INTRAVENOUS VALPROATE - ONSET AND DURATION OF ANTICONVULSANT ACTIVITY AGAINST A SERIES OF ELECTROCONVULSIONS IN COMPARISON WITH DIAZEPAM AND PHENYTOIN

A series of 5 generalized tonic-clonic seizures within 30 min was induced by repeated transauricular electrical stimulation in mice. In this model, the anticonvulsant potency of intravenous valproate was compared with diazepam and phenytoin. All 3 drugs proved capable of rapidly suppressing the seizures after intravenous bolus injection. Potent anticonvulsant activity of diazepam and valproate was already obtained after 30 s, while phenytoin's onset of action was somewhat slower. In contrast to diazepam, valproate and phenytoin suppressed the seizures at non-sedative doses. ED50s for blockade of generalized tonic-clonic seizures throughout the 30-min period of repeated electrical stimulation were 6.6 mg/kg for diazepam, 28 mg/kg for phenytoin and 212 mg/kg for valproate. Determination of valproate in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. The data indicate that an intravenous formulation of valproate might be a useful alternative to phenytoin as a non-sedative anticonvulsant for diazepam-resistant status epilepticus.