Novel anticonvulsant and neuroprotective therapies for TETS and OP intoxication

针对 TETS 和 OP 中毒的新型抗惊厥药和神经保护疗法

基本信息

批准号：
9142832
负责人：
Pamela J Lein
金额：
$ 13万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9142832
关键词：
Acute Analytical Chemistry Anticonvulsants Antidotes Behavioral Biological Biological Markers Brain Injuries Chemicals Cholinesterase Inhibitors Communities Data Detection Development Diagnostic Drug Combinations Drug Targeting Emergency Situation Evaluation Goals Imaging technology Immunoassay In Vitro Injury Interdisciplinary Study Intoxication Isoflurophate Medical Molecular Monitor Neurologic Neuropathy Neuropharmacology Neurosciences Neurosciences Research Outcome Patients Pharmaceutical Chemistry Pharmacology Readiness Research Research Project Grants Seizures Staging Testing Therapeutic Translational Research Translations Treatment Efficacy United States National Institutes of Health Work base behavioral pharmacology chemical release chemical threat drug discovery drug market experience gamma-Aminobutyric Acid imaging modality improved in vivo Model in vivo imaging innovation metabolomics molecular/cellular imaging mortality neuroimaging neuropathology neurotoxicology novel prevent response screening tetramethylenedisulfotetramine treatment strategy

项目摘要

The unifying goal of the UC Davis CounterACT Center of Excellence is to identify improved medical countermeasures for treating acute intoxication with seizure-inducing chemical threat agents. Research will focus on the organophosphorus (OP) cholinesterase inhibitor diisopropylfluorophosphate (DFP) and the GABA-inhibiting agent tramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure inducing chemical threats, with the goal of identifying therapeutic approaches with broad-spectrum efficacy. The specific objectives of the Center are to: (1) identify improved treatments for acute seizures and lethality; and (2) identify therapeutic strategies for mitigating seizure-induced brain damage in patients that survive acute intoxication. This will be accomplished by repositioning marketed drugs and drug combinations for treatment of seizures triggered by chemical threat agents, in parallel with evaluation of new antidotes based on strong preliminary efficacy data. The molecules to be tested for anticonvulsant and neuroprotective efficacy range from compounds approaching readiness for IND enabling studies to early stage chemical probes. In all cases, these efforts in translation of anti-seizure agents are supported by innovative work on diagnostics employing emerging in vivo imaging technologies and analytical chemistry for monitoring pathological effects as well as target engagement and therapeutic efficacy. Additional outcomes from Center research that will benefit the CounterACT community include: (1) a high content in vitro/ex vivo platform for rapid screening of compounds to identify anticonvulsant and neuroprotective potential as well as mechanistically relevant novel drug targets; (2) in vivo models of DFP and TETS-induce seizures for studying neuropathic mechanisms and therapeutic rescue of neurologic sequelae triggered by seizurogenic exposures; (3) innovative in vivo imaging modalities for non-invasive longitudinal monitoring of neurologic damage and response to therapeutic candidates; (4) focused metabolomic profiling to identify biomarkers of seizure damage; and (5) innovative immunoassays for the detection of TETS in biological and environmental matrices. A highly integrated, interdisciplinary (pharmacology, medicinal chemistry, neurotoxicology, analytical chemistry, behavioral neuroscience, imaging, cellular/molecular neuroscience) research team with experience in drug discovery and translational research will work cooperatively and synergistically to achieve the Center's goal of identifying improved medical countermeasures that can be readily deployed during a chemical emergency to stop seizures and mitigate the neurological sequelae of seizures triggered by TETS and OPs.

加州大学戴维斯分校抵消卓越中心的统一目标是确定改进的医学对策，以癫痫发作的化学威胁药物治疗急性中毒。研究将重点关注有机磷（OP）胆碱酯酶抑制剂三异丙氟磷酸酯（DFP）和抑制GABA抑制剂tramethylynysulenendiporminine（TET），可以说，这些胺的机械谱诱导了靶向化学范围，具有更广泛的靶向范围，具有识别剂量的方法。该中心的具体目标是：（1）确定改进的急性癫痫发作和致死性的治疗方法；（2）确定用于减轻急性中毒患者癫痫发作诱导的脑损伤的治疗策略。这将通过重新定位销售的药物和药物组合来治疗由化学威胁剂触发的癫痫发作，并与基于强大初步疗效数据的新解毒剂进行评估。要测试的抗惊厥药和神经保护功效的分子范围从接近IND的化合物促进研究到早期化学探针。在所有情况下，这些抗塞氏剂转化方面的努力都得到了对诊断技术的创新工作的支持，该诊断方法采用了新兴的体内成像技术和分析化学，以监测病理效应以及目标参与和治疗功效。中心研究的其他结果将受益于应对社区，包括：（1）快速筛选化合物以鉴定抗惊厥药和神经保护潜力以及机械上相关的新型药物靶标的高度含量；（2）DFP和TETS-引诱癫痫发作的体内模型，用于研究神经性后遗症的神经性疾病机制和治疗性挽救，这是由塞济氏菌暴露触发的；（3）非侵入性纵向监测神经系统损伤和对治疗候选者的反应的创新体内成像方式；（4）聚焦的代谢组学分析，以识别癫痫发作损害的生物标志物；（5）用于检测生物和环境矩阵中TET的创新免疫测定。高度综合的跨学科（药理学，药理学，神经毒理学，分析化学，行为神经科学，成像，细胞/分子神经科学）研究团队，具有药物发现和转化研究方面经验的经验，将在合作和协同过程中起作用，以实现改善的既定医学柜台，以识别出既定的医学柜台，以识别出对核对医学的进展，以识别出良好的医疗态度，以供核对核对范围内的核对范围，以识别出良好的医学柜台，以鉴定出良好的医学逆转性。 TET和OP触发的癫痫发作的后遗症。