Abstracts

Rationale: Lacosamide is an investigational anticonvulsant with effects in a large variety of animal models with predictivity for partial and generalized seizures. In addition, it attenuated the development of amygdale kindling - evidence for an anti-epileptogenic effect. Lacosamide has successfully completed phase III clinical testing and has been submitted to US and EU regulatory authorities for marketing approval. Since lacosamide is also developed in an intravenous formulation, the aim of the current experiments was to characterize its acute and long-term effects in an animal model for status epilepticus. Methods: Male rats were implanted with stimulating and recording electrodes in the perforant path. Self-sustaining status epilepticus was induced by stimulation with 10s 20 Hz trains of 1 ms/30V pulses delivered every 1 min over 30 min. Seizure frequency was assessed by continuous EEG and video monitoring immediately afterwards (acute experiments) and following a longer waiting period of at least 6 weeks (long-term experiments). Lacosamide was administered either 10 min (early treatment) or 40 min (late treatment) following onset of self-sustaining status epilepticus. Results: Early treatment dose-dependently and potently reduced self-sustaining status epilepticus (number of seizures and cumulative seizure time). Late treatment with lacosamide had similar but less potent effects. Hippocampal damage when assessed 72 hours following induction of status epilepticus was greatly reduced following the highest dose tested (50 mg/kg). All untreated rats developed spontaneous recurrent seizures as assessed at least 6 weeks following induction of status epilepticus. Early treatment with lacosamide resulted in a dose-dependent reduction of the number of spontaneous recurrent seizures, with a maximum of 70% reduction at the highest dose tested (50 mg/kg). A significant reduction in the number of spikes and cumulative time spent in seizures with lacosamide treatment was observed. Late treatment with lacosamide resulted in a 50% reduction in the frequency of spontaneous recurrent seizures in the highest dose groups (30 and 50 mg/kg). At the same time, the number of seizure-free animals increased from 0% in the untreated group to 65% in the highest dose groups. Conclusions: Lacosamide demonstrated very potent effects on acute status epilepticus and showed a potential for disease modification in this rat model.