Drug Development for Epilepsy
For a long time it was assumed that a single antiepileptic drug(AED) could be developed for the treatment of all forms of epi-lepsy. However, the causes of epilepsy are extremely diverse, encompassing genetic and developmental defects and infective, traumatic, neoplastic, and degenerative disease processes. Drug therapy to date shows little evidence of etiologic specificity. There is some specificity according to seizure type (Table 24–1), which is most clearly seen with generalized seizures of the absence type. These are typically seen with 2–3 Hz spike-and-wave
discharges on the electroencephalogram, which respond to etho-suximide and valproate but can be exacerbated by phenytoin and carbamazepine. Drugs acting selectively on absence seizures can be identified by animal screens, using either threshold pentyle-netetrazol clonic seizures in mice or rats or mutant mice showing absence-like episodes (so-called lethargic, star-gazer, or tottering mutants). In contrast, the maximal electroshock (MES) test, with suppression of the tonic extensor phase, identifies drugs such as phenytoin, carbamazepine, and lamotrigine, which are active against generalized tonic-clonic seizures and complex par-tial seizures. The maximal electroshock test as the major initial screen for new drugs has led predominantly to the identification of drugs with a mechanism of action involving prolonged inac-tivation of the voltage-gated Na+ channel. Limbic seizures induced in rats by the process of electrical kindling (involving repeated episodes of focal electrical stimulation) probably pro-vide a better screen for predicting efficacy in complex partial seizures.
Existing antiseizure drugs provide adequate seizure control in about two thirds of patients. So-called “drug resistance” may be observed from the onset of attempted therapy or may develop after a period of relatively successful therapy. Explanations are being sought in terms of impaired access of the drugs to target sites or insensitivity of target molecules to them. In children, some severe seizure syndromes associated with pro-gressive brain damage are very difficult to treat. In adults, some focal seizures are refractory to medications. Some, particularly in the temporal lobe, are amenable to surgical resection. Some of the drug-resistant population may respond to vagus nervestimulation (VNS), a nonpharmacologic treatment for epilepsynow widely approved for treatment of patients with partial sei-zures. VNS is indicated for refractory cases or for patients in whom antiseizure drugs are poorly tolerated. Stimulating elec-trodes are implanted on the left vagus nerve, and the pacemaker is implanted in the chest wall or axilla. Use of this device may permit seizure control with lower doses of drugs. Other devices,using various paradigms of electrical stimulation, are in clinical development.
New antiseizure drugs are being sought not only by the screen-ing tests noted above but also by more focused approaches. Compounds are sought that act by one of three mechanisms: (1) enhancement of GABAergic (inhibitory) transmission, (2) diminution of excitatory (usually glutamatergic) transmission, ormodification of ionic conductances. Presynaptic effects ontransmitter release appear particularly important, and some molecular targets are known, eg, SV2A .
Although it is widely recognized that current antiseizure drugs are palliative rather than curative, successful strategies for identify-ing drugs that are either disease modifying or that prevent epilep-togenesis have proved elusive. Neuronal targets for current and potential antiseizure drugs include both excitatory and inhibitory synapses. Figure 24–1 represents a glutamatergic (excitatory) synapse, and Figure 24–2 indicates targets in a GABAergic (inhibitory) synapse.