Neurosteroid Treatment for OP Intoxication

OP 中毒的神经类固醇治疗

• 批准号: 8546037
• 负责人: Doodipala Samba Reddy
• 金额: $ 66.45万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546037
• 关键词: Acute; Address; Animals; Anticonvulsants; Antidotes; Atropine; Behavioral; Benzodiazepines; Brain; Brain Injuries; Certification; Chemicals; Chemistry; Cholinergic Agents; Cholinesterase Inhibitors; Chronic; Clinical; Clinical Trials; Data; Development; Diazepam; Drug Formulations; Drug Kinetics; Electroencephalography; Emergency Situation; Evaluation; Exhibits; Exposure to; FDA approved; GABA-A Receptor; Gases; Goals; Half-Life; Hormonal; Injection of therapeutic agent; Injection product; Intoxication; Intramuscular Injections; Lead; Lethal Dose 50; Letters; Magnetic Resonance Imaging; Mediating; Medical; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Nerve; Nerve Degeneration; Neuronal Injury; Neurons; Neuroprotective Agents; Organophosphates; Outcome; Outcome Measure; Paraoxon; Parathion; Pathway interactions; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Pilocarpine; Pilot Projects; Play; Population; Prevention; Prodrugs; Rattus; Readiness; Role; Safety; Sarin; Seizures; Soman; Status Epilepticus; Synapses; System; Therapeutic; Time; Toxic effect; Treatment Effectiveness; Treatment Protocols; United States National Institutes of Health; Validation; analog; animal rule; aqueous; base; cholinergic; cyclosarin; design; efficacy testing; gamma-Aminobutyric Acid; ganaxolone; improved; mortality; nerve agent; nerve gas; neuroprotection; neurosteroids; neurotoxicity; nonhuman primate; novel; novel therapeutics; organophosphate poisoning; pesticide intoxication; preclinical safety; preclinical study; preclinical toxicity; prevent; primary outcome; public health relevance; receptor; research study; success; tabun

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel, broad-spectrum neurosteroid therapy that will mitigate the morbidity and mortality caused by acute exposure to nerve agents and organophosphate (OP) pesticides, which are credible threat agents for military and civilian populations. Exposure to nerve agents or OP poisoning can result in persistent seizures, status epilepticus (SE), and permanent brain injury. Current anticonvulsant countermeasures (benzodiazepines) for nerve intoxication do not sufficiently protect the brain from SE, a prolonged seizure activity lasting 30 min or longer with significant neuronal injury and mortality. We propose that neurosteroids and selective drugs that enhance phasic and extrasynaptic tonic inhibition produce more effective protection against persistent SE than benzodiazepines, prevent irreversible brain injury, and extend the therapeutic window. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE, a common neurotoxicity by nerve agents. Neurosteroids are the most powerful anticonvulsants against seizures induced by cholinergic agents. Since OP nerve agents cause persistent seizures and brain damage through cholinergic hyperactivation, it is proposed that neurosteroids are more effective anticonvulsants for OP nerve intoxication than benzodiazepines. We have pilot evidence that late post-exposure neurosteroid therapy can rapidly control SE and be neuroprotective after SE in pilocarpine and DFP models, suggesting the promising efficacy of neurosteroid therapy. The objective of this project is to investigate the efficacy and safety of the synthetic neurosteroid ganaxolone and its analogs as 'broad-spectrum' medical countermeasures for nerve agent and OP pesticide intoxication. This is a logical extension of our R21s for further efficacy validation, lead optimization, and IND application. The primary emphasis is to generate requisite data on the efficacy and safety of the lead candidate and submit an IND application within a 5 year period. To develop neurosteroids as superior countermeasures than diazepam, we will address three specific aims: (Aim 1): Determine the efficacy of ganaxolone against DFP- and soman-induced SE and brain damage; (Aim 2): Develop ganaxolone analogs with improved formulation pharmacokinetics and efficacy against DFP- and soman-induced SE and brain damage; and (Aim 3): Determine the preclinical safety and toxicity of ganaxolone or its lead analog and submit an IND for clinical development under the FDA Animal Rule Pathway. The project will be implemented as per the progressive "go/no-go" milestones plan, which includes quantitative criteria for the success of key studies focusing on three primary outcome measures: (i) anticonvulsant efficacy; (ii) neuroprotectant efficacy; and (iii) prevention of neurodegeneration. The outcome from this project will identify an effective antidote for OP intoxication and enhance readiness for emergencies.

描述（由申请人提供）：该项目的总体目标是开发一种新型的，广泛的神经固醇疗法，该治疗将减轻因急性暴露于神经剂和有机磷酸盐（OP）农药而引起的发病率和死亡，这是军事和平民种群可信的威胁者。暴露于神经药物或OP中毒会导致持续性癫痫发作，癫痫持续状态（SE）和永久性脑损伤。当前的抗惊厥药（苯二氮卓类药物）用于神经中毒不能充分保护大脑免受SE的侵害，持续30分钟或更长的癫痫发作活性持续30分钟或更长，具有明显的神经元损伤和死亡率。我们建议，与苯二氮卓类药物相比，可以增强阶段性和间氨调节性抑制作用的神经类动物和选择性药物对持续的SE产生更有效的保护，防止不可逆的脑损伤，并扩展治疗窗口。这种新型的治疗策略基于神经类固醇的新兴分子机制以及SE中涉及的细胞变化，SE是神经毒剂的常见神经毒性。神经类似物是针对胆碱能诱导的癫痫发作的最强大的抗惊厥药。由于神经毒剂通过胆碱能过度激活引起持续的癫痫发作和脑损伤，因此提出神经类固醇比苯二氮卓类药物更有效地抗毒性。我们有试验证据表明，在毛果钙和DFP模型中SE后SE后，暴露后神经蛋白酶治疗可以迅速控制SE并受到神经保护作用，这表明神经类固醇治疗的有前途的功效。该项目的目的是研究合成神经固醇甘氧酮及其类似物的疗效和安全性，作为神经剂和OP农药中毒的“广谱”医学对策。这是我们的R21的逻辑扩展，用于进一步的功效验证，铅优化和IND应用。主要的重点是生成有关主要候选人功效和安全性的必要数据，并在5年内提交IND申请。为了将神经类固醇作为比地西ep的优越的对策，我们将解决三个具体目标：（目标1）：确定Ganaxolone对DFP和SOMAN诱导的SE和脑损伤的疗效； （AIM 2）：开发具有改进的配方药代动力学和针对DFP和SOMAN诱导的SE和脑损伤的功效的Ganaxolone类似物； （AIM 3）：确定Ganaxolone或其铅类似物的临床前安全性和毒性，并在FDA动物规则途径下提交IND进行临床发育。该项目将根据进步的“ GO/No-Go”里程碑计划实施，该计划包括针对关注三种主要结果指标的主要研究成功的定量标准：（i）抗惊厥效力； （ii）神经保护剂功效； （iii）预防神经变性。该项目的结果将确定一种有效的解毒剂，以提高紧急情况的准备情况。