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PURPOSE: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D2/D3 receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg. METHODS: Occupancy was measured at 4 and 23.5 h post-dose using the D2/D3 receptor antagonist [11C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel. RESULTS: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D2/D3 receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (Omax) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of Omax (EC50) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC∞) and maximum plasma concentration (Cmax) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort. CONCLUSION: By extrapolating the observed single-dose D2/D3 receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT00805454 December 9, 2008.
Assuntos
Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Quinolonas/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Tiofenos/farmacologia , Adulto , Área Sob a Curva , Corpo Estriado/diagnóstico por imagem , Agonistas de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Tomografia por Emissão de Pósitrons , Quinolonas/farmacocinética , Tiofenos/farmacocinéticaRESUMO
BACKGROUND: This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). METHOD: GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient's PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays. RESULTS: FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays. CONCLUSIONS: The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/análogos & derivados , Células Dendríticas/imunologia , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioma/imunologia , Imunoterapia/métodos , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Regulação para CimaRESUMO
Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 : or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.
Assuntos
Aripiprazol/farmacologia , Benzodiazepinas/farmacologia , Canabidiol/farmacologia , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Memória/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Risperidona/farmacologia , Animais , Antagonistas de Dopamina/farmacologia , Masculino , Modelos Animais , Olanzapina , Ratos , Receptores de Dopamina D2/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Comportamento SocialRESUMO
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.
Assuntos
Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dopamina/fisiologia , Serotonina/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Cognição/fisiologia , Relação Dose-Resposta a Droga , Macaca fascicularis , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Dopamina D2/fisiologia , Resultado do TratamentoRESUMO
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.
Assuntos
Dopaminérgicos/química , Dopaminérgicos/metabolismo , Dopamina/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Serotoninérgicos/química , Serotoninérgicos/metabolismo , Serotonina/metabolismo , Tiofenos/química , Tiofenos/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Humanos , Masculino , Ligação Proteica/fisiologia , Quinolonas/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Tiofenos/farmacologiaRESUMO
Using the GEOS-Chem atmosphere-land-ocean coupled mercury model, we studied the significances of two processes, soil emission and atmospheric oxidation-reduction, in the global biogeochemical cycling of mercury and their parametrization to improve model performance. Implementing an empirical equation for soil emission flux (Esoil) including soil mercury concentration, solar radiation, and surface air temperature as parameters enabled the model to reproduce the observed seasonal variations of Esoil, whereas the default setting, which uses only the former two parameters, failed. The modified setting of Esoil also increased the model-simulated atmospheric concentration in the summertime surface layer of the lower- and midlatitudes and improved the model reproducibility for the observations in Japan and U.S. in the same period. Implementing oxidation of atmospheric gaseous elemental mercury (Hg(0)) by ozone with an updated rate constant, as well as the oxidation by bromine atoms (Br) in the default setting, improved the model reproducibility for the dry deposition fluxes observed in Japan. This setting, however, failed to reproduce the observed seasonal variations of atmospheric concentrations in the Arctic sites due to the imbalance between oxidation and reduction, whereas the model with Br as the sole Hg(0) oxidant in the polar atmosphere could capture the variations.
Assuntos
Atmosfera/química , Mercúrio/análise , Modelos Teóricos , Solo/química , Regiões Árticas , Simulação por Computador , Japão , Oxirredução , Reprodutibilidade dos Testes , Estações do Ano , Poluentes do Solo/análise , Estados UnidosRESUMO
Dissolved organic matter (DOM) plays important roles not only in maintaining the productivity and functioning of aquatic ecosystems but also in the global carbon cycle, although the sources and biogeochemical functions of terrestrially derived DOM have not been fully elucidated, particularly in the tropics and subtropics. This study aimed to evaluate the factors influencing spatiotemporal variability in (i) the concentration and composition of DOM, including dissolved organic carbon (DOC), ultraviolet absorption coefficient at 254-nm wavelength (a254), and components identified by fluorescence excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC), and (ii) the concentration of dissolved iron (DFe) across freshwater systems (rivers, forested streams, and dam reservoirs) on a tropical island (Ishigaki Island, Japan) based on the results of water quality monitoring at 2-month intervals over a 2-year period. Random forests (RF) machine learning algorithm was employed, with the catchment characteristics (land use, soil type) and water temperature as the predictor variables for DOM and the composition of DOM (EEM-PARAFAC components) and hydrochemistry (water temperature, pH, and concentrations of divalent cations) as the predictor variables for DFe. The RF models for DOC, a254, and three humic-like components exhibited excellent predictive performance, indicating that these DOM properties are not only seasonally variable but also strongly influenced by the compositions of land uses and soil types in the upstream watershed. Poorly drained riparian lowland soil (Gleyic Fluvisols) was identified as the most important catchment parameter that positively influences these DOM variables. The RF model also explained a large portion of the variation in DFe, while terrestrial humic-like components were the most important parameters, emphasizing their significance as organic ligands for iron. These results improve our understanding of the impacts of terrestrial DOM and iron loadings on tropical and subtropical coastal ecosystems as well as on regional and global carbon budgets.
RESUMO
Excessive loadings of terrestrial nitrogen and phosphorus, as well as their imbalances with silicon, have been recognized as one of the major causes of water quality and ecosystem deterioration in receiving waters. In this study, a periodic water quality monitoring was conducted in the rivers and streams of a tropical island (Ishigaki Island, Japan) to identify the factors controlling the concentrations of dissolved inorganic nitrogen (DIN), total phosphorus (TP) and dissolved silicon (DSi) with a special focus on the catchment characteristics (e.g., land use, surface geology, topography). Random Forest (RF) machine learning algorithm was employed to develop predictive models for nutrient concentrations from the catchment properties. The developed models could predict nutrient concentrations with sufficient accuracy, demonstrating that the studied nutrients are strongly affected by catchment properties. Agricultural land uses (e.g., livestock barn, sugarcane field) were ranked as the most important parameters for DIN and TP, while broadleaf forest was the most influential factor for DSi. Using the RF models, the contributions of DIN originating from sugarcane fields (i.e., fertilizers) and barns (i.e., manure) to riverine DIN were estimated, which were up to 60% in total in the studied river basins. Furthermore, the yield of DIN from sugarcane fields, calculated as the concentration of DIN derived from sugarcane fields divided by the percent area of sugarcane fields, strongly positively correlated with the areal coverage of limestone, suggesting that fertilizer-derived DIN is more prone to leaching out from cropland soil to groundwater and rivers in catchments with a higher dominance of calcareous geology. These results, including the methodology employed, have implications for water quality assessment and management in inland and coastal waters not only at the study site but also other regions.
Assuntos
Monitoramento Ambiental , Poluentes Químicos da Água , Ecossistema , Silício , Poluentes Químicos da Água/análise , Fósforo/análise , Nitrogênio/análise , Fertilizantes , Nutrientes , Aprendizado de MáquinaRESUMO
AIM: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. METHODS: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. RESULTS: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). CONCLUSION: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.
Assuntos
Transtorno Depressivo Maior , Inibidores Seletivos de Recaptação de Serotonina , Camundongos , Animais , Fluoxetina/farmacologia , Paroxetina/farmacologia , Paroxetina/uso terapêutico , Sertralina/farmacologia , Natação , Transtorno Depressivo Maior/tratamento farmacológico , Escitalopram , Antidepressivos/uso terapêuticoRESUMO
Aripiprazole is a dopamine D/D3 and serotonin 5-HT1A receptor partial agonist which is approved for treatment of schizophrenia. We evaluated the pharmacological properties of aripiprazole, dopamine D2 receptor partial agonists and antipsychotics using forskolin-stimulated cAMP accumulation in cells expressing human dopamine D2 and D3 receptors. In cells expressing high densities of D2 receptor with high sensitivity for dopamine, the maximal agonist effects of partial agonists were higher than in cells expressing low densities of D2 receptor with low sensitivity for dopamine. Aripiprazole's intrinsic activities at D2 and D9 receptors were lower than those observed with partial agonists (terguride, bifeprunox, OPC-4392 and (-)-3-PPP), which demonstrated clinically suboptimal improvement of positive symptoms of schizophrenia patients, and higher than that of SDZ 208-912, which demonstrated incidence of extrapyramidal symptoms similar to haloperidol. Aripiprazole's appropriate intrinsic activities at D2 and D: receptors may contribute to desired results in a clinical profile. Antipsychotics (risperidone, olanzapine, amisulpride, sulpiride and perphenazine) which displayed antidepressive effects in schizophrenia patients behaved as preferential antagonists in cells expressing D2 receptors compared to cells expressing D3 receptors. Preferential antagonism at dopamine D2 receptors may play a role in the antidepressive effects of these antipsychotics.
Assuntos
Antipsicóticos/farmacologia , Piperazinas/farmacologia , Quinolonas/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Antipsicóticos/uso terapêutico , Aripiprazol , Células Cultivadas , Colforsina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Humanos , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/tratamento farmacológicoRESUMO
Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify® ). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti® ), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists.
Assuntos
Transtorno Depressivo Maior , Agonistas de Dopamina , Aripiprazol/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Dopamina , Agonistas de Dopamina/uso terapêutico , Humanos , Quinolonas , Pesquisa , Tiofenos , Estados UnidosRESUMO
Memantine, an n-methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer's disease, has a good safety profile and is increasingly being studied for possible use in a variety of non-dementia psychiatric disorders. There is an abundance of basic and clinical data that support the hypothesis that NMDA receptor hypofunction contributes to the pathophysiology of schizophrenia. However, there are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits. It remains unclear why memantine does not show undesirable central nervous system (CNS) side effects in humans unlike other NMDA receptor antagonists, such as phencyclidine and ketamine. However, the answer could lie in the fact that it would appear that memantine works as a low-affinity, fast off-rate, voltage-dependent, and uncompetitive antagonist with preferential inhibition of extrasynaptic receptors. It is reasonable to assume that the effects of memantine as adjunctive therapy on negative symptoms and cognitive deficits in schizophrenia may derive primarily, if not totally, from its NMDA receptor antagonist activity at NMDA receptors including extrasynaptic receptors in the CNS.
Assuntos
Antipsicóticos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Combinação de Medicamentos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Humanos , Memantina/administração & dosagem , Memantina/efeitos adversosRESUMO
Concentrations of heavy metals in water of the Nhue River (a suburban/rural river) and one of its tributaries, the To Lich River (an urban river), in Hanoi, Vietnam had been monitored, and spatial and seasonal variations in their composition were evaluated by means of principal component analysis and cluster analysis. Heavy metal concentrations in water of the two rivers were generally lower than the surface water quality standard in Vietnam, except for manganese in several sites, although they were higher than the median values in freshwater of the world by 0.42-43 times in Nhue and 0.13-32 times in To Lich. The two multivariate analyses represented that the composition of heavy metals in river water of To Lich was distinctly different from that of Nhue. It was also suggested that metal concentrations and their composition in Nhue river water would be affected by inflowing water of To Lich and wastewater discharged from the up- and middle-stream basin, and that they gradually recovered along the direction of water flow in the downstream area in rainy season.
Assuntos
Metais Pesados/análise , Rios , Poluentes da Água/análise , Monitoramento Ambiental , Análise Multivariada , VietnãRESUMO
Brexpiprazole (Rexulti®) is the second antipsychotic agent in the world with dopamine D2 receptor partial agonist which was developed by Otsuka Pharmaceutical Co. Ltd. It is categorized as ãSerotonin- dopamine Activity Modulator (SDAM)ã that regulates both serotoninergic and dopaminergic systems by acting as a partial agonist for serotonin 5-HT1A receptors and D2 receptors and as an antagonist for 5-HT2A receptors. In preclinical pharmacological studies, brexpiprazole showed the equivalent antipsychotic-like effects to those of other atypical antipsychotics. And it was suggested that brexpiprazole has the low potentials to induce extrapyramidal symptoms, hyperprolactinemia and tardive dyskinesia, with improvement effects on cognitive dysfunction. Furthermore, brexpiprazole has the weak effects on histamine H1 receptors which are associated with sedation and weight gain in clinical. In the clinical trials in patients with schizophrenia in both acute and maintenance phase, brexpiprazole showed improvement of antipsychotic effects against placebo, and low incidence of adverse events, e.g., extrapyramidal symptoms, hyperprolactinemia, and weight gain, as suggested in preclinical studies. Furthermore, brexpiprazole showed low incidence of metabolic abnormalities. In particular, brexpiprazole showed relatively low incidences of akathisia, insomnia and agitation which has been commonly reported with aripiprazole. This would be based on the pharmacological features of brexpiprazole that is more potent antagonism at 5-HT2A receptors and D2 receptors partial agonism with lower intrinsic activity compared to those of aripiprazole. In conclusion, brexpiprazole could be one of the antipsychotics with the most rational mechanism of action, and the better efficacy and safety/tolerability profiles would contribute to the treatment of patients with schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Quinolonas/farmacologia , Tiofenos/farmacologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Esquizofrenia/tratamento farmacológico , Comprimidos , Resultado do TratamentoRESUMO
BACKGROUND: Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D2 receptor sensitization. We evaluated the effects of brexpiprazole on D2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D2 receptors in rats subchronically dosed with another atypical antipsychotic. METHODS: The maximum D2 receptor density (Bmax ) and apomorphine (a D2 receptor agonist)-induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for Bmax , 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine-induced hyperlocomotion and (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI: a 5-HT2A receptor agonist)-induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. RESULTS: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED50 of anti-apomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the Bmax and apomorphine-induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine-induced hyperlocomotion and also DOI-induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine-induced hyperlocomotion. CONCLUSION: Brexpiprazole has a low risk of D2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D2 and 5-HT2A receptors after a repeated administration of risperidone.
Assuntos
Antipsicóticos/farmacologia , Discinesia Induzida por Medicamentos/metabolismo , Quinolonas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Tiofenos/farmacologia , Animais , Antipsicóticos/efeitos adversos , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Haloperidol/farmacologia , RatosRESUMO
Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and unipolar depression in the US. To explore the functional activity of aripiprazole at dopamine D3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human dopamine D3 receptors and compared aripiprazole's dopamine D3 pharmacological properties with other marketed and non-approved dopamine D3 receptor modulating agents on inhibition of forskolin-stimulated cAMP accumulation. Maximal cell responses for dopamine were dependent on receptor expression levels, and all cells had similar potency for dopamine responses. Aripiprazole, terguride, bifeprunox, OPC-4392 (7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone), (-)-3-PPP ((-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine), SDZ 208-912 (N-[(8 alpha)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide), BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide) behaved as partial agonists. Aripiprazole's intrinsic activity was similar to that of BP897 and GR103691, lower than that of terguride, bifeprunox, OPC-4392, and (-)-3-PPP, and higher than that of SDZ 208-912. The Gly-9 variant did not differ from the Ser-9 variant with respect to those agonist potencies and intrinsic activities. These compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. ACR16 (4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine), quetiapine, clozapine, olanzapine, ziprasidone, risperidone, and haloperidol acted as antagonists. Aripiprazole's unique activity at dopamine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders.
Assuntos
Antipsicóticos/farmacologia , Agonistas de Dopamina/farmacologia , Piperazinas/farmacologia , Quinolonas/farmacologia , Receptores de Dopamina D3/agonistas , Animais , Antipsicóticos/metabolismo , Aripiprazol , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Agonistas de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Agonismo Parcial de Drogas , Humanos , Mutação , Piperazinas/metabolismo , Quinolonas/metabolismo , Ensaio Radioligante , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Tetra-Hidronaftalenos/metabolismo , TransfecçãoRESUMO
The objective of this study is to assess the applicability of a commercial magnesium oxide (MgO) and a composite material containing MgO and natural minerals ('MgO-SH-A') as the soil amendments for suppression of cadmium (Cd) uptake and accumulation into rice grains. Firstly, the mineralogical and physicochemical properties, soil neutralizing capacities and Cd sorption characteristics of these materials were investigated. Both materials were strongly alkaline and possessed large surface areas. The X-ray diffraction pattern of MgO-SH-A indicated the presence of MgO and a magnesium-silicate mineral (antigorite) as the main components. MgO-SH-A showed a milder soil neutralizing capacity as compared to commercial MgO. The sorptions of Cd on commercial MgO and MgO-SH-A both fitted Langmuir isotherm. The maximum Cd sorption capacity of commercial MgO (46.8 mmol g(-1) DW) was higher than that of MgO-SH-A (5.87 mmol g(-1) DW), although the latter material showed higher affinity to Cd as compared to the former one. The dominant reaction involved in the Cd sorptions was suggested to be precipitation of Cd(OH)2 on the material surface. About 40% of Cd sorbed on MgO-SH-A was resistant to desorption by 0.1 M HCl, implying that this portion was strongly retained on the material surface.
Assuntos
Cádmio/metabolismo , Grão Comestível/metabolismo , Óxido de Magnésio/química , Oryza/metabolismo , Poluentes do Solo/metabolismo , Adsorção , Cádmio/química , Poluentes do Solo/químicaRESUMO
The objective of this study is to assess the applicability of a commercial magnesium oxide (MgO) and a composite material containing MgO and natural minerals ('MgO-SH-A') as the soil amendments for suppression of cadmium (Cd) uptake and accumulation into rice grains. A cultivation experiment of rice plants (Oryza sativa L. cv. Kinuhikari) was conducted in an actual Cd-contaminated alluvial paddy field to evaluate the effectiveness of these materials. The 'plant available' fractions of Cd in the paddy soil significantly decreased by application of commercial MgO at 2250 kg ha(-1) or MgO-SH-A at 4500 kg ha(-1). These decreases would be primarily attributed to the increase in soil pH due to applications of the MgO materials because these soil Cd fractions were significantly negatively correlated with the soil pH. Even under a suppressive condition for Cd uptake by rice plants, i.e., continuous flooding of the paddy field around the heading stage, applications of these materials further reduced Cd concentration in brown rice as compared to that from the control. It was concluded that the two MgO materials examined would be effective in preventing Cd contamination of rice grains grown in Cd-polluted paddy fields.