Abstracts

There is a need for more effective drugs for the treatment of status epilepticus (SE) but testing potential SE drugs in human patients is difficult. The cobalt-homocysteine model of generalized convulsive status epilepticus (GCSE) (Epilepsy Res 2:79-86, 1988) can be used to predict the median effective dose (ED[sub]50[/sub]) and median effective concentration (EC[sub]50[/sub]) of drugs against SE. We used this experimental model to study the potential efficacy of levetiracetam in the treatment of GCSE., 135 male 200-300 gm male Sprague-Dawley rats were implanted with 4 stainless steel epidural electrodes for EEG recording. 2.5 mg powered cobalt was placed under the left frontal electrode. When the rat exhibited interictal polyspikes and/or right UE twitching, SE was induced by injecting 8 mM homocysteine thiolactone IP. Immediately after the 2nd GTC seizure, levetiracetam (LTA) was administered IP and was considered effective if no further seizures occurred 10-30 minutes after injection. Animals were euthanized at 30 minutes after onset of SE and blood and brains collected for LTA determination by HPLC. Because LTA was not effective alone, its ED[sub]50[/sub] was determined after administration of 0.1 mg/kg diazepam (ED[sub]50[/sub] of DZM alone = [sim] 5 mg/kg), using doses from 0 to 1000 mg/kg. The neuroprotective potential of LTA was determined by comparing visual-spatial performance in a Morris Water maze at various EEG stages of SE with and without LTA (500 mg/kg)., LTA alone at doses of 10 to 6000 mg/kg was not effective at stopping GCSE in the cobalt-homocysteine model. The ED[sub]50[/sub] of LTA, when given in combination with 0.1 mg/kg DZM, was 550 mg/kg (CI 385-800 mg/kg), based on doses from 0-800 mg/kg. Paradoxically, at 1000 mg/kg only 14% of the rats stopped GCSE. 500 mg/kg LTA had no neuroprotective effect on water maze performance in rats in which SE was stopped at EEG stage V, whether given during SE (Stage III), or when SE was stopped at Stage V. Serum and brain LTA concentrations 30 minutes after administration will be shown., LTA is not effective alone in the cobalt-homocysteine model of GCSE. Its efficacy is enhanced by prior- or co-administration of a subtherapeutic dose of diazepam, but the ED[sub]50[/sub] is still [sim] 550 mg/kg. Whether or not LTA should be considered for use in human SE will at least partially depend on the serum concentration that corresponds to the ED[sub]50[/sub] of 550 mg/kg in this model. If the serum concentration is in a range safe for human administration, it can serve as a target concentration in further study of the potential of LTA in the treatment of human SE. It may be that LTA will be an effective second treatment that should be used to provide long-term protection against relapse in human GCSE after initial use of a benzodiazepine such as diazepam or lorazepam., (Supported by UCB and the Barrow Neurological Foundation.)