Aurbek N, Thiermann H, Szinicz L, Eyer P, Worek F
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
Toxicology. 2006 Jul 5;224(1-2):74-80. doi: 10.1016/j.tox.2006.04.031. Epub 2006 Apr 27.
The rife use of organophosphorus compounds (OP) as pesticides and the exertion of highly toxic OP-type chemical warfare agents (nerve agents) during military conflicts and terrorist attacks in the past emphasize the necessity of the development of effective therapeutic countermeasures. Presently, standard treatment of poisoning by OP includes administration of atropine as an antimuscarinic agent and of oximes, e.g. obidoxime or pralidoxime, as reactivators of OP-inhibited acetylcholinesterase (AChE), but is considered to be rather ineffective with certain nerve agents. The evaluation of new oximes as antidotes is only possible by implementation of animal experiments for ethical reasons and therefore complicated by a limited extrapolation of animal data to humans due to marked species differences. A computer simulation based on combination of AChE kinetic data (inhibition, reactivation, aging) with OP toxicokinetics and oxime pharmacokinetics allows the calculation of AChE activities at different scenarios and may facilitate to define effective oxime concentrations and to optimize oxime dosage in OP poisoning. On the base of species-specific kinetic data this model was used to calculate AChE activities in humans and pigs after percutaneous exposure to 5 x LD50 VX and treatment with HI 6. Due to marked species differences between human and pig AChE the HI 6 dose that is necessary to cause a comparable reactivation of VX-inhibited pig AChE is conspicuously higher. Hence, designing animal experiments with the aid of computer modeling may reduce the number of animal experiments and allow a more reliable extrapolation of animal data to humans.
过去，有机磷化合物（OP）作为杀虫剂被广泛使用，且在军事冲突和恐怖袭击中使用了高毒性的OP类化学战剂（神经毒剂），这凸显了开发有效治疗对策的必要性。目前，OP中毒的标准治疗方法包括使用阿托品作为抗毒蕈碱剂，以及使用肟类药物，如双复磷或氯解磷定，作为OP抑制的乙酰胆碱酯酶（AChE）的重活化剂，但对于某些神经毒剂而言，这种治疗方法被认为效果相当不佳。由于伦理原因，只有通过进行动物实验才能评估新型肟类药物作为解毒剂的效果，因此，由于显著的物种差异，将动物数据外推至人类时存在局限性，这使得评估变得复杂。基于AChE动力学数据（抑制、重活化、老化）与OP毒代动力学和肟类药物药代动力学相结合的计算机模拟，可以计算不同情况下的AChE活性，并可能有助于确定有效的肟类药物浓度，以及优化OP中毒时的肟类药物剂量。基于物种特异性动力学数据，该模型被用于计算经皮暴露于5倍半数致死剂量（LD50）的VX并接受HI 6治疗后人类和猪体内的AChE活性。由于人类和猪的AChE之间存在显著的物种差异，导致VX抑制的猪AChE达到可比重活化所需的HI 6剂量明显更高。因此，借助计算机建模设计动物实验可能会减少动物实验的数量，并使动物数据更可靠地外推至人类。
