Comparison of Anticonvulsant Efficacy of Valproate During Prolonged Treatment with One and Three Daily Doses or Continuous (“Controlled Release”) Administration in a Model of Generalized Seizures in Rats

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Abstract
Summary: Recently, sustained‐release (SR) preparations of valproate (VPA) have been developed to minimize or prevent problems associated with plasma level fluctuations during therapy with conventional preparations. In the present experiments, the anticonvulsant activity of VPA was assessed during prolonged treatment with different administration protocols using the intravenous (i.v.) pentylenetetrazol (PTZ)‐infusion seizure threshold model in rats. To simulate a controlled‐release (CR) preparation, VPA was infused at a constant rate through chronically implanted intrajugular catheters in some of the experiments. In all experiments, the PTZ seizure threshold was repeatedly determined in individual rats with chronically implanted intrajugular catheters at daily intervals. Injection of saline three times daily in a control group showed that the PTZ seizure threshold was stable throughout the experiment. Acute administration of VPA 200 mg/kg intraperitoneally (i.p.) significantly increased the seizure threshold. During prolonged treatment with three daily doses of 200 mg/kg i.p., anticonvulsant activity markedly increased on the second day of treatment and thereafter compared to the acute effect of VPA, although plasma levels measured at each seizure threshold determination did not differ significantly. This increase in anticonvulsant activity of VPA during prolonged treatment was much less pronounced with one instead of three daily doses. One daily intraperitoneal injection of VPA (200 mg/kg) plus continuous, constant‐rate intravenous infusion of 400 mg/kg/day led to a marked increase in anticonvulsant activity similar to that in the experiment with three daily doses, indicating that not the peak levels but the duration of maintenance of active drug concentrations was important for development of enhanced anticonvulsant activity. Continuous constant‐rate intravenous infusion of VPA (600 mg/kg/day) without additional bolus injections led to significant increases in seizure threshold for the duration of treatment, although drug levels at time of threshold determination were much lower as compared with those in the experiments with conventional administration, confirming that high peak levels of VPA are not needed for development of anticonvulsant efficacy. In contrast to the experiments with single‐dose injections, continuous infusion of VPA was the only treatment devoid of behavioral adverse effects. The experiments indicate that CR preparations of VPA lead to anticonvulsant efficacy of VPA in the absence of high peak levels in plasma and the adverse effects (AE) associated with such peak levels.

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