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Heart Rhythm ; 18(12): 2177-2186, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34481984

RESUMO

BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.


Assuntos
Arritmias Cardíacas , Canal de Potássio ERG1/antagonistas & inibidores , Compostos de Espiro/farmacocinética , Tiofenos/farmacocinética , Analgésicos Opioides/farmacocinética , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/prevenção & controle , Linhagem Celular , Cricetulus , Humanos , Concentração Inibidora 50 , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Moduladores de Transporte de Membrana/farmacologia , Quinidina/farmacocinética , Distribuição Tecidual , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
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