Combined Use of Cobinamide and a 3-Mercaptopyruvate Prodrug for Cyanide Poisoning

描述（由申请人提供）： 氰化物是对平民和军事人员的主要化学威胁，有许多潜在的氰化物暴露来源，包括火灾和恐怖袭击。在严重的氰化物中毒中，快速干预是关键，治疗需要“三分钟解决方案”，类似于神经毒剂解毒剂试剂盒。目前没有符合这些标准的解毒剂选择。我们（Nagasawa等人）最近开发了一系列原型氰化物解毒剂，通过将氰化物转化为无毒的硫氰酸盐来解毒氰化物。我们还开发了一种独特的小鼠模型，最大限度地减少了所需的动物数量，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功效。上述药物的一种解毒剂是高度水溶性的，速效的，不需要IV输注，并且已被选为进一步临床前开发的主要候选药物。此外，我们（博斯和同事）已经证明，钴胺素生物合成中的倒数第二个前体--钴氨酰胺在保护小鼠免受氰化物侵害方面非常有效。这种解毒剂的工作原理，彻底螯合氰化物和排泄所产生的复杂的尿液，一个不同的机制比上述解毒剂。Cobinamide具有高度水溶性，作用迅速，不需要静脉输注。我们（Brenner等人）还开发了一种可靠的、可重复的氰化物毒性兔模型，并证明了贝克曼激光研究所开发的扩散光学光谱（DOS）技术能够非侵入性地评估氰化物毒性和标准解毒剂逆转期间发生的病理生理事件。这种使用新型的，经过验证的非侵入性光学技术定量测量氰化物毒性和治疗反应的一系列生理终点，应允许加速开发和完善测试的候选药物开发的老板和Nagasawa/帕特森实验室。已经建立了我们的解毒剂在小鼠中保护免于氰化物毒性的“概念证明”，我们将a）在Brenner兔模型和Nagasawa/Patterson小鼠模型和仔猪模型中同时评估化合物单独和组合的功效B）加速临床前毒性，这些化合物单独和组合的ADME研究等c）向FDA提交IND和d）启动I期和有限的II期临床试验。我们预计这些组合将比单一药物更有效。如果发现是这种情况，这种组合（鸡尾酒）可能会成为军队以及第一反应者防止氰化物暴露的标准。

DESCRIPTION (provided by applicant): Cyanide constitutes a major chemical threat to civilians and military personnel with numerous sources of potential cyanide exposure, including fires and terrorist attacks. In severe cyanide poisonings, rapid intervention is the key, and treatments require a "three minute solution", akin to the nerve agent antidote kit. Currently there are no antidote options that meet these criteria. We (Nagasawa et al) have recently developed a series of prototype cyanide antidotes that detoxify cyanide by converting cyanide to the non-toxic thiocyanate. We have also developed a unique mouse model-that minimizes the numbers of animals required-for assessing the toxicity of sub-lethal doses of cyanide, which is highly amenable for evaluating the antidotal efficacy of our compounds. One antidote of the above is highly water soluble, rapid acting, does not require IV infusion and has been selected as a prime candidate for further preclinical development. In addition, we (Boss and colleagues) have shown that cobinamide, the penultimate precursor in the biosynthesis of cobalamin, is highly effective in protecting mice from cyanide. This antidote works, thorough sequestration of cyanide and excretion of the resulting complex in urine, a different mechanism than the above antidotes. Cobinamide is highly water soluble, rapid acting and does not require IV infusion. We (Brenner et al.) have also developed a reliable, reproducible rabbit model of cyanide toxicity and demonstrated the ability of diffuse optical spectroscopy (DOS) technologies developed at Beckman Laser Institute to noninvasively assess the pathophysiologic events occurring during cyanide toxicity and reversal with standard antidotes. This use of novel, validated non-invasive optical technologies for quantitative measurement of a range of physiologic endpoints of cyanide toxicity and treatment response, should allow accelerated development and refinement of testing of the drug candidates developed by the Boss and Nagasawa/Patterson labs. Having already established "proof of concept" that our antidotes protect against cyanide toxicity in mice, we will a) simultaneously evaluate the efficacy of the compounds individually and in combination in the Brenner rabbit model and the Nagasawa/Patterson mouse model and piglet model b) accelerate preclinical toxicity, ADME studies etc. for these compounds individually and in combination c) file an IND to the FDA and d) initiate Phase I and limited Phase 2 clinical trials. We anticipate that these combinations will be more effective than the single drugs. If this is found to be the case, such a combination (cocktail) may become the standard for protection against cyanide exposure by the military as well as by first responders.