OXCARBAZEPINE - MECHANISMS OF ACTION

The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly form ed 10-monohydroxy metabolite (MHD) protect against electroshock-induce d tonic hindlimb extension in rodents (ED(50) 14-21 mg/kg p.o.). Both stereoisomers of MI-ID also protect. As with carbamazepine (CBZ), thes e 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 centra l neurons and reduce V-max progressively in a use-dependent manner at concentrations below therapeutic plasma concentrations in OCBZ-treated patients. This suggests that blockade of voltage-sensitive sodium cha nnels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin-induced epileptiform discharges in hippocampal slices b y MHD and its stereoisomers was diminished when the potassium channel blocker 4-aminopyridine was added to the bath fluid. This indicates th at additional mechanisms of action, e.g., an effect on potassium chann els, might be clinically important. In addition, both stereoisomers ar e equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such a ctions could confer broad clinical utility on OCBZ.