Countermeasures Against Chemical Threats: Countermeasures Against Cyanide

化学威胁对策：氰化物对策

基本信息

批准号：
7294943
负责人：
STEVEN E PATTERSON
金额：
$ 67.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7294943
关键词：
3-Mercaptopyruvate sulfurtransferase Acetaminophen Acute Amino Acids Amyl Nitrite Animal Model Animals Antidotes Antioxidants Bioavailable Biological Availability Biological Factors Bioshield Bismuth Burn injury Chemical Warfare Agents Chemicals Clinical Complex Condition Cyanides Cysteine Cytoplasm Development Disodium Salt Nitroprusside Disulfides Dose Drug Metabolic Detoxication Emergency Situation Environment Enzymes Erythrocytes Event Explosion Exposure to Fire - disasters Generations Glutathione Goals Grant Heart Hepatic Housing Hydrogen Cyanide Injury Intervention Intoxication Kidney Left Life Liver Long-Term Survivors Mammalian Cell Methods Military Personnel Mitochondria Modality Modeling Molecular Structure Mus Neuraxis Neurologic Numbers Panic Pharmaceutical Chemistry Plants Poisoning Population Prodrugs Property Publications Reflex action Relative (related person)Request for Applications Research Personnel Risk Factors Robin bird Security Series Site Sodium Nitrite Solutions Stress Sulfur Survivors Testing Therapeutic Therapeutic Intervention Therapeutic Uses Thiocyanates Thiosulfate Sulfurtransferase Tissues Toxic effect Transferase Treatment Protocols United States Food and Drug Administration United States National Institutes of Health Vasodilator Agents War Water World War II analog base beta-mercaptopyruvate concept design disulfide bond reduction emergency service responder enzyme substrate functional group hazard improved in vivo mouse model nerve agent physical property preclinical study preference programs prophylactic prototype research study response sodium thiosulfate sulfurtransferase thiocyanate transamination water solubility

项目摘要

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;

描述（由申请人提供）：尽管不同国家对氰化物中毒的具体解毒剂有不同的偏好，但美国 30 多年来选择的解毒剂一直是亚硝酸钠和硫代硫酸钠的组合，两者均按顺序静脉注射。近年来，已通过鼻腔给予挥发性亚硝酸戊酯来补充其血管舒张作用。然而，这些药物通常不仅作用缓慢，而且如果使用不当，还可能产生毒性和严重并发症。最近由 USAMRICD 专家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，治疗需要三分钟的解决方案，类似于神经毒剂解毒剂套件（Baskin 等人，2004 年）。军事人员在受到威胁时或氰化物紧急情况下的急救人员可以预防性地使用无毒制剂，这也是一个理想的要求。迄今为止，这些目标尚未实现，目前的治疗方式不适合军事环境，或者在实际大规模使用氰化物作为针对平民的威胁剂的情况下。我们最近开发了（未发表）一系列原型氰化物解毒剂，可在体内释放酶 3-巯基丙酮酸硫转移酶 (3-MPST) 的底物，从而为利用这种普遍存在的细胞酶解毒氰化物提供了一种可行的替代方法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，从而绕过了通过L-半胱氨酸的转氨作用内源产生它的必要性，L-半胱氨酸是一种已知在组织中含量较低的巯基氨基酸。我们还开发了一种独特的小鼠模型 - 最大限度地减少大量动物的使用 - 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。我们已经建立了我们的原型化合物可防止小鼠免受氰化物毒性的概念证明，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功效、生物利用度和物理性质，b) ）在上述方案中叠加内源性抗氧化剂谷胱甘肽（以其生物可利用形式；见下文），以评估这种抗氧化剂联合治疗是否会提高生存能力并预防长期出现的神经缺陷急性氰化物中毒的幸存者，以及 c) 加速对那些已被证明具有保护作用的化合物的临床前研究（急性和长期毒性、ADME、其他动物模型等），目标是在不久的将来向 FDA 提交 IND 申请。本补助期。尽管我们系列的大多数化合物起效迅速，但至少一种原型（可能更多）起效较慢（根据设计），但口服时具有充分的保护作用；