2/26/2024 0 Comments Cyanide antidoteConsider consultation with a poison control center at 1-80. Thiosulfate: ~3 hours (Howland 2011) Thiocyanate: 2.7 days, prolonged with renal impairment to ~9 days Use: Labeled IndicationsĬyanide poisoning: Treatment of acute, life-threatening cyanide poisoning in combination with sodium nitrite. Urine (~20% to 50% thiosulfate as unchanged drug) Half-Life Elimination IV: V d: Thiosulfate: 0.15 L/kg (Howland 2011) Thiocyanate: 0.25 L/kg Excretion In anticipation of having a FDA pre-IND meeting, we propose to conduct the requisite studies on sodium tetrathionate, a highly effective cyanide antidote that could be administered by emergency personnel via an autoinjector.Cyanide toxicity: Serves as a sulfur donor in rhodanese-catalyzed formation of thiocyanate (much less toxic than cyanide)Įxtravasation management: Neutralizes the reactive species of mechlorethamine reduces the formation of hydroxyl radicals which cause tissue injury Pharmacokinetics/Pharmacodynamics Distribution Public Health RelevanceĬyanide poisoning on a large-scale is a genuine threat?either in an industrial accident or a terrorist attack?but no cyanide antidote is currently available that can be administered by emergency medical personnel quickly in the field. The latter will position us to transition to BARDA funding after project completion. In addition to a pre- IND meeting during the last year, we plan to have a BARDA Tech Watch meeting, and submit a BARDA White Paper. We will develop a User Requirements Document for a future human factors study, a Target Product Profile suitable for FDA submission, and a detailed Product Development Plan. For the Animal Rule Pathway, the FDA requires that the pivotal animal studies be done using the exact device that will ultimately be marketed and that stability testing be initiated in the device prior to starting Phase I clinical studies although the pivotal animal studies and Phase I studies would be done after completion of the proposed work, we need to arrange for the injection devices at this time to allow for smooth and uninterrupted future work. We will identify companies capable of large-scale synthesis of sodium tetrathionate, syringe and auto-injector manufacturers, and fill-and-finish contract organizations. To that end, we will conduct FDA-required studies, including determining the pharmacokinetic and safety profile of sodium tetrathionate in two animal species?rats and dogs, and testing if tetrathionate causes genetic mutations. The proposed project is for three years, and, during the last year, we plan to have a FDA pre-IND meeting. We also propose to determine if sodium tetrathionate is effective in pregnant, neonatal, juvenile, and old animals, using mice for these studies due to the large number of animals required. We have found that sodium tetrathionate rescues rabbits, pigs, and mice from lethal cyanide poisoning, and now propose to determine the human dose in rigorous, randomized, blinded studies in rabbits and pigs because cyanide antidotes will be approved by the FDA via the ?Animal Rule Pathway,? human doses of antidote are established in animal studies. Although tetrathionate is unstable in aqueous solutions, we devised a method to stabilize tetrathionate solutions by adding low concentrations of dimethyl sulfoxide this would allow sodium tetrathionate to be pre-loaded into syringes at the time of manufacturing. It can neutralize two cyanide molecules by a direct reaction with cyanide generating thiocyanate and thiosulfate, and then by a rhodanese- dependent reaction of thiosulfate with cyanide, also generating thiocyanate. Sodium tetrathionate (Na2S4O6) has been known for some time to be an effective cyanide antidote. For treating mass casualties in the field?as could occur after a major industrial accident or a terrorist attack?probably the best mode of treatment is intramuscular injection using a pre-filled syringe or autoinjector. Cyanide is a rapidly acting poison, and, thus, antidotes must be administered quickly.
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