Antiepileptic drug development program: a cooperative effort of government and industry.

Abstract

The most important step in antiepileptic drug discovery is the choice of an appropriate animal model for the initial screening as well as for the more complex procedures that elucidate mechanisms of action. The currently available models fall short in their inability to identify all drugs for all types of seizures in a mechanism-independent manner. Nevertheless, spontaneous models of epilepsy are the most commonly used, and chemically or electrically induced seizures in rodents can also identify potential anticonvulsants. In the latter models, the intensity of the seizure stimulus is of paramount importance. The Antiepileptic Drug Development Program evaluates approximately 800 compounds each year, using two models for preliminary screening. One model assesses the ability of a compound to prevent seizure spread; the other weighs the ability to raise seizure threshold. In vivo tests, featuring amygdala- and corneal-kindled seizures, and in vitro assays, employing gamma-aminobutyric acid (GABA) receptors and synaptosomal uptake of adenosine, define drug-drug interactions and elucidate the pharmacological profiles of potential anticonvulsants.