A PHARMACOLOGICAL AND CLINICAL REVIEW ON TOPIRAMATE, A NEW ANTIEPILEPTIC DRUG

Topiramate is a new antiepileptic drug which has recently become avail able in the United States and in a number of European countries. Pharm acological studies suggest that its mode of action is multifactorial a nd involves blockade of voltage-dependent sodium channels, potentiatio n of GABAergic transmission and inhibition of excitatory pathways thro ugh an action at AMPA receptor sites. Carbonic anhydrase inhibiting pr operties have also been demonstrated but they are considered not to be relevant to anticonvulsant activity. Topiramate is well absorbed from the gastrointestinal tract, peak plasma levels being usually attained in 2-3 hours. The drug is negligibly (9-17%) bound to plasma proteins and is eliminated partly by renal excretion in unchanged form and par tly by oxidation and hydrolysis. In healthy volunteers, the half-life is about 20-30 hours, but elimination rate is accelerated in patients taking concomitant enzyme inducing drugs such as phenytoin, carbamazep ine and barbiturates. Topiramate has no major effects on plasma levels of concurrent anticonvulsants, except for a rise in plasma phenytoin in occasional patients. In double-blind add-on trials in refractory pa rtial epilepsy, a significant reduction in seizure frequency has been demonstrated in over 40% of topiramate-treated patients (vs about 10% of those treated with placebo), a response rate which compares favoura bly with that observed with other new antiepileptic drugs, Dosages fou nd to be effective in add-on controlled trials range between 200 and 1 000 mg day(-1), although most patients are likely to benefit from rece iving 400 mg day(-1) or less, Preliminary data suggest that topiramate may be effective also in generalized epilepsies, but this needs to be confirmed in prospective studies. The most common adverse effects of topiramate are CNS-related and include dizziness, fatigue, visual dist urbances, ataxia, mental slowing and impaired concentration. Paresthes ias, anorexia, weight loss and increased risk of nephrolithiasis have been also reported. Many of these effects are related to dose and/or t o rate of dose titration. Based on these data, topiramate appears to b e a valuable new drug, whose main current indication is in the add-on management of refractory partial and secondarily generalized seizures. Studies on its potential value as monotherapy are in progress. (C) 19 97 The Italian Pharmacological Society.