EVIDENCE FOR A UNIQUE PROFILE OF LEVETIRACETAM IN RODENT MODELS OF SEIZURES AND EPILEPSY

The protective and adverse effect potentials of levetiracetam ((S)-alp ha-ethyl-2-oxo-pyrrolidine acetamide) in rodent models of seizures and epilepsy were compared with the profile of several currently prescrib ed and newly developed antiepileptic drugs. Levetiracetam was devoid o f anticonvulsant activity in the acute maximal electroshock seizure te st and in the maximal pentylenetetrazol seizure test in mice (up to 54 0 mg/kg, i.p.) but exhibited potent protection against generalised epi leptic seizures in electrically and pentylenetetrazol-kindled mice (ED 50 values = 7 and 36 mg/kg, respectively, i.p.). This differs markedly from established and most new antiepileptic drugs which induce signif icant protection in both the acute seizure tests and the kindling mode ls. Furthermore, levetiracetam was devoid of anticonvulsant activity i n several maximal chemoconvulsive seizure tests although an interestin g exception was the potent protection observed against secondarily gen eralised activity from focal seizures induced by pilocarpine in mice ( ED50 value = 7 mg/kg, i.p.), pilocarpine and kainic acid in rats (mini mum active dose = 17 and 54 mg/kg, respectively, i.p.). The protection afforded by levetiracetam on the threshold for 6,7-dimethoxy-4-ethyl- beta-carboline-3-carboxylate (DMCM)-induced seizures persisted after c hronic administration (17-170 mg/kg, i.p., twice daily/14 days) and le vetiracetam did not lower the seizure threshold for the proconvulsant action of the inverse benzodiazepine receptor agonist, N-methyl-beta-c arboline-3-carboxamide (FG 7142). The main metabolite of levetiracetam (ucb L057; (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid) was found to be inactive in sound-sensitive mice after acute administration of doses up to 548 mg/kg, i.p. Levetiracetam induced only minor behaviour al alterations in both normal and amygdala-kindled rats (54-1700 mg/kg , i.p.) resulting in an unusually high safety margin between rotarod i mpairment and seizure suppression of 148 in corneally kindled mice and 235 in Genetic Absence Epilepsy Rats from Strasbourg. In comparison, existing antiepileptic drugs have ratios between 2 and 17 in the corne ally kindled mouse model. These studies reveal a unique profile of lev etiracetam in rodent models. Characteristics are a general lack of ant iconvulsant activity against maximal, acute seizures and selective pro tection with a very high safety margin in genetic and kindled animals and against chemoconvulsants producing partial epileptic seizures. Thi s activity differs markedly from that of the established and newly int roduced antiepileptic drugs and appears to derive from the parent comp ound since its major metabolite was inactive in all models studied. To gether these results therefore suggest that levetiracetam may offer an effective, broad-spectrum treatment of epileptic seizures in patients , with a minimum of adverse effects. (C) 1998 Elsevier Science B.V. Al l rights reserved.