Oe. Dellapaschoa et al., PHARMACODYNAMIC INTERACTION BETWEEN PHENYTOIN AND SODIUM VALPROATE CHANGES SEIZURE THRESHOLDS AND PATTERN, British Journal of Pharmacology, 125(5), 1998, pp. 997-1004
1 In this study we used cortical stimulation to assess the effects of
phenytoin (PHT), sodium valproate (VPA), and their interaction on tota
l motor seizure and on the constituent elements of the seizure. 2 PHT
(40 mg kg(-1)) was administered as an intravenous bolus infusion to an
imals receiving either a continuous infusion of VPA or saline. VPA pla
sma concentration was maintained at levels that produced no detectable
anticonvulsant effect. 3 Analysis of ictal components (eyes closure,
jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations
revealed both qualitative and quantitative differences in drug effects
. 4 The anticonvulsant effect is represented by the increase in the du
ration of the stimulation required to reach a given seizure threshold.
PHT significantly increased the duration of the stimulation and of th
e motor seizure. This increase was greatly enhanced by VPA. In additio
n, ictal component analysis revealed that the combination of PHT and V
PA causes the reduction of a specific seizure component (JERK). 5 Neit
her the free fraction of PHT nor the biophase equilibration kinetics c
hanges in the presence of VPA. It is concluded that the synergism may
be due to a pharmacodynamic rather than a pharmacokinetic interaction.