Novel Water-Soluble Adjunct Anticonvulsants for Nerve Agents

用于神经毒剂的新型水溶性辅助抗惊厥药

• 批准号: 10475109
• 负责人: Doodipala Samba Reddy
• 金额: $ 44.45万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475109
• 关键词: Acute; Address; Animals; Anticonvulsants; Antidotes; Behavior; Behavioral; Benzodiazepines; Biological Products; Brain; Brain Death; Brain Injuries; Chemical Warfare; Cholinergic Agents; Chronic; Combined Modality Therapy; Data; Development; Diazepam; Drug Kinetics; Effectiveness; Electroencephalography; Evaluation; Event; Exposure to; FDA approved; Formulation; Functional disorder; GABA-A Receptor; Goals; Half-Life; Injection product; Injections; Intoxication; Intramuscular Injections; Investments; Isoflurophate; Lead; Legal patent; Life; Mediating; Midazolam; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurons; Neuroprotective Agents; Organophosphates; Outcome; Outcome Measure; Paraoxon; Parathion; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Powder dose form; Prevention; Property; Rattus; Refractory; Resistance; Rodent; Safety; Sarin; Seizures; Soman; Status Epilepticus; Synapses; System; Terrorism; Time; Toxic effect; Water; analog; animal rule; aqueous; base; biodefense; chemical threat; design; drug development; drug testing; experimental study; hydrophilicity; improved; innovation; lead candidate; lipophilicity; medical countermeasure; nerve agent; neuropathology; neuroprotection; neurosteroids; neurotoxic; novel; novel therapeutics; pre-clinical; primary outcome; programs; safety study; secondary outcome; sex; toxic organophosphate insecticide exposure

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.

项目摘要 该提案的总体目标是确定将控制的新型“水溶性”神经类动物抗惊厥药 急性有机磷酸盐（OP）中毒引起的苯二氮卓抗癫痫发作和脑损伤。接触 神经剂或OP化合物可能导致持续性癫痫发作，状态癫痫症（SE）和永久性大脑 受伤。苯二氮卓类抗惊厥药是对OP诱导的SE的主要疗法，但它们不正确 暴露后的后来保护大脑免受SE的侵害。神经类似是对SE的强大抗惊厥药 由各种OP代理引起的，因此它们可以克服苯二氮卓类药物的关键局限性。这 该项目的目的是调查新水溶性合成的效率和试点安全性 Brexanolone（FDA批准）的类似物作为辅助抗惊厥药治疗的类似物 中毒。测试药物是用咪达唑仑或咪达唑仑的辅助治疗给药的 无法控制SE。目标是快速停止癫痫发作，减少进一步的脑损伤。这种新颖的疗法是 基于神经类固醇的分子机制以及由难治性SE涉及的细胞变化引起的 OP代理。拟议的辅助疗法是基于中心假设，即合成神经类固醇是 增强屈肌和突触外强调抑制更有效地控制神经剂诱导的SE和 神经元损害比单独的苯二氮卓类药物，从而完全减轻发病率。神经类固醇 Brexanolone对于控制大鼠模型的操作诱导的SE和神经元损伤非常有效，但具有确定 它作为医疗对策的限制。谷氨酸酮和淋巴龙是两个铅亲水性 神经类固醇的类似物，具有改进的生物药物和药物（外部抗脱落抗逆转） 特性。测试药物可以作为干粉配制，以进行延长稳定性，并且已承诺 作为运算引起的SE的医学对策的功效。关键重点是生成有关 铅候选者的功效和安全性，并至少确定一种铅药物以进一步开发。 提出的目标将通过解决三个具体目标来实现：（目标1）确定辅助效率 与DFP诱导的SE和脑损伤相对的亲水性神经类似的类似物； （目标2）确定辅助 亲水性神经固醇对SOMAN诱导的SE和脑损伤的功效； （目标3） 确定铅药物的临床前药代动力学和试点安全性。该项目将根据 渐进的“ go/no-go”里程碑计划着重于三个主要结果指标：（i）抗惊厥药 效率; （ii）神经保护剂效率； （iii）预防神经变性和行为功能障碍。这 该项目的结果将确定一种新颖的辅助抗惊厥药，以进行操作实现，并且 “注射干式注射”系统将为军事和平民中心的储存提供漫长的保质期。 这就是这种神经类促进剂的组合将是生物浮雕计划的高效投资。