Kovarik Zrinka, Calić Maja, Sinko Goran, Bosak Anita, Berend Suzana, Vrdoljak Ana Lucić, Radić Bozica
Institute for Medical Research and Occupational Health, Ksaverska c. 2, Zagreb, Croatia.
Chem Biol Interact. 2008 Sep 25;175(1-3):173-9. doi: 10.1016/j.cbi.2008.04.011. Epub 2008 May 23.
One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime, found as the most effective reactivators, have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE. Three of our tested pyridinium oximes K027, K048, K074, along with TMB-4, were the most promising for AChE reactivation. Promising oximes were further tested in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. Herein, we showed that a promising treatment in tabun poisoning by selected oximes and atropine could be improved if oximes are also used in pretreatment. Since the reactivating efficacy of the oximes in vitro corresponded to their therapeutic efficacy in vivo, it seems that pharmacological effect of these oximes is indeed primarily related to the reactivation of tabun-phosphorylated AChE.
有机磷中毒的一种治疗方法是使用肟类等定点亲核试剂使乙酰胆碱酯酶（AChE）重新活化。然而，吡啶肟类药物2-解磷定、HI-6、TMB-4和双复磷被发现是最有效的重新活化剂，但在塔崩中毒中其重新活化效力有限。我们测试了环类型（吡啶鎓和/或咪唑鎓）、环之间连接基的长度和类型以及环上肟基位置不同的肟类，以寻找更有效的肟类来重新活化被塔崩抑制的人红细胞乙酰胆碱酯酶。我们测试的三种吡啶肟类药物K027、K048、K074以及TMB-4，在AChE重新活化方面最具潜力。对有潜力的肟类不仅作为与阿托品联用的解毒剂，还作为预处理药物在塔崩中毒小鼠体内进行了进一步测试。在此，我们表明，如果肟类也用于预处理，那么通过选择的肟类和阿托品对塔崩中毒进行的有前景的治疗可以得到改善。由于肟类在体外的重新活化效力与其在体内的治疗效力相对应，这些肟类的药理作用似乎确实主要与塔崩磷酸化的AChE的重新活化有关。
