OF UO1 GRANTCyanide 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 thepotential to come into the hands of terrorists, and to be used as a weapon of mass destruction. Cyanide wouldbe particularly lethal when released as a gas in closed spaces such as airports or train stations. Only two cyanideantidotes are available in the United States-sodium thiosulfate, and nitrites in the form of sodium nitrite and amylnitrite. Both agents have significant side effects and serious limitations, including they would be impractical intreating a large number of unconscious persons from mass cyanide exposure, because sodium thiosulfate andsodium nitrite must be administered intravenously, and amyl nitrite must be inhaled for several minutes.Cobinamide, the pentultimate compound in the biosynthesis of cobalamin (vitamin B12), binds two cyanidemolecules with extremely high affinity (~1022 M'1). We have shown that cobinamide is a remarkably effectivecyanide antidote in mice, cultured mammalian cells, and Drosophila melanogaster. Mice can be rescued from acyanide dose of two times the LD50with a subcutaneous injection of cobinamide, making cobinamide an attractiveagent for treating mass casualties. We now propose to perform the requisite pre-clinical studies of cobinamideto obtain Investigator's New Drug (IND) approval from the Food and Drug Administration (FDA). The pre-clinicalstudies will be completed during the first three grant years, and during grant years four and five, we propose toperform Phase I and Ha clinical studies. The Phase II studies will be performed on acutely hypertensive patientstreated with nitroprusside; cobinamide could allow nitroprusside to be given for longer periods and at higher dosesbecause nitroprusside therapy is limited by cyanide toxicity. Cobinamide would be a welcome addition to drugtherapies directed against cyanide exposure; in addition to countering a terrorist attack and reducing nitroprussidetoxicity, cobinamide could be used to treat smoke inhalation victims, occupational and industrial cyanideexposures, cigarette smokers, and hemodialysis patients.
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