Preclinical evaluation of newly approved and potential antiepileptic drugs against 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 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 (approximately 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 TD(50)/anticonvulsive ED(50)) 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 gamma-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 Ca(2+) 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.
Gasior
M
M
Drug Development Group, Behavioral Neuroscience Branch, Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA. mgasior@intra.nida.nih.gov
Ungard
J T
JT
Witkin
J M
JM
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000633:toxicity*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control*
D000927:Anticonvulsants; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine