Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Chem Biol Interact. 2010 Sep 6;187(1-3):259-64. doi: 10.1016/j.cbi.2009.11.009. Epub 2009 Nov 13.
Despite extensive research for more than six decades on medical countermeasures against poisoning by organophosphorus compounds (OP) the treatment options are meagre. The presently established acetylcholinesterase (AChE) reactivators (oximes), e.g. obidoxime and pralidoxime, are insufficient against a number of nerve agents and there is ongoing debate on the benefit of oxime treatment in human OP pesticide poisoning. Up to now, the therapeutic efficacy of oximes was mostly evaluated in animal models but substantial species differences prevent direct extrapolation of animal data to humans. Hence, it was considered essential to establish relevant experimental in vitro models for the investigation of oximes as antidotes and to develop computer models for the simulation of oxime efficacy in different scenarios of OP poisoning. Kinetic studies on the various interactions between erythrocyte AChE from various species, structurally different OP and different oximes provided a basis for the initial assessment of the ability of oximes to reactivate inhibited AChE. In the present study, in vitro enzyme-kinetic and pharmacokinetic data from a minipig model of dimethoate poisoning and oxime treatment were used to calculate dynamic changes of AChE activities. It could be shown that there is a close agreement between calculated and in vivo AChE activities. Moreover, computer simulations provided insight into the potential and limitations of oxime treatment. In the end, such data may be a versatile tool for the ongoing discussion of the pros and cons of oxime treatment in human OP pesticide poisoning.
尽管在医学对抗有机磷化合物（OP）中毒的对策上已经进行了超过六十年的广泛研究，但治疗选择仍然很少。目前已建立的乙酰胆碱酯酶（AChE）重激活剂（肟类），例如碘解磷定和氯解磷定，对于一些神经毒剂的效果不足，并且关于肟类治疗在人类 OP 农药中毒中的益处仍存在争议。迄今为止，肟类的治疗效果主要在动物模型中进行评估，但大量的物种差异阻止了将动物数据直接推断到人类。因此，建立相关的体外实验模型来研究肟类作为解毒剂，并开发计算机模型来模拟不同 OP 中毒情况下肟类的疗效，被认为是至关重要的。不同物种红细胞 AChE 与结构不同的 OP 和不同肟类之间的各种相互作用的动力学研究为肟类重新激活抑制的 AChE 的能力的初步评估提供了依据。在本研究中，使用二甲氧酯中毒和肟类治疗的小型猪模型的体外酶动力学和药代动力学数据来计算 AChE 活性的动态变化。结果表明，计算出的和体内的 AChE 活性之间有密切的一致性。此外，计算机模拟提供了对肟类治疗的潜力和限制的深入了解。最终，这些数据可能成为正在讨论肟类治疗在人类 OP 农药中毒中的优缺点的多功能工具。
