RESUMO
Glutamate (GLU) and gamma-amino butyric acid (GABA) are essential amino acids (AA) for brain function serving as excitatory and inhibitory neurotransmitter respectively. Their tablets are available in market for improving gut function and muscle performance. Despite of having a major role during memory formation and processing, effects of these tablets on brain functioning like learning and memory have not been investigated. Therefore, present study is aimed to investigate the effects of orally supplemented GLU and GABA on learning and memory performance and further to monitor related effects of these orally supplemented GLU and GABA on brain levels of these AA. Three groups of rats were supplemented orally with drinking water (control group) or suspension of tablets of GABA and Glutamate, respectively for four weeks. Cognitive performance was determined using behavioral tests (Novel object recognition test, Morris water maze, Passive avoidance test) measuring recognition, spatial reference and aversive memory. Levels of GLU, GABA and acetylcholine (ACh) were estimated in rat hippocampus. Results showed that chronic oral administration of GLU and GABA tablets has a significant impact on brain function and can alter GLU and GABA content in rat hippocampus. Compared to GABA, GLU supplementation specifically enhances memory performance via increasing ACh. Thus, GLU can be suggested as a useful supplement for improving learning and memory performance and neurochemical status of brain and in future could be effective in the treatment of neurological disorders affecting learning and memory performance.
Assuntos
Química Encefálica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Acetilcolina/metabolismo , Animais , Cognição/efeitos dos fármacos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/farmacocinética , Hipocampo/química , Hipocampo/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos Wistar , Fatores de Tempo , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.
Assuntos
Aminas/administração & dosagem , Analgésicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/administração & dosagem , Hiperalgesia/tratamento farmacológico , Morfina/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Ácido gama-Aminobutírico/administração & dosagem , Aminas/farmacocinética , Aminas/uso terapêutico , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Gabapentina , Masculino , Morfina/farmacocinética , Morfina/uso terapêutico , Estimulação Física , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
γ-Aminobutyric acid (GABA) transporters (GATs) are promising drug targets for various diseases associated with imbalances in GABAergic neurotransmission. For the development of new drugs or pharmacological tools addressing GATs, screening techniques to identify new inhibitors and to characterize their potency at each GAT subtype are indispensable. By now, the technique by far dominating is based on radiolabeled GABA. We recently described "MS Transport Assays" for hGAT-1 by employing ((2) H6 )GABA as the substrate. In the present study, we applied this approach to all four human GAT subtypes and determined the KM values for GAT-mediated transport of ((2) H6 )GABA at each subtype. Furthermore, a comprehensive set of GAT inhibitors reflecting the whole range of potency and subtype selectivity known so far was evaluated for their potency. The comparison of pIC50 values obtained in conventional [(3) H]GABA uptake assays with those obtained in MS Transport Assays indicated the reliability of the latter. The MS Transport Assays enable a throughput similar to that of conventional radiometric transport assays performed in a 96-well format but avoid the use of radiolabeled substrates.
Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Animais , Ligação Competitiva , Células COS , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas da Membrana Plasmática de Transporte de GABA/análise , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Inibidores da Captação de GABA/química , Inibidores da Captação de GABA/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Espectrometria de Massas em Tandem/métodos , Fluxo de Trabalho , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
AIMS: This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption. METHODS: Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg. RESULTS: Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CLR ) of gabapentin occurred after intake of the mushroom diet (91.1 ± 25.1 vs. 76.9 ± 20.6 ml min(-1) , P = 0.031). No significant changes in AUC(0,tlast ) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin. CONCLUSIONS: These data suggest that diet-drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,tlast ) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies.
Assuntos
Agaricales , Aminas/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacocinética , Dieta , Ergotioneína/sangue , Voluntários Saudáveis , Interações Ervas-Drogas , Ácido gama-Aminobutírico/farmacocinética , Administração Oral , Adulto , Agaricales/química , Aminas/administração & dosagem , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Povo Asiático/genética , China , Ácidos Cicloexanocarboxílicos/administração & dosagem , Gabapentina , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Cátions Orgânicos/genética , Simportadores , Ácido gama-Aminobutírico/administração & dosagemRESUMO
We have previously shown how screening experiments for neuropathic pain can be optimised taking into account parameter and model uncertainty. Here we demonstrate how optimised protocols can be used to screen and rank candidate molecules. The concept is illustrated by pregabalin as a new chemical entity and gabapentin as a reference compound. ED-optimality was applied to a logistic regression model describing the relationship between drug exposure and response to evoked pain in the complete Freund's adjuvant (CFA) model in rats. Design variables for optimisation of the experimental protocol included dose levels and sampling times. Prior information from the reference compound was used in conjunction with relative in vitro potency as priors. Results from simulated scenarios were then combined with fitting of experimental data to estimate precision and bias of model parameters for the empirical and optimised designs. The pharmacokinetics of pregabalin was described by a two-compartment model. The expected value of EC(50) of pregabalin was 637.5 ng ml(-1). Model-based analysis of the data yielded median (range) of EC(50) values of 1,125 (898-2412) ng ml(-1) for the empirical protocol and 755 (189-756) ng ml(-1) for the optimised design. In contrast to current practice, optimal design entails different sampling schedule across dose levels. ED-optimised designs should become standard practice in the screening of candidate molecules. It ensures lower bias when estimating the drug potency, facilitating accurate ranking and selection of compounds for further development.
Assuntos
Analgésicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Biológicos , Neuralgia/tratamento farmacológico , Aminas/farmacocinética , Aminas/farmacologia , Analgésicos/farmacocinética , Animais , Estudos de Coortes , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Método Duplo-Cego , Gabapentina , Modelos Logísticos , Neuralgia/metabolismo , Pregabalina , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologiaRESUMO
In spite of the evidence regarding high variability in the response to evoked pain, little attention has been paid to its impact on the screening of drugs for inflammatory and neuropathic pain. In this study, we explore the feasibility of introducing optimality concepts to experimental protocols, enabling estimation of parameter and model uncertainty. Pharmacokinetic (PK) and pharmacodynamic data from different experiments in rats were pooled and modelled using nonlinear mixed effects modelling. Pain data on gabapentin and placebo-treated animals were generated in the complete Freund's adjuvant model of neuropathic pain. A logistic regression model was applied to optimise sampling times and dose levels to be used in an experimental protocol. Drug potency (EC(50)) and interindividual variability (IIV) were considered the parameters of interest. Different experimental designs were tested and validated by SSE (stochastic simulation and estimation) taking into account relevant exposure ranges. The pharmacokinetics of gabapentin was described by a two-compartment PK model with first order absorption (CL = 0.159 l h(-1), V(2) = 0.118 l, V(3) = 0.253 l, Ka = 0.26 h(-1), Q = 1.22 l h(-1)). Drug potency (EC(50)) for the anti-allodynic effects was estimated to be 1400 ng ml(-1). Protocol optimisation improved bias and precision of the EC50 by 6 and 11.9. %, respectively, whilst IIV estimates showed improvement of 31.89 and 14.91 %, respectively. Our results show that variability in behavioural models of evoked pain response leads to uncertainty in drug potency estimates, with potential impact on the ranking of compounds during screening. As illustrated for gabapentin, ED-optimality concepts enable analysis of discrete data taking into account experimental constraints.
Assuntos
Analgésicos/farmacologia , Analgésicos/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Aminas/farmacocinética , Aminas/farmacologia , Animais , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Método Duplo-Cego , Adjuvante de Freund/farmacologia , Gabapentina , Modelos Logísticos , Modelos Biológicos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologiaRESUMO
No disponible
The aim of the present study was to investigate the effects of bisphenol A (BPA) on the neuroendocrine mechanism of control of the reproductive axis in adult male rats exposed to it during pre- and early postnatal periods. Wistar mated rats were treated with either 0.1% ethanol or BPA in their drinking water until their offspring were weaned at the age of 21 days. The estimated average dose of exposure to dams was approximately 2.5 mg/kg body weight per day of BPA. After 21 days, the pups were separated from the mother and sacrificed on 70 day of life. Gn-RH and gamma-aminobutyric acid (GABA) release from hypothalamic fragments was measured. LH, FSH, and testosterone concentrations were determined, and histological and morphometrical studies of testis were performed. Gn-RH release decreased significantly, while GABA serum levels were markedly increased by treatment. LH serum levels showed no changes, and FSH and testosterone levels decreased significantly. Histological studies showed abnormalities in the tubular organization of the germinal epithelium. The cytoarchitecture of germinal cells was apparently normal, and a reduction of the nuclear area of Leydig cells but not their number was observed. Taken all together, these results provide evidence of the effect caused by BPA on the adult male reproductive axis when exposed during pre- and postnatal period. Moreover, our findings suggest a probable GABA involvement in its effect at the hypothalamic level (AU)
Assuntos
Animais , Ratos , Ácido gama-Aminobutírico/farmacocinética , Fenóis/farmacocinética , Hipotálamo , Reprodução/fisiologiaRESUMO
In the present study, the effects of Bacopa monnieri and its active component, bacoside A, on motor deficit and alterations of GABA receptor functional regulation in the cerebellum of epileptic rats were investigated. Scatchard analysis of [(3)H]GABA and [(3)H]bicuculline in the cerebellum of epileptic rats revealed a significant decrease in B(max) compared with control. Real-time polymerase chain reaction amplification of GABA(A) receptor subunits-GABA(Aalpha1), GABA(Aalpha5,) and GABA(Adelta)-was downregulated (P<0.001) in the cerebellum of epileptic rats compared with control rats. Epileptic rats exhibit deficits in radial arm and Y-maze performance. Treatment with B. monnieri and bacoside A reversed these changes to near-control levels. Our results suggest that changes in GABAergic activity, motor learning, and memory deficit are induced by the occurrence of repetitive seizures. Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity, motor learning, and memory deficit.
Assuntos
Sintomas Comportamentais , Cerebelo/efeitos dos fármacos , Epilepsia/complicações , Epilepsia/patologia , Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Receptores de GABA/metabolismo , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Anticonvulsivantes/uso terapêutico , Sintomas Comportamentais/tratamento farmacológico , Sintomas Comportamentais/etiologia , Bicuculina/farmacocinética , Carbamazepina/uso terapêutico , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Antagonistas GABAérgicos/farmacocinética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pilocarpina , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Trítio/farmacocinética , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
In schizophrenia, a psychiatric disorder that affects approximately 1% of the global population and is associated with substantial disability, a significant proportion of patients (usually estimated to be at least 30%) fail to respond to treatment, and many patients have difficulty continuing treatment because of side effects. At the time of publication, all available medications for schizophrenia targeted dopamine and other monoamine neurotransmitters. However, a substantial amount of research suggests that patients with schizophrenia have underlying deficits within the GABA neurotransmitter system. BL-1020, being developed by BioLineRx Ltd under license from Tel Aviv University Ltd and Bar-Ilan Research & Development Co Ltd, is a novel compound consisting of the well-established antipsychotic drug perphenazine and GABA. Preclinical studies of BL-1020 indicated that the compound penetrated the brain and was efficacious in rodents, with a significant reduction in side effects compared with the administration of perphenazine. BL-1020 was well tolerated in all clinical trials conducted, and clinically meaningful improvements were demonstrated in phase II trials in patients with schizophrenia. Further data from phase II and subsequent phase III trials will be required to derive conclusions for BL-1020 regarding overall efficacy.
Assuntos
Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Dopamina/metabolismo , Perfenazina/análogos & derivados , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Esquizofrenia/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/toxicidade , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Contraindicações , Avaliação Pré-Clínica de Medicamentos , Humanos , Patentes como Assunto , Perfenazina/efeitos adversos , Perfenazina/farmacocinética , Perfenazina/farmacologia , Perfenazina/uso terapêutico , Perfenazina/toxicidade , Relação Quantitativa Estrutura-Atividade , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêutico , Ácido gama-Aminobutírico/toxicidadeRESUMO
PURPOSE: Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with the objective of informing the design of a quantitative pharmacodynamic (PD) study. METHODS: The pharmacokinetics were determined in rats following 2-hr intravenous infusions of pregabalin at doses of 4 mg/kg/hr and 10 mg/kg/hr with and without a sildenafil bolus (2.2 mg) and steady state infusion (12 mg/kg/hr for 6 h). This PK model was utilized in a preclinical trial simulation with the aim of selecting the optimal sampling strategy to characterize the PK-PD profile in a future study. Eight logistically feasible PK sampling strategies were simulated in NONMEM and examined through trial simulation techniques. RESULTS: A two-compartment population PK model best described pregabalin pharmacokinetics. Significant model covariates included either a binary effect of sildenafil administration (30.2% decrease in clearance) or a concentration-dependent effect due to sildenafil's active metabolite. CONCLUSIONS: Analysis of simulations indicated that three post-PD samples had the best cost/benefit ratio by providing a significant increase in the precision (and minor improvement in bias) of both PK and PD parameters compared with no PK sampling.
Assuntos
Simulação por Computador , Modelos Biológicos , Piperazinas/farmacologia , Piperazinas/farmacocinética , Sulfonas/farmacologia , Sulfonas/farmacocinética , Ácido gama-Aminobutírico/análogos & derivados , Animais , Estudos Cross-Over , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas/fisiologia , Masculino , Pregabalina , Purinas/farmacocinética , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologiaRESUMO
The neurotransmission mediated by gamma-aminobutyric acid (GABA) in the mammalian brain is terminated by a family of four GABA transporters (GATs). Inhibition of GATs is currently used in the treatment of epilepsy and these proteins are generally considered as important drug targets. In this study, we perform the first elaborate pharmacological characterization of all four human GAT subtypes. We conduct the experiments in parallel in a [3H]GABA uptake assay using 14 standard GAT substrates and inhibitors. This setup enables direct comparison of the absolute values of inhibitory activities of the compounds between the different GAT subtypes. The results are overall in agreement with data reported by other groups for the orthologous murine GATs. However, there do seem to be some minor variations among species. In contrast to the several subtype selective ligands identified for the GAT-1 subtype, no subtype selective ligands have been reported for the three remaining GATs. Given the potential therapeutic relevance of the individual GAT subtypes, a search for novel structures displaying selectivities for specific GAT subtypes is important. In this study, we validate our [3H]GABA uptake assay for use in high throughput screening. We find that the assay is categorized by high Z'-factors (Z' > 0.5) for all four GAT subtypes, demonstrating that the assay is excellent for a high throughput screen. This [3H]GABA uptake assay therefore enables future high throughput screening of compound libraries at the four human GATs.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas da Membrana Plasmática de Transporte de GABA/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacocinética , Humanos , TrítioRESUMO
Restless Legs Syndrome (RLS) is a sleep-related movement disorder characterized by an urge to move the legs accompanied by unpleasant symptoms. Dopaminergic agents currently represent the first-line therapy for RLS. However, some patients are unable to continue with this pharmacological approach in the long term because of augmentation or other adverse events. Limited studies with the anticonvulsant/analgesic agent gabapentin have demonstrated that this drug might be useful in the treatment of primary and uremic RLS. Unfortunately, gabapentin has an unfavorable pharmacokinetic profile characterized by a dose-dependent bioavailability. Gabapentin enacarbil, a prodrug of gabapentin, is currently being developed by XenoPort Inc/Astellas Pharma Inc/GlaxoSmithKline plc in order to overcome this limitation. In vitro and in vivo studies have demonstrated that gabapentin enacarbil provides a dose-proportional exposure to gabapentin when orally administered. Gabapentin enacarbil has proved to be beneficial in treating RLS symptoms in several phase II and III clinical trials. In addition, these trials have demonstrated that gabapentin enacarbil is safe and well tolerated, causing transient and mild or moderate adverse events. Gabapentin enacarbil is an interesting compound, which is potentially useful in treating RLS patients who report severe adverse events under dopaminergic agents. The author concludes that additional studies are required in order to better assess the efficacy and safety of gabapentin enacarbil on RLS.
Assuntos
Carbamatos/uso terapêutico , Pró-Fármacos , Síndrome das Pernas Inquietas/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Animais , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Resultado do Tratamento , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
The pharmacological actions of 2,6-di-tert-butyl-4-(3-hydroxy-2-spiropentylpropyl)-phenol (BSPP), a putative presynaptic GABA(B) receptor modulator, were examined in electrically stimulated rat neocortical brain slices preloaded with [3H]-GABA or [3H]-glutamic acid. At 10 mmol/L, BSPP inhibited the release of [3H]-GABA in the presence of baclofen, but not that of [3H]-glutamic acid. This effect was sensitive to the GABA(B) receptor antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911). Alone, BSPP had no effect on the release of [3H]-GABA or [3H]-glutamic acid. It is concluded that BSPP selectively potentiates the action of baclofen at GABA(B) autoreceptors, but not heteroreceptors and may be a useful ligand to discriminate between presynaptic GABA(B) receptor subtypes.
Assuntos
Baclofeno/farmacologia , Antagonistas de Receptores de GABA-B , Neocórtex/efeitos dos fármacos , Fenóis/farmacologia , Compostos de Espiro/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Ácido Glutâmico/farmacocinética , Masculino , Morfolinas/farmacologia , Neocórtex/metabolismo , Técnicas de Cultura de Órgãos , Fenóis/química , Ratos , Ratos Sprague-Dawley , Receptores de GABA-B/metabolismo , Trítio/farmacocinética , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, approximately 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.
Assuntos
Anticonvulsivantes/química , Desenho de Fármacos , Aminas/química , Aminas/farmacocinética , Aminas/uso terapêutico , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/análogos & derivados , Carbamazepina/química , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Epilepsia/tratamento farmacológico , Gabapentina , Humanos , Estrutura Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto , Relação Estrutura-Atividade , Ácido Valproico/análogos & derivados , Ácido Valproico/química , Ácido Valproico/farmacocinética , Ácido Valproico/uso terapêutico , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Twenty novel N-diarylalkenyl-piperidinecarboxylic acid derivatives were synthesized and evaluated as gamma-aminobutyric acid uptake inhibitors. The biological assay showed that (R)-1-[4,4-bis(3-phenoxymethyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic hydrochloride possessed almost as strong GAT1 inhibitory activity as tiagabine. The synthesis and structure-activity relationships are discussed.
Assuntos
Ácidos Carboxílicos/química , Agonistas GABAérgicos/farmacologia , Ácidos Pipecólicos/química , Ácido gama-Aminobutírico/metabolismo , Animais , Transporte Biológico , Ácidos Carboxílicos/síntese química , Química Farmacêutica/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Agonistas GABAérgicos/química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Neurônios/metabolismo , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Ácidos Pipecólicos/síntese química , Relação Estrutura-Atividade , Tiagabina , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
The ability of 2,6 Di-tert-butyl-4-(-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), a positive allosteric modulator of GABA(B) receptors, to regulate GABA(B) receptor-induced stimulation and inhibition of adenylyl cyclase activity in rat brain was investigated. In olfactory bulb granule cell layer and in frontal cortex, CGP7930 potentiated the stimulatory effects of (-)-baclofen and gamma-aminobutyric acid (GABA) on basal and corticotropin-releasing hormone-stimulated adenylyl cyclase activities, respectively. In these stimulatory responses, CGP7930 enhanced both agonist potencies and maximal effects. When GABA(B) receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase activity of frontal cortex was examined, CGP7930 increased the agonist potencies but failed to affect the maximal effect of (-)-baclofen and modestly increased that of GABA. Similar results were obtained for the inhibition of Ca(2+)/calmodulin-stimulated adenylyl cyclase in striatum and cerebellum. Western blot analysis of each membrane preparation showed the presence of GABA(B2) receptor subunit, a putative site of action of CGP7930. These data indicate that CGP7930 positively modulates brain GABA(B) receptors coupled to either stimulation or inhibition of cyclic AMP signalling.
Assuntos
Regulação Alostérica/efeitos dos fármacos , AMP Cíclico/metabolismo , Fenóis/farmacocinética , Receptores de GABA-B/efeitos dos fármacos , Receptores de GABA-B/metabolismo , Adenilil Ciclases/metabolismo , Regulação Alostérica/fisiologia , Animais , Baclofeno/administração & dosagem , Baclofeno/farmacocinética , Calmodulina/antagonistas & inibidores , Calmodulina/farmacocinética , Colforsina/farmacocinética , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacocinética , AMP Cíclico/biossíntese , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/metabolismo , Sinergismo Farmacológico , Lobo Frontal/citologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/enzimologia , Expressão Gênica , Masculino , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Fenóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de GABA/biossíntese , Receptores de GABA/imunologia , Transdução de Sinais , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
Two forms of GABAergic inhibition coexist: fast synaptic neurotransmission and tonic activation of GABA receptors due to ambient GABA. The mechanisms regulating ambient GABA have not been well defined. Here we examined the role of the GABA transporter in the increase in ambient [GABA] induced by the anticonvulsant vigabatrin. Pretreatment of cultured rat hippocampal neurons with vigabatrin (100 microM) for 2-5 days led to a large increase in ambient [GABA] that was measured as the change in holding current induced by bicuculline during patch-clamp recordings. In contrast, there was a decrease in the frequency of spontaneous miniature inhibitory postsynaptic currents mIPSCs with no change in their amplitude distribution, and a decrease in the magnitude of IPSCs evoked by presynaptic stimulation during paired recordings. The increase in ambient [GABA] was not prevented by blockade of vesicular GABA release with tetanus toxin or removal of extracellular calcium. During perforated patch recordings, the increase in ambient [GABA] was prevented by blocking the GABA transporter, indicating that the GABA transporter was continuously operating in reverse and releasing GABA. In contrast, blocking the GABA transporter increased ambient [GABA] during whole cell patch-clamp recordings unless GABA and Na(+) were added to the recording electrode solution, indicating that whole cell recordings can lead to erroneous conclusions about the role of the GABA transporter in control of ambient GABA. We conclude that the equilibrium for the GABA transporter is a major determinant of ambient [GABA] and tonic GABAergic inhibition. We propose that fast GABAergic neurotransmission and tonic inhibition can be independently modified and play complementary roles in control of neuronal excitability.
Assuntos
Anticonvulsivantes/farmacologia , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Inibição Neural/efeitos dos fármacos , Neurônios/fisiologia , Transportadores de Ânions Orgânicos , Vigabatrina/farmacologia , Animais , Proteínas de Transporte/antagonistas & inibidores , Células Cultivadas , Proteínas da Membrana Plasmática de Transporte de GABA , Hipocampo/citologia , Potenciais da Membrana/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neurônios/citologia , Ácidos Nipecóticos/farmacologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de GABA/metabolismo , Sódio/farmacologia , Vesículas Sinápticas/metabolismo , Toxina Tetânica/farmacologia , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
The objectives of this study were to determine the single-dose pharmacokinetics of pregabalin in subjects with various degrees of renal function, determine the relationship between pregabalin clearance and estimated creatinine clearance (CLcr), and measure the effect of hemodialysis on plasma levels of pregabalin. Results form the basis of recommended pregabalin dosing regimens in patients with decreased renal function. Thirty-eight subjects were enrolled to ensure a wide range of renal function (CLcr < 30 mL/min, n = 8; 30-50, n = 5; 50-80, n = 7; and > 80, n = 6). Also enrolled were 12 subjects with renal impairment requiring hemodialysis. Each subject received 50 mg of pregabalin as two 25-mg capsules in this open-label, parallel-group study. Pregabalin concentrations were measured using previously validated liquid chromatographic methods. Pregabalin pharmacokinetic parameters were evaluated by established noncompartmental methods. Pregabalin was rapidly absorbed in all subjects. Total and renal pregabalin clearance were proportional (56% and 58%, respectively) to CLcr. As a result, area under the plasma concentration-time profile (AUC) and terminal elimination half-life (t1/2) values increased with decreasing renal function. Pregabalin dosage adjustment should be considered for patients with CLcr < 60 mL/min. A 50% reduction in pregabalin daily dose is recommended for patients with CLcr between 30 and 60 mL/min compared to those with CLcr > 60 mL/min. Daily doses should be further reduced by approximately 50% for each additional 50% decrease in CLcr. Pregabalin was highly cleared by hemodialysis. Supplemental pregabalin doses may be required for patients on chronic hemodialysis treatment after each hemodialysis treatment to maintain steady-state plasma pregabalin concentrations within desired ranges.
Assuntos
Anticonvulsivantes/farmacocinética , Insuficiência Renal/metabolismo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Área Sob a Curva , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Pregabalina , Diálise Renal , Insuficiência Renal/fisiopatologia , Insuficiência Renal/terapia , Ácido gama-Aminobutírico/sangue , Ácido gama-Aminobutírico/urinaRESUMO
Although the neurotransmitter uptake system is considered a possible target for the presynaptic action of anesthetic agents, observations are inconsistent concerning effects on the transporter and their clinical relevance. The present study examined the effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine in COS cells heterologously expressing the transporters for these neurotransmitters and in the rat brain synaptosomes. Halothane and isoflurane, but not thiamylal or thiopental, significantly inhibited uptake by COS cell systems of GABA, dopamine and glutamic acid in a concentration-dependent manner within clinically relevant ranges for anesthesia induced by these agents. Similarly, in synaptosomes halothane and isoflurane but not thiopental significantly suppressed the uptake of GABA and glutamic acid, respectively. These results do not support the hypothesis that volatile and intravenous anesthetics exert their action via specific inhibition of GABA uptake to enhance inhibitory GABAergic neuronal activity. Rather, they suggest that presynaptic uptake systems for various neurotransmitters including GABA may be the molecular targets for volatile anesthetic agents.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Encéfalo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Neurotransmissores/farmacocinética , Inibidores da Captação de Neurotransmissores/farmacologia , Transportadores de Ânions Orgânicos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Sistema X-AG de Transporte de Aminoácidos , Animais , Encéfalo/metabolismo , Células COS , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , DNA Complementar/genética , Dopamina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Proteínas da Membrana Plasmática de Transporte de GABA , Ácido Glutâmico/farmacocinética , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Ratos , Ratos Sprague-Dawley , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Transfecção , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
Extracts of St. John's Wort are widely used for the treatment of depressive disorders. The active principles have not yet been finally elucidated. We have recently shown that hyperforin, a major active constituent of St. John's Wort, not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine, but also that of L-glutamate and GABA. No other antidepressant compound exhibits a similar broad uptake inhibiting profile. To investigate this unique kind of property, kinetic analyses were performed regarding the uptake of 3H-L-glutamate and 3H-GABA into synaptosomal preparations of mouse brain. Michaelis-Menten kinetics revealed a reduction of Vmax (8.27 to 1.80 pmol/mg/min for 3H-L-glutamate, 2.76 to 0.77 pmol/mg/min for 3H-GABA) while Km was nearly unchanged in both cases, suggesting non-competitive inhibition. The unselective uptake inhibition by hyperforin could be mimicked by the Na+-ionophore monensin and by the Na+-K+-ATPase inhibitor ouabain. However, both mechanisms can be discarded for hyperforin. Several amiloride derivatives known to affect sodium conductance significantly enhance 3H-GABA and 3H-L-glutamate uptake and inhibit the uptake inhibition by hyperforin, while monensin or ouabain inhibition were not influenced. Selective concentrations of benzamil for amiloride sensitive Na+-channels and selective concentrations of 5'-ethylisopropylamiloride (EIPA) for the Na+-H+-exchangers both had an attenuating effect on the hyperforin inhibition of L-glutamate uptake, suggesting a possible role of amiloride sensitive Na+-channels and Na+-H+-exchangers in the mechanism of action of hyperforin.