RT Journal Article
SR Electronic
T1 Preclinical Evaluation of Newly Approved and Potential Antiepileptic Drugs Against Cocaine-Induced Seizures
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1148
OP 1156
VO 290
IS 3
A1 Gasior, Maciej
A1 Ungard, Jesse T.
A1 Witkin, Jeffrey M.
YR 1999
UL http://jpet.aspetjournals.org/content/290/3/1148.abstract
AB Seizures and status epilepticus are among the neurological complications of cocaine overdose in humans. The aim of the present study was to evaluate the protective effectiveness and therapeutic index (separation between anticonvulsive and side effect profiles) of 14 newly approved and potential antiepileptic drugs using a murine model of acute cocaine toxicity and the inverted-screen test for behavioral side effect testing. Cocaine (75 mg/kg i.p.) produces clonic seizures (∼90% of mice), and conventional antiepileptic drugs have been reported to be either ineffective or only effective at doses producing significant sedative/ataxic effects. Clobazam, flunarizine, lamotrigine, topiramate, and zonisamide were ineffective against seizures up to doses producing significant motor impairment. In contrast, felbamate, gabapentin, loreclezole, losigamone, progabide, remacemide, stiripentol, tiagabine, and vigabatrin produced dose-dependent protection against cocaine-induced convulsions with varied separations between their anticonvulsant and side effect profiles: the protective index values (toxic TD50/anticonvulsive ED50) ranged from 1.26 (felbamate) to 7.67 (loreclezole), and gabapentin had the highest (protective index >152). Thus, several drugs were identified with greater protective efficacy and reduced motor impairment compared with classic antiepileptic drugs. Based on the proposed mechanism of action of these new anticonvulsants, it is noteworthy that 1) drugs that enhance γ-aminobutyric acid-mediated neuronal inhibition in a manner distinct from barbiturates and benzodiazepines offer the best protective/behavioral side effect profiles, and 2) functional antagonists of Na+ and Ca2+ channels are generally ineffective. Overall, this study provides the first description of the effectiveness of new antiepileptic drugs against experimentally induced cocaine seizures and points to several drugs that deserve clinical scrutiny for this indication. U.S. Government