RESUMO
The current drug cardiac safety risk assessment paradigm is about to be changed. The discussed modifications cover clinical as well as pre-clinical sides. As for the latter, the pre-clinical assessment, it is planned to be based on the analysis of the drug-triggered multiple ion currents inhibition. Considering the variability in the in vitro patch clamp studies results, it would be of benefit to assess how these apparatus- and protocol-dependent differences influence the risk prediction and, eventually, the decision making. Four compounds, namely dextromethorphan, ketoconazole, terfenadine, and quinidine were screened for hERG inhibition with an automated patch clamp apparatus (CytoPatch(TM)2). The results were then compared against the literature published data, and after being complemented with information about other current inhibitions and effective therapeutic plasma concentration, utilized for the in silico based safety assessment. Two endpoints were used: (1) the concentration dependent potential to induce early afterdepolarizations in the simulated action potential and (2) the arrhythmia-like disruption in the simulated pseudo-ECG signals. Data analysis results prove that IC50 values, describing the inhibition potential, significantly differ among studies, and the choice of input data can greatly influence the in silico based safety assessment and thus the decision making process.
Assuntos
Arritmias Cardíacas/metabolismo , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Modelos Cardiovasculares , Animais , Arritmias Cardíacas/induzido quimicamente , Dextrometorfano/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1 , Técnicas In Vitro , Cetoconazol/farmacologia , Técnicas de Patch-Clamp/métodos , Projetos Piloto , Quinidina/farmacologia , Terfenadina/farmacologiaRESUMO
The lupin alkaloid sparteine is a well-known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage-gated sodium channels (VGSCs). However, there is only scarce information on the VGSC-blocking activity of sparteine derivatives where the structure of the parent alkaloid is retained. Building on the recent renewed availability of sparteine and derivatives we report herein how modification of sparteine at positionâ 2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long-lasting local anesthetics.
Assuntos
Bloqueadores dos Canais de Sódio/farmacologia , Esparteína/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Estrutura Molecular , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Esparteína/síntese química , Esparteína/química , Relação Estrutura-AtividadeRESUMO
Here we characterize several new lines of transgenic mice useful for optogenetic analysis of brain circuit function. These mice express optogenetic probes, such as enhanced halorhodopsin or several different versions of channelrhodopsins, behind various neuron-specific promoters. These mice permit photoinhibition or photostimulation both in vitro and in vivo. Our results also reveal the important influence of fluorescent tags on optogenetic probe expression and function in transgenic mice.