Pyridinium oxime reactivators of cholinesterase inhibited by diisopropyl-fluorophosphate (DFP): predictive value of in-vitro testing for in-vivo efficacy.
Pyridinium oxime reactivators of cholinesterase inhibited by diisopropyl-fluorophosphate (DFP): predictive value of in-vitro testing for in-vivo efficacy.
复制标题
二异丙基氟磷酸盐 (DFP) 抑制胆碱酯酶的吡啶肟再激活剂：体外测试对体内功效的预测价值。
DOI：
10.2174/138955708786369555
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
D. Lorke
中科院分区：
文献类型：
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作者：
G. Petroianu;D. Lorke
有机磷胆碱酯酶抑制剂中毒是一个严重的全球性威胁。治疗包括使用阿托品和吡啶肟来重新激活乙酰胆碱酯酶（AChE）。已确定肟（解磷定和双肟）的临床经验令人失望，已开发出几种实验性潜在替代品（肟K）。这篇综述总结了这些肟的数据，当用于暴露于OPC二异丙基氟磷酸盐（DFP）。体外试验包括测定IC（50）（固有肟AChE抑制活性）、tan α（再活化能力）和计算机模拟估算各肟的LogP（亲脂性/亲水性）。体内方法包括测定毒性（LD（50））和保护效力（大鼠暴露于DFP后死亡的相对风险降低）。不同的体外和体内数据之间的相关性表明，具有低体外AChE抑制活性（高IC（50））的肟是相当无毒的，并降低了DFP诱导的死亡率（低累积相对风险）。具有高体外AChE再活化效力（高tan α）的肟也具有高体外AChE抑制活性（低IC（50））和低体内LD（50），这意味着高毒性。亲水性较低的肟具有较强的体外AChE抑制活性，是更好的体外AChE再活化剂，但在体内也更具毒性，并且与大鼠暴露于DFP后的高累积死亡风险相关，这意味着体内疗效低。在体外再活化能力的人红细胞（RBC）-乙酰胆碱酯酶在体内（大鼠）的疗效没有预测价值，至少在DFP暴露的情况下。
Poisoning with organophosphorus cholinesterase inhibitors (OPCs) poses a serious global threat. Therapy comprises the use of atropine and pyridinium oximes to reactivate acetylcholinesterase (AChE). Clinical experience with established oximes (pralidoxime and obidoxime) is disappointing and several experimental potential alternatives (K oximes) have been developed. This review summarizes data on these oximes, when used in exposure to the OPC diisopropylfluorophosphate (DFP). In vitro testing includes determination of IC(50) (intrinsic oxime AChE inhibitory activity), of tan alpha (reactivation capacity) and in silico estimation of LogP (lipophilicity/hydrophilicity) of the individual oximes. In vivo approaches encompass determination of toxicity (LD(50)) and of protective efficacy (reduction of relative risk of death after DFP exposure in rats). Correlations between the different in vitro and in vivo data available reveal that an oxime with a low in vitro AChE inhibitory activity (high IC(50)) is rather non-toxic and reduces DFP-induced mortality (low cumulative relative risk). Oximes with a high in vitro AChE reactivation potency (high tan alpha) also have a high in vitro AChE inhibitory activity (low IC(50)) and have a low LD(50) in vivo, implying high toxicity. Less hydrophilic oximes have strong in vitro AChE inhibitory activity, are better in vitro AChE reactivators, but are also more toxic in vivo and are associated with a high cumulative risk of death after DFP exposure in rats, implying low in vivo efficacy. In vitro reactivation capacity of human red blood cell (RBC)-AChE has no predictive value for in vivo (rat) efficacy, at least in the case of DFP exposure.