Countermeasures against cyanide

虽然不同的国家对氰化物中毒的特定解毒剂有不同的偏好， 在美国，30多年来的解毒剂选择一直是亚硝酸钠和钠的组合。 硫代硫酸盐，两者都及时顺序静脉内施用。近年来，这一点得到了补充， 一种挥发性的亚硝酸戊酯，通过鼻腔给药，有血管扩张作用。然而，这些代理商一般不仅速度慢， 但如果使用不当，可能会产生毒性和严重并发症。最近一篇观点文章 由USAMRICD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套件。 军事人员在受到威胁时可使用的无毒剂的供应情况 或由氰化物紧急情况的第一响应者进行，也代表了理想的要求。这些目标尚未 目前的治疗方式不适合军事环境，或在发生 实际使用氰化物作为威胁剂大规模危害平民。 我们最近开发了（未发表）一系列原型氰化物解毒剂， 对于酶，3-巯基丙酮酸硫转移酶（3-MPST）在体内，从而提供了一个可行的替代 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 需要从L-半胱氨酸的转氨作用内源性地产生它， 在组织中含量较少。我们还开发了一种独特的鼠标模型， 动物数量~用于评估亚致死剂量氰化物的毒性，这是非常适合 评估我们的化合物的解毒效果 已经建立了"概念验证"，我们的原型化合物可以防止氰化物毒性， 小鼠，我们将同时a）扩大原型系列，并围绕这些设计和合成类似物 系列以改善这些化合物的解毒功效、生物利用度和物理性质，B） 内源性抗氧化剂谷胱甘肽（作为其生物可利用的形式）在上述方案中，以评估是否 抗氧化剂联合治疗将提高生存率，并防止长期观察到的神经功能缺损。 急性氰化物中毒的幸存者，和c）加速临床前研究（急性和长期毒性，ADME， 其他动物模型等）对于那些已经证明具有保护作用的化合物， 向FDA提交IND申请。虽然我们系列中的大多数化合物都是速效的，但至少有一种原型化合物 （也许更多）作用较慢（通过设计），但口服时完全保护;因此，它可能是 作为预防用途的候选药物。

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 We have recently developed (unpublished) a series of prototype cyanide antidotes that release the substrate for the enzyme, 3-mercaptopyruvate sulfurtransferase (3-MPST) in vivo, thereby providing a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.