Past,present and future of cyanide antagonism research:From the early remedies to the current therapies

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.

LC-MS/MS analysis of 2-aminothiazoline-4-carboxylic acid as a forensic biomarker for cyanide poisoning

AIM: To demonstrate the potential of using 2-aminothiazoline-4-carboxylic acid(ATCA) as a novel biomarker/forensic biomarker for cyanide poisoning. METHODS: A sensitive method was developed and employed for the identification and quantification of ATCA in biological samples, where the sample extraction and clean up were achieved by solid phase extraction(SPE). After optimization of SPE procedures, ATCA was analyzed by high performance liquid chromatographytandem mass spectrometry. ATCA levels following the administration of different doses of potassium cyanide(KCN) to mice were measured and compared to endogenous ATCA levels in order to study the significance of using ATCA as a biomarker for cyanide poisoning.RESULTS: A custom made analytical method was established for a new(mice) model when animals were exposed to increasing KCN doses. The application of this method provided important new information on ATCA as a potential cyanide biomarker. ATCA concentration in mice plasma samples were increased from 189 ± 28 ng/mL(n = 3) to 413 ± 66 ng/mL(n = 3) following a 10 mg/kg body weight dose of KCN introduced subcutaneously. The sensitivity of this analytical method proved to be a tool for measuring endogenous level of ATCA in mice organs as follows: 1.2 ± 0.1 μg/g for kidney samples, 1.6 ± 0.1 μg/g for brain samples, 1.8 ± 0.2 μg/g for lung samples, 2.9 ± 0.1 μg/g for heart samples, and 3.6 ± 0.9 μg/g for liver samples. CONCLUSION: This finding suggests that ATCA has the potential to serve as a plasma biomarker / forensic biomarker for cyanide poisoning.

Confidence limit calculation for antidotal potency ratio derived from lethal dose 50

AIM:To describe confidence interval calculation for antidotal potency ratios using bootstrap method.METHODS:We can easily adapt the nonparametric bootstrap method which was invented by Efron to construct confidence intervals in such situations like this.The bootstrap method is a resampling method in which the bootstrap samples are obtained by resampling from the original sample.RESULTS:The described confidence interval calculation using bootstrap method does not require the sampling distribution antidotal potency ratio.This can serve as a substantial help for toxicologists,who are directed to employ the Dixon up-and-down method with the application of lower number of animals to determine lethal dose 50 values for characterizing the investigated toxic molecules and eventually for characterizing the antidotal protections by the test antidotal systems.CONCLUSION:The described method can serve as a useful tool in various other applications.Simplicity ofthe method makes it easier to do the calculation using most of the programming software packages.