Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Methodol. Jun 26, 2015; 5(2): 88-100
Published online Jun 26, 2015. doi: 10.5662/wjm.v5.i2.88
Past, present and future of cyanide antagonism research: From the early remedies to the current therapies
Ilona Petrikovics, Marianna Budai, Kristof Kovacs, David E Thompson
Ilona Petrikovics, Kristof Kovacs, David E Thompson, Department of Chemistry, Sam Houston State University, Huntsville, TX 77341, United States
Marianna Budai, Department of Pharmaceutics, Semmelweis University, H-1092 Budapest, Hungary
Author contributions: Petrikovics I set up the format and the frame of the review article, and wrote up the “Introduction”, “From Research to Therapy”, and “Conclusion” sections; Budai M prepared the “Cobinamide” and “Sulfanegen” sections and edited the references and the format; Kovacs K prepared the “Hydroxocobalamin” section; Thompson DE wrote up the “Abstract”, “Core tip”, “Table 2”, and edited the entire article including language adjustments.
Supported by Robert A. Welch Foundation (x-0011) at Sam Houston State University.
Conflict-of-interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ilona Petrikovics, PhD, Department of Chemistry, Sam Houston State University, 1806 Avenue J, Huntsville, TX 77341, United States. ixp004@shsu.edu
Telephone: +1-936-2944389 Fax: +1-936-2944996
Received: August 26, 2014
Peer-review started: August 27, 2014
First decision: November 27, 2014
Revised: January 9, 2015
Accepted: April 16, 2015
Article in press: April 20, 2015
Published online: June 26, 2015
Processing time: 315 Days and 0.5 Hours
Abstract

This paper reviews milestones in antidotal therapies for cyanide (CN) spanning early remedies, current antidotal systems and research towards next generation therapies. CN has been a part of plant defense mechanisms for millions of years. It became industrially important in the nineteenth century with the advent of CN assisted gold mining and the use of CN as a pest control agent. The biochemical basis of CN poisoning was actively studied and key mechanisms were understood as early as 1929. These fundamental studies led to a variety of antidotes, including indirect CN binders that generate methemoglobin, direct CN binders such as hydroxocobalamin, and sulfur donors that convert CN to the less toxic thiocyanate. Research on blood gases at the end of the twentieth century shed new light on the role of nitric oxide (NO) in the body. The discovery of NO’s ability to compete with CN for enzymatic binding sites provided a previously missed explanation for the rapid efficacy of NO generating antidotes such as the nitrites. Presently used CN therapies include: methemoglobin/NO generators (e.g., sodium nitrite, amyl nitrite, and dimethyl aminophenol), sulfur donors (e.g., sodium thiosulfate and glutathione), and direct binding agents [(e.g., hydroxocobalamin and dicobalt salt of ethylenediaminetetraacetic acid (dicobalt edetate)]. A strong effort is being made to explore novel antidotal systems and to formulate them for rapid administration at the point of intoxication in mass casualty scenarios. New antidotes, formulations, and delivery systems are enhancing bioavailability and efficacy and hold promise for a new generation of improved CN countermeasures.

Keywords: Cyanide; Hydrocyanic acid; Antagonist; Antidote; Cobinamide; Sulfanegen; Sulfane sulfur donor

Core tip: This paper reviews milestones in antidotal therapies for cyanide (CN) spanning early history, current antidotal systems, and research towards next generation therapies. Presently used CN therapies include: methemoglobin/nitric oxide generators (e.g., sodium nitrite, amyl nitrite, and dimethyl aminophenol), sulfur donors (e.g., sodium thiosulfate and glutathione), and direct binding agents (e.g., hydroxocobalamin and dicobalt edetate). New antidotes, formulations, and delivery systems are presently being developed for rapid administration at the point of intoxication in mass casualty scenarios. These hold promise for a new generation of improved CN countermeasures.