Extransynaptic GABAA modulators for benzodiazepine refractory status epilepticus

突触外 GABAA 调节剂治疗苯二氮卓类难治性癫痫持续状态

• 批准号: 10372824
• 负责人: F. Edward DUDEK
• 金额: $ 43.28万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372824
• 关键词: Anesthetics; Animal Model; Anticonvulsants; Antiepileptic Agents; Appearance; Barbiturates; Benzodiazepines; Binding; Brain; Brain region; Coma; Consensus; Data; Development; Diagnosis; Dose; Electroencephalogram; Epileptogenesis; Exhibits; Goals; Grant; Hour; Human; Implant; Intervention; Intravenous; Intravenous Anesthetics; Label; Medical; Medical emergency; Midazolam; Modeling; Molecular Target; Morbidity - disease rate; Nerve Degeneration; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pilocarpine; Plasma; Rattus; Refractory; Role; Seizures; Severities; Site; Slice; Status Epilepticus; Synapses; Testing; Therapeutic; Time; Weaning; Whole-Cell Recordings; base; clinically relevant; dentate gyrus; experience; experimental study; fluoro jade; gamma-Aminobutyric Acid; granule cell; hippocampal pyramidal neuron; in vivo; kainate; mortality; nerve agent; neuron loss; neurosteroids; patient population; positive allosteric modulator; prevent; primary outcome; receptor; receptor internalization; sex; standard of care; therapeutic candidate; weapons

Status epilepticus (SE) is a time-sensitive medical emergency that often becomes refractory to current standard-of-care interventions. As seizures persist, medical treatments increase in severity from simple intravenous benzodiazepines (BZDs) administered within the first 15-30 minutes of SE, to anti-epileptic drugs after 30 minutes, to anesthetic and/or barbiturate induced coma. Treatment course beyond the initial BZDs is not clinically defined and the ability to stop SE even when treated in a timely manner is insufficient. Therefore, there exists a need for superior medical interventions for both rapid and delayed treatment of SE. We have identified a new compound that could fill this role. In preliminary testing, this compound was found to be far superior to BZDs in the treatment of nerve-agent induced SE. In this project we seek to determine if the compound may be efficacious in the treatment of SE induced by more standard chemoconvulsants that produce BZD-refractory SE. The second goal of the proposal is to determine the specific molecular target of this compound in live brain slices. Together, these data will help to support the development of this compound for potential use as a first-line treatment of SE, or second-line treatment of refractory SE, in human patients.

癫痫持续状态(SE)是一种时间敏感的医疗紧急情况，通常 对目前的护理标准干预措施难以奏效。随着癫痫的持续，医疗治疗 单纯静脉注射苯二氮卓类药物(BZD)可增加患者病情严重程度 前15-30分钟SE，30分钟后至抗癫痫药物，至麻醉剂和/或 巴比妥酸盐诱导昏迷。最初的BZDS以外的治疗过程没有临床定义， 即使及时治疗，阻止SE的能力也是不够的。因此，在那里 对于SE的快速和延迟治疗，都需要更好的医疗干预。我们 已经确定了一种可以填补这一角色的新化合物。在初步测试中，这种化合物 在治疗神经毒剂诱发的SE方面明显优于BZDS。在这个项目中 我们试图确定该化合物是否可以有效地治疗由 产生BZD难治性SE的更多标准化学惊厥药。第二个目标是 建议在活体脑片中确定这种化合物的特定分子靶点。 总而言之，这些数据将有助于支持这种化合物的开发，作为潜在的用途 人类SE的一线治疗，或难治性SE的二线治疗。