RESUMO
BACKGROUND: The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism. RESULTS: It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics.
Assuntos
Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/farmacocinética , Fármacos Gastrointestinais/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Monitoramento de Medicamentos , Fármacos Gastrointestinais/efeitos adversos , Humanos , Farmacogenética , Indução de Remissão , Resultado do TratamentoRESUMO
Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.