Strategies for the development of drugs for pharmacoresistant XXXX .

@entity410 @entity1246 @entity2915 @entity302 @entity734 @entity159
Presently, most strategies for development of @entity734 ( @entity734 ) center around @entity410 models that are known to respond to presently marketed @entity734 . These strategies do not take into account that @entity302 can be a progressive disease. Moreover, region-specific aspects of epileptogenesis are rarely considered when new @entity734 are developed. @entity410 in the temporal lobe are often difficult to treat. Animal studies on various @entity410 models in the hippocampus and the entorhinal cortex (EC) suggest that these structures do not a priori produce @entity410 that are difficult to treat. However, @entity410 -like events in the EC tend to progress to a state of @entity159 -like activity that cannot be suppressed by presently marketed @entity734 . Loss of @entity1246 ( @entity1246 )ergic neurotransmission and increased excitatory synaptic coupling seem to cooperate for induction of this state. @entity302 induced alterations in the interaction between the EC and the hippocampus may lead to alterations that facilitate precipitation of @entity410 . Because of the recurrent interaction between the hippocampus and the EC, these @entity410 may reach an intensity that is no longer controllable by presently available @entity734 . Ontogenetic alterations of the circuitry between the EC and the hippocampus, @entity410 -induced stabilization of synaptic connections overexpressed during ontogenesis, @entity410 -induced lesions and subsequent rearrangements of internal cell properties, and synaptic arrangements and kindling-like alterations of nerve cell and glial behavior may all be involved in the generation of a neuronal aggregate whose balance between inhibitory and excitatory processes becomes readily disturbed. Strategies for the development of @entity734 treating such @entity410 should suppress @entity2915 and prevent progression of epileptogenesis. @entity734 directed against @entity410 may be effective if they can be given in sufficient concentrations to suppress very intense local @entity410 .
