Cyanide is a potent metabolic poison which binds to and inhibits cytochrome c oxidase (cytochrome a3), resulting in the rapid inhibition of oxidative phosphorylation (Hall & Rumack 1986). As a result, cells can't utilise oxygen, giving rise to central nervous system, cardiovascular and respiratory dysfunction that can result in permanent neurological defects and, in severe cases, death. At body's pH, cyanide exists mainly in the undissociated form hydrogen cyanide (HCN) which can cross cellular and subcellular membranes such as the blood brain barrier and mitochondrial membranes. Although humans are not typically exposed to cyanide,
cyanide intoxication can occur after smoke inhalation, industrial exposure, ingestion of cyanogenic substances and cyanogenic food sources such as cassava. Antidotes for HCN poisoning cases include HCN binders, sulfur donors that convert HCN to the less toxic thiosulfate and competitors for HCN enzymatic binding sites such as NO (Petrikovics et al. 2015).
Two pathways in mammals are able to detoxify cyanide as thiocyanate via transfer of a sulfur atom: thiosulfate sulfurtransferase (TST aka rhodanese) in mitochondria and 3-mercaptopyruvate sulfurtransferase (MPST aka 3MST) in cytosol and mitochondria. 3MPYR has been investigated for the potential treatment of HCN poisoning but its half life is very short, being rapidly metabolised when given intravenously (Nagahara & Sawada 2003). Also, it is a metabolite of cysteine metabolism but cysteine is present in low amounts in the brain and heart, limiting the ability of MPST to be effective in acute HCN poisoning. The pro-drug sulfanegen is the hemithioacetal cyclic dimer of 3MPYR and has been demonstrated to be effective against HCN poisoning in animal studies (Brenner et al. 2010, Belani et al. 2012). Sulfanegen provides the sulfur atom for the transsulfuration of HCN by MPST (Belani et al. 2012). HSCN can be excreted in urine via the kidneys (Hamel 2011). In a mass exposure scenario (such as terrorism or industrial accident), a rapidly-acting antidote that can be administered quickly to a large number of people is essential; sulfanegen can be rapidly administered by intramuscular injection (Patterson et al. 2016).