Kiss Lóránd, Holmes Secondra, Chou Ching-En, Dong Xinmei, Ross James, Brown Denise, Mendenhall Brooke, Coronado Valerie, De Silva Deepthika, Rockwood Gary A, Petrikovics Ilona, Thompson David E
Department of Chemistry, Sam Houston State University, PO Box 2117, Huntsville, TX, 77341, USA.
U.S. Army Medical Research Institute of Chemical Defense, 2900 Rickets Point Road, Aberdeen Proving Ground, MD, 21010, USA.
J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Feb 15;1044-1045:149-157. doi: 10.1016/j.jchromb.2017.01.010. Epub 2017 Jan 9.
The antidotal potency of dimethyl trisulfide (DMTS) against cyanide poisoning was discovered and investigated in our previous studies. Based on our results it has better efficacy than the Cyanokit and the Nithiodote therapies that are presently used against cyanide intoxication in the US. Because of their absence in the literature, the goal of this work was to develop analytical methods for determining DMTS from blood and brain that could be employed in future pharmacokinetic studies. An HPLC-UV method for detection of DMTS from blood, a GC-MS method for detection of DMTS from brain, and associated validation experiments are described here. These analytical methods were developed using in vitro spiking of brain and blood, and are suitable for determining the in vivo DMTS concentrations in blood and brain in future pharmacokinetic and distribution studies. An important phenomenon was observed in the process of developing these methods. Specifically, recoveries from fresh blood spiked with DMTS were found to be significantly lower than recoveries from aged blood spiked in the same manner with DMTS. This decreased DMTS recovery from fresh blood is important, both because of the role it may play in the antidotal action of DMTS in the presence of cyanide, and because it adds the requirement of sample stabilization to the method development process. Mitigation procedures for stabilizing DMTS samples in blood are reported.
我们之前的研究发现并研究了二甲基三硫醚（DMTS）对氰化物中毒的解毒效力。根据我们的研究结果，它比目前美国用于治疗氰化物中毒的Cyanokit和Nithiodote疗法更有效。由于文献中没有相关内容，这项工作的目标是开发用于测定血液和大脑中DMTS的分析方法，以便未来用于药代动力学研究。本文描述了一种用于检测血液中DMTS的HPLC-UV方法、一种用于检测大脑中DMTS的GC-MS方法以及相关的验证实验。这些分析方法是通过对大脑和血液进行体外加标开发的，适用于未来药代动力学和分布研究中测定血液和大脑中的体内DMTS浓度。在开发这些方法的过程中观察到了一个重要现象。具体而言，发现用DMTS加标的新鲜血液的回收率明显低于以相同方式加标的陈旧血液的回收率。新鲜血液中DMTS回收率的降低很重要，这既是因为它可能在氰化物存在时对DMTS的解毒作用中发挥作用，也是因为它给方法开发过程增加了样品稳定化的要求。本文报道了稳定血液中DMTS样品的缓解程序。
