Novel Water-Soluble Adjunct Anticonvulsants for Nerve Agents

项目摘要 这项提议的总体目标是确定新型的水溶的神经类固醇抗惊厥药物，它将控制 急性有机磷(OP)中毒引起的苯二氮卓类抗药性癫痫和脑损伤。暴露量 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 受伤。苯二氮卓类抗惊厥药物是OP诱发SE的主要治疗药物，但效果不够理想 在暴露后的稍后时间保护大脑免受SE的影响。神经类固醇是治疗SE的强效抗惊厥药物 由多种OP试剂诱导，因此可以克服苯二氮类药物的关键限制。这个 本项目的目的是研究新型水溶性合成制剂的有效性和中试安全性。 灯盏花素类似物(FDA批准)作为咪达唑仑治疗OP的辅助抗惊厥药物 喝醉了。试验药物作为咪达唑仑的辅助治疗或在咪达唑仑有 未能控制SE。其目标是迅速阻止癫痫发作，减少进一步的脑损伤。这种新的疗法是 基于神经类固醇的分子机制和细胞变化在难治性SE中的研究进展 行动特工。拟议的辅助治疗基于中心假设，即合成神经类固醇可以 加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和 比单独使用苯二氮卓类药物对神经元的损害更大，从而完全减轻发病率。神经类固醇 灯盏花素对OP诱导的大鼠SE和神经元损伤有显著的控制作用，但有一定的作用。 作为医学对策，它的推出受到限制。伐黄诺酮和利沙诺酮是两种铅亲水性化合物 神经类固醇的类似物，具有改进的生物制药和药理(突触外首选) 属性。为了延长稳定性，试验药物可制成注射用干粉，前景看好。 作为治疗OP所致SE的药物对策的有效性。关键的重点是在 评估候选铅的有效性和安全性，并确定至少一种可供进一步开发的铅药物。这个 拟议的目标将通过处理三个具体目标来实施：(目标1)确定辅助效果 亲水性神经类固醇类似物对DFP诱导的SE和脑损伤的保护作用；(目标2)确定辅助成分 亲水性神经类固醇类似物对梭曼诱发的SE和脑损伤的疗效；以及(目标3) 确定先导药物的临床前药代动力学和试点安全性。本项目将按以下规定实施 循序渐进的“去/不去”里程碑计划侧重于三个主要结果措施：(1)抗惊厥药 (2)神经保护剂的功效；(3)防止神经退行性变和行为功能障碍。这个 该项目的成果将确定咪达唑仑的一种新的辅助抗惊厥药物用于OP中毒，并且 “干粉注射”系统将为军事和民用中心的储存提供较长的保质期。 因此，这种神经类固醇咪达唑仑的组合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.