Novel pediatric anticonvulsants for nerve agents
用于神经毒剂的新型儿科抗惊厥药
基本信息
- 批准号:10693904
- 负责人:
- 金额:$ 73.44万
- 依托单位:
- 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:2020-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdultAgeAmendmentAnticonvulsantsAntidotesAtropineBehaviorBenzodiazepinesBiologicalBrainBrain InjuriesChildChildhoodCholinergic AgentsChronicClinicalClinical TrialsConsultationsDataDevelopmentDoseDrug KineticsElderlyEpilepsyEventExhibitsExposure toFDA approvedFemaleFormulationGABA-A ReceptorGlial Fibrillary Acidic ProteinGoalsInjectionsIntoxicationLeadLettersLifeMediatingMemoryMetabolicMidazolamModelingMolecularMorbidity - disease rateNerve DegenerationNeurologicNeurologic DysfunctionsNeuronal InjuryNeuronsNeuroprotective AgentsOrganophosphatesOutcomeOutcome MeasurePathway interactionsPesticidesPharmaceutical PreparationsPhasePilot ProjectsPopulationPredispositionPreventionProtocols documentationRattusRefractoryRegimenRiskSafetySarinSchoolsSeizuresSex DifferencesSomanSpecial PopulationStatus EpilepticusSynapsesTestingTherapeuticToxicokineticsTreatment EffectivenessTreatment ProtocolsValidationWorkagedaging populationanimal ruleattenuationbehavior testcohortdesignefficacy evaluationefficacy testingefficacy validationexperimental studyganaxolonelead optimizationmalemedical countermeasuremortalitynerve agentneuroinflammationneuropathologyneuroprotectionneurosteroidsneurotoxicitynovelnovel therapeuticsorganophosphate poisoningpesticide poisoningpreventprimary outcomeprogramssafety studysecondary outcomesexstemsuccess
项目摘要
Project Summary
The main goal of this project is to develop a neurosteroid therapy to mitigate seizures and morbidity caused by
nerve agents and organophosphate (OP) compounds in children and elderly population. Exposure to nerve agents
or OP poisoning can result in persistent seizures, status epilepticus (SE), and severe brain injury. Current
benzodiazepine anticonvulsants do not sufficiently protect from SE, a prolonged seizure activity lasting 30 min or
longer with significant neuronal injury and mortality. Recently neurosteroids have been identified as anticonvulsants
that can effectively control OP seizures and brain injury in adult models. However, the children and elderly are
more vulnerable to nerve agent neurotoxicity, but very few medical countermeasures are available to
protect these populations. This project seeks to address this gap by optimizing a specific anticonvulsant against
nerve agents to stop seizures and prevent brain damage in the pediatric and elderly population. Recent studies
shows that neurosteroids that enhance phasic and extrasynaptic tonic inhibition are strong anticonvulsants against
seizures and brain damage caused by nerve agents. Post-exposure neurosteroid therapy has been shown to be
more effective anticonvulsant and neuroprotective than midazolam in OP intoxication models. The objective of
this project is to determine the efficacy and safety of the synthetic neurosteroid ganaxolone (GX) as ‘broad-
spectrum’ anticonvulsant for nerve agent and OP intoxication in pediatric and aged models. The main
emphasis is focused on IND-enabling efficacy optimization, mechanism, and safety validation of GX in pediatric
rats. The project will address three specific aims: (Aim 1): To determine the efficacy of GX against DFP- and soman-
induced seizures and neuropathology in pediatric rats; (Aim 2): To determine the efficacy of GX against DFP- and
soman-induced seizures and neuropathology in aged rats; and (Aim 3): To determine the pharmacokinetic and
safety profile of GX in pediatric and aged rats and prepare a pre-IND application under the Animal Rule pathway.
The progressive “go/no-go” milestones plan includes quantitative criteria for the success of key studies focusing
on four primary outcome measures: (i) anticonvulsant efficacy; (ii) acute neuroprotectant efficacy; (iii) prevention of
chronic neurodegeneration and neuroinflammation; and (iv) attenuation of epilepsy and long-term neurological
dysfunction. The overall impact of the project’s outcomes will be very high for the development of lifesaving
anticonvulsant drug for OP intoxication in pediatric and elderly population, which is a high priority civilian therapeutic
field for the CounterACT program.
项目总结
项目成果
期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration.
- DOI:10.1124/jpet.123.001794
- 发表时间:2024-01-17
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.
FDA 批准的大麻二酚与神经类固醇和苯二氮卓类药物在成人难治性局灶性癫痫中的辅助抗癫痫活性的等辐射分析。
- DOI:10.1016/j.expneurol.2022.114294
- 发表时间:2023
- 期刊:
- 影响因子:5.3
- 作者:Golub,Victoria;Ramakrishnan,Sreevidhya;Reddy,DoodipalaSamba
- 通讯作者:Reddy,DoodipalaSamba
Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women.
- DOI:10.1111/jne.13028
- 发表时间:2022-03
- 期刊:
- 影响因子:3.2
- 作者:
- 通讯作者:
Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.
- DOI:10.1124/jpet.123.001819
- 发表时间:2024-01-17
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers.
- DOI:10.1124/jpet.123.001817
- 发表时间:2024-01-17
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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Doodipala Samba Reddy其他文献
Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures
- DOI:
10.1016/j.expneurol.2022.114240 - 发表时间:
2023-01-01 - 期刊:
- 影响因子:
- 作者:
Doodipala Samba Reddy;Robert H. Mbilinyi;Sreevidhya Ramakrishnan - 通讯作者:
Sreevidhya Ramakrishnan
Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability
- DOI:
10.1007/s00213-013-3276-5 - 发表时间:
2013-09-27 - 期刊:
- 影响因子:3.300
- 作者:
Chase Matthew Carver;Doodipala Samba Reddy - 通讯作者:
Doodipala Samba Reddy
Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis
- DOI:
10.1016/j.expneurol.2022.114238 - 发表时间:
2023-01-01 - 期刊:
- 影响因子:
- 作者:
Ashna Talwar;Emily Estes;Rajender Aparasu;Doodipala Samba Reddy - 通讯作者:
Doodipala Samba Reddy
Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies
大麻二酚疗法对难治性癫痫儿童和成人难治性癫痫发作的治疗和临床基础
- DOI:
10.1016/j.expneurol.2022.114237 - 发表时间:
2023-01-01 - 期刊:
- 影响因子:4.200
- 作者:
Doodipala Samba Reddy - 通讯作者:
Doodipala Samba Reddy
Doodipala Samba Reddy的其他文献
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{{ truncateString('Doodipala Samba Reddy', 18)}}的其他基金
Novel pediatric anticonvulsants for nerve agents
用于神经毒剂的新型儿科抗惊厥药
- 批准号:
10004277 - 财政年份:2020
- 资助金额:
$ 73.44万 - 项目类别:
Novel pediatric anticonvulsants for nerve agents
用于神经毒剂的新型儿科抗惊厥药
- 批准号:
10475298 - 财政年份:2020
- 资助金额:
$ 73.44万 - 项目类别:
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:
10013749 - 财政年份:2020
- 资助金额:
$ 73.44万 - 项目类别:
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:
10266034 - 财政年份:2020
- 资助金额:
$ 73.44万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 73.44万 - 项目类别:
Novel pediatric anticonvulsants for nerve agents
用于神经毒剂的新型儿科抗惊厥药
- 批准号:
10248384 - 财政年份:2020
- 资助金额:
$ 73.44万 - 项目类别:
A Neurosteroid-based Novel Treatment for OP-Intoxication
基于神经类固醇的 OP 中毒新疗法
- 批准号:
8580681 - 财政年份:2011
- 资助金额:
$ 73.44万 - 项目类别:
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