Evaluation of Topiramate Neuroprotective Effect in Severe TBI Using Microdialysis

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Abstract
Despite recent advances in our understanding of human traumatic brain injury (TBI) pathophysiology, we still need effective neuroprotective agents. The lack of rigorous drug pharmacokinetic studies in the "living" brain is an important cause of neuroprotection trials failure in human TBI research. In the past, several drugs have been labeled as inefficient, and even withdrawn from expensive trials, without knowing their actual penetration in the traumatized human brain. The injured brain is characterized by an increased diffusion distance, due to edema, and reduced blood flow that modulates drug transport across the blood-brain barrier (BBB). In the study reported in this paper, we used cerebral microdialysis to provide a safe and efficient tool for continuous in vivo evaluation of bioavailability and pharmacologic efficacy of topiramate, a glutamate release inhibitor. Topiramate crossed the BBB in neuroprotective concentrations, and showed a lowering effect on glutamate levels, thereby modifying the natural history of glutamate release after TBI. The use of cerebral microdialysis in phase II drug studies will allow the detection of the appropriate therapeutic window and dosage for the neuroprotective agent. This strategy represents a clear improvement compared to traditional clinical trial design, and will reduce the trial costs.