Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Neuropharmacology ; 72: 88-95, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23639435

RESUMO

Inhibition of central α4ß2 nAChRs by antidepressants, proposed to contribute to their clinical efficacy, was assessed for monoamine reuptake inhibitors (amitriptyline, nortriptyline, fluoxetine, sertraline, paroxetine, citalopram) by comparing projected human unbound brain drug concentrations (Cu,b) at therapeutic doses with concentrations that inhibit human α4ß2 nAChRs in vitro. Inhibitory concentrations (IC50) were determined by patch clamp and ranged from 0.8-3.2 µM, except for nortriptyline (IC50 = 100 nM). Cu,b values were calculated from human unbound plasma drug concentrations (Cu,p) and rat-derived brain-to-plasma and extracellular fluid-to-plasma ratios for the unbound drug, which are near unity, due to much higher brain tissue binding than plasma protein binding of these drugs. Accordingly in humans, antidepressant Cu,b are projected to essentially equal Cu,p, with average values from 3-87 nM, which are 30-to-250-fold below their IC50 concentrations. Based on our model, monoaminergic antidepressants minimally inhibit central nAChRs and it is unlikely that α4ß2 nAChR antagonism contributes to their antidepressant activity. Nortriptyline is an exception with a Cu,b that is 2-fold below its IC50, which is comparable to the nAChR antagonist (±)-mecamylamine, for which Cu,b is 4-fold below its IC50; both drugs will inhibit a substantial fraction of α4ß2 nAChRs. The Cu,b of the α4ß2 nAChR partial agonist varenicline, which has antidepressant-like activity in a murine model, is higher than its IC50 and varenicline is projected to cause ~70% inhibition of α4ß2 nAChRs. Taken together these data may help explain the negative outcome of recent antidepressant augmentation trials with mecamylamine and the partial agonist CP-601927.


Assuntos
Antidepressivos/farmacologia , Nortriptilina/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Área Sob a Curva , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida , Humanos , Concentração Inibidora 50 , Masculino , Microdiálise , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Agonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Espectrometria de Massas em Tandem , Fatores de Tempo
2.
Drug Metab Dispos ; 40(10): 1909-16, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22736307

RESUMO

A significant barrier to realization of the full potential of clozapine as a therapeutic agent in the treatment of schizophrenia is the substantial interpatient variability that exists along the therapeutic continuum of no response-efficacious response-adverse response. Genetic polymorphisms that manifest as highly variable pharmacodynamic and pharmacokinetic measures are its expected causes. To support investigations that seek to understand these causes, the plasma and central nervous system pharmacokinetics of clozapine were determined in rats, the latter using microdialysis sampling. Results obtained with clozapine and N-desmethylclozapine, a pharmacologically active human metabolite that was administered to a separate group of animals, support a conclusion of net carrier-mediated efflux of both compounds across the blood-brain barrier. These results are supported by the replication of published findings regarding the passive transport and net efflux transport of two model compounds, escitalopram and risperidone, respectively. The results obtained with clozapine and N-desmethylclozapine are considered a first step in the development of preclinical pharmacokinetic-pharmacodynamic models that will support deeper mechanistic studies of clozapine in in vivo pharmacology, as well as the development of translational models that augment pharmacogenetic investigations that seek to improve the safety and efficacy of clozapine therapeutic intervention in the treatment of schizophrenia.


Assuntos
Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Clozapina/análogos & derivados , Microdiálise , Animais , Antipsicóticos/administração & dosagem , Biotransformação , Barreira Hematoencefálica/metabolismo , Clozapina/administração & dosagem , Clozapina/farmacocinética , Injeções Subcutâneas , Masculino , Modelos Biológicos , Permeabilidade , Ratos , Ratos Wistar
3.
Neurosci Res ; 70(3): 334-7, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21420449

RESUMO

A large percentage of depressed individuals use drugs of abuse, like cannabis. This study investigates the impact of cannabis on the pharmacological effects of the antidepressant citalopram. Using microdialysis in the prefrontal cortex of rats we monitored serotonin levels before and after cannabinoid (WIN55,212-2 or rimonabant) and citalopram administration. Stimulating CB-1 decreased the effect of citalopram on increasing serotonin levels in the prefrontal cortex. Blocking CB-1 augmented this effect of citalopram. Although repeating these experiments in a chronical setting is recommended the present results might have implication for the clinical effects of citalopram.


Assuntos
Citalopram/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Animais , Benzoxazinas/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Interações Medicamentosas/fisiologia , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Masculino , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto , Inibidores Seletivos de Recaptação de Serotonina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...