Preclinical evaluation of newly approved and potential antiepileptic drugsagainst cocaine-induced seizures

Seizures and status epilepticus are among the neurological complications of cocaine overdose in humans. The aim of the present study was to evaluate t he protective effectiveness and therapeutic index (separation between antic onvulsive and side effect profiles) of 14 newly approved and potential anti epileptic drugs using a murine model of acute cocaine toxicity and the inve rted-screen test for behavioral side effect testing. Cocaine (75 mg/kg l.p. ) produces clonic seizures (similar to 90% of mice), and conventional antie pileptic drugs have been reported to be either ineffective or only effectiv e at doses producing significant sedative/ataxic effects. Clobazam, flunari zine, lamotrigine, topiramate, and zonisamide were ineffective against seiz ures up to doses producing significant motor impairment. In contrast, felba mate, gabapentin, loreclezole, losigamone, progabide, remacemide, stiripent ol, tiagabine, and vigabatrin produced dose-dependent protection against co caine-induced convulsions with varied separations between their anticonvuls ant and side effect profiles: the protective index values (toxic TD60/danti convulsive ED50) ranged from 1.26 (felbamate) to 7.67 (loreclezole), and ga bapentin had the highest (protective index >152). Thus, several drugs were identified with greater protective efficacy and reduced motor impairment co mpared with classic antiepileptic drugs. Based on the proposed mechanism of action of these new anticonvulsants, it is noteworthy that 1) drugs that e nhance gamma-aminobulyric acid-mediated neuronal inhibition in a manner dis tinct from barbiturates and benzodiazepines offer the best protective/behav ioral side effect profiles, and 2) functional antagonists of Na+ and Ca2+ c hannels are generally ineffective. Overall, this study provides the first d escription of the effectiveness of new antiepileptic drugs against experime ntally induced cocaine seizures and points to several drugs that deserve cl inical scrutiny for this indication.