Topiramate: current status and therapeutic potential
Topiramate (TPM) is a structurally unique, highly effective new antiepileptic drug (AED). Three mechanisms of action that may contribute to TPM anticonvulsant activity include modulation of voltage-dependent sodium channels, potentiation of gamma-aminobutyric acid (GABA)-induced chloride fluxes and blockade of kainate glutamate receptors. TPM is rapidly absorbed, has linear pharmacokinetics, a half-life of 20 - 30 h in the absence of hepatic-enzyme-inducing AEDs, and few pharmacokinetic interactions with other drugs. TPM is not extensively metabolised and is excreted renally. The most common adverse effects reported in controlled trials were mild to moderate in severity, mainly CNS-related, and occurred most frequently during the titration period when the TPM dosage was rapidly increased. Combined data from five double-blind, placebo-controlled trials showed TPM produced statistically significant reductions in seizures regardless of age, gender or baseline seizure frequency. Seizure control appears to be maintained with long-term TPM therapy; no evidence of tolerance was seen in patients receiving TPM for periods of up to 7 years. Preliminary findings on TPM as monotherapy for partial epilepsy and as adjunctive therapy for generalised tonic-clonic seizures of non-focal origin, Lennox-Gastaut syndrome, and partial epilepsy in children have been promising.