CHARACTERIZATION OF THE PHARMACODYNAMICS OF SEVERAL ANTIEPILEPTIC DRUGS IN A DIRECT CORTICAL STIMULATION MODEL OF ANTICONVULSANT EFFECT IN THE RAT

In this investigation a newly developed direct cortical stimulation te chnique was evaluated for measurement of anticonvulsant efficacy in ra ts. The kinetics of drug action for carbamazepine, phenytoin, valproat e, phenobarbital, ethosuximide and oxazepam were studied in conjunctio n with their pharmacokinetics. Motor cortex stimulation with a ramp-sh aped pulse train allowed successive determination of a threshold for l ocalized seizure activity (TLS) and for generalized seizure activity ( TGS). For each drug the time course of effect was followed in individu al animals. Differential effects on the pharmacodynamic parameters wer e seen. Phenytoin and carbamazepine clearly elevated the TGS. However, phenytoin did not affect TLS and carbamazepine only marginally. Valpr oate increased both TLS and TGS to the same extent. Phenobarbital and oxazepam elevated both thresholds, but the effect on TGS was more pron ounced. Ethosuximide had little effect on both thresholds. Comparison with other animal models suggested that elevation of TLS reflects an e ffect on seizure initiation, whereas elevation of TGS above TLS reflec ts an effect on seizure propagation. All drugs exhibited a nonlinear r elationship between plasma concentration and anticonvulsant efficacy, without ceiling of anticonvulsant intensity at the highest concentrati ons. The effective concentration range of most compounds coincided wit h the ''therapeutic'' range in humans. The direct cortical stimulation technique is useful for preclinical monitoring of anticonvulsant effi cacy with most antiepileptic drugs because it allows detection of both qualitative and quantitative differences. In addition the model is pa rticularly useful for time course studies.