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.

氰化物构成了对平民和军事人员的主要化学威胁，其中包括大量潜在的氰化物暴露，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，而治疗需要“三分钟的溶液”，类似于神经剂解毒剂套件。 目前没有符合这些标准的解毒剂选项。 我们（Nagasawa等人）最近开发了一系列原型氰化物解毒剂，这些解毒剂通过将氰化物转化为无毒硫氰酸盐来对氰化物进行排毒。我们还开发了一种独特的小鼠模型 - 该模型可以最大程度地减少评估亚致死剂量氰化物的毒性所需的动物数量，这对于评估化合物的抗原疗效是高度友好的。上述解毒剂是高度水溶性的，快速起作用，不需要静脉输注，已被选为 进一步临床前发展的主要候选人。 此外，我们（Boss及其同事）表明，钴胺素生物合成的倒数第二个前体Cobinamide在保护小鼠免受氰化物侵害的情况下非常有效。这种解毒剂起作用，彻底隔离氰化物和尿液中所得复合物的排泄，这是一种与上述解毒剂不同的机制。核酰胺是高度水溶性的，迅速作用，不需要IV输注。 我们（Brenner等人）还开发了一种可靠的，可重复的兔子毒性兔模型，并证明了贝克曼激光研究所开发的弥漫性光谱（DOS）技术的能力，可以非抗化地评估与氰化物毒性和标准毒性相反的病理生理事件，解毒剂。这种新型，经过验证的非侵入性光学技术用于定量测量氰化物毒性和治疗反应的一系列生理终点，应允许加速发展和改进由老板开发的药物候选者的测试 长川/帕特森实验室。 已经建立了“概念证明”，表明我们的解毒剂可以预防小鼠的氰化物毒性，我们将a）同时评估化合物在Brenner Rabbit模型和Nagasawa/Patterson Mouse Model和Piglet模型中的单独和结合的化合物的功效。加速临床前毒性，ADME研究等。对于这些化合物，并组合组合c）向FDA和d）启动I期和有限的2期临床试验。 我们预计这些组合将比单一药物更有效。如果发现这种情况，这种组合（鸡尾酒）可能成为保护军队和第一响应者氰化物暴露的标准。