Identification of Novel Brain-penetrating Phenoxyalkyl Pyridinium Oxime Countermeasures

新型脑穿透性苯氧基烷基吡啶肟对策的鉴定

基本信息

  • 批准号:
    9928535
  • 负责人:
  • 金额:
    $ 4.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-01 至 2021-06-30
  • 项目状态:
    已结题

项目摘要

7. Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases are highly toxic and have been developed as either nerve agents or insecticides. Prolonged acetylcholinesterase (AChE) inhibition results in glutamate-induced seizures with subsequent permanent brain damage. Some OPs are relatively easy to synthesize and could become threat agents of great concern from potential terrorist action where the specific OP employed might not be immediately known. Terrorist actions or accidents could lead to mass casualties in adults and children of both sexes. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited AChE (2-PAM in the US). However 2-PAM is not broad-spectrum and cannot effectively penetrate the blood brain barrier, so it would leave victims poorly protected against some OP chemistries and would not attenuate the hypercholinergic activity in the brain and resultant brain damage. Therefore an improved oxime therapeutic is needed which can counteract both nerve agent and insecticidal chemistries and can restore brain cholinergic function to attenuate or prevent long-term central nervous system damage, so that both life and brain function may be preserved. Our laboratories have invented and patented (US Patent 9,277,937) a platform of substituted phenoxyalkyl pyridinium oximes that have shown broader based survival efficacy than 2-PAM and also attenuation of signs of seizure-like behavior and neuropathology in male rats exposed to high levels of both nerve agent and insecticidal chemistries. Limited studies in male guinea pigs against sarin have also showed efficacy. Only limited preliminary information exists at present with respect to the novel oximes' pharmacokinetics and no information exists on their therapeutic efficacy in female or juvenile animals. Preliminary data indicate that combinations of a novel oxime and 2-PAM are more efficacious than the single oximes. A combination of these two or combinations of two novel oximes with different specificities for nerve agent and insecticidal chemistries could provide a broader spectrum of efficacy than single oximes and provide a more effective therapeutic in the event of mass casualties induced by an unidentified OP. Therefore this application proposes the generation of additional efficacy data against a highly relevant sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) and paraoxon (PXN; the active metabolite of the insecticide parathion) in adult female and juvenile (both sexes) rats, on our three most efficacious novel oximes and combinations of two oximes. Initial pharmacokinetic and initial oxime toxicity data will be generated. Lastly efficacy tests will be performed in male and female adult guinea pigs with sarin and VX. The goal of this Lead Identification project is to down-select to a lead and an alternate novel oxime or novel oxime binary combination that will be ready to enter into optimization studies through a subsequent Lead Optimization U01 project, that will move the novel oximes into advanced development toward FDA approval.
7. 项目总结/摘要 许多有机磷酸酯 (OP) 抗胆碱酯酶具有剧毒,已被开发为 神经毒剂或杀虫剂。长期抑制乙酰胆碱酯酶 (AChE) 会导致谷氨酸诱导的 癫痫发作并随后造成永久性脑损伤。有些OP相对容易合成,可以 成为潜在恐怖行动中令人高度关注的威胁代理人,其中所使用的特定OP可能会 不会立即被知道。恐怖活动或事故可能导致成人和儿童大规模伤亡 男女皆宜。目前的疗法包括毒蕈碱受体拮抗剂阿托品和肟 受抑制的 AChE 的再激活剂(美国为 2-PAM)。然而 2-PAM 不是广谱的,不能 有效地穿透血脑屏障,因此它会使受害者对某些 OP 的保护很差 化学物质,不会减弱大脑中的高胆碱能活动和由此产生的脑损伤。 因此需要一种改进的肟治疗剂,它可以对抗神经毒剂和杀虫剂 化学物质,可以恢复大脑胆碱能功能,从而减弱或预防长期中枢神经系统 损伤,从而可以保留生命和大脑功能。我们的实验室已发明并获得专利 (美国专利 9,277,937)取代的苯氧基烷基吡啶鎓肟平台,已显示出更广泛的用途 与 2-PAM 相比,基于生存率的疗效以及癫痫样行为和神经病理学迹象的减弱 暴露于高浓度神经毒剂和杀虫化学品的雄性大鼠。男性研究有限 豚鼠也显示出对抗沙林的功效。目前仅存在有限的初步信息 关于新型肟的药代动力学,尚无关于其对女性的治疗效果的信息 或幼年动物。初步数据表明,新型肟和 2-PAM 的组合更有效。 比单一肟有效。这两种的组合或两种新型肟的组合 神经毒剂和杀虫化学物质的不同特异性可以提供更广泛的功效 比单一肟更有效的治疗方法 身份不明的OP。因此,该应用建议针对高度 相关沙林替代品(甲基膦酸硝基苯异丙酯,NIMP)和对氧磷(PXN;活性物质) 杀虫剂对硫磷的代谢物)在成年雌性和幼年(两性)大鼠中,在我们最重要的三种 有效的新型肟和两种肟的组合。初始药代动力学和初始肟毒性数据 将被生成。最后,将对雄性和雌性成年豚鼠进行沙林毒气和沙林毒气的功效测试。 VX。该先导物识别项目的目标是向下选择先导物和替代的新型肟或 新型肟二元组合将准备通过后续的先导进入优化研究 优化 U01 项目,该项目将使新型肟进入高级开发阶段,以获得 FDA 批准。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Janice Elaine Chambers其他文献

Janice Elaine Chambers的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Janice Elaine Chambers', 18)}}的其他基金

Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning
取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化
  • 批准号:
    10660985
  • 财政年份:
    2021
  • 资助金额:
    $ 4.32万
  • 项目类别:
Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning
取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化
  • 批准号:
    10459573
  • 财政年份:
    2021
  • 资助金额:
    $ 4.32万
  • 项目类别:
Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning
取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化
  • 批准号:
    10281742
  • 财政年份:
    2021
  • 资助金额:
    $ 4.32万
  • 项目类别:
Identification of novel brain-penetrating oxime antidotes for phorate toxicity
新型脑穿透性肟解毒剂甲拌磷毒性的鉴定
  • 批准号:
    9633107
  • 财政年份:
    2018
  • 资助金额:
    $ 4.32万
  • 项目类别:
Identification of novel brain-penetrating oxime antidotes for phorate toxicity
新型脑穿透性肟解毒剂甲拌磷毒性的鉴定
  • 批准号:
    9788116
  • 财政年份:
    2018
  • 资助金额:
    $ 4.32万
  • 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
  • 批准号:
    8544717
  • 财政年份:
    2014
  • 资助金额:
    $ 4.32万
  • 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
  • 批准号:
    9331890
  • 财政年份:
    2014
  • 资助金额:
    $ 4.32万
  • 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
  • 批准号:
    9091668
  • 财政年份:
    2014
  • 资助金额:
    $ 4.32万
  • 项目类别:
Brain-penetrating acetylcholinesterase reactivators for several organophosphates
几种有机磷酸酯的脑穿透性乙酰胆碱酯酶再激活剂
  • 批准号:
    8846691
  • 财政年份:
    2014
  • 资助金额:
    $ 4.32万
  • 项目类别:
Relationship of Blood Esterases, Pesticide Exposure and Cardiovascular Disease
血酯酶、农药暴露与心血管疾病的关系
  • 批准号:
    7906342
  • 财政年份:
    2009
  • 资助金额:
    $ 4.32万
  • 项目类别:

相似国自然基金

伪旋毛虫乙酰胆碱酯酶破坏肠道ILC2s的ChAT-ACh通路实现免疫逃逸的机制研究
  • 批准号:
    32302960
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
元宝枫种子中抑制乙酰胆碱酯酶活性成分的高效发现及其作用机理研究
  • 批准号:
  • 批准年份:
    2021
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
肠神经元芳香烃受体/乙酰胆碱酯酶信号通路介导的青黛肠道不良反应研究
  • 批准号:
  • 批准年份:
    2020
  • 资助金额:
    55 万元
  • 项目类别:
    面上项目
乙酰胆碱酯酶在氧化应激诱导视网膜色素上皮细胞变性凋亡中的作用机制
  • 批准号:
    81960178
  • 批准年份:
    2019
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
新型溴代阻燃剂五溴甲苯对斑马鱼的神经毒性效应及分子机制研究
  • 批准号:
    21906181
  • 批准年份:
    2019
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Evaluation of a structure-function model for auditory consequences of impact acceleration brain injury and protection via the olivocochlear system
冲击加速脑损伤的听觉后果的结构功能模型评估以及通过橄榄耳蜗系统的保护
  • 批准号:
    10605573
  • 财政年份:
    2022
  • 资助金额:
    $ 4.32万
  • 项目类别:
RNA encoded nanobody-based immunotherapeutics targeting essential, host-interactive schistosome ectoenzymes
RNA 编码的基于纳米抗体的免疫疗法,靶向与宿主相互作用的重要血吸虫胞外酶
  • 批准号:
    10571150
  • 财政年份:
    2022
  • 资助金额:
    $ 4.32万
  • 项目类别:
Molecular and Behavioral Impacts of Developmental OP Neurotoxicity
发育性 OP 神经毒性的分子和行为影响
  • 批准号:
    10202963
  • 财政年份:
    2021
  • 资助金额:
    $ 4.32万
  • 项目类别:
The role of NMDA receptor subunit GluN3A in age and Alzheimer's disease-related dementia
NMDA 受体亚基 GluN3A 在年龄和阿尔茨海默病相关痴呆中的作用
  • 批准号:
    10491045
  • 财政年份:
    2021
  • 资助金额:
    $ 4.32万
  • 项目类别:
The 2020 ESPINA study follow-up Exam: Fungicides, Insecticides, Inflammation and Child Development
2020年ESPINA研究后续考试:杀菌剂、杀虫剂、炎症和儿童发育
  • 批准号:
    10457234
  • 财政年份:
    2020
  • 资助金额:
    $ 4.32万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了