Countermeasures Against Chemical Threats: Countermeasures Against Cyanide

描述(申请人提供)：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硫代硫酸钠的组合，这两种药物都是及时静脉注射的。近年来，鼻腔给药补充了挥发性亚硝酸戊酯的血管扩张作用。然而，这些药物通常不仅起效慢，而且如果使用不当，还有可能产生毒性和严重的并发症。美国疾病控制与预防中心专家最近撰写的一篇关于氰化物的观点文章指出，在严重的氰化物中毒中，快速干预是关键，治疗需要三分钟的溶液，类似于神经毒剂解毒剂工具包(Baskin等人)。2004年)。军事人员在受到威胁时或在氰化物紧急情况下的第一反应人员可以预防性地使用无毒制剂，这也是一项理想的要求。到目前为止，这些目标尚未实现，目前的治疗模式不适合在军事环境中或在实际使用氰化物作为威胁剂大规模威胁平民人口的情况下使用。我们最近开发了(未发表)一系列氰化物解毒剂原型，在体内释放酶的底物3-巯基丙酮酸硫转移酶(3-MPST)，从而提供了一种可行的替代方法，通过利用这种普遍存在的细胞酶将氰化物转化为无毒的硫氰酸盐。这里的基本原理是直接为这种酶提供其天然底物，从而绕过从L-半胱氨酸的转氨反应中内源产生它的必要性，半胱氨酸是一种已知在组织中含量较少的巯基氨基酸。我们还开发了一种独特的小鼠模型--最大限度地减少使用大量动物--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非常有利。由于已经确定了我们的原型化合物可在小鼠身上防止氰化物中毒的概念证据，我们将同时a)扩展原型系列，并围绕这些系列设计和合成类似物，以提高这些化合物的解毒效力、生物利用度和物理性能，b)在上述方案中叠加内源性抗氧化剂谷胱甘肽(其生物可利用形式；见下文)，以评估此类抗氧化剂联合治疗是否会提高存活率，防止急性氰化物中毒长期幸存者的神经功能缺失，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，目标是在这一授权期内向FDA提交IND申请。虽然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(可能更多)作用较慢(按设计)，但口服时完全具有保护作用；

DESCRIPTION (provided by applicant): 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 (Baskin et al. 2004). 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 We have recently developed (unpublished) a series of prototype cyanide antidotes that release the substrate for the enzyme, 3-mercaptopyruvate sulfur-transferase (3-MPST) in vivo, thereby providing a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; vide infra) 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 well within this grant period. 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;