Cyanide Toxicity in Juvenile Pigs and Its Reversal by a New Prodrug, Sulfanegen Sodium

Abstract

Background Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP), accidental smoke inhalation, industrial mishaps and bio-terrorism. In this study we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate. Methods SNP study: A pilot study in eleven anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, eight anesthetized pigs received a high-dose IV infusion of SNP (100mg/hr) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5g IV) every hour after induction of severe CN toxicity, while 4 pigs received placebo. NaCN study A pilot study was conducted in four spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of six pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g IV) followed by a repeat dose 60 minutes later in surviving animals. Results SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (p<0.05) accompanied by severe lactic acidemia (p<0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (p<0.05), whereas the placebo-treated pigs deteriorated and did not survive (p<0.05). NaCN study NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote. Conclusions CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.

Determination of 3-mercaptopyruvate in rabbit plasma by high performance liquid chromatography tandem mass spectrometry

“…2 shows representative chromatograms of spiked and nonspiked 3-MPB in plasma, with 3-MPB eluting at approximately 2.75 min. The method shows good selectivity for 3-MPB with no co-eluting peaks ( R s = 3.07 from the nearest peak at 3.3 min), although the nonspiked rabbit sample shows a small endogenous 3-MP concentration [19,21,22,24]. Considering the rabbit plasma analyzed for this study in aggregate, it is estimated that the endogenous concentration of 3-MP in rabbits is between 0.05 and 0.1 µM.…”

“…The validated HPLC-MS-MS method was applied to the analysis of plasma from rabbits exposed to cyanide and subsequently treated with sulfanegen [14,20,21,24]. The HPLC-MS-MS analysis of the plasma of sulfanegen treated and untreated rabbits is shown in Fig.…”

“…Similar to sodium thiosulfate, 3-MP acts as a sulfur donor to produce thiocyanate but is instead catalyzed by 3-mercaptopyruvate sulfurtransferase (3-MST) [19,21,22]. Sulfanegen, a prodrug of 3-MP (i.e., sulfanegen converts to 3-MP upon administration), has been found to be highly effective in reversing cyanide toxicity [14,20,21,23,24]. Although a method for the detection of 3-MP by HPLC from mouse tissue has been proposed [25], a multistep, lengthy (>60 min), and high temperature (95 ° C) modification of 3-MP is necessary.…”

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

“…Sulfanegen sodium is a prodrug of 3-mercaptopyruvate that converts cyanide to thiocyanate (164,168). It was shown to be effective in reversing cyanide toxicity in a juvenile pig model, but work is ongoing to develop it into a antidote that is safe for use in humans (169). …”

Cyanide Antidotes for Mass Casualties: Water-Soluble Salts of the Dithiane (Sulfanegen) from 3-Mercaptopyruvate for Intramuscular Administration

“…7, 8 However, it became clear that this salt could not fulfill the above role, since its aqueous solubility was not greater than 128 mg/mL (0.35 M), and dose calculations suggested that a minimum water solubility of 1.05 M was required for antidotal efficacy by the IM route for humans, based on a 60 kg human with a maximum injectable volume of 5 mL. 9 …”