A new antiepileptic drug: levetiracetam, a pyrrolidone recently licensed as an antiepileptic drug. (Epilepsy).

Recently a new antiepileptic drug, levetiracetam (LEV), was approved for the add on treatment of partial epilepsy, both in the United States and in Europe. This is of potential importance, because this drug is from a class not previously used in epilepsy, although piracetam, a compound with a structure similar to that of levetiracetam, is useful in myoclonus. Both drugs are pyrrolidone derivatives, a class of drugs of interest for both psychotropic and nootropic applications and potentially as neuroprotectants. Levetiracetam (available under the registered trademark of UCB S.A., Keppra (R)) is the S-enantiomer of [alpha]-ethyl-2-oxo-1 -pyrrolidine acetamide (fig 1). Homologues sharing the S configuration include a range of other compounds, some of which also have antiepileptic action. (1) The range and extent of the compounds activity in experimental models of epilepsy and other conditions varies considerably with minor changes to chemical structure, but the full extent of the range of properties of these dru gs in humans has not been explored. This article reviews the experimental and clinical data relating to the antiepileptic action of levetiracetam.

EXPERIMENTAL STUDIES

Levetiracetam shows an unusual profile of antiepileptic activity in experimental animal models of partial and generalised epilepsy. (2) Unlike other antiepileptic drugs, levetiracetam has no effect on tonic seizures induced by maximal electroshock or clonic seizures induced by pentylenetetrazol (PTZ) stimulation in the classic rodent models. (2-4) It however has very marked protection against seizures in audiogenic mice, mice kindled with corneal electroshock or PTZ, and amygdaloid kindled rats. It protects against spontaneous spike and wave discharges in the GAERS model and in piocarpine or kainic acid induced focal seizures in rats. (2 4 5) The dose dependent ability of levetiracetam to inhibit the development of kindling suggests a potential antiepileptogenic effect as well. (6) Levetiracetam is the most effective of any of the pyrrolidone drugs in these epilepsy models. Its R-enantiomer has no antiepileptic activity.

The dose at which toxic effects on the rotarod test are produced is much higher than the effective antiseizure dose in both the GAERS model and the corneally kindled mice. The safety margin of levetiracetam in these models is much greater than for other drugs. In acute and chronic toxicity studies in animals, levetiracetam shows generally low toxicity. Oral doses up to 5000 mg/kg acutely (maximum tested dose) are not lethal in mice and rats. Levetiracetam has not displayed any teratogenic, mutagenic, or carcinogenic properties.

The mechanism of action of levetiracetam (or indeed the other -acetam drugs) is not clearly understood, and it does not seem to involve any conventional modulation of the three main mechanisms relevant for the action of classic antiepileptic drugs. (7) The drug does not bind to receptors associated with excitatory or inhibitory neurotransmitters (for example, [gamma]-aminobutyric acid (GABA), glutamate, glycine, adenosine), has no effect on sodium or T-type calcium channel function, and does not affect GABA transaminase or glutamic acid decarboxylase (GAD) activity or second messenger systems (cyclic adenosine monophosphate, protein kinase C). (2) By contrast, it has recently been reported that levetiracetam reduces high voltage activated [Ca.sup.2+] currents, (8) reverses inhibition of GABA and glycine gated currents induced by negative allosteric modulators, (9) and effects voltage gated potassium channel conductance, (10) suggesting that its mechanism of action differs from other antiepileptic drugs. Leve tiracetam also has a specific stereoselective binding site in the CNS, and cannot be displaced from this site by other …