Abstracts

Rationale: The conventional anti-seizure formulation of valproate (VPA) leads to highly fluctuating peak and trough plasma levels which can be associated with adverse side effects and lack of efficacy, respectively. Peak plasma levels have been thought to be required for effective seizure suppression. If a continuous or ‘sustained release’ VPA formulation provides to be just as effective as conventional VPA without the side effects; this would be clinically advantage. The aim of this study was to compare the degree of seizure suppression of intermittent and continuous VPA infusions in two animal models of epilepsy. Methods: Sixteen (300-400g), 4 month old Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and 25 non-epileptic control (NEC) rats received i.p. kainic acid (KA) were all implanted with 4-6 epidural EEG electrodes. In addition the KA rats received a unilateral bipolar electrode in the hippocampus. One week after recovery from surgery all rats received a right jugular vein catheter for fluid infusion. A saline infusion was followed by two infusions periods with VPA (42mg/kg) which were separated by a two day washout period of saline (all at a rate of 1ml/hr). Percentage time in seizure was quantitated in 24hr of EEG in GAERS on the last day of each infusion protocol. In the KA rats, the number of convulsive seizures were counted using 24hr video-EEG. At completion, rats were euthanised and plasma samples were extracted for VPA analysis. Statistical analysis was carried out using Wilcoxon signed rank test on the KA data and paired t-test was used on the GAERS data. This study was approved by the Melbourne Health Animal Ethics Committee in 2006 and conformed to all set guidelines. Results: Simular results were observed in both GAERS and KA treated rats. There was a significant decrease in % time in seizure during continuous and intermittent VPA administration when compared to saline in GAERS (51% and 60%, respectively, p<0.01) but no difference between the two VPA infusion protocols (p=0.06). The number of convulsive seizures in KA treated rats was significantly decreased in both VPA infusions compared to saline (81% and 97% for continuous and intermittent, respectively, p<0.01). There was no significant difference between VPA treatments in KA rats (p=0.42). Plasma samples confirmed that VPA levels were in the therapeutic range at the end of both VPA infusions. Conclusions: Chronic VPA infused either continuously or intermittently results in significant seizure suppression in both genetic generalised and temporal lobe rodent models of epilepsy. These results provide evidence that continuous infusion of VPA is equally as effective as intermittent infusion. This study could have important implications for VPA treatment, specifically regarding the rationale for the use of controlled release formulations that provide less variable VPA plasma levels and side effects. Funded by Abbott Laboratories