measured by alamarBlue®), caspase-3 activity (measured by fluorimetric assay) and cell death (by measuring the externalization of phosphatidylserine). Haloperidol significantly decreased cell viability and increased caspase-3 activity and cell death. Risperidone and paliperidone did not affect cell viability or cell death. Both second-generation APs decreased caspase-3 activity, especially paliperidone. In cells treated with dopamine in combination with antipsychotics, only paliperidone (10 µM) induced a slight improvement in cell viability. While haloperidol potentiated the dopamine-induced increase in caspase-3 activity, risperidone and paliperidone reduced this effect. The results indicate that haloperidol induces apoptosis, whereas risperidone and paliperidone may afford protection against it. Of the APs tested, paliperidone always showed the strongest neuroprotective effect. The different antipsychotic effects on survival and cell death might be related to differences in their capacity to induce EPS.


Assuntos
Haloperidol/toxicidade , Isoxazóis/toxicidade , Neuroblastoma/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pirimidinas/toxicidade , Risperidona/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Haloperidol/uso terapêutico , Humanos , Isoxazóis/uso terapêutico , Neuroblastoma/patologia , Palmitato de Paliperidona , Pirimidinas/uso terapêutico , Risperidona/uso terapêutico
20.
Schizophr Bull ; 38(1): 153-66, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20494946

RESUMO

Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague-Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition. The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.


Assuntos
Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos não Esterificados/metabolismo , Resistência à Insulina/fisiologia , Lipólise/efeitos dos fármacos , Animais , Antipsicóticos/toxicidade , Benzodiazepinas/toxicidade , Carnitina/análogos & derivados , Carnitina/metabolismo , Clozapina/farmacologia , Clozapina/toxicidade , Feminino , Haloperidol/farmacologia , Haloperidol/toxicidade , Masculino , Malonil Coenzima A/metabolismo , Camundongos , Olanzapina , Piperazinas/farmacologia , Piperazinas/toxicidade , Ratos , Ratos Sprague-Dawley , Risperidona/farmacologia , Risperidona/toxicidade , Tiazóis/farmacologia , Tiazóis/toxicidade , Complexo Vitamínico B/metabolismo
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