HYMR1

Thursday, January 3, 2013

Out With the Old, In With the New: Sulfanegen for Cyanide Toxicity

Look out, Tox/EM/Pharm World: there is a new antidote for cyanide toxicity coming soon to an ED near you.

It goes by the name of sulfanegen.

The compound is being developed as a joint collaborative effort between the University of Minnesota and a startup pharmaceutical company called Vytacera Pharma, Inc.

In terms of how sulfanegen exerts its antidotal effects in the setting of cyanide toxicity, it is actually a water-soluble prodrug of 3-mercaptopyruvate (3-MPV). The endogenous enzyme 3-mercaptopyruvate sulfur transferase (3-MPST) catalyzes the transfer of sulfur from 3-MPV to cyanide to result in the formation of thiocyanate and pyruvate. 3-MPV is relatively unstable when administered intravenously due to the fact that it is rapidly inactivated in the bloodstream, so sulfanegen was developed to overcome this effect.

So why the need? Compared to rhodanese, the enzyme that we get the most bang for our buck for through the administration of our trusty three-agent Cyanide Antidote Kit, a significantly greater amount of 3-MPST exists in the tissue of the brain, specifically in the cerebellum. In addition, the advantage of making use of 3-MPST as an alternative pathway for the detoxification of cyanide is the fact that 3-MPST is available in both the mitochondria and cytoplasm, whereas rhodanese is present only in the mitochondria of hepatic and renal tissues. This is somewhat concerning in the setting of cyanide toxicity, as the organs where much of the damage occurs are the heart and brain.

So you may be thinking...why not just use hydroxocobalamin, then? The other potential advantage with sulfanegen is the fact that it can be administered very rapidly...in fact, it begins to exert its effects in under three minutes. With hydroxocobalamin, a 15-minute IV infusion is necessary before any effect can be demonstrated. Another benefit of sulfanegen: it can be administered as both an IM and IV injection, which is certainly not the case with hydroxocobalamin, where the IM route was attempted in a previous study, due to the large volume required for administration.

Interestingly enough, sulfanegen has been in development since the early 1990s and is in the final stages of development and testing for efficacy and safety. The hope is that the compound will receive approval by the FDA under the Animal Rule, where only animal studies proving efficacy and Phase I studies conducted in humans proving safety are necessary.

It will be interesting to see the results of the safety studies conducted in humans and how the FDA approval process overall will unfold. Some food for thought regarding this new antidote:
  • What will its place in therapy be for cyanide toxicity? Prophylactic? First-line? Salvage therapy? 
  • What will be the optimal route of administration (IM or IV)?
  • Is there a potential for re-dosing of sulfanegen if the first dose is not effective?
  • What potential adverse events are to be experienced with treatment?
  • Will dual therapy with three-agent antidotal therapy (amyl nitrite, sodium nitrite, sodium thiosulfate) or hydroxocobalamin be indicated in severe cases of cyanide toxicity such as mass casualty events?
  • How much will sulfanegen cost? Will the benefits of treatment offset the costs associated with therapy?
Only time will tell us the answers to these and other questions regarding the utility of sulfanegen for the treatment of cyanide toxicity.

References:
Belani KG, Singh H, Beebe DS, et al. Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium. Anesth Analg 2012; 114:956-961. [PMID: 22392971]
Brenner M, Kim JG, Lee J, et al. Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity. Toxicol Appl Pharmacol 2010; 248:269-276. [PMID: 20705081]
Chan A, Cranshaw DL, Monteil A, et al. The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning. Clin Toxicol 2011; 49:366-373. [PMID: 21740135
Kim JG, Lee J, Mahon SB, et al. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism. J Biomed Opt 2012; 17:105005. [PMID: 23223999]

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