Bajgar Jiri, Fusek Josef, Kuca Kamil, Bartosova Lucie, Jun Daniel
Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Mini Rev Med Chem. 2007 May;7(5):461-6. doi: 10.2174/138955707780619581.
Basic part of the current standard treatment of organophosphate (OP) agent poisoning is administration of cholinesterase reactivators. It includes different types of oximes with a similar basic structure differing by the number of pyridinium rings and by the position of the oxime group in the pyridinium ring. Oximes hydrolytically cleave the organophosphates from acetylcholinesterase (AChE), restoring enzymatic function. This reactivation of AChE is dependent on the type of the agent and, on the reactivator used. From the common oximes, mono- and bisquaternary pyridinium oximes are more or less frequently used in clinical practice such as pralidoxime, obidoxime, trimedoxime, and HI-6. Though there are data on a good therapeutic effects of reactivators, some attempts to undermine the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisoning, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. An universality of oximes able to reactivate AChE inhibited by all OP is questioned and trends (molecular modelling using neural network, structure-activity relationship, combination of reactivation and anticholinergic properties in one molecule) for future research are characterized.
有机磷酸酯（OP）类药物中毒当前标准治疗的基本部分是给予胆碱酯酶复活剂。它包括不同类型的肟，其基本结构相似，但吡啶环数量以及肟基在吡啶环中的位置不同。肟能水解切断乙酰胆碱酯酶（AChE）上的有机磷酸酯，恢复酶的功能。AChE的这种复活取决于中毒药物的类型以及所使用的复活剂。在常见的肟类中，单季铵和双季铵吡啶肟在临床实践中或多或少被频繁使用，如解磷定、双复磷、氯磷定和HI - 6。尽管有数据表明复活剂具有良好的治疗效果，但仍有人试图削弱复活剂作为OP中毒有效解毒剂的作用。本文讨论了OP中毒后给予复活剂的必要性相关的一些观点，旨在解决其有效使用的问题、OP中毒治疗中可能的重复给药问题、它们的外周和中枢作用，包括其透过血脑屏障的问题以及在脑中达到AChE复活有效浓度的可能性。本文描述了外周和中枢神经系统中胆碱酯酶的复活情况，并强调了其对OP中毒机体存活或死亡的重要性。能够复活被所有OP抑制的AChE的肟的通用性受到质疑，并对未来研究的趋势（使用神经网络的分子建模、构效关系、在一个分子中结合复活和抗胆碱能特性）进行了描述。
