Evaluation of topiramate neuroprotective effect in severe TBI using microdialysis
Evaluation of topiramate neuroprotective effect in severe TBI using microdialysis
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DOI：
10.1111/j.1749-6632.2003.tb07508.x
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Bullock, R
中科院分区：
文献类型：
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作者：
Alves, OL;Doyle, AJ;Bullock, R
尽管近年来我们对人类创伤性脑损伤（TBI）病理生理的理解取得了进展，但我们仍然需要有效的神经保护剂。缺乏严格的药物在“活的”大脑中的药代动力学研究是人类创伤性脑损伤研究中神经保护试验失败的重要原因。在过去，有几种药物被贴上无效的标签，甚至从昂贵的试验中退出，而不知道它们在受伤的人脑中的实际作用。脑损伤的特点是由于水肿导致扩散距离增加，以及调节药物通过血脑屏障（BBB）运输的血流量减少。在本文报道的研究中，我们使用脑微透析为谷氨酸释放抑制剂托吡酯的生物利用度和药理功效的持续体内评价提供了一种安全有效的工具。托吡酯以神经保护浓度穿过血脑屏障，显示出降低谷氨酸水平的作用，从而改变TBI后谷氨酸释放的自然历史。在II期药物研究中使用脑微透析将允许检测神经保护剂的适当治疗窗口和剂量。与传统的临床试验设计相比，这一策略是一种明显的改进，并将降低试验成本。
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 In the past, several drugs have been labeled as inefficient, and even withdrawn from expensive trials, without knowing their actual penetration in the traumatized human brain.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.