This R21 application outlines an approach to catalytically and rapidly remove cyanide from the body by metabolizing the cyanide in the bloodstream rather than using the rhodanese enzyme in the liver. The accelerated bioelimination of cyanide is accomplished by administration of a catalyst with a polymer-bound cysteine that rapidly reacts with cyanide to produce inert thiocyanate, thereby antagonizing cyanide toxicity. Preliminary results using a prototype compound demonstrate conversion of cyanide into the inert product, thiocyanate, in a screening reaction at physiological pH. Cyanide poisoning is rapid and treatment options are limited. Cyanide is increasingly recognized as a toxin in building fires and is easily accessible for use in suicides, homicides, and warfare. It is used industrially in tasks such as fumigation, electroplating, and mining, and accidental exposure can be life-threatening. An efficient mass treatment for cyanide poisoning is essential for public health, counter-defense, and improving recovery for inhalation injuries. Several international organizations have designated cyanide a priority chemical in terms of its potential impact on human health and the environment. The natural substrates for cyanide metabolism in the liver become depleted rapidly with excessive absorption of cyanide into the body. Thiosulfate's limited solubility in the liver leads to a slow reaction while facilitating sulfane sulfur transfer to rhodanese. Proposed here is catalytic sulfur transfer by a catalyst to a polymer-bound cysteine in the bloodstream, which will form an activated cysteine that reacts rapidly with cyanide. Key compounds will be screened for toxicity and efficacy in vitro and in vivo. The long-term goal of this work is to develop a catalytic detoxification treatment suitable for intramuscular (IM) administration. A small dose is key to the success of an IM development effort, and catalytic detoxification is key to a small dose. IM is easier to perform than intravenous (IV) injection and therefore suitable for rapid treatment of large numbers of casualties or for self-administration. The advantages of the proposed mechanism are: (1) small dose;lower risk of toxicity;(2) plasma solubility, (3) high bioavailability, and (4) IM administration.
The specific aims for this work are to (1) develop molybdenum-sulfur compounds to catalytically serve as sulfane sulfur transfer agents;(2) develop a non-toxic cysteine-bearing polymer that has a balance of lipid and plasma solubility and high cysteine loading;(3) conduct reactivity studies to identify a novel sulfur donor able to convert 90%+ of the cyanide to thiocyanate in 20 min or less;(4) conduct in vitro efficacy studies of a catalytic system, and (5) perform in vivo efficacy studies in an animal model to demonstrate equal or better efficacy compared to Hydroxocobalamin (Cyanokit(tm)), which is 5 to 20 g per patient per treatment.
This study proposes to develop a catalytic detoxification treatment to rapidly remove cyanide from the bloodstream rather than by way of the liver. The survival rate from cyanide poisoning is low because the poison is fast-acting and treatment options are limited. Cyanide is a serious health hazard in building fires and as an industrial hazard, and an efficient mass treatment for cyanide poisoning is lacking.
