title: Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin.
abstract: The mechanisms of paradoxical aggravation of epileptic seizures induced by selected antiepileptic drugs (AEDs) remain unclear. The present study addressed this issue by determining the seizure-threshold doses of carbamazepine (CBZ) and phenytoin (PHT), as well the dose-dependent effects of CBZ, PHT, and carbonic anhydrase-inhibiting AEDs, acetazolamide (AZM), topiramate (TPM), and zonisamide (ZNS), on neurotransmitter release in rat hippocampus. The dose-dependent effects of AEDs on hippocampal extracellular levels of glutamate (Glu), GABA, norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were determined by microdialysis with high-speed and high-sensitive extreme liquid chromatography. Proconvulsive effects of AEDs were determined by telemetric-electrocorticography. Therapeutically relevant doses of AZM, CBZ, TPM, and ZNS increased hippocampal extracellular levels of GABA, NE, DA, and 5-HT, while PHT had no effect. Supratherapeutic doses of AZM, CBZ, PHT, TPM, and ZNS decreased extracellular levels of GABA, NE, DA, and 5-HT, without affecting Glu levels. Toxic doses of CBZ and PHT produced seizures (paradoxical intoxication), markedly increasing all transmitter levels, but TPM and ZNS even at toxic doses did not produce seizure. Co-administration experiments showed that therapeutically relevant doses of CBZ or PHT reduced the seizure-threshold doses of PHT or CBZ, respectively. In contrast, therapeutically relevant doses of AZM, TPM, and ZNS elevated the seizure-threshold doses of CBZ and PHT. These results suggested that blockade of high percentage of the population of voltage-dependent sodium channels by CBZ and PHT might be important in inducing paradoxical intoxication/reaction, and that inhibition of carbonic anhydrase inhibits this effect. TPM and ZNS are candidate first-choice agents in treatment of epilepsy when first-line AEDs are ineffective.
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohoyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Dai
authors.initials: D
authors.lastname: Suzuki
authors.forename: Shinich
authors.initials: S
authors.lastname: Kanehara
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Eishi
authors.initials: E
authors.lastname: Motomura
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tanii
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiroyama
authors.forename: Motohiro
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002220:Carbamazepine / Q000097:blood / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D009068:Movement / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D010672:Phenytoin / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077236:Topiramate; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D018377:Neurotransmitter Agents; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000078305:Zonisamide; D010672:Phenytoin