In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: insights into the mechanisms of pharmacoresistance.
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 naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.
Oby
Emily
E
Cerebrovascular Research Center, The Cleveland Clinic, OH 44195, USA.
Caccia
Silvio
S
Vezzani
Annamaria
A
Moeddel
Gabriel
G
Hallene
Kerri
K
Guiso
Giovanna
G
Said
Tamer
T
Bingaman
William
W
Marchi
Nicola
N
Baumgartner
Christoph
C
Pirker
Susanne
S
Czech
Thomas
T
Lo Russo
Giorgio
G
Janigro
Damir
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008875:Middle Aged; D018408:Patch-Clamp Techniques / Q000379:methods; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats
D000927:Anticonvulsants; D011189:Potassium Chloride