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

基本信息

批准号：
10013749
负责人：
Doodipala Samba Reddy
金额：
$ 45.45万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013749
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

项目摘要

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.

项目概要该提案的总体目标是确定新型“水溶性”神经类固醇抗惊厥药，以控制急性有机磷（OP）中毒引起的苯二氮卓类耐药性癫痫发作和脑损伤。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 引起的 SE 的主要治疗方法，但效果还不够。神经类固醇是针对 SE 的强效抗惊厥剂。由多种OP药物诱导，因此它们可以克服苯二氮卓类药物的关键局限性。该项目的目的是研究新型水溶性合成物的功效和中试安全性 brexanolone 类似物（FDA 批准）作为咪达唑仑治疗 OP 的辅助抗惊厥药试验药物作为咪达唑仑的辅助治疗或在咪达唑仑服用后施用。未能控制 SE 的目标是迅速停止癫痫发作，减少进一步的脑损伤。基于神经类固醇的分子机制和涉及难治性SE引起的细胞变化所提出的辅助治疗基于合成神经类固醇的中心假设。增强阶段性和突触外强直性抑制，更有效地控制神经毒剂引起的 SE 和神经元损伤比单独使用苯二氮卓类药物更明显，从而完全减轻发病率。 brexanolone 对于控制大鼠模型中 OP 诱导的 SE 和神经损伤非常有效，但也有一定的局限性 Valaxanolone 和 lysaxanolone 是两种主要的亲水性药物，其推出的局限性。具有改进的生物制药和药理学作用的神经类固醇类似物（突触外优先）测试药物可以配制成注射用干粉，以延长稳定性，并且具有良好的前景。作为 OP 引起的 SE 的医疗对策的有效性，重点是生成有关 OP 引起的 SE 的必要数据。主要候选药物的功效和安全性概况，并确定至少一种主要药物以供进一步开发。拟议的目标将通过解决三个具体目标来实现：（目标 1）确定辅助功效亲水性神经类固醇类似物对抗 DFP 引起的 SE 和脑损伤（目标 2）确定辅助剂；亲水性神经类固醇类似物对 Soman 诱导的 SE 和脑损伤的功效；以及（目标 3）确定先导药物的临床前药代动力学和中试安全性。该项目将按此实施。渐进式“继续/不继续”里程碑计划重点关注三个主要结果指标：(i) 抗惊厥药物功效；(ii) 神经保护功效；以及 (iii) 预防神经退行性变和行为功能障碍。该项目的成果将确定一种新型的咪达唑仑辅助抗惊厥药，用于治疗 OP 中毒 “注射干粉”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-咪达唑仑组合将是生物防御计划的高效投资。