Abstracts

Although there has been a consensus that the use of animal models with spontaneous seizures to identify new therapies may enhance the discovery process for new drugs, there are a number of technical issues that may limit or prevent the implementation of this approach. One of the greatest impediments is the maintenance of steady drug levels in the blood throughout the day over multiple days to ensure that there will be adequate levels in the system at the time the animals may have unpredictable spontaneous seizures. We describe a method for chronically administering antiepileptic drugs and measuing levels while the animals are on continuous video EEG monitoring. Adult male rats with chronic limbic epilepsy following an episode of limbic status epilepticus were implanted with bilateral bipolar hippocampal electrodes and an intraperitoneal catheter. Through a linked fluid swivel/electrical swivel the animals underwent continuous EEG monitoring while receiving a continuous infusion of the study antiepileptic (phenobarbital, phenytoin). Each dose was infused for two weeks, and at the end of this period blood levels were taken by collecting 25 microliters of tail blood on filter paper and measuring with a standardized mass spectrometry analysis. To each drug there was a clear dose response effect with reduction in seizure frequency. The effect on seizure duration and behavior was more variable. The drugs demonstrated efficacy with blood levels that were comparable to established human therapeutic ranges. This early examination of a system for continuous administration of antiepileptic drugs in an animal model of chronic limbic epilepsy demonstrates the feasibility of prolonged drug infusions while performing continuous video EEG monitoring. These findings suggest that this approach may be a useful addition to the process of therapy discovery. The demonstration of efficacy with drug levels relevant to established human levels raises the possibility that effective drug levels found for experimental therapies in this model may provide treatment targets for humans. (Supported by NINDS grant NS 049617.)