Although different nations have variable preferences for specific antidotes against cyanide poisoning, the antidotes of choice in the U.S. for over 30 years have been the combination of sodium nitrite and sodium thiosulfate, both administered intravenously in timely sequence. In recent years, this has been supplemented with the volatile amyl nitrite given nasally for its vasodilatory effect. However, these agents are generally not only slow acting, but have potential for toxicity and serious complications if not used properly. A recent perspective article on cyanide, authored by experts at the USAMRICD, pointed out that in severe cyanide poisonings, rapid intervention is the key, and treatments require a three minute solution, akin to the nerve agent antidote kit (Baskin et al. 2004). The availability of non-toxic agents that could be taken prophylactically by military personnel on threatened exposure or by first responders to a cyanide emergency, also represents an ideal requirement. These goals have not yet been achieved to date, and the present treatment modalities are unsuitable in a military setting, or in the event of actual use of cyanide as a threat agent on a large scale against the civilian population. We have recently developed (unpublished) a series of prototype cyanide antidotes that release the substrate for the enzyme, 3-mercaptopyruvate sulfur-transferase (3-MPST) in vivo, thereby providing a viable alternative method for detoxifying cyanide by utilizing this ubiquitous cellular enzyme to convert cyanide to the non-toxic thiocyanate. The rationale here is to provide this enzyme with its natural substrate directly, thereby by-passing the necessity for generating it endogenously from the transamination of L-cysteine, a sulfhydryl amino acid known to be less abundant in tissues. We have also developed a unique mouse model-that minimizes the use of large numbers of animals-for assessing the toxicity of sub-lethal doses of cyanide, which is highly amenable for evaluating the antidotal efficacy of our compounds. Having already established proof of concept that our prototype compounds protect against cyanide toxicity in mice, we will simultaneously a) expand the prototype series, and design and synthesize analogs around these series to improve antidotal efficacy, bioavailability, and physical properties of these compounds, b) superimpose the endogenous antioxidant glutathione (as its bioavailable form; vide infra) in the above regimen to evaluate whether such antioxidant co-treatment would improve survivability and protect against the neurological deficits seen in long term survivors of acute cyanide intoxication, and c) accelerate preclinical studies (acute and long term toxicity, ADME, other animal models, etc.) for those compounds already demonstrated to be protective, with the goal of filing an IND application to the FDA well within this grant period. Although most of the compounds of our series are rapid acting, at least one prototype (perhaps more) is slower acting (by design), but fully protective when administered orally; ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS058087-02
Application #
7294943
Study Section
Special Emphasis Panel (ZNS1-SRB-R (22))
Program Officer
Jett, David A
Project Start
2006-09-30
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$671,375
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Social Sciences
Type
Schools of Public Health
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Summerhill, Eleanor M; Hoyle, Gary W; Jordt, Sven-Eric et al. (2017) An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness. Ann Am Thorac Soc 14:1060-1072
Patterson, Steven E; Moeller, Bryant; Nagasawa, Herbert T et al. (2016) Development of sulfanegen for mass cyanide casualties. Ann N Y Acad Sci 1374:202-9
Stutelberg, Michael W; Vinnakota, Chakravarthy V; Mitchell, Brendan L et al. (2014) Determination of 3-mercaptopyruvate in rabbit plasma by high performance liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 949-950:94-8
Patterson, Steven E; Monteil, Alexandre R; Cohen, Jonathan F et al. (2013) Cyanide antidotes for mass casualties: water-soluble salts of the dithiane (sulfanegen) from 3-mercaptopyruvate for intramuscular administration. J Med Chem 56:1346-9
Belani, Kumar G; Singh, Harpreet; Beebe, David S et al. (2012) Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium. Anesth Analg 114:956-61
Chan, Adriano; Crankshaw, Daune L; Monteil, Alexandre et al. (2011) The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning. Clin Toxicol (Phila) 49:366-73
Nagasawa, Herbert T; Goon, David J W; Crankshaw, Daune L et al. (2007) Novel, orally effective cyanide antidotes. J Med Chem 50:6462-4
Crankshaw, Daune L; Goon, David J W; Briggs, Jacquie E et al. (2007) A novel paradigm for assessing efficacies of potential antidotes against neurotoxins in mice. Toxicol Lett 175:111-7