Over two billion pounds of cyanide are produced annually in the United States for use in a variety of industries, and thus accidental or intentional exposure of civilians to cyanide is a real concern. Current treatments of cyanide poisoning must be given intravenously, limiting their use in a setting of mass casualties. Under support of the CounterACT Program, we have been developing the vitamin B12 analog cobinamide as a cyanide antidote, and have found it to be an extremely potent cyanide countermeasure in several animal species. Because of its high potency, and, additionally, high degree of water solubility, sufficient amounts can be given by intramuscular injection to rescue animals from two times the LD100 of cyanide. Cobinamide is stable in solution, and we are in serious negotiations with a company to package cobinamide in an autoinjector. We expect to have all preclinical chemical and animal studies completed by December, 2011, and be ready to embark on Phase I Clinical Trials in January, 2012. We will have sufficient funds to complete the preclinical studies through a no-cost extension of the current CounterACT grant. As a cyanide antidote, cobinamide will need to be approved by the Food and Drug Administration (FDA) through the "Animal Rule Pathway," which is used when efficacy studies cannot ethically be performed in humans. Rigorous animal studies conducted under Good Laboratory Practice (GLP) conditions substitute for Phase II and III clinical trials. Phase I studies must, therefore, be correspondingly larger, and include la dose escalation and Ib extended safety studies. We now propose to conduct Phase la and Ib studies of cobinamide, first in healthy adults, and then in three special populations that would likely be exposed to cyanide in a civilian disaster: children, the aged, and renal-impaired subjects. The latter subjects are included, because cobinamide is excreted by the kidneys. Prior to the studies in children, toxicology and pharmacokinetic studies in juvenile animals will be performed at SRI International, Menlo Park, CA. As part of the proposed work, we plan to conduct GLP efficacy studies in one animal species at Battelle Memorial Institute, Cincinnati, OH, and to submit a New Drug Application (NDA) to the FDA. To document cobinamide's efficacy and determine its relative potency in humans, we plan to study cobinamide's effects on blood cyanide and thiocyanate concentrations in cigarette smokers. At the completion of the proposed work, cobinamide would be available to treat a large number of civilians exposed to cyanide. Public Health Relevance: Cyanide is a rapidly acting poison that requires immediate treatment. Current cyanide therapies do not lend themselves well to treating a large number of poisoned persons. We propose to conduct Phase I clinical trials of a new cyanide antidote that could be given rapidly by intramuscular injection to many cyanide-exposed victims.

Public Health Relevance

Cyanide is a rapidly acting poison that requires immediate treatment. Current cyanide therapies do not lend themselves well to treating a large number of poisoned persons. We propose to conduct Phase I clinical trials of a new cyanide antidote that could be given rapidly by intramuscular injection to many cyanide-exposed victims.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS058030-08
Application #
8520401
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (50))
Program Officer
Jett, David A
Project Start
2006-09-27
Project End
2016-02-29
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$482,259
Indirect Cost
$150,455
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Bebarta, Vikhyat S; Tanen, David A; Boudreau, Susan et al. (2014) Intravenous cobinamide versus hydroxocobalamin for acute treatment of severe cyanide poisoning in a swine (Sus scrofa) model. Ann Emerg Med 64:612-9
Lee, Jangwoen; Kim, Jae G; Mahon, Sari B et al. (2014) Noninvasive optical cytochrome c oxidase redox state measurements using diffuse optical spectroscopy. J Biomed Opt 19:055001
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Swezey, Robert; Shinn, Walter; Green, Carol et al. (2013) Comparison of a new cobinamide-based method to a standard laboratory method for measuring cyanide in human blood. J Anal Toxicol 37:382-5
Dereven'kov, Ilia A; Salnikov, Denis S; Makarov, Sergei V et al. (2013) Comparative study of reaction of cobalamin and cobinamide with thiocyanate. J Inorg Biochem 125:32-9
Dereven'kov, Ilia A; Salnikov, Denis S; Makarov, Sergei V et al. (2013) Kinetics and mechanism of oxidation of super-reduced cobalamin and cobinamide species by thiosulfate, sulfite and dithionite. Dalton Trans 42:15307-16
Salnikov, Denis S; Silaghi-Dumitrescu, Radu; Makarov, Sergei V et al. (2011) Cobalamin reduction by dithionite. Evidence for the formation of a six-coordinate cobalamin(II) complex. Dalton Trans 40:9831-4

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