Identification of treatments for chemical threat agent seizures
确定化学威胁剂缉获的治疗方法
基本信息
- 批准号:8851849
- 负责人:
- 金额:$ 0.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazoleADME StudyAMPA ReceptorsAcuteAcute Toxicity TestsAdverse effectsAffectAllopregnanoloneAnimal ModelAnimalsAnticonvulsantsAntiepileptic AgentsAreaAtropineAttentionBehavioralBiological AvailabilityBlood PressureBrain InjuriesCessation of lifeChemical ExposureChemical Warfare AgentsChemical WeaponsChemicalsChokingCholinesterase InhibitorsCollaborationsConvulsantsCountryDataDepressed moodDevelopmentDiazepamDoseDrug FormulationsDrug InteractionsDrug KineticsEffectivenessEmergency treatmentEnvironmentEvaluationExhibitsGABA AntagonistsHumanIndividualInjuryIntoxicationIntramuscularIsoflurophateKetamineLaboratoriesLifeLiteratureMarketingMedicalMedical ResearchMidazolamModelingMolecularMusN-Methyl-D-Aspartate ReceptorsNMDA receptor antagonistNeurologicNeurotoxinsOralOrganophosphatesOutcomeOutcome MeasurePeripheralPharmaceutical PreparationsPoisonPoisoningPropertyProtein IsoformsProtocols documentationRattusResearch InstituteResistanceRespirationRodent ModelRodenticidesRouteSafetySalesScheduleSeizuresSeriesSomanStagingSystemTestingTherapeuticTherapeutic AgentsTimeToxicologyWorkanthrax lethal factorbasechemical threatcomparative efficacygamma-Aminobutyric Acidhuman dataimprovedinhibitor/antagonistmass casualtymeetingsnerve agentnovelnovel therapeuticspreventprimary outcomereceptorresearch studystandard of caretetramethylenedisulfotetramine
项目摘要
Summary: The overall objective of this project is to identify new, more effective medical countermeasures for the acute seizures produced by organophosphate (OP) anticholinesterase inhibitor and GABAA receptor antagonist chemical threat agents. By preventing or stopping the acute seizures, these countermeasures will improve the survival and long-term outcome of individuals exposed to seizure-inducing doses of these agents.
We have selected two OP agents diisopropylfluorophosphate (DFP) and soman (0-pinacolyl methylphosphonofluoridate; GD) and one GABAA receptor antagonist tetramethylenedisulfotetramine (TETS) to represent the two broad classes of chemical threat agents. Soman, a representative of the OP neurotoxin chemical warfare agents ("nerve agents"), is classified as a Schedule 1 substance under the Chemical
Weapons Convention of 1993. DFP, while less potent than the nerve agents in the Chemical Weapons Convention toxic chemicals list, has nearly identical effects. As a volatile agent that could rapidly spread inside closed areas, it could cause many injuries and deaths and is therefore a credible threat agent. TETS, a representative of the GABAA receptor antagonist convulsants is a highly lethal toxin that has been used as a
rodenticide but is now banned in most countries of the world. Nevertheless, lethal poisoning with TETS occur regularly. On a mg basis, TETS is equal in lethality to the OP chemical warfare agents. Recently, we have had the opportunity to characterize the convulsant activity of TETS in mice and rats when administered by the i.p., i.v., oral and intracerebroventricular routes. As a result of this work, we have developed the first animal model in which to evaluate potential treatments for TETS when administered before and after exposure. In this project, DFP and soman are administered to rats and TETS is administered to mice to induce seizures. The animals are treated before or at various intervals following exposure with various potential therapeutic agents
(or combinations) to assess the ability of the test agent to prevent or terminate behavioral or electrographic seizure activity. Testing in the OP models occurs in a step-wise fashion, first against DFP seizures because DFP has reduced safety concerns and can be used in a regular laboratory environment, and then with soman,
which requires extreme safety precautions available at the US Army Medical Research Institute of Chemical Defense. All test agents are compared with diazepam, the current standard of care for the emergency treatment of chemical exposure seizures. Diazepam may be effective if administered early in the course of seizures but seizures may recur and the drug may be inactive if administered later in the course of seizures. In
addition, diazepam can depress blood pressure and respiration. A further concern is that diazepam is erratically absorbed when administered by the i.m. route (as with the injector systems stockpiled for use in mass casualty situations). We are seeking agents (or combinations) that improve upon diazepam with respect to any of these liabilities. We have identified a series of potential therapies (Tier 1) that are either currently
approved for sale in the U.S. or for which human data is available and can therefore be rapidly deployed. In addition, novel potential therapies that are new molecular entities (Tier 2) will be developed in Core B and Project 3. Therapies that exhibit superior activity to diazepam will be studied in Project 2 for their ability to mitigate seizure-induced brain damage. Finally, in order to advance the most promising therapies, we will
complete various additional studies, including formulation development and safety, toxicology and ADME studies in conjunction with Cores A and B, to assist in making go/no-go decisions regarding further development.
总结:本项目的总体目标是确定新的,更有效的医疗对策的急性发作所产生的有机磷(OP)抗胆碱酯酶抑制剂和GABAA受体拮抗剂化学威胁剂。通过预防或停止急性癫痫发作,这些对策将改善暴露于这些药剂的癫痫诱导剂量的个体的存活率和长期结果。
我们选择了两种OP剂二异丙基氟磷酸盐(DFP)和梭曼(0-频哪醇甲基膦酰氟; GD)和一种GABAA受体拮抗剂四亚甲基二磺基四胺(TETS)代表两大类化学威胁剂。梭曼是OP神经毒素化学战剂(“神经剂”)的代表,被列为《化学武器公约》附表1物质。
1993年武器公约。DFP虽然不如化学武器公约有毒化学品清单中的神经毒剂有效,但具有几乎相同的效果。作为一种可在封闭地区内迅速扩散的挥发性物剂,它可造成许多伤亡,因此是一种可信的威胁物剂。TETS是GABAA受体拮抗剂惊厥剂的代表,是一种高致死性毒素,已被用作
灭鼠剂,但现在在世界上大多数国家被禁止。然而,TETS的致命中毒经常发生。按毫克计算,TETS的致命性与OP化学战剂相同。最近,我们有机会在小鼠和大鼠中表征TETS通过i. p.给药时的惊厥活性,静脉注射,口服和脑室内途径。作为这项工作的结果,我们已经开发出第一个动物模型,以评估潜在的治疗TETS时,暴露前后管理。在这个项目中,DFP和梭曼被给予大鼠和TETS被给予小鼠诱导癫痫发作。动物在暴露于各种潜在治疗剂之前或之后的不同时间间隔接受治疗
(or组合)以评估测试剂预防或终止行为或电图癫痫发作活动的能力。OP模型中的测试以逐步的方式进行,首先针对DFP癫痫发作,因为DFP减少了安全性问题,可以在常规实验室环境中使用,然后使用梭曼,
这需要美国陆军化学防御医学研究所提供的极端安全预防措施。将所有测试试剂与地西泮进行比较,地西泮是目前用于化学品暴露癫痫发作的紧急治疗的护理标准。如果在癫痫发作的早期给药,地西泮可能有效,但如果在癫痫发作的后期给药,癫痫发作可能复发,药物可能无效。在
此外,安定可降低血压和呼吸。另一个问题是,地西泮是不规则的吸收时,通过i.m.路线(如储存用于大规模伤亡情况的注射器系统)。我们正在寻求代理商(或组合),改善安定方面的任何这些责任。我们已经确定了一系列潜在的治疗方法(第1层),这些方法目前
已批准在美国销售,或具有人体数据,因此可以快速部署。此外,将在核心B和项目3中开发作为新分子实体(第2层)的新型潜在疗法。将在项目2中研究表现出比地西泮上级活性的治疗方法减轻癫痫诱导的脑损伤的能力。最后,为了推进最有前途的疗法,我们将
完成各种其他研究,包括与核心A和B一起进行的制剂开发和安全性、毒理学和ADME研究,以帮助做出关于进一步开发的通过/不通过决定。
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)
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MICHAEL A. ROGAWSKI其他文献
MICHAEL A. ROGAWSKI的其他文献
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{{ truncateString('MICHAEL A. ROGAWSKI', 18)}}的其他基金
Training in Neurotherapeutics for Academic Scientists
学术科学家神经治疗学培训
- 批准号:
10666685 - 财政年份:2022
- 资助金额:
$ 0.96万 - 项目类别:
Training in Neurotherapeutics for Academic Scientists
学术科学家神经治疗学培训
- 批准号:
10539175 - 财政年份:2022
- 资助金额:
$ 0.96万 - 项目类别:
TRAINING IN NEUROTHERAPUETICS AND DEVELOPMENT FOR ACADEMIC SCIENTISTS
学术科学家的神经治疗学和发展培训
- 批准号:
9910467 - 财政年份:2017
- 资助金额:
$ 0.96万 - 项目类别:
Identification of Treatments for Chemical Threat Agent Seizures
查获化学威胁剂的治疗方法的确定
- 批准号:
10204124 - 财政年份:2012
- 资助金额:
$ 0.96万 - 项目类别:
Ion Channels in Epilepsy and as Targets for Antiepilepti
癫痫中的离子通道和抗癫痫靶标
- 批准号:
7143853 - 财政年份:
- 资助金额:
$ 0.96万 - 项目类别:
ION CHANNELS IN EPILEPSY AND AS TARGETS FOR ANTIEPILEPTIC DRUGS
癫痫中的离子通道及其作为抗癫痫药物的靶标
- 批准号:
6290637 - 财政年份:
- 资助金额:
$ 0.96万 - 项目类别: