Treatment of Status Epilepticus: A Translational Proposal

癫痫持续状态的治疗：转化建议

• 批准号: 7687862
• 负责人: CLAUDE G WASTERLAIN
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687862
• 关键词: Accident and Emergency department; Acute; Affect; Agonist; Ambulatory Care Facilities; Anticonvulsants; Behavior; Behavioral; Benzodiazepines; Chemical Stimulation; Chronic; Clinical; Computer software; Conscious; Depressed mood; Development; Diagnosis; Dose; Drug Combinations; Drug usage; Early treatment; Electric Stimulation; Electroencephalogram; Epilepsy; Epileptogenesis; FDA approved; Frequencies; Future; Glutamate Receptor; Gold; Histology; Hour; Human; Injury; Intensive Care Units; Investigation; Ketamine; Lead; Left; Length; Lithium; Lorazepam; Mediating; Modeling; Movement; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurological emergencies; Neuronal Injury; Outcome; Patients; Perforant Pathway; Pharmaceutical Preparations; Pharmacopoeias; Pilocarpine; Progress Reports; Role; Seizures; Severities; Status Epilepticus; Synapses; System; Testing; Therapeutic; Time; Toxic effect; Translating; Traumatic Brain Injury; Treatment Effectiveness; Veterans; Work; base; cooperative study; design; dizocilpine; effective therapy; felbamate; improved; indexing; mortality; neuron loss; population based; prevent; public health relevance; receptor; success; trafficking

DESCRIPTION (provided by applicant): Treatment Of Status Epilepticus: A Translational Proposal Epilepsy is the most common diagnosis in VA outpatient clinics, and the large number of traumatic brain injuries in OEF/OIF is expected to result in a significant increase in its frequency among veterans. This study translates our investigations of the role of receptor trafficking in experimental SE into principles of treatment, using drugs available in the US pharmacopeia. Treatment of status epilepticus (SE) remains ineffective, with a mortality of 27% in recent population-based studies. Once seizures have started, they become self-sustaining, independent of their original trigger, and develop time-dependent pharmacoresistance. Our work (Naylor et al J Neurosci 2005) has shown that repeated seizures cause an internalization (and temporary inactivation) of synaptic GABAA receptors and an increase in synaptic NMDA receptors, which both result from seizure-induced, maladaptive receptor trafficking. These changes suggest a mechanism for the development of self-sustaining seizures (fewer GABAA receptors and more NMDA receptors in synapses) and for pharmacoresistance (fewer synaptic targets for GABAergic drugs). They also suggest that, in SE, polytherapy is more likely to be successful than monotherapy (the current gold standard), since treatment should have at least 2 targets: GABAA receptors (either preventing their internalization and/or maximally stimulating those that are left in the synapse), and NMDA receptors (preventing their movement to the synapse, or reducing their activity). Combination treatments aimed at the GABAA and NMDA systems simultaneously have not been tested extensively. Our preliminary studies explored the use of such combinations, using drugs which are currently approved for human use or are close to approval, and were able to stop severe experimental SE with low subanesthetic doses of anticonvulsants. Therapeutic success with this receptor-based approach to drug selection would confirm the importance of receptor trafficking in the pathophysiologiy of SE, and could greatly improve the effectiveness of treatment of SE. We will induce SE chemically with lithium and pilocarpine, or electrically by stimulating the perforant path, and will treat at 3 time points: after the second intense seizure, 30minutes after seizure onset, or 2 hours after seizure onset. Electroencephalogram and behavior will be recorded for 24 hours and analyzed with appropriate software. Acute histological outcome will be assessed at 72 hours, chronic epileptogenesis, behavior and histology will be studied > 3 months after SE. The importance of timing of treatment will be studied. Our preliminary results suggest that combinations of low doses of anticonvulsants which include GABAA agonists and NMDA blockers are far more effective than monotherapy with the same agents in stopping severe experimental SE, and we hope that the principles of treatment established in this study will lead to improvements in the way we treat status epilepticus clinically. PUBLIC HEALTH RELEVANCE: NARRATIVE Status epilepticus affects 126,000 to 195,000 cases a year in the USA, with an estimated mortality of 22- 42,000 patients yearly. It is one of the most common neurological emergencies in V.H.A. Emergency Rooms, and indeed the largest study of status epilepticus ever carried out was a VA Cooperative study. Status epilepticus is also a frequent consequence of traumatic brain injury (TBI), the most frequent physical injury in OEF/OIF veterans.

描述（由申请人提供）： 癫痫持续状态的治疗：转化建议 癫痫是 VA 门诊中最常见的诊断，OEF/OIF 中的大量创伤性脑损伤预计将导致退伍军人中癫痫发作的频率显着增加。这项研究将我们对实验 SE 中受体运输作用的研究转化为治疗原则，使用美国药典中的药物。癫痫持续状态 (SE) 的治疗仍然无效，最近基于人群的研究显示死亡率为 27%。一旦癫痫发作开始，它们就会自我维持，独立于最初的触发因素，并产生时间依赖性的耐药性。我们的工作（Naylor 等 J Neurosci 2005）表明，反复癫痫发作会导致突触 GABAA 受体的内化（和暂时失活）以及突触 NMDA 受体的增加，这两者都是由癫痫发作引起的适应不良受体贩运造成的。这些变化表明了一种自我维持癫痫发作（突触中 GABAA 受体较少，NMDA 受体较多）和药物耐药性（GABA 能药物的突触靶标较少）发生的机制。他们还表明，在 SE 中，综合疗法比单一疗法（当前的黄金标准）更有可能成功，因为治疗应该至少有 2 个目标：GABAA 受体（阻止其内化和/或最大程度地刺激突触中残留的受体）和 NMDA 受体（阻止其移动到突触，或减少其活动）。同时针对 GABAA 和 NMDA 系统的联合治疗尚未经过广泛测试。我们的初步研究探索了此类组合的使用，使用目前已批准用于人类使用或接近批准的药物，并且能够用低亚麻醉剂量的抗惊厥药来阻止严重的实验性 SE。这种基于受体的药物选择方法的治疗成功将证实受体运输在 SE 病理生理学中的重要性，并可以大大提高 SE 治疗的有效性。我们将用锂和毛果芸香碱以化学方式诱导 SE，或通过刺激穿通路径以电方式诱导 SE，并在 3 个时间点进行治疗：第二次剧烈癫痫发作后、癫痫发作后 30 分钟或癫痫发作后 2 小时。脑电图和行为将被记录 24 小时并使用适当的软件进行分析。急性组织学结果将在 72 小时进行评估，慢性癫痫发生、行为和组织学将在 SE 后 > 3 个月进行研究。将研究治疗时机的重要性。我们的初步结果表明，低剂量抗惊厥药（包括 GABAA 激动剂和 NMDA 阻滞剂）的组合在阻止严重的实验性 SE 方面比使用相同药物的单一疗法更有效，我们希望本研究中建立的治疗原则将导致我们临床上治疗癫痫持续状态的方式得到改进。 公共卫生相关性： 叙述 在美国，癫痫持续状态每年影响 126,000 至 195,000 例病例，估计每年有 22-42,000 名患者死亡。这是 V.H.A. 最常见的神经急症之一。急诊室，事实上，有史以来最大规模的癫痫持续状态研究是退伍军人管理局合作研究。癫痫持续状态也是创伤性脑损伤 (TBI) 的常见后果，TBI 是 OEF/OIF 退伍军人最常见的身体伤害。