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Cyanides: Toxicology, Clinical Presentation, and Medical Management
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Gary A. Rockwood, Gennady E. Platoff Jr., Harry Salem
Sulfur Donors. These enhance the endogenous sulfurtransferase mechanisms for the detoxification of CN to SCN. Sodium thiosulfate is often used in combination with other antidotes having different modes of antidotal action; for example, with sodium nitrite or 4-dimethylaminophenol (4-DMAP). As a generalization, sodium thiosulfate is used as a supplementary treatment on the basis that it is slow acting, possibly due to limited penetration into mitochondria. Recent reports have demonstrated that the sulfur donor dimethyl trisulfide (DMTS) shows promise of being more efficient than sodium thiosulfate in countering CN toxicity (Rockwood et al., 2016) using both KCN injection and HCN inhalation models of CN poisoning in mice (DeLeon et al., 2018). Importantly, DMTS does not require intravenous administration and is efficacious when administered intramuscularly. Sulfanegen, another sulfur donor, has also shown promise as a CN countermeasure (Patterson et al., 2016).
Cyanogenic Glycosides
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Sulfanegen (as the sodium or triethanolamine salt) generates 3-mercaptopyruvic acid (3-MP), an intermediate in cysteine metabolism, and acts as a decoy receptor for cyanide. As sulfanegen is water soluble, it can be administered intramuscularly (IM).
Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning
Published in Clinical Toxicology, 2020
Adrian Thompson, Michael Dunn, Robert D Jefferson, Kosala Dissanayake, Frances Reed, Rachael Gregson, Stephen Greenhalgh, R Eddie Clutton, Peter G Blain, Simon HL Thomas, Michael Eddleston
In these porcine studies, we found modest beneficial effects from double doses of hydroxocobalamin or dicobalt edetate given immediately before a just lethal exposure to cyanide. Increased doses may improve effectiveness but have not been tested either pre-clinically or clinically. More effective antidotes are urgently required. Candidates include cobinamide, an analogue of hydroxocobalamin with twice the molar cyanide binding capacity [15,22], and sulfanegen, a dimeric prodrug of 3-mercaptopyruvate that is a substrate for the cyanide-detoxifying enzyme 3-mercaptopyruvate sulfurtransferase [15,24]. Recently, a liposomal construct containing rhodanase and a novel sulphur donor has been reported to increase the LD50 of KCN 15-fold when given prophylactically to mice [44], a far higher level of protection than given by the antidotes discussed here.
Revisiting the physiological effects of methylene blue as a treatment of cyanide intoxication
Published in Clinical Toxicology, 2018
Philippe Haouzi, Maxime Gueguinou, Takashi Sonobe, Annick Judenherc-Haouzi, Nicole Tubbs, Mohamed Trebak, Joseph Cheung, Frederic Bouillaud
Cyanide (CN), one of the most feared mitochondrial poisons, remains a significant source of intoxication in victims of smoke inhalation [1]. High intake of CN from the plant cassava is also linked to dreadful outbreaks of spastic paralysis with myoclonus in tropical regions of Africa [2]. The optimal strategy of treatment of CN intoxication is still debated, relying on symptomatic measures and antidotes [3–5]. These antidotes are aimed at (1) scavenging “free” CN, using cobalt containing molecules [6–8] and nitrite compounds [9–12] and/or (2) increasing CN elimination as thiocyanate, using sodium thiosulfate [10,13–15] or other sulfur donors, such as sulfanegen [16,17]. The present paper is revisiting the potential interest of a different therapeutic approach based on the redox cycle dye methylene blue (MB).
A bona fide need for a non-intravenous cyanide medical countermeasure
Published in Clinical Toxicology, 2019
Human exposure to cyanide can result in rapid morbidity or lethality and most commonly occurs through inhalation of combustion smoke [1]. Cyanide exposure can also occur through ingestion, dermal contact and/or gaseous fume inhalation—which may occur through intentional or accidental means. Infamous documented uses of cyanide show an intent to inflict or threaten mass casualties, as do more recent insidious attempts and threats to utilize cyanide as a weapon of terror. In this context, while the current FDA-approved cyanide countermeasures Cyanokit® (hydroxocobalamin) and Nithiodote® (sodium nitrite and sodium thiosulfate) are demonstrably efficacious against cyanide poisoning [2,3], both require intravenous (IV) administration and are consequently unsuitable for use in treating multiple cyanide victims, particularly at or near exposure sites which are a distance away from a hospital. Preparing and placing IV lines require trained personnel and adequate time, both of which would be improbable in a (frantic) mass cyanide poisoning scenario. There is a clear, bona fide international need for a non-IV cyanide medical countermeasure—at a minimum, to care for multiple cyanide victims in remote (i.e., non-hospital) locations. It is, therefore, encouraging that several cyanide medical countermeasure candidates (e.g., dimethyl trisulfide, cobinamide, sulfanegen, and intramuscularly [IM] administered sodium thiosulfate and IM administered sodium nitrite) have been described in recent years which use the IM, intranasal and/or oral route of delivery [4–8]. Relatedly, intraosseous (IO) administration has also been recommended for mass exposures as an emergency administration technique more rapid than IV [9], and successful IO administration of hydroxocobalamin has been reported in cyanide-poisoned swine [10]. Ultimately, clinical safety trials will help advance the most promising non-IV cyanide candidate countermeasure(s). Limitations of otherwise effective hospital-setting treatments may severely hamper or fully preclude the use of these treatments in non-hospital environments or in the case of an atypical or catastrophic exposure event.