Wille Timo, Neumaier Katharina, Koller Marianne, Ehinger Christina, Aggarwal Nidhi, Ashani Yacov, Goldsmith Moshe, Sussman Joel L, Tawfik Dan S, Thiermann Horst, Worek Franz
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Toxicol Lett. 2016 Sep 6;258:198-206. doi: 10.1016/j.toxlet.2016.07.004. Epub 2016 Jul 7.
The recent attacks with the nerve agent sarin in Syria reveal the necessity of effective countermeasures against highly toxic organophosphorus compounds. Multiple studies provide evidence that a rapid onset of antidotal therapy might be life-saving but current standard antidotal protocols comprising reactivators and competitive muscarinic antagonists show a limited efficacy for several nerve agents. We here set out to test the newly developed phosphotriesterase (PTE) mutant C23AL by intravenous (i.v.), intramuscular (i.m.; model for autoinjector) and intraosseous (i.o.; model for intraosseous insertion device) application in an in vivo guinea pig model after VX challenge (∼2LD50). C23AL showed a Cmax of 0.63μmolL(-1) after i.o. and i.v. administration of 2mgkg(-1) providing a stable plasma profile up to 180min experimental duration with 0.41 and 0.37μmolL(-1) respectively. The i.m. application of C23AL did not result in detectable plasma levels. All animals challenged with VX and subsequent i.o. or i.v. C23AL therapy survived although an in part substantial inhibition of erythrocyte, brain and diaphragm AChE was detected. Theoretical calculation of the time required to hydrolyze in vivo 96.75% of the toxic VX enantiomer is consistent with previous studies wherein similar activity of plasma containing catalytic scavengers of OPs resulted in non-lethal protection although accompanied with a variable severity of cholinergic symptoms. The relatively low C23AL plasma level observed immediately after its i.v. or i.o load, point at a possible volume of distribution greater than the guinea pig plasma content, and thus underlines the necessity of in vivo experiments in antidote research. In conclusion the i.o. application of PTE is efficient and resulted in comparable plasma levels to the i.v. application at a given time. Thus, i.o. vascular access systems could improve the post-exposure PTE therapy of nerve agent poisoning.
近期叙利亚发生的沙林神经毒剂袭击事件表明，必须针对高毒性有机磷化合物采取有效的应对措施。多项研究表明，迅速开始解毒治疗可能挽救生命，但目前包括重活化剂和竞争性毒蕈碱拮抗剂的标准解毒方案对几种神经毒剂的疗效有限。我们在此通过静脉内（i.v.）、肌肉内（i.m.；自动注射器模型）和骨内（i.o.；骨内插入装置模型）给药，在VX攻击（约2LD50）后的豚鼠体内模型中测试新开发的磷酸三酯酶（PTE）突变体C23AL。在静脉内和骨内给予2mg/kg的C23AL后，其Cmax为0.63μmol/L(-1)，在长达180分钟的实验期间分别提供了0.41和0.37μmol/L(-1)的稳定血浆水平。肌肉内给予C23AL未导致可检测到的血浆水平。所有接受VX攻击并随后接受骨内或静脉内C23AL治疗的动物均存活，尽管检测到红细胞、脑和膈肌乙酰胆碱酯酶（AChE）有部分显著抑制。体内水解96.75%有毒VX对映体所需时间的理论计算与先前的研究一致，在先前的研究中，含有有机磷催化清除剂的血浆具有类似活性，可产生非致命性保护，尽管伴有不同严重程度的胆碱能症状。静脉内或骨内注射C23AL后立即观察到的相对较低的血浆水平表明，其分布容积可能大于豚鼠血浆含量，因此强调了解毒剂研究中进行体内实验的必要性。总之，骨内应用PTE是有效的，并且在给定时间内产生的血浆水平与静脉内应用相当。因此，骨内血管通路系统可以改善神经毒剂中毒暴露后的PTE治疗。
