Steven I. Baskin

The Antidotal Action of Sodium Nitrite and Sodium Thiosulfate Against Cyanide Poisoning

The combination of sodium thiosulfate and sodium nitrite has been used in the United States since the 1930s as the primary antidote for cyanide intoxication. Although this combination was shown to exhibit much greater efficacy than either ingredient alone, the two compounds could not be used prophylactically because each exhibits a number of side effects. This review discusses the pharmacodynamics, pharmacokinetics, and toxicology of the individual agents, and their combination.

Oxidants, antioxidants, and free radicals

Redox, radicals and antioxidants analysis of free radicals their products and antioxidants vitamin E - vitamin E and polyunsturated fats antioxidants and pro-oxidant relationship alpha-tocopheral, beta- Carotene and oxidative modification of human, low-density lipoprotein response of antioxidant system to physical and chemical stress zinc as a cardioprotective antioxidant ascorbic acid, melatonin and the adrenal gland - a commentary antioxidant properties of Glutathione and its role in tissue protection antioxidant effects of hypotaurine and taurine antioxidative activity of ergothionine and ovothiol the toxicology of antioxidants toxicity of oxygen and ozone peroxidation of lipids and liver damage role of free radicals in alcohol-induced tissue injury oxidant injury from inhaled particle matter edmagenic gases cause lung toxicity by generating reactive intermediates species RIS lipid peroxidation and antioxidant depletion induced by blast overpressure food antioxidants - their dual role in carcinogenesis anticarcinogenic effects of synthetic phenolic antioxidants.

The Analysis of Cyanide and its Breakdown Products in Biological Samples

Cyanide is a toxic chemical that may be introduced into living organisms as a result of natural processes and/or anthropogenic uses (legal or illicit). Exposure to cyanide can be verified by analysis of cyanide or one of its breakdown products from biological samples. This verification may be important for medical, law-enforcement, military, forensic, research, or veterinary purposes. This review will discuss current bioanalytical techniques used for the verification of cyanide exposure, identify common problems associated with the analysis of cyanide and its biological breakdown products, and briefly address the metabolism and toxicokinetics of cyanide and its breakdown products in biological systems.

In vitro and in vivo comparison of sulfur donors as antidotes to acute cyanide intoxication

Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur donors (SSDs), such as thiosulfate, which increase the conversion of CN to thiocyanate by the enzyme rhodanese. To develop pretreatments that might be useful against CN, SSDs with greater lipophilicity than thiosulfate were synthesized and assessed. The ability of SSDs to protect mice against 2LD50 of sodium cyanide (NaCN) administered either 15 or 60 min following administration of an SSD was assessed. To study the mechanism of action of the SSD, the candidate compounds were examined in vitro for their effect on rhodanese and 3‐mercaptopyruvate sulfurtransferase (MST) activity under increasing SSD concentrations. Tests were conducted on nine candidate SSDs: ICD1021 (3‐hydroxypyridin‐2‐yl N‐[(N‐methyl‐3‐aminopropyl)]‐2‐aminoethyl disulfide dihydrochloride), ICD1022, (3‐hydroxypyridin‐2‐yl N‐[(N‐methyl‐3‐aminopropyl)]‐2‐aminoethyl disulfide trihydrochloride), ICD1584 (diethyl tetrasulfide), ICD1585 (diallyl tetrasulfide), ICD1587 (diisopropyl tetrasulfide); ICD1738 (N‐(3‐aminopropyl)‐2‐aminoethyl 2‐oxopropyl disulfide dihydrochloride), ICD1816 (3,3′‐tetrathiobis‐N‐acctyl‐l‐alanine), ICD2214 (2‐aminoethyl 4‐methoxyphenyl disulfide hydrochloride) and ICD2467 (bis(4‐methoxyphenyl) disulfide). These tests demonstrated that altering the chemical substituent of the longer chain sulfide modified the ability of the candidate SSD to protect against CN toxicity. At least two of the SSDs at selected doses provided 100% protection against 2LD50 of NaCN, normally an LD99. All compounds were evaluated using locomotor activity as a measure of potential adverse behavioral effects. Positive hypoactivity relationships were found with several disulfides but none was found with ICD1584, a tetrasulfide. Separate studies suggest that the chemical reaction of potassium cyanide (KCN) and cystine forms the toxic metabolite 2‐iminothiazolidine‐4‐carboxylic acid. An alternative detoxification pathway, one not primarily involving the sulfur transferases. may be important in pretreatment for CN intoxication. Although studies to elucidate the precise mechanisms are needed. it is clear that these newly synthesized compounds provide a new rationale for anti‐CN drugs, with fewer side‐effects than the methemoglobin formers. Copyright

In vivo detoxification of cyanide by cystathionase γ-lyase

Abstract The results of several in vitro studies have suggested that the enzyme cystathionase γ-lyase (EC 4.4.1.1) may function in the endogenous detoxification of cyanide; however, this possibility has not been investigated in vivo . If cystathionase γ-lyase is involved in the endogenous detoxification of cyanide, it logically follows that inhibiting cystathionase γ-lyase should increase the toxicity of cyanide. To test this hypothesis, the activity of cystathionase γ-lyase was inhibited with a suicide inhibitor, 2-amino-4-pentynoic acid (propargylglycine). The activity of liver cystathionase γ-lyase activity was decreased 96.8% by administration of propargylglycine, indicating that the propargylglycine treatment was effective. The propargylglycine treatment did not alter the activity of thiosulfate:cyanide sulfurtransferase (EC 2.8.1.1) or 3-mercaptopyruvate:cyanide sulfurtransferase (EC 2.8.1.2), two other enzymes that have been proposed to be involved in the detoxification of cyanide. The ld 50 of cyanide in rats treated with propargylglycine was 5.14 ± 0.029 mg NaCN/kg, which was significantly ( P ld 50 of cyanide determined in control rats. The results of these studies suggest that cystathionase γ-lyase may participate in the detoxification of cyanide in vivo .

Neurotoxicological and Behavioral Effects of Cyanide and Its Potential Therapies

The use of the blood agent cyanide (CN) as a military threat agent has been recognized not only historically (Nero and Napoleon III) but also more currently in World War I, World War II, in the Iran–Iraq War in the 1980s, and elsewhere where terrorist activities have occurred. CN is easy and inexpensive to produce and can be obtained from normal commercial trade. CN can act very rapidly (within seconds) to prevent the normal utilization of oxygen by tissues. Excitable tissues, for example, heart and brain, are particularly affected. Hypoxia, convulsions, heart arrhythmias, and death can follow. If exposed, it is best to leave the affected area rapidly. Treatments such as nitrite, which forms methemoglobin that binds CN, and thiosulfate, which converts CN to thiocyanate, act within an appropriate time but produce central nervous system side effects. This article examines the literature on the neurotoxicological and behavioral effects of CN and its treatments. Sites and mechanisms of actions involved in these effects are evaluated. Factors that significantly alter the action of CN and may influence morbidity and mortality are discussed.

Enzyme-based intravascular defense against organophosphorus neurotoxins: Synergism of dendritic-enzyme complexes with 2-PAM and atropine

Novel, enzyme-complexed, nano-delivery systems have been developed to antagonize the lethal effects of organophosphorus (OP) molecules such as diisopropylfluorophosphate and paraoxon. Polymeric nanocapsules can be used to deliver metabolizing enzymes to the circulation, often increasing the enzymes efficacy by extending their circulatory life and, in some cases, enhancing their specific activity. The bacterial enzymes organophosphorus hydrolase (OPH) and organophosphorus anhydrolase (OPAA) were encapsulated within a nanocapsule, polyoxazoline-based dendritic polymer carrier and employed in combination with the OP antagonists pralidoxime (2-PAM) and atropine. The effective doses for OPH and OPAA, respectively, were 500–550 and 1500–1650 units/kg mice; the size of the entire complex is approximately 200 nm in diameter. These studies compare the efficacy of the two enzymes as prophylactic systems encapsulated within the dendritic polymer. When used in combination with 2-PAM and atropine, the dendritic encapsuled OPAA provided a 25×LD50 protection against DFP intoxication, while the similarly constructed OPH complex showed a more dramatic protection (780×LD50) against paraoxon intoxication in Balb/c mice. The studies demonstrate a synergistic enhancement of the antagonist, since the antidotal protection of 2-PAM+atropine against DFP and paraoxon is approximately 8 and 60×LD50, respectively.

The effect of three α-keto acids on 3-mercaptopyruvate sulfurtransferase activity†

: 3-Mercaptopyruvate sulfurtransferase catalyzes the transfer of sulfur from 3-mercaptopyruvate to several possible acceptor molecules, one of which is cyanide. Because the transsulfuration of cyanide is the primary in vivo mechanism of detoxification, 3-mercaptopyruvate sulfurtransferase may function in the enzymatic detoxification of cyanide in vivo. Three alpha-keto acids (alpha-ketobutyrate, alpha-ketoglutarate, and pyruvate) have previously been demonstrated to be cyanide antidotes in vivo, and it has been suggested that this is due to the nonenzymatic binding of cyanide by the alpha-keto acid. However, it has also been proposed that alpha-keto acids may increase the activity of enzymes involved in the transsulfuration of cyanide. Thus, the effect of these three alpha-keto acids on the enzyme 3-mercaptopyruvate sulfurtransferase was examined. All three alpha-keto acids inhibited 3-mercaptopyruvate sulfurtransferase in a concentration-dependent manner and were determined to be uncompetitive inhibitors of MST with respect to 3-mercaptopyruvate. The inhibitor constant Ki was estimated by two methods for each inhibitor and ranged from 4.3 to 6.3 mM. The I50, which is the inhibitor concentration that produces 50% inhibition, was calculated for all three alpha-keto acids and ranged between 9.5 and 13.7 mM. These observations add further support to the hypothesis that the mechanism of the alpha-keto acid antidotes is the nonenzymatic binding of cyanide, not stimulation of enzymes involved in the transsulfuration of cyanide to thiocyanate.

Spectrophotometric Analysis of the Cyanide Metabolite 2-Aminothiazoline-4-Carboxylic Acid (ATCA).

Methods of directly evaluating cyanide levels are limited by the volatility of cyanide and by the difficulty of establishing steady-state cyanide levels with time. We investigated the measurement of a stable, toxic metabolite, 2-aminothiazoline-4-carboxylic acid (ATCA), in an attempt to circumvent the challenge of directly determining cyanide concentrations in aqueous media. This study was focused on the spectrophotometric ATCA determination in the presence of cyanide, thiocyanate (SCN−), cysteine, rhodanese, thiosulfate, and other sulfur donors. The method involves a thiazolidine ring opening in the presence of p-(hydroxy-mercuri)-benzoate, followed by the reaction with diphenylthiocarbazone (dithizone). The product is spectrophotometrically analyzed at 625 nm in carbon tetrachloride. The calibration curve was linear with a regression line of Y = 0.0022x (R2 = 0.9971). Interference of cyanide antidotes with the method was determined. Cyanide, thiosulfate, butanethiosulfonate (BTS), and rhodanese did not appreciably interfere with the analysis, but SCN− and cysteine significantly shifted the standard curve. This sensitive spectrophotometric method has shown promise as a substitute for the measurement of the less stable cyanide.

The effects of cyanide and its interactions with norepinephrine on isolated aorta strips from the rabbit, dog, and ferret

Effects of sodium cyanide on isolated strips of rabbit, dog, and ferret aorta were determined. In the rabbit aorta strip, cumulatively added cyanide caused small contractions beginning at approximately 10(-11) M cyanide and reaching a maximum response at 10(-5) M. A concentration of cyanide between 10(-5) M and 10(-3) M produced relaxation. When cyanide was cumulatively added to norepinephrine (NE)-contracted rabbit aorta strips, no contractions were observed. Cyanide concentrations above 10(-5) M produced relaxation in the NE-contracted vessels. Sensitivity of the aorta strips to NE differed among the species examined. The ED50 for contractions in the dog and ferret aorta was 4 X 10(-4) M and in the rabbit was 5 X 10(-6) M. Pretreatment with cyanide in concentrations up to 10(-2) M did not reduce contractions of dog aorta to NE, although 10(-2) M cyanide abolished contractions of rabbit aorta to NE and reversed NE-contractions of ferret aorta to relaxation. The antagonism of cyanide for NE-induced contractions was completely reversible with cyanide concentrations up to 10(-3) M. Cyanide pretreatment of strips of aorta increased the rate of contraction to NE. A concentration of 10(-2) M cyanide caused small contractions of aorta strips from each species. Thus, cyanide exerts dose and species dependent responses on vascular smooth muscle.