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:10475109
- 负责人:
- 金额:$ 44.45万
- 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:2020-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAnimalsAnticonvulsantsAntidotesBehaviorBehavioralBenzodiazepinesBiological ProductsBrainBrain DeathBrain InjuriesChemical WarfareCholinergic AgentsChronicCombined Modality TherapyDataDevelopmentDiazepamDrug KineticsEffectivenessElectroencephalographyEvaluationEventExposure toFDA approvedFormulationFunctional disorderGABA-A ReceptorGoalsHalf-LifeInjection productInjectionsIntoxicationIntramuscular InjectionsInvestmentsIsoflurophateLeadLegal patentLifeMediatingMidazolamMilitary PersonnelModelingMolecularMorbidity - disease rateNerve DegenerationNeuronsNeuroprotective AgentsOrganophosphatesOutcomeOutcome MeasureParaoxonParathionPathway interactionsPharmaceutical PreparationsPharmacologyPhasePilot ProjectsPowder dose formPreventionPropertyRattusRefractoryResistanceRodentSafetySarinSeizuresSomanStatus EpilepticusSynapsesSystemTerrorismTimeToxic effectWateranaloganimal ruleaqueousbasebiodefensechemical threatdesigndrug developmentdrug testingexperimental studyhydrophilicityimprovedinnovationlead candidatelipophilicitymedical countermeasurenerve agentneuropathologyneuroprotectionneurosteroidsneurotoxicnovelnovel therapeuticspre-clinicalprimary outcomeprogramssafety studysecondary outcomesextoxic 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 neurosteroidmidazolam combination will be highly efficient investment for the biodefense program.
项目摘要
这项提案的总体目标是确定新的“水溶性”神经类固醇抗惊厥药,将控制
苯二氮卓类耐药性癫痫发作和急性有机磷(OP)中毒引起的脑损伤。暴露
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诱导SE的主要治疗方法,但它们不足以
在暴露后的后期保护大脑免受SE的影响。神经甾体是抗SE的强效抗惊厥药
由各种OP药物诱导,因此它们可以克服苯二氮卓类药物的关键限制。的
本项目的目的是研究新型水溶性合成药物的有效性和中试安全性
Brexanolone类似物(FDA批准)作为咪达唑仑治疗OP的辅助抗惊厥药
中毒试验药物作为连续治疗与咪达唑仑一起给药或在咪达唑仑治疗后给药。
无法控制SE。目标是迅速停止癫痫发作,减少进一步的脑损伤。这种新疗法是
基于神经类固醇的分子机制和细胞变化参与难治性SE引起的
行动特工所提出的辅助治疗是基于中心假设,即合成神经类固醇,
增强时相性和突触外紧张性抑制,更有效地控制神经毒剂诱导的SE,
与单独的苯二氮卓类相比,神经元损伤更小,从而完全减轻发病率。述神经类固醇
Brexanolone对于控制大鼠模型中OP诱导的SE和神经元损伤是高度有效的,但具有一定的
作为医疗对策发射的局限性。Valaxanolone和lysaxanolone是两个铅亲水
具有改进的生物药剂学和药理学(突触外偏好)的神经类固醇类似物
特性.测试药物可以配制成用于注射的干粉以延长稳定性,并且它们具有前景。
有效性作为OP诱导SE的医学对策。关键的重点是生成关于
并确定至少一种先导药物以供进一步开发。的
提出的目标将通过解决三个具体目标来实现:(目标1)确定辅助疗效
亲水性神经甾体类似物对DFP诱导的SE和脑损伤的作用;(目的2)确定其辅助治疗药物
亲水性神经类固醇类似物对梭曼诱导的SE和脑损伤的功效;和(目的3)
确定先导药物的临床前药代动力学和先导安全性。该项目将按照
渐进的“去/不去”里程碑计划,重点是三个主要结果指标:(i)抗惊厥药
功效;(ii)神经保护功效;和(iii)预防神经变性和行为功能障碍。的
该项目的结果将确定一种新的辅助抗惊厥药物,以咪达唑仑治疗OP中毒,
“注入干动力”系统将为军事和民用中心的储存提供很长的保存期。
因此,这种神经类固醇与咪达唑仑的组合将是生物防御计划的高效投资。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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- 作者:
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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:
$ 44.45万 - 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:
$ 44.45万 - 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:
$ 44.45万 - 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:
10693904 - 财政年份:2020
- 资助金额:
$ 44.45万 - 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:
$ 44.45万 - 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:
$ 44.45万 - 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:
$ 44.45万 - 项目类别:
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