Topiramate: Preclinical Evaluation of a 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.

Molecular Targets for Antiepileptic Drug Development

“…392,393 The action of topiramate on carbonic anhydrase has been assumed not to contribute to its clinical efficacy, because cross-tolerance to the anticonvulsant activity of topiramate does not occur with acetazolamide in mice. 394 However, a recent study finds closely comparable potency for acetazolamide and the two AEDs against cytosolic carbonic anydrase isozyme II and mitochondrial carbonic anhydrase isozyme V. 395 Carbonic anhydrase is a zinc-containing enzyme that is inhibited by interaction of sulfonamide or sulfamate compounds with the Zn(II) ion and specific residues of the protein. X-ray crystallography of human carbonic anhydrase II with zonisamide demonstrates a classical interaction with the protein that is characteristic of sulfonamides, as is zonisamide.…”

Comparison of the Steady‐State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

“…Topiramate (TPM), a promising new antiepileptic agent (AED) derived from the monosaccharide Dfructose, is a structurally novel compound (1). In animal models, TPM has exhibited a broad spectrum of anticonvulsant activity similar to that of carbamazepine (CBZ) and phenytoin (PHT).…”

“…In animal models, TPM has exhibited a broad spectrum of anticonvulsant activity similar to that of carbamazepine (CBZ) and phenytoin (PHT). Its activity appears to be attributable to a block of seizure spread rather than to an increase of seizure threshold (1). Clinical trials to date have demonstrated that TPM greatly enhances seizure control when used as adjunctive treatment in adults with partialonset seizures (2).…”

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

“…TPM appears to have multiple antiepileptic actions in rodent models (13)(14)(15)(16)(17). In vitro studies show enhanced ␥-aminobutyric acid subtype A (GABA A )-receptor mediated chloride flux.…”