Oxcarbazepine: mechanisms of action.
The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly formed 10-monohydroxy metabolite (MHD) protect against electroshock-induced tonic hindlimb extension in rodents (ED50 14-21 mg/kg p.o.). Both stereoisomers of MHD also protect. As with carbamazepine (CBZ), these findings suggest clinical efficacy against generalized tonic-clonic and, to some extent, partial seizures. OCBZ (IC50 5 x 10(-8) M), MHD (IC50 2 x 10 (-8) M), and CBZ (IC50 6 x 10(-7) M) limit the frequency of firing of sodium-dependent action potentials by cultured mouse central neurons and reduce Vmax progressively in a use-dependent manner at concentrations below therapeutic plasma concentrations in OCBZ-treated patients. This suggests that blockade of voltage-sensitive sodium channels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin-induced epileptiform discharges in hippocampal slices by MHD and its stereoisomers was diminished when the potassium channel blocker 4-aminopyridine was added to the bath fluid. This indicates that additional mechanisms of action, e.g., an effect on potassium channels, might be clinically important. In addition, both stereoisomers are equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such actions could confer broad clinical utility on OCBZ.
McLean
M J
MJ
Department of Neurology, Department of Veterans Affairs Medical Center, Nashville, Tennessee.
Schmutz
M
M
Wamil
A W
AW
Olpe
H R
HR
Portet
C
C
Feldmann
K F
KF
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004597:Electroshock; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D000078330:Oxcarbazepine; D012377:Rodentia; D012640:Seizures / Q000517:prevention & control; D013116:Spinal Cord / Q000166:cytology
D000927:Anticonvulsants; D002220:Carbamazepine; D000078330:Oxcarbazepine