Novel Water-Soluble Adjunct Anticonvulsants for Nerve Agents

项目摘要 这项提案的总体目标是确定新的“水溶性”神经类固醇抗惊厥药，将控制 苯二氮卓类耐药性癫痫发作和急性有机磷（OP）中毒引起的脑损伤。暴露 神经毒剂或OP化合物可导致持续性癫痫发作、癫痫持续状态（SE）和永久性脑 损伤苯二氮卓类抗惊厥药是OP诱导SE的主要治疗方法，但它们不足以 在暴露后的后期保护大脑免受SE的影响。神经甾体是抗SE的强效抗惊厥药 由各种OP药物诱导，因此它们可以克服苯二氮卓类药物的关键限制。的 本项目的目的是研究新型水溶性合成药物的有效性和中试安全性 Brexanolone类似物（FDA批准）作为咪达唑仑治疗OP的辅助抗惊厥药 中毒试验药物作为连续治疗与咪达唑仑一起给药或在咪达唑仑治疗后给药。 无法控制SE。目标是迅速停止癫痫发作，减少进一步的脑损伤。这种新疗法是 基于神经类固醇的分子机制和细胞变化参与难治性SE引起的 行动特工所提出的辅助治疗是基于中心假设，即合成神经类固醇， 增强时相性和突触外紧张性抑制，更有效地控制神经毒剂诱导的SE， 与单独的苯二氮卓类相比，神经元损伤更小，从而完全减轻发病率。述神经类固醇 Brexanolone对于控制大鼠模型中OP诱导的SE和神经元损伤是高度有效的，但具有一定的 作为医疗对策发射的局限性。Valaxanolone和lysaxanolone是两个铅亲水 具有改进的生物药剂学和药理学（突触外偏好）的神经类固醇类似物 特性.测试药物可以配制成用于注射的干粉以延长稳定性，并且它们具有前景。 有效性作为OP诱导SE的医学对策。关键的重点是生成关于 并确定至少一种先导药物以供进一步开发。的 提出的目标将通过解决三个具体目标来实现：（目标1）确定辅助疗效 亲水性神经甾体类似物对DFP诱导的SE和脑损伤的作用;（目的2）确定其辅助治疗药物 亲水性神经类固醇类似物对梭曼诱导的SE和脑损伤的功效;和（目的3） 确定先导药物的临床前药代动力学和先导安全性。该项目将按照 渐进的“去/不去”里程碑计划，重点是三个主要结果指标：（i）抗惊厥药 功效;（ii）神经保护功效;和（iii）预防神经变性和行为功能障碍。的 该项目的结果将确定一种新的辅助抗惊厥药物，以咪达唑仑治疗OP中毒， “注入干动力”系统将为军事和民用中心的储存提供很长的保存期。 因此，这种神经甾体类化合物咪达唑仑将是生物防御计划的高效投资。

Project Summary The overall goal of this proposal is to identify novel ‘water-soluble’ neurosteroid anticonvulsants that will control benzodiazepine-resistant seizures and brain injury caused by acute organophosphate (OP) intoxication. Exposure to nerve agents or OP compounds can result in persistent seizures, status epilepticus (SE), and permanent brain injury. Benzodiazepine anticonvulsants are the primary therapy for OP-induced SE but they do not sufficiently protect the brain from SE at later time after exposure. Neurosteroids are robust anticonvulsants against SE induced by a variety of OP agents and hence they can overcome key limitations of benzodiazepines. The objective of this project is to investigate the efficacy and pilot safety of new water-soluble synthetic analogs of brexanolone (FDA-approved) as adjunct anticonvulsants to midazolam therapy for OP intoxication. Test drugs are administered as adjunctive treatment either with midazolam or after midazolam has failed to control SE. The goal is to rapidly stop seizures, reducing the further brain damage. This novel therapy is based on the molecular mechanisms of neurosteroids and cellular changes involved in refractory SE caused by OP agents. The proposed adjunct therapy is based on central hypothesis that synthetic neurosteroids that enhance phasic and extrasynaptic tonic inhibition more effectively control nerve agent-induced SE and neuronal damage than benzodiazepines alone and thereby completely mitigate morbidity. The neurosteroid brexanolone is highly effective for controlling OP-induced SE and neuronal damage in rat models, but has certain limitations for its launch as medical countermeasure. Valaxanolone and lysaxanolone are two lead hydrophilic analogs of the neurosteroid with improved biopharmaceutical and pharmacological (extrasynaptic-preferring) properties. Test drugs can be formulated as dry powder for injection for extended stability and they have promising efficacy as medical countermeasures for OP-induced SE. The key emphasis is to generate requisite data on the efficacy and safety profile of lead candidates and identify at least one lead drug for further development. The proposed goals will be implemented by addressing three specific aims: (Aim 1) To determine the adjunct efficacy of hydrophilic neurosteroid analogs against DFP-induced SE and brain damage; (Aim 2) To determine the adjunct efficacy of hydrophilic neurosteroid analogs against Soman-induced SE and brain damage; and (Aim 3) To determine the preclinical pharmacokinetics and pilot safety of lead drugs. The project will be implemented as per the progressive “go/no-go” milestones plan focusing on three primary outcome measures: (i) anticonvulsant efficacy; (ii) neuroprotectant efficacy; and (iii) prevention of neurodegeneration and behavior dysfunction. The outcome from this project will identify a novel adjunct anticonvulsant to midazolam for OP intoxication and that the “dry-power for injection” system would provide a lengthy shelf-life for stockpiling at the military and civilian centers. Thus, such neurosteroidmidazolam combination will be highly efficient investment for the biodefense program.