Abstracts

Rationale: Monotherapy is the best option for treatment of epilepsy, but the major advantages of monotherapy may not apply to status epilepticus (SE), an acute, life-threatening event of limited duration. Recent studies have shown that seizure-induced trafficking of synaptic GABAA and glutamate receptors causes both a failure of GABAergic inhibition and an increase in glutamatergic excitation during SE (Naylor et al 2005, Goodkin et al 2008). This might suggest that combination therapy aimed at correcting the consequences of both changes may be more effective than monotherapy targeting only one of them. Further benefit might derive from enhancing non-GABAergic inhibition. In the present study, we compared the effect of a single drug to those of two- or three-drug combinations. Methods: We used a rat model of severe SE induced by high-dose lithium and pilocarpine (Tetz et al 2006), and designed to mimic the effects of 1.2 x LD50 dose of nerve agent. The EEG was recorded for 24 hrs after onset, and intermittently thereafter. Because this might apply to battlefield or terrorism situations, we selected the ability to move about and to retain consciousness as key measures of drug toxicity. Outcome measures were termination of SE, using a variety of behavioral and EEG criteria. Our treatment stimulated remaining synaptic GABAA receptors with benzodiazepines. We added a drug which enhanced inhibition at a non-GABA site, since GABA agonists can only partially restore GABA inhibition in this model. We tried to reduce excitation due to an increased number of synaptic NMDA receptors with NMDA antagonists. We administered treatment intraperitoneally after benzodiazepine pharmacoresistance was established. Results: Benzodiazepine monotherapy reduced mortality but did not stop SE. The number of post-treatment seizures was 100 7 in sham-injected controls and 100 8 after 20 mg/kg diazepam (N.S.). Monotherapy with ketamine 10 mg/kg (K), valproate 30 mg/kg (V), brivaracetam 10 mg/kg (Brv), diazepam (1, 5 or 10 mg/kg) (Dz), and other antiepileptic drugs also failed to stop SE. Combinations of low-dose diazepam (1 mg/kg) with ketamine (10 mg/kg) + valproate (30 mg/kg) (Dz1 + K + V), reduced the number of post-treatment seizures to 8 2 (p<0.001 vs Dz or C) while preserving the righting reflex (toxicity score 1 0.4). Combination of diazepam (1 mg/kg) with ketamine (10 mg/kg) + brivaracetam (10 mg/kg) (Dz1 + K + Brv), reduced the number of post-treatment seizures to 8 4 (p<0.01 vs DZ or C) and preserved the righting reflex (toxicity score 1.4 0.9), while DZ20 severely impaired locomotion and the righting reflex (toxicity score 11.2 0.9). Some two-drug combinations were also significantly more effective than monotherapy in this model. Synergism between drugs was strongly suggested by isobolograms . Conclusions: These results suggest that polytherapy can be more effective and less toxic than monotherapy in the treatment of experimental SE.