Worek F, Eyer P, Szinicz L
Institut für Pharmakologie und Toxikologie, Sanitätsakademie der Bundeswehr, Garching, Germany.
Arch Toxicol. 1998 Sep;72(9):580-7. doi: 10.1007/s002040050546.
Cyclohexylmethylphosphonofluoridate (cyclosarin) is a highly toxic organophosphate, which was shown to be rather resistant to conventional oxime therapy. To give more insight into the inhibition, reactivation and aging kinetics, human acetyl-(AChE) and butyrylcholinesterase (BChE) were inhibited by cyclosarin (k2 of 7.4 and 3.8 x 10(8) M(-1) min(-1), respectively; pH 7.4, 37 degrees C) and reactivated with obidoxime, pralidoxime and three experimental oximes. The new oxime HLö 7 (1-[[[4-aminocarbonyl)-pyridinio]-methoxy]-methyl]-2,4-bis-[ (hydroxyimino)methyl] pyridinium dimethanesulphonate) was shown to be superior to the other oximes. At oxime concentrations anticipated to be relevant in humans, obidoxime and pralidoxime were extremely weak reactivators of AChE. Aging velocity of BChE was almost fourfold higher compared to AChE (ka of 0.32 h(-1) and 0.08 h(-1), respectively). A substantial spontaneous reactivation was observed with AChE. These results support previous in vivo findings that obidoxime and pralidoxime are insufficient antidotes in cyclosarin poisoning. By contrast, HLö 7 was shown to be an extremely potent reactivator of human AChE and BChE, which supports its position as a broad-spectrum oxime.
环己基甲基磷酰氟（环沙林）是一种剧毒有机磷酸酯，已证明其对传统肟类疗法具有相当的抗性。为了更深入了解抑制、复活和老化动力学，用环沙林抑制人乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）（k2分别为7.4和3.8×10⁸ M⁻¹ min⁻¹；pH 7.4，37℃），并用双复磷、氯解磷定和三种实验性肟进行复活。新型肟HLö 7（1-[[[4-氨基羰基）-吡啶基]-甲氧基]-甲基]-2,4-双-[（羟基亚氨基）甲基]吡啶鎓二甲磺酸盐）被证明优于其他肟类。在预期与人体相关的肟浓度下，双复磷和氯解磷定对AChE的复活作用极弱。BChE的老化速度几乎比AChE高四倍（ka分别为0.32 h⁻¹和0.08 h⁻¹）。观察到AChE有大量自发复活现象。这些结果支持了先前的体内研究结果，即双复磷和氯解磷定在环沙林中毒时作为解毒剂是不足的。相比之下，HLö 7被证明是一种极其有效的人AChE和BChE复活剂，这支持了它作为一种广谱肟的地位。
