Combination therapy of levetiracetam and gabapentin against nonconvulsive seizures induced by penetrating traumatic brain injury.

Background: Post-traumatic seizures are a medical problem affecting patients with traumatic brain injury. Yet effective treatment is lacking owing to the limitations of anti-epileptic drugs (AEDs) applicable to these patients. Method: In this study, we evaluated the dose-response efficacy of levetiracetam (12.5-100.0mg/kg) and gabapentin (1.25-25.0mg/kg) administered either individually or in pairs at fixed-dose ratios as a combination in mitigating post-traumatic nonconvulsive seizures induced by severe penetrating ballistic-like brain injury (PBBI) in rats. Seizures were detected by continuous EEG monitoring for 72h post-injury. Animals were treated twice per day for 3 days by intravenous injections. Results: Both levetiracetam (25-100mg/kg) and gabapentin (6.25-25mg/kg) significantly reduced PBBI-induced seizure frequency by 44-73% and 61-69%, and seizure duration by 45-64% and 70-78%, respectively. However the two drugs manifested different dose-response profiles. Levetiracetam attenuated seizure activity in a dose-dependent fashion, whereas the beneficial effects of gabapentin plateaued across the 3 highest doses tested. Combined administration of levetiracetam and gabapentin mirrored the more classic dose-response profile of levetiracetam monotherapy. However, no additional benefit was derived from the addition of gabapentin. Furthermore, isobolicgraphic analysis of the combination dose-response profile of levetiracetam and gabapentin failed to reach the expected level of additivity, suggesting an unlikelihood of favorable interactions between these two drugs against spontaneously occurring post-traumatic seizure activities at the particular set of dose ratios tested. Discussion: This study was the first attempt to apply isobolographic approach to studying AED combination therapy in the context of spontaneously occurring post-traumatic seizures. Despite the failure to achieve additivity from levetiracetam and gabapentin combination, it is important to recognize the objectivity of the isobolographic approach in the evaluation of AED combination therapy in the context of seizures directly associated with brain injuries. (C) 2017 Lippincott Williams & Wilkins, Inc.

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