Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action.
Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Ciba-Geigy Ltd., Pharmaceuticals Division, Research and Development Department, Basel, Switzerland.
M
M
Schmutz
F
F
Brugger
C
C
Gentsch
M J
MJ
McLean
H R
HR
Olpe
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007696:Kindling, Neurologic / Q000187:drug effects; D051379:Mice; D000078330:Oxcarbazepine; D010433:Pentylenetetrazole; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology
C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; D015221:Potassium Channels; D017981:Receptors, Neurotransmitter; D015222:Sodium Channels; D002220:Carbamazepine; D000078330:Oxcarbazepine; D010433:Pentylenetetrazole