title: Topiramate: preclinical evaluation of structurally novel anticonvulsant.
abstract: Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776.
authors.forename: R P
authors.initials: RP
authors.lastname: Shank
authors.forename: J F
authors.initials: JF
authors.lastname: Gardocki
authors.forename: J L
authors.initials: JL
authors.lastname: Vaught
authors.forename: C B
authors.initials: CB
authors.lastname: Davis
authors.forename: J J
authors.initials: JJ
authors.lastname: Schupsky
authors.forename: R B
authors.initials: RB
authors.lastname: Raffa
authors.forename: S J
authors.initials: SJ
authors.lastname: Dodgson
authors.forename: S O
authors.initials: SO
authors.lastname: Nortey
authors.forename: B E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004347:Drug Interactions; D004597:Electroshock; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole; D010852:Picrotoxin; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D013747:Tetrabenazine / Q000494:pharmacology; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D005632:Fructose; D010433:Pentylenetetrazole; D010852:Picrotoxin; D012110:Reserpine; D013747:Tetrabenazine; D000077236:Topiramate