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

Cobinamide 与 3-巯基丙酮酸前药联合使用治疗氰化物中毒

• 批准号: 8267857
• 负责人: STEVEN E PATTERSON
• 金额: $ 7.64万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267857
• 关键词: ADME Study; Anabolism; Animals; Antidotes; Chemicals; Cobalamin; Complex; Cyanides; Development; Diffuse; Dose; Event; Excretory function; Fire - disasters; Institutes; Intervention; Intravenous infusion procedures; Lasers; Measurement; Military Personnel; Modeling; Mus; Optics; Oryctolagus cuniculus; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Poisoning; Prodrugs; Series; Solutions; Source; Spectrum Analysis; Technology; Testing; Thiocyanates; Toxic effect; Urine; Water; Work; beta-mercaptopyruvate; cobinamide; drug candidate; emergency service responder; meetings; mouse model; nerve agent; novel; pre-clinical; preclinical toxicity; prototype; treatment response

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.

氰化物对平民和军事人员构成重大化学威胁，有许多潜在的氰化物接触来源，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，治疗需要一种类似于神经毒剂解毒剂试剂盒的“三分钟溶液”。目前还没有符合这些标准的解毒剂选择。 我们(长泽等人)最近开发了一系列氰化物解毒剂原型，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--将所需的动物数量降至最低--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。上述解毒剂中的一种高度水溶性，起效快，不需要静脉输液，已被选为 进一步临床前开发的最佳候选者。 此外，我们(博斯和他的同事)已经证明，钴胺是钴胺生物合成的倒数第二个前体，在保护小鼠免受氰化物伤害方面非常有效。这种解毒剂的作用机制与上述解毒剂不同，它可以彻底隔离氰化物，并在尿液中排泄产生的络合物。考宾胺是高度水溶性的，起效快，不需要静脉输液。 我们(Brenner等人)我们还开发了可靠、可重现的氰化物中毒兔模型，并展示了贝克曼激光研究所开发的漫反射光学光谱(DOS)技术非侵入性评估氰化物中毒和标准解毒剂逆转过程中发生的病理生理事件的能力。使用新的、经过验证的非侵入性光学技术来定量测量氰化物毒性和治疗反应的一系列生理终点，应该可以加速开发和改进由Boss和 长泽/帕特森实验室。 我们已经确定了我们的解毒剂可在小鼠身上防止氰化物毒性的“概念证明”，我们将a)在Brenner兔模型、长泽/Patterson小鼠模型和仔猪模型中同时单独和联合评估化合物的有效性；b)加速临床前毒性、ADME研究等。对于这些化合物的单独和组合，c)向FDA提交IND，d)启动第一阶段和有限的第二阶段临床试验。 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)可能会成为军方和急救人员防止氰化物暴露的标准。