In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: insights into the mechanisms of pharmacoresistance

Brain Research
Emily ObyD Janigro

Abstract

Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15-34 microM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg(2+)-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60-200 microM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from...Continue Reading

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Citations

Nov 23, 2006·Epilepsia·Emily Oby, Damir Janigro
Oct 4, 2015·Nutrition Reviews·Amene SaghazadehNima Rezaei
Jun 18, 2016·Drug Discovery Today·Chaitali GhoshDamir Janigro
Dec 3, 2009·Expert Review of Neurotherapeutics·Tiziana GranataDamir Janigro

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