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Antipsicóticos/antagonistas & inhibidores , Piperazinas/antagonistas & inhibidores , Psicosis Inducidas por Sustancias/etiología , Té/efectos adversos , Tiazoles/antagonistas & inhibidores , Antipsicóticos/uso terapéutico , Interacciones Alimento-Droga , Humanos , Masculino , Piperazinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Tiazoles/uso terapéutico , Adulto JovenRESUMEN
Epstein-Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in infected cultured cells by drugs such as sodium butyrate and azacytidine. Lytic reactivation can be inhibited by natural products and pharmaceuticals. The anticonvulsant drugs valproic acid and valpromide inhibit EBV in Burkitt lymphoma cells. Therefore, other drugs that treat neurological and psychological disorders were investigated for effects on EBV lytic reactivation. Clozapine, an atypical antipsychotic drug used to treat schizophrenia and bipolar disorder, was found to inhibit the reactivation of the EBV lytic cycle. Levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 were decreased by treatment with clozapine in induced Burkitt lymphoma cells. The effects on viral gene expression were dependent on the dose of clozapine, yet cells were viable at an inhibitory concentration of clozapine. One metabolite of clozapine-desmethylclozapine-also inhibited EBV lytic reactivation, while another metabolite-clozapine-N-oxide-had no effect. These drugs may be used to study cellular pathways that control the viral lytic switch in order to develop treatments for diseases caused by EBV.
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Antipsicóticos/antagonistas & inhibidores , Clozapina/antagonistas & inhibidores , Herpesvirus Humano 4/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Linfoma de Burkitt , Línea Celular Tumoral , Clozapina/análogos & derivados , Clozapina/química , Relación Dosis-Respuesta a Droga , Infecciones por Virus de Epstein-Barr/virología , Regulación Viral de la Expresión Génica/efectos de los fármacos , Herpesvirus Humano 4/genética , Humanos , Proteínas Inmediatas-Precoces/metabolismo , Fosfoproteínas/metabolismo , Transactivadores/metabolismo , Activación Viral/efectos de los fármacos , Latencia del Virus/genéticaRESUMEN
BACKGROUND: Olanzapine (OLZ) is a second-generation antipsychotic drug used for treatment of schizophrenia, bipolar disorder, and other neuropsychiatric conditions. Undesirable side effects of OLZ include metabolic alterations associated with chronic oxidative-inflammation events. It is possible that lithium (Li), a mood modulator that exhibits anti-inflammatory properties may attenuate OLZ-induced oxi-inflammatory effects. METHODOLOGY: To test this hypothesis we activated RAW 264.7 immortalized macrophages with OLZ and evaluated oxidation and inflammation at the gene and protein levels. Li and OLZ concentrations were determined using estimated plasma therapeutic concentrations. RESULTS: OLZ triggered a significant increase in macrophage proliferation at 72 h. Higher levels of oxidative markers and proinflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, with a concomitant reduction in IL-10, were observed in OLZ-exposed macrophages. Lithium (Li) exposure triggered a short and attenuated inflammatory response demonstrated by elevation of superoxide anion (SA), reactive oxygen species (ROS), IL-1ß, and cellular proliferation followed by elevation of anti-inflammatory IL-10 levels. Li treatment of OLZ-supplemented macrophages was able to reverse elevation of oxidative and inflammatory markers and increase IL-10 levels. CONCLUSIONS: Despite methodological limitations related to in vitro protocols, results suggested that Li may attenuate OLZ-induced oxidative and inflammatory responses that result from metabolic side effects associated with OLZ.
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Antipsicóticos/efectos adversos , Antipsicóticos/antagonistas & inhibidores , Litio/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Olanzapina/efectos adversos , Olanzapina/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos , Proliferación Celular/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/prevención & control , Macrófagos/citología , Ratones , Estrés Oxidativo/efectos de los fármacos , Células RAW 264.7RESUMEN
This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m2) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. Trial registration PROSPERO: CRD42016039735.
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Antipsicóticos/efectos adversos , Sustancias Protectoras/uso terapéutico , Ranitidina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Aumento de Peso/efectos de los fármacos , Adulto , Antipsicóticos/antagonistas & inhibidores , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Femenino , Humanos , Masculino , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto , Esquizofrenia/fisiopatologíaRESUMEN
The aim of this study was to investigate the mechanisms underlying the inhibitory effects of berberine (BBR) on olanzapine (OLZ)-induced adipogenesis in a well-replicated 3T3-L1 cell model. Oil-Red-O (ORO) staining showed that BBR significantly decreased OLZ-induced adipogenesis. Co-treatment with OLZ and BBR decreased the accumulation of triglyceride (TG) and total cholesterol (TC) by 55.58% ± 3.65% and 49.84% ± 8.31%, respectively, in 3T3-L1 adipocytes accompanied by reduced expression of Sterol regulatory element binding proteins 1 (SREBP1), fatty acid synthase (FAS), peroxisome proliferator activated receptor-γ (PPARγ), SREBP2, low-density lipoprotein receptor (LDLR), and hydroxymethylglutaryl-coenzyme A reductase (HMGR) genes compared with OLZ alone. Consistently, the co-treatment downregulated protein levels of SREBP1, SREBP2, and LDLR by 57.71% ± 9.42%, 73.05% ± 11.82%, and 59.46% ± 9.91%, respectively. In addition, co-treatment reversed the phosphorylation level of AMP-activated protein kinase-α (AMPKα), which was reduced by OLZ, determined via the ratio of pAMPKα:AMPKα (94.1%) compared with OLZ alone. The results showed that BBR may prevent lipid metabolism disorders caused by OLZ by reversing the degree of SREBP pathway upregulated and the phosphorylation of AMPKα downregulated. Collectively, these results indicated that BBR could be used as a potential adjuvant to prevent dyslipidemia and obesity caused by the use of second-generation antipsychotic medication.
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Proteínas Quinasas Activadas por AMP/genética , Adipocitos/efectos de los fármacos , Antipsicóticos/antagonistas & inhibidores , Benzodiazepinas/antagonistas & inhibidores , Berberina/farmacología , Hipolipemiantes/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos/citología , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Animales , Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Diferenciación Celular , Colesterol/biosíntesis , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Regulación de la Expresión Génica , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/genética , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Ratones , Olanzapina , PPAR gamma/genética , PPAR gamma/metabolismo , Fosforilación/efectos de los fármacos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/antagonistas & inhibidores , Triglicéridos/biosíntesisRESUMEN
Tardive Dyskinesia is a severe side effect of chronic neuroleptic treatment consisting of abnormal involuntary movements, characterized by orofacial dyskinesia. The study was designed to investigate the protective effect of lycopene against haloperidol induced orofacial dyskinesia possibly by neurochemical and neuroinflammatory modulation in rats. Rats were administered with haloperidol (1mg/kg, i.p for 21 days) to induce orofacial dyskinesia. Lycopene (5 and 10mg/kg, p.o) was given daily 1hour before haloperidol treatment for 21 days. Behavioral observations (vacuous chewing movements, tongue protrusions, facial jerking, rotarod activity, grip strength, narrow beam walking) were assessed on 0th, 7th(,) 14th(,) 21st day after haloperidol treatment. On 22nd day, animals were killed and striatum was excised for estimation of biochemical parameters (malondialdehyde, nitrite and endogenous enzyme (GSH), pro-inflammatory cytokines [Tumor necrosis factor, Interleukin 1ß, Interleukin 6] and neurotransmitters level (dopamine, serotonin, nor epinephrine, 5-Hydroxyindole acetic acid (5-HIAA), Homovanillic acid, 3,4- dihydroxyphenylacetic acid. Haloperidol treatment for 21 days impaired muscle co-ordination, motor activity and grip strength with an increased in orofacial dyskinetic movements. Further free radical generation increases MDA and nitrite levels, decreasing GSH levels in striatum. Neuroinflammatory markers were significantly increased with decrease in neurotransmitters levels. Lycopene (5 and 10mg/kg, p.o) treatment along with haloperidol significantly attenuated impairment in behavioral, biochemical, neurochemical and neuroinflammatory markers. Results of the present study attributed the therapeutic potential of lycopene in the treatment (prevented or delayed) of typical antipsychotic induced orofacial dyskinesia.
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Antioxidantes/farmacología , Antipsicóticos/antagonistas & inhibidores , Carotenoides/farmacología , Haloperidol/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Trastornos del Movimiento/tratamiento farmacológico , Neurotransmisores/metabolismo , Animales , Antiinflamatorios/farmacología , Antipsicóticos/toxicidad , Conducta Animal/efectos de los fármacos , Haloperidol/toxicidad , Fuerza de la Mano , Peroxidación de Lípido/efectos de los fármacos , Licopeno , Masculino , Actividad Motora/efectos de los fármacos , Trastornos del Movimiento/psicología , Neostriado/efectos de los fármacos , Neostriado/enzimología , Neostriado/metabolismo , Ratas , Ratas WistarRESUMEN
Loxapine substitution is a promising option for patients with autism spectrum disorder (ASD) who develop antipsychotic-induced metabolic illness. We performed a chart review of 15 adolescents and adults meeting DSM-IV-TR criteria for ASD, all with antipsychotic-associated weight gain, who received low dose loxapine in an attempt to taper or discontinue the weight gain-associated antipsychotic. Mean weight loss was -5.7 kg, mean BMI reduction was -1.9, and mean triglyceride reduction was -33.7 mg/dl. At chart review, 14 of 15 subjects were rated 2 (Much Improved) or 1 (Very Much Improved) on the Clinical Global Impressions-Improvement scale (CGI-I). Low dose loxapine addition in most cases enabled taper of offending antipsychotics, significantly reversed drug-induced metabolic disturbances and improved irritability.
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Antipsicóticos/efectos adversos , Antipsicóticos/antagonistas & inhibidores , Trastorno del Espectro Autista/tratamiento farmacológico , Loxapina/uso terapéutico , Registros Médicos , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/tratamiento farmacológico , Adolescente , Adulto , Antipsicóticos/uso terapéutico , Trastorno del Espectro Autista/complicaciones , Femenino , Humanos , Genio Irritable/efectos de los fármacos , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Adulto JovenRESUMEN
Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p < 0.0005 and p < 0.0001, respectively). The study demonstrated the effectiveness of metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone.
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Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Antipsicóticos/antagonistas & inhibidores , Bloqueadores de los Canales de Calcio/uso terapéutico , Diltiazem/uso terapéutico , Síndrome de QT Prolongado/prevención & control , Metoprolol/uso terapéutico , Piperazinas/antagonistas & inhibidores , Tiazoles/antagonistas & inhibidores , Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Anestesia , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/uso terapéutico , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Bloqueadores de los Canales de Calcio/administración & dosificación , Diltiazem/administración & dosificación , Electrocardiografía , Corazón/efectos de los fármacos , Corazón/fisiología , Inyecciones Intraperitoneales , Síndrome de QT Prolongado/inducido químicamente , Masculino , Metoprolol/administración & dosificación , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Distribución Aleatoria , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/antagonistas & inhibidores , Tiazoles/administración & dosificación , Tiazoles/efectos adversosRESUMEN
Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisia-like behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A2A receptor antagonists for the treatment of antipsychotic-induced movement disorders.
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Antagonistas del Receptor de Adenosina A2/farmacología , Acatisia Inducida por Medicamentos/tratamiento farmacológico , Acatisia Inducida por Medicamentos/fisiopatología , Acatisia Inducida por Medicamentos/psicología , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/antagonistas & inhibidores , Antipsicóticos/toxicidad , Aripiprazol , Conducta Animal/efectos de los fármacos , Cebus , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Haloperidol/administración & dosificación , Haloperidol/antagonistas & inhibidores , Haloperidol/toxicidad , Humanos , Masculino , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/toxicidad , Piperazinas/administración & dosificación , Piperazinas/antagonistas & inhibidores , Piperazinas/toxicidad , Pirazoles/administración & dosificación , Pirazoles/antagonistas & inhibidores , Pirazoles/toxicidad , Pirimidinas/farmacología , Quinolinas/administración & dosificación , Quinolinas/antagonistas & inhibidores , Quinolinas/toxicidad , Quinolonas/administración & dosificación , Quinolonas/antagonistas & inhibidores , Quinolonas/toxicidad , Triazoles/farmacologíaRESUMEN
Lurasidone is a novel atypical antipsychotic with high affinity for dopamine D2, serotonin 5-HT7 and 5-HT2A receptors. We previously reported that lurasidone and the selective 5-HT7 receptor antagonist, SB-656104-A improved learning and memory deficits induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, in the rat passive avoidance test. In this study, we first examined the role of the 5-HT7 receptor antagonistic activity of lurasidone in its pro-cognitive effect to ameliorate MK-801-induced deficits in the rat passive avoidance test. The 5-HT7 receptor agonist, AS19, (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin, (3 mg/kg, s.c.) completely blocked the attenuating effects of lurasidone (3 mg/kg, p.o.), highlighting the importance of 5-HT7 receptor antagonism in the pro-cognitive effect of lurasidone. AS19 (3 mg/kg, s.c.) also blocked the ameliorating effect of SB-656104-A (10 mg/kg, i.p.) in the same experimental paradigm. To further extend our observation, we next tested whether 5-HT7 receptor antagonism still led to the amelioration of MK-801-induced deficits when combined with D2 and 5-HT2A receptor antagonists, and found that SB-656104-A (10 mg/kg, i.p.) significantly ameliorated MK-801-induced deficits even in the presence of the D2 receptor antagonist raclopride (0.1 mg/kg, s.c.) and 5-HT2A receptor antagonist ketanserin (1 mg/kg, s.c.). Taken together, these results suggest that the 5-HT7 receptor antagonistic activity of lurasidone plays an important role in its effectiveness against MK-801-induced deficits, and may contribute to its pharmacological actions in patients with schizophrenia.
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Reacción de Prevención/efectos de los fármacos , Maleato de Dizocilpina/antagonistas & inhibidores , Isoindoles/farmacología , Memoria/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Tiazoles/farmacología , Animales , Antipsicóticos/antagonistas & inhibidores , Antipsicóticos/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Dopamina/farmacología , Isoindoles/antagonistas & inhibidores , Ketanserina/farmacología , Clorhidrato de Lurasidona , Masculino , Fenoles/farmacología , Pirazoles/farmacología , Pirrolidinas/farmacología , Racloprida/farmacología , Ratas , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Tetrahidronaftalenos/farmacología , Tiazoles/antagonistas & inhibidoresAsunto(s)
Anciano , Antipsicóticos/efectos adversos , Antipsicóticos/antagonistas & inhibidores , Catatonia/tratamiento farmacológico , Isoxazoles/administración & dosificación , Isoxazoles/efectos adversos , Isoxazoles/uso terapéutico , Lorazepam/uso terapéutico , Síndrome Neuroléptico Maligno/etiología , Palmitatos/administración & dosificación , Palmitatos/efectos adversos , Trastornos Psicóticos/tratamiento farmacológico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Femenino , Humanos , MasculinoRESUMEN
Quetiapine overdose is a clinical entity commonly encountered in emergency departments. Quetiapine is a drug with many mechanisms, including antimuscarinic effects. Traditionally, treatment of quetiapine toxicity has been primarily supportive care. Case reports exist documenting improvement in mental status in these patients after administration of physostigmine, a carbamate capable of reversing antimuscarinic toxicity. In this descriptive case series, 3 patients with quetiapine toxicity treated with physostigmine are reported. In each case, the patient had significant altered mental status that was rapidly reversed with administration of physostigmine. In all 3 cases, patient disposition was changed to a lower level of care, requiring less invasive monitoring. In 1 case, intubation was prevented. Because quetiapine toxicity is commonly encountered and the use of physostigmine in this setting is a potentially practice-altering treatment, emergency physicians should be aware of this phenomenon.
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Antipsicóticos/efectos adversos , Inhibidores de la Colinesterasa/uso terapéutico , Trastornos de la Conciencia/inducido químicamente , Dibenzotiazepinas/efectos adversos , Fisostigmina/uso terapéutico , Adulto , Antipsicóticos/antagonistas & inhibidores , Trastornos de la Conciencia/tratamiento farmacológico , Dibenzotiazepinas/antagonistas & inhibidores , Sobredosis de Droga/tratamiento farmacológico , Servicio de Urgencia en Hospital , Femenino , Escala de Coma de Glasgow , Humanos , Masculino , Fumarato de Quetiapina , Adulto JovenRESUMEN
Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects (EPS). Role of 5-HT-2A/2C receptors in the attenuation of acute Parkinsonian-like effects of typical antipsychotics is investigated by prior administration of mianserin and mesulergine to rats injected with haloperidol. In the first part of study effects of various doses of haloperidol (0.5, 1.0, 2.5 and 5.0 mg/kg) were determined on motor activity and a selected dose (1 mg/kg) was used to monitor attenuation of parkinsonian effects by two different doses of 5-HT-2A/2C receptor antagonists mianserin (2.5 & 5.0 mg/kg) and mesulergine (1.0 & 3.0 mg/kg). Rats treated with haloperidol at doses of 0.5-5.0 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity in an open field. The dose response curve showed that at a dose of 1 mg/kg significant and submaximal effects are produced on motor coordination and exploratory activity. Coadministration of mianserin and mesulergine attenuated and reversed haloperidol-induced motor deficits in a dose dependent manner. The mechanism involved in the attenuation / reversal of haloperidol-induced parkinsonian like symptoms by mianserin and mesulergine is discussed. Prior administration of mianserin or mesulergine may be of use in the alleviation of EPS induced by conventional antipsychotic drugs.The findings have potential implication in the treatment of schizophrenia and motor disorders.
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Antipsicóticos/antagonistas & inhibidores , Agonistas de Dopamina/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Ergolinas/uso terapéutico , Haloperidol/antagonistas & inhibidores , Mianserina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Animales , Antipsicóticos/toxicidad , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Discinesia Inducida por Medicamentos/fisiopatología , Haloperidol/toxicidad , Masculino , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacosRESUMEN
OBJECTIVE: The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. METHODS: Behavioral experiments and electrophysiological recordings were performed in the present study. RESULTS: Bilateral infusions of neurotensin into the globus pallidus reversed haloperidol-induced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin. CONCLUSION: Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.
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Catalepsia/fisiopatología , Discinesia Inducida por Medicamentos/fisiopatología , Globo Pálido/fisiopatología , Haloperidol/toxicidad , Neurotensina/farmacología , Trastornos Parkinsonianos/fisiopatología , Animales , Antipsicóticos/antagonistas & inhibidores , Antipsicóticos/toxicidad , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/metabolismo , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Haloperidol/antagonistas & inhibidores , Masculino , Neurotensina/metabolismo , Neurotensina/uso terapéutico , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Ratas , Ratas WistarRESUMEN
RATIONALE: H(3)-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated. OBJECTIVES: We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H(3)-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine. RESULTS: Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine. CONCLUSIONS: Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.
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Antipsicóticos/antagonistas & inhibidores , Apomorfina/antagonistas & inhibidores , Maleato de Dizocilpina/antagonistas & inhibidores , Agonismo Inverso de Drogas , Inhibición Psicológica , Fenciclidina/antagonistas & inhibidores , Conducta Estereotipada/efectos de los fármacos , Animales , Antipsicóticos/farmacología , Apomorfina/farmacología , Benzofuranos/antagonistas & inhibidores , Maleato de Dizocilpina/farmacocinética , Haloperidol/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/antagonistas & inhibidores , Masculino , Metanfetamina/antagonistas & inhibidores , Metanfetamina/farmacología , Ratones , Fenciclidina/farmacología , Piperidinas/antagonistas & inhibidores , Pirrolidinas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
Novel thiazolotriazolopyrimidine derivatives (23-33) designed as potential adenosine A(2A) receptor (A(2A)R) antagonists were synthesized. Molecular docking studies revealed that all compounds (23-33) exhibited strong interaction with A(2A)R. The strong interaction of the compounds (23-33) with A(2A)R in silico was confirmed by their high binding affinity with human A(2A)R stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24-26 demonstrated substantial binding affinity and selectivity for A(2A)R as compared to SCH58261, a standard A(2A)R antagonist. Decrease in A(2A)R-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A(2A)R antagonist potential of the compounds 24-26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24-26 further supports their role in the alleviation of PD symptoms.
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Antagonistas del Receptor de Adenosina A2 , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tionas/síntesis química , Tionas/farmacología , Animales , Antipsicóticos/antagonistas & inhibidores , Antipsicóticos/farmacología , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cromatografía en Capa Delgada , Simulación por Computador , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Evaluación Preclínica de Medicamentos , Discinesia Inducida por Medicamentos/prevención & control , Haloperidol/antagonistas & inhibidores , Haloperidol/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Unión Proteica , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
The effect of risperidone and olanzapine on beta-cell function and mass was investigated in 90% pancreatectomized and ovariectomized female rats, of which some were treated with estrogen replacement and some were not. Ovariectomized diabetic rats were divided into two groups: one group received daily estrogen replacement (30 mug 17beta-estradiol/kg body weight) and the other group received a vehicle. Each group was further divided into three subgroups and orally given either a placebo, risperidone (0.5 mg/kg body weight), or olanzapine (2 mg/kg body weight) each day in conjunction with a high-fat diet for eight weeks. Ovariectomy reduced serum prolactin levels, while risperidone and estrogen replacement increased them. Olanzapine, not risperidone, increased body weight gain and epididymal fats, and impaired glucose tolerance in ovariectomized diabetic rats, while estrogen replacement improved them. This was related to changes in insulin secretion capacity. Ovariectomized rats had decreased beta-cell mass, due to decreasing beta-cell proliferation, compared with Sham rats, and olanzapine, but not risperidone, caused further reduction. Olanzapine reduced IRS2 protein levels in the islets of ovariectomized rats. Decreased IRS2 attenuated the phosphorylation of Akt and, subsequently, PDX-1 protein levels were lowered in olanzapine-treated rats. Estrogen replacement activated insulin/IGF-1 signaling regardless of treatment. In conclusion, olanzapine, but not risperidone, exacerbated glucose homeostasis partly by attenuating beta-cell function and mass in ovariectomized diabetic rats, while estrogen replacement reversed its negative impact. Further human studies are needed to support the claim that olanzapine should be avoided in the treatment of schizophrenic postmenopausal patients with diabetes.
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Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Diabetes Mellitus Experimental/metabolismo , Terapia de Reemplazo de Estrógeno , Células Secretoras de Insulina/efectos de los fármacos , Risperidona/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/crecimiento & desarrollo , Animales , Antipsicóticos/antagonistas & inhibidores , Benzodiazepinas/antagonistas & inhibidores , Western Blotting , Separación Celular , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Estradiol/sangre , Femenino , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Resistencia a la Insulina , Factor I del Crecimiento Similar a la Insulina/metabolismo , Olanzapina , Ovariectomía , Pancreatectomía , Prolactina/sangre , Ratas , Ratas Sprague-Dawley , Risperidona/antagonistas & inhibidores , Aumento de Peso/efectos de los fármacosRESUMEN
Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.
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Antagonistas del Receptor de Adenosina A2 , Cuerpo Estriado/efectos de los fármacos , Pimozida/antagonistas & inhibidores , Purinas/farmacología , Temblor/tratamiento farmacológico , Tropicamida/farmacología , Animales , Antipsicóticos/efectos adversos , Antipsicóticos/antagonistas & inhibidores , Biomarcadores/análisis , Biomarcadores/metabolismo , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Músculos Masticadores/inervación , Músculos Masticadores/fisiopatología , Antagonistas Muscarínicos/farmacología , Pimozida/efectos adversos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/metabolismo , Temblor/inducido químicamente , Temblor/fisiopatología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaAsunto(s)
Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Aumento de Peso/efectos de los fármacos , Adulto , Animales , Antipsicóticos/antagonistas & inhibidores , Antipsicóticos/uso terapéutico , Benzodiazepinas/antagonistas & inhibidores , Benzodiazepinas/uso terapéutico , Composición Corporal , Femenino , Humanos , Ratones , Olanzapina , Escalas de Valoración Psiquiátrica , Esquizofrenia/complicaciones , Esquizofrenia/tratamiento farmacológicoRESUMEN
The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age>or=18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.