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

描述（由申请人提供）：氰化物是一种高毒性化合物，在科学实验室和工业环境中很容易获得。此外，它相对容易从廉价的、可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，并被用作大规模毁灭性武器。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--硫代硫酸钠和亚硝酸钠和亚硝酸戊酯。这两种药剂都有明显的副作用和严重的局限性，包括它们在治疗大量因大规模氰化物暴露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内给药，亚硝酸戊酯必须吸入几分钟。钴酰胺是钴胺素（维生素B12）生物合成中的倒数第二个化合物，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，可宾酰胺是一种非常有效的氰化物解毒剂。通过肌肉注射可宾胺，小鼠可以从两倍于LD 50的氰化物剂量中获救，这使得可宾胺成为治疗大规模伤亡的有吸引力的药剂。我们现在建议进行必要的cobinamide临床前研究，以获得美国食品药品监督管理局（FDA）的研究者新药（IND）批准。临床前研究将在前三个资助年度完成，在第四和第五个资助年度，我们建议进行I期和IIa期临床研究。II期研究将在接受硝普钠治疗的急性高血压患者中进行;由于硝普钠治疗受到氰化物毒性的限制，可宾胺可以使硝普钠的给药时间更长，剂量更高。除了对抗恐怖袭击和降低硝普钠毒性外，可宾酰胺还可用于治疗烟雾吸入受害者、职业和工业氰化物暴露、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.