We used 8-12 week old male C57BL/6J mice, purchased from Jackson Laboratories, and injected them in the right gastrocnemius muscle with either 50 μl saline (control group), or 50 μl of the indicated concentrations of sodium nitrite or sodium thiosulfate.
As required by our Institutional Animal Care and Use Committee (IACUC), the mice were anesthetized by injecting isoflurane into the chamber to a final concentration of 2% at 30✬, the isoflurane rapidly vaporizes and anesthetizes the mice. This model assumes about 15 min are required for emergency medical personnel to arrive at a disaster scene, and another 25 min are required to treat and evacuate the victims.
The mice were exposed to 587 ppm HCN gas for 15 min, injected with test antidote, and then re-exposed to the gas for 25 min ( Fig. Mice are small enough that they can be exposed to cyanide gas within a sealed chamber this minimizes the risk of exposing laboratory personnel to cyanide, but it allows for only visual monitoring of the animals.
Antidote for cyanide poisoning cost full#
The following sections provide a general description of the three animal models full experimental details are in Supplementary Data. Assuming 90% survival in treated animals, sample sizes were calculated for the mice, rabbits, and pigs as 6, 11, and 5, respectively. From pilot studies and previous work, we expected 100% lethality in untreated mice and pigs, and 80% lethality in untreated rabbits ( 8- 16). Sample size was determined by a Chi-square test, setting alpha at 0.05 and power at 0.9 for the mice and rabbits and 0.8 for the pigs (the pigs are 50 kg in size and we wanted to use the absolute minimal number of animals). Animals were randomized to the control or treated group using a block randomization procedure, to assure equal numbers of animals in each group. The investigation was conducted as a randomized, non-blinded, parallel-group study. We studied three different species, because we wanted to ensure our findings were not limited to one or two species: since efficacy testing cannot be performed in humans for a cyanide antidote, greater assurance is important in pre-clinical studies compared to most drug development programs. This makes the models extremely rigorous, because the antidote has to neutralize not just the amount of cyanide that triggered treatment-cardiovascular and respiratory collapse in the rabbits and pigs, respectively-but also cyanide that continued to be administered to a profoundly sick animal ( Fig. In consideration of these worse-case scenarios, our three animal models incorporate continued exposure to cyanide, even after treatment. In these cases, it would be useful to treat the victims as quickly as possible, prior to or simultaneous with evacuation from the contaminated area. However, as part of our work of developing the cobalamin analog cobinamide as a cyanide antidote, we found recently that sodium nitrite and sodium thiosulfate showed some anti-cyanide activity when given by intramuscular injection ( 8- 10).Īccording to general HAZMAT principles, persons exposed to toxic chemicals should be evacuated immediately from the contaminated area, but it would be difficult to remove a large number of victims quickly from a confined, hard-to-access location such as a subway station. Nithiodote contains 12.5 grams of sodium thiosulfate, an amount far greater than could be given by intramuscular injection, and published data indicate that neither sodium nitrite nor sodium thiosulfate are effective via intramuscular injection ( 6 7). Sodium nitrite and sodium thiosulfate are very soluble in water and stable under anaerobic conditions. This requires that the antidote(s) is/are: ( i) stable in solution ( ii) sufficiently soluble to be administered in 1-3 ml ( iii) highly potent such that only a relatively small amount needs to be administered and ( iv) rapidly absorbed after intramuscular injection. In a mass casualty scenario, probably the best treatment mode of critically ill patients would be intramuscular injection of antidote by first responders, preferably from a pre-filled autoinjector. Available treatments for cyanide poisoning such as hydroxocobalamin (Cyanokit®) and the combination of sodium nitrite with sodium thiosulfate (Nithiodote®) are administered by intravenous injection, which is not practical for treating a large number of cyanide-poisoned victims in the pre-hospital setting. Thus, cyanide exposure can occur under a variety of situations and mass casualties are possible. It can be made relatively easily, and terrorists could poison food or medicines or detonate a cyanide bomb in an enclosed space ( 4 5). Cyanide is a highly toxic chemical used in a wide variety of industries, and is generated in industrial and residential fires ( 1- 3).
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