Countermeasures against cyanide

尽管不同的国家对特定的氰化物中毒解毒剂有不同的偏好，但 30多年来，美国选择的解毒剂一直是亚硝酸钠和钠的组合 硫代硫酸盐，两者均按时间顺序静脉给药。近年来，这一点得到了补充 一种挥发性的亚硝酸戊酯，因其血管扩张作用而鼻腔给药。然而，这些代理通常不仅速度慢 作用，但有潜在的毒性和严重的并发症，如果使用不当。最近的一篇观点文章 由USAMRICD的专家撰写的关于氰化物的报告指出，在严重的氰化物中毒中， 干预是关键，治疗需要“三分钟解决方案”，类似于神经毒剂解毒剂试剂盒。 军事人员在受到威胁接触时可以预防性服用的无毒制剂的可用性 或者由氰化物紧急情况的第一反应人员，也是一种理想的要求。这些目标还没有 到目前为止已经取得了进展，目前的治疗模式不适合军事环境，或者在 实际使用氰化物作为威胁剂，大规模侵害平民。 我们最近开发了(未发表)一系列原型氰化物解毒剂，可以释放底物 对于该酶，3-巯基丙酮酸硫基转移酶(3-MPST)在体内，从而提供了一种可行的替代方法 利用这种普遍存在的细胞酶将氰化物转化为无毒的氰化物的脱毒方法 硫氰酸盐。这里的基本原理是直接为这种酶提供其天然底物，从而绕过 L-半胱氨酸是一种已知的巯基氨基酸，需要内源性地生成它 组织不那么丰富。我们还开发了一种独特的鼠标模型-它最大限度地减少了大型 动物数量~用于评估亚致死剂量氰化物的毒性，这对 评估我们化合物的解毒效果。 已经建立了我们的原型化合物可防止氰化物中毒的“概念证明” 鼠标，我们将同时a)扩展原型系列，并围绕这些设计和合成类似物 改善这些化合物的解毒效果、生物利用度和物理性能的系列，b)叠加 上述方案中的内源性抗氧化剂谷胱甘肽(作为其生物有效形式)，以评估是否 从长远来看，抗氧化剂联合治疗将提高存活率并保护神经功能不全。 急性氰化物中毒的幸存者，以及c)加快临床前研究(急性和长期毒性，ADME， 其他动物模型等)对于那些已经被证明具有保护作用的化合物，目标是提交 向FDA申请IND。尽管我们系列中的大多数化合物都是快速起作用的，但至少有一个原型 (也许更多)作用较慢(故意)，但口服时完全保护；因此，它可能是 作为预防用药的候选药物。

Although different nations have variable preferences for specific antidotes against cyanide poisoning, the antidotes of choice in the U.S. for over 30 years have been the combination of sodium nitrite and sodium thiosulfate, both administered intravenously in timely sequence. In recent years, this has been supplemented with the volatile amyl nitrite given nasally for its vasodilatory effect. However, these agents are generally not only slow acting, but have potential for toxicity and serious complications if not used properly. A recent perspective article on cyanide, authored by experts at the USAMRICD, pointed out that in severe cyanide poisonings, rapid intervention is the key, and treatments require a "three minute solution", akin to the nerve agent antidote kit.3 The availability of non-toxic agents that could be taken prophylactically by military personnel on threatened exposure or by first responders to a cyanide emergency, also represents an ideal requirement. These goals have not yet been achieved to date, and the present treatment modalities are unsuitable in a military setting, or in the event of actual use of cyanide as a threat agent on a large scale against the civilian population. We have recently developed (unpublished) a series of prototype cyanide antidotes that release the substrate for the enzyme, 3-mercaptopyruvate sulfurtransferase (3-MPST) in vivo, thereby providing a viable alternative method for detoxifying cyanide by utilizing this ubiquitous cellular enzyme to convert cyanide to the non-toxic thiocyanate. The rationale here is to provide this enzyme with its natural substrate directly, thereby by-passing the necessity for generating it endogenously from the transamination of L-cysteine, a sulfhydryl amino acid known to be less abundant in tissues. We have also developed a unique mouse model-that minimizes the use of large numbers of animals~for assessing the toxicity of sub-lethal doses of cyanide, which is highly amenable for evaluating the antidotal efficacy of our compounds. Having already established "proof of concept" that our prototype compounds protect against cyanide toxicity in mice, we will simultaneously a) expand the prototype series, and design and synthesize analogs around these series to improve antidotal efficacy, bioavailability, and physical properties of these compounds, b) superimpose the endogenous antioxidant glutathione (as its bioavailable form) in the above regimen to evaluate whether such antioxidant co-treatment would improve survivability and protect against the neurological deficits seen in long term survivors of acute cyanide intoxication, and c) accelerate preclinical studies (acute and long term toxicity, ADME, other animal models, etc.) for those compounds already demonstrated to be protective, with the goal of filing an IND application to the FDA. Although most of the compounds of our series are rapid acting, at least one prototype (perhaps more) is slower acting (by design), but fully protective when administered orally; hence, it may be advanced as a candidate for prophylactic use.