BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
批准号:
8610134
负责人:
Zoran Radic
金额:
$41.27万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-09-30 至 2015-08-31
关键词:
AcuteAlveolarAntidotesBiological AvailabilityBlood - brain barrier anatomyBlood CirculationButyrylcholinesteraseCatalysisChronicDataDrug KineticsDrug Metabolic DetoxicationDrug or chemical Tissue DistributionExcisionExhibitsGoalsGrantHumanHydrolysisImidazoleIn VitroIndividualInstitutesIntestinesIntoxicationKineticsLeadLiteratureLungMembraneMindMusOralOrganophosphatesOximesPesticidesPlasmaPropertyRecoveryRegimenResearchResortRiskSarinSeriesSiteSkeletal MuscleStructureTestingTissuesToxic effectTreatment Efficacybasebioscavengerdosagefortificationhuman tissueimprovedin vivonerve agentnovelprogramsprotective effectpublic health relevanceresearch studytabuntertiary aminetoxic organophosphate insecticide exposuretoxicant
中文摘要
BChE再活化剂用于人体组织中神经毒剂和农药OP解毒
项目概述:我们提出开发一种以前未探索的神经治疗方法,
基于内源BChE有效再活化的制剂和农药OP暴露
直接进入人体循环和组织。这种方法主要基于加速OP
直接在组织中降解,在组织中,OP首先进入和/或积累,
exposure.肟通过天然存在于肺、肠和胃中的BChE辅助OP水解。
血浆,从而提供了一个障碍,随后分布的OP的目标位点,在骨骼
肌肉和中枢神经系统我们最近展示了作为原理的证明,肟的功能
体外、离体和体内辅助的、基于BChE的催化OP生物清除剂(Radi et
例如,Biochem J 450,2013,231 - 242)。我们证明了TAB 2OH,一种新开发的肟,
人BChE的再活化剂具有足够的能力快速再活化无活性的共价OP-
BChE在体外缀合物,并增强OP暴露小鼠的保护和治疗,
与纯化的BChE组合施用。我们现在建议利用内源性人类
BChE以nM浓度天然存在于肺、肠和血浆中,而不是
施用纯化的BChE,并且仅施用高效的BChE再活化剂以辅助
内源BChE在OP降解中的作用。我们认为这是可能的,因为我们最近
开发了一系列基于叔和季咪唑的hBChE再活化剂,
在体外比TAB2OH有效数倍。叔胺具有额外的
血脑屏障和肺泡膜渗透的潜力和口服生物利用度。我们
建议研究新的BChE再激活剂在OP暴露小鼠中的体内功效,并进一步
细化其结构以改善其再活化性能。这项R21提出的研究,
通过在体外积累hBChE的再活化和周转的动力学参数,
OP的存在并将最佳化合物用于小鼠体内分析,
揭示内源性BChE再激活在解毒治疗中的潜力。还应当
导致确定最有效的剂量方案和评估的限制,
通过肟辅助提高内源性BChE的潜力
催化作用简而言之,口服或胃肠外肟是否有一个OP暴露水平,
重新激活BChE是有效的,而不必诉诸繁琐和风险-
在田间和非无菌条件下加强相关的BChE活性?
英文摘要
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
Project Summary: We propose to develop a previously unexplored approach in therapy of nerve
agent and pesticide OP exposure based on efficient reactivation of endogeneous BChE
directly in human circulation and tissues. This approach is largely based on accelerated OP
degradation of OPs directly in tissues where OPs enter and/or accumulate first during an
exposure. Oxime assisted OP hydrolysis by BChE naturally present in lungs, intestine and
plasma, thus provides a barrier to subsequent distribution of OPs to target sites in skeletal
muscle and CNS. We recently demonstrated as a proof of principle, the functioning of oxime
assisted, BChE based, catalytic OP bioscavenger in vitro, ex vivo and in vivo (Radi et
al.,Biochem J 450, 2013,231-242). We demonstrated that TAB2OH, a newly developed oxime
reactivator of human BChE had sufficient capacity to rapidly reactivate inactive, covalent OP-
BChE conjugates in vitro, and enhance both protection and therapy of OP exposed mice when
administered in combination with purified BChE. We now propose to utilize endogenous human
BChE naturally present in lungs, intestine and plasma at nM concentrations instead of
administering purified BChE, and to administer only highly efficient BChE reactivator to assist
endogenous BChE in OP degradation. We assume that this will be possible since we recently
developed a series of tertiary and quaternary imidazole based hBChE reactivators that are
several fold more efficient in vitro than TAB2OH. The tertiary amines have the additional
potential for blood-brain barrier and alveolar membrane permeation and oral bioavailability. We
propose to investigate in vivo efficacy of new BChE reactivators in OP exposed mice and further
refine their structure to improve their reactivation properties. This R21 proposed research,
through accumulating in vitro kinetic parameters of reactivation and turnover of hBChE in the
presence of an OP and taking the optimal compounds to an in vivo analysis in mouse, should
uncover the potential of endogenous BChE reactivation in antidotal therapy. It should also
lead to ascertaining the most efficacious dosage regimen and to assessing the limits of
capitalizing on enhancing the potential of endogenous BChE through oxime-assisted
catalysis. In short, is there an OP exposure level where oral or parenteral oximes directed to
reactivating BChE are efficacious without having to resort to the cumbersome and risk-
associated BChE fortification of activity in field and non-sterile conditions?
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
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批准号:10412696
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项目类别:
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资助金额:$20.98万
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财政年份:2022
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负责人:Zoran Radic
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依托单位:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
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批准号:10582723
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项目类别:
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资助金额:$19.27万
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依托单位:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
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批准号:10407766
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In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
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依托单位:
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
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批准号:9356345
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资助金额:$15.5万
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财政年份:2016
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依托单位:
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
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批准号:9209336
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项目类别:
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财政年份:2016
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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项目类别:
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财政年份:2014
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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批准号:9632884
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项目类别:
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资助金额:$3.16万
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财政年份:2014
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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批准号:8892277
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项目类别:
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资助金额:$67.02万
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财政年份:2014
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负责人:Zoran Radic
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依托单位:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
-
批准号:8738731
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项目类别:
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资助金额:$38.52万
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财政年份:2013
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负责人:Zoran Radic
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依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8020885
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项目类别:
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资助金额:$41.58万
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财政年份:2010
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负责人:Zoran Radic
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依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8153134
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项目类别:
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资助金额:$41.38万
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财政年份:2010
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负责人:Zoran Radic
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依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8508593
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项目类别:
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资助金额:$7.75万
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依托单位:
海外基金