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: 7691355
• 负责人: STEVEN E PATTERSON
• 金额: $ 100.55万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691355
• 关键词: Combined; Use; Cobinamide; Mercaptopyruvate; Prodrug

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.

描述（由申请人提供）： 氰化物对平民和军事人员构成重大化学威胁，潜在的氰化物暴露来源众多，包括火灾和恐怖袭击。对于严重的氰化物中毒，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套件。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 - 最大限度地减少所需的动物数量 - 用于评估亚致死剂量氰化物的毒性，这非常适合评估我们化合物的解毒功效。上述一种解毒剂具有高度水溶性、起效快、不需要静脉输注，并已被选为进一步临床前开发的主要候选药物。此外，我们（Boss 和同事）已经证明，钴胺素生物合成中的倒数第二个前体钴酰胺能够非常有效地保护小鼠免受氰化物的侵害。这种解毒剂起作用，彻底隔离氰化物并将所得复合物排泄到尿液中，其机制与上述解毒剂不同。 Cobinamide 具有高度水溶性、起效快且不需要静脉输注。我们（Brenner 等人）还开发了一种可靠、可重复的氰化物毒性兔子模型，并证明了贝克曼激光研究所开发的扩散光谱 (DOS) 技术能够以标准方式无创评估氰化物毒性和逆转过程中发生的病理生理事件。解毒剂。这种使用新颖的、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，应该能够加速开发和完善 Boss 和 Nagasawa/Patterson 实验室开发的候选药物的测试。已经建立了我们的解毒剂可以防止小鼠氰化物毒性的“概念证明”，我们将 a) 同时评估这些化合物在布伦纳兔模型、Nagasawa/Patterson 小鼠模型和仔猪模型中单独和组合的功效 b)加速这些化合物单独和组合的临床前毒性、ADME 研究等 c) 向 FDA 提交 IND 申请，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。如果情况确实如此，这种组合（鸡尾酒）可能会成为军队和急救人员防止氰化物暴露的标准。