Abstracts

Rationale: Traditional formulations of anti-epileptic drugs like valproate (VPA) result in rapid fluctuations in blood levels and can cause significant side effects. In contrast, the controlled release VPA formulation results in fewer side effects. Whether continuous administration of VPA also improves anti-seizure efficacy has received relatively little attention. The aim of this study was to explore the pharmacodynamic effect on seizures of several doses and investigate the efficacy of continuous versus highly fluctuating levels of VPA in Genetic Absence Epilepsy Rats from Strasbourg (GAERS).Methods: Ten GAERS, four months of age (300-400g), were implanted with six epidural EEG electrodes. After one week of recovery, a catheter was implanted in the jugular vein for drug delivery and blood sampling. A dose response study was performed in five animals, which each received a bolus of 50, 100 and 200mg/kg iv in random order. EEG was recorded 1h before till 3h after drug delivery. A second group of animals (n=5) received three days of saline infusion (0.7ml/h) followed by two randomly assigned treatment regimes (3 days, 42mg/kg/h of VPA at 0.7ml/h) separated by two days of wash-out: 1) continuous infusion, and 2) intermittent hourly bolus injections. Seizure activity was quantified with 4 hour EEG on treatment Day 3. Results: All single bolus injections of 50, 100 and 200mg/kg similarly decreased the number of seizures vs. baseline (77%, 84% and 71% respectively, all p< 0.01). The two highest doses significantly reduced mean seizure duration (38% and 48% respectively, p<0.05) and % time in seizure (91% and 75% respectively, p<0.01). Time course analysis per 15 min showed that seizure suppression with 50 and 100 mg/kg VPA was not significantly different from baseline after 120 min after bolus injection and after 90 min for 200 mg/kg. During the continuous VPA administration the number of seizures and % time in seizure were significantly reduced compared to the saline infusion (72% and 87% respectively, both p<0.05). In contrast, no significant differences in seizure expression from that of the saline infusions were found with the intermittent VPA injections. Blood plasma samples confirmed that VPA levels were in the therapeutic range during both treatment periods.Conclusions: We demonstrated that continuous VPA delivery results in better seizure suppression than intermittent VPA administration in GAERS. This study could have important implications for VPA treatment for generalised epilepsies, specifically regarding the rationale for the use of controlled release formulations that provide less fluctuating blood levels. (Sources of funding Abbott Laboratories)