Pre-clinical and Clinical Studies of Cobinamide, a New Cyanide Detoxifying Agent

描述（由申请人提供）：氰化物是一种剧毒化合物，在科学实验室和工业环境中很容易获得。此外，它相对容易从廉价，广泛获得的试剂合成。因此，氰化物有可能落入恐怖分子之手，并被用作大规模杀伤性武器。氰化物在机场或火车站等封闭空间以气体形式释放时尤其致命。在美国，只有两种氰化物解毒剂可用——硫代硫酸钠和亚硝酸钠和亚硝酸酯形式的亚硝酸盐。这两种药物都有明显的副作用和严重的局限性，包括它们在治疗大量接触氰化物而失去知觉的人时是不切实际的，因为硫代硫酸钠和亚硝酸钠必须静脉注射，而亚硝酸盐戊酯必须吸入几分钟。钴胺酰胺是钴胺素（维生素B12）生物合成中的倒数第二种化合物，以极高的亲和力（~1022 M-1）结合两个氰化物分子。我们已经证明，在小鼠、培养的哺乳动物细胞和果蝇中，cobinamide是一种非常有效的氰化物解毒剂。通过肌肉注射cobinamide，小鼠可以从两倍LD50的氰化物剂量中获救，这使得cobinamide成为治疗大规模伤亡的有吸引力的药物。我们现在建议对cobinamide进行必要的临床前研究，以获得食品和药物管理局（FDA）的研究者新药（IND）批准。临床前研究将在前3年完成，在第4年和第5年，我们建议进行I期和lla临床研究。II期研究将在硝普塞治疗的急性高血压患者中进行；由于硝普苷的治疗受到氰化物毒性的限制，Cobinamide可以使硝普苷的使用时间更长，剂量更高。在针对氰化物暴露的药物治疗中，Cobinamide将是一个受欢迎的补充；除了对抗恐怖袭击和降低硝普苷毒性外，cobinamide还可用于治疗烟雾吸入受害者、职业和工业氰化物暴露者、吸烟者和血液透析患者。

DESCRIPTION (provided by applicant): Cyanide is a highly toxic compound that is readily available in scientific laboratories and industrial settings. Moreover, it is relatively easy to synthesize from inexpensive, widely obtainable reagents. Thus, cyanide has the potential to come into the hands of terrorists, and to be used as a weapon of mass destruction. Cyanide would be particularly lethal when released as a gas in closed spaces such as airports or train stations. Only two cyanide antidotes are available in the United States -- sodium thiosulfate, and nitrites in the form of sodium nitrite and amyl nitrite. Both agents have significant side effects and serious limitations, including they would be impractical in treating a large number of unconscious persons from mass cyanide exposure, because sodium thiosulfate and sodium nitrite must be administered intravenously, and amyl nitrite must be inhaled for several minutes. Cobinamide, the penultimate compound in the biosynthesis of cobalamin (vitamin B12), binds two cyanide molecules with extremely high affinity (~1022 M-1). We have shown that cobinamide is a remarkably effective cyanide antidote in mice, cultured mammalian cells, and Drosophila melanogaster. Mice can be rescued from a cyanide dose of two times the LD50 with an intramuscular injection of cobinamide, making cobinamide an attractive agent for treating mass casualties. We now propose to perform the requisite pre-clinical studies of cobinamide to obtain Investigator's New Drug (IND) approval from the Food and Drug Administration (FDA). The pre-clinical studies will be completed during the first three grant years, and during grant years four and five, we propose to perform Phase I and lla clinical studies. The Phase II studies will be performed on acutely hypertensive patients treated with nitroprusside; cobinamide could allow nitroprusside to be given for longer periods and at higher doses because nitroprusside therapy is limited by cyanide toxicity. Cobinamide would be a welcome addition to drug therapies directed against cyanide exposure; in addition to countering a terrorist attack and reducing nitroprusside toxicity, cobinamide could be used to treat smoke inhalation victims, occupational and industrial cyanide exposures, cigarette smokers, and hemodialysis patients.