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The Biochemical Journal 1933
PubMed: 16745233
DOI: 10.1042/bj0270983 -
Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity.Clinical Toxicology (Philadelphia, Pa.) Apr 2019Cyanide is a deadly compound used as a terrorist agent. Current FDA approved antidotes require intravenous administration, limiting their utility in a mass casualty...
BACKGROUND
Cyanide is a deadly compound used as a terrorist agent. Current FDA approved antidotes require intravenous administration, limiting their utility in a mass casualty scenario. Dimethyl trisulfide (DMTS), a sulfur-based molecule, binds cyanide converting it to the less toxic by-product thiocyanate. Studies evaluating efficacy in rodents have been performed, but a large, clinically relevant animal model has not been reported.
OBJECTIVE
This study evaluates the efficacy of intramuscular DMTS on survival and clinical outcomes in a swine model of acute, severe cyanide toxicity.
METHODS
Anesthetized swine were instrumented for continuous monitoring of hemodynamics. Prior to potassium cyanide infusion animals were acclimated and breathing spontaneously. At 5-minutes post-apnea animals were treated with DMTS or saline. Vital signs, hemodynamics, and laboratory values were evaluated at various time points.
RESULTS
Baseline values and time to apnea were similar in both groups. Survival in the DMTS treated group was 83.3% and 0% in saline controls (p = .005). The DMTS group returned to breathing at a mean time of 19.3 ± 10 min after antidote, control animals did not return to breathing (CI difference 8.8, 29.8). At the end of the experiment or time of death, mean lactate was 9.41 mmol/L vs. 4.35 mmol/L (CI difference -10.94,0.82) in the saline and DMTS groups, respectively and pH was 7.20 vs. 7.37 (CI difference -0.04, 0.38). No adverse effects were observed at the injection site.
CONCLUSION
Intramuscular administration of DMTS improves survival and clinical outcomes in our large animal swine model of acute cyanide toxicity.
Topics: Animals; Antidotes; Disease Models, Animal; Female; Injections, Intramuscular; Potassium Cyanide; Sulfides; Swine; Toxicity Tests, Acute; Treatment Outcome
PubMed: 30306816
DOI: 10.1080/15563650.2018.1511800 -
The Journal of Biological Chemistry May 1983Fibronectin purified from a plasma protein side fraction in the absence of denaturant contained 1.5 to 1.9 cryptic free sulfhydryl groups per 200- to 250-kDa subunit....
Fibronectin purified from a plasma protein side fraction in the absence of denaturant contained 1.5 to 1.9 cryptic free sulfhydryl groups per 200- to 250-kDa subunit. Exposure of sulfhydryl groups in physiologic salt solutions required at least 1 M guanidine, and 3 M guanidine was required for optimal exposure. The sulfhydryl groups were not exposed by collagen, a fibronectin-binding collagen fragment, fibrinogen, heparin, hyaluronic acid, calcium ion, EDTA, deoxycholate, or methylamine. One- and two-dimensional gel electrophoresis indicated that a molecule of 40-60 kDa was disulfide-bonded to a minor portion of the fibronectin in whole human plasma and in preparations of purified fibronectin. In addition, traces of disulfide-bonded multimers were present in preparations of purified fibronectin. The proportion of fibronectin in disulfide-bonded multimers increased in guanidine-containing solutions. Compared to dimeric fibronectin, these multimers had limited solubility in physiologic buffers, could be readily cross-linked by Factor XIIIa, and exhibited altered tryptic susceptibility. In free sulfhydryl groups were blocked by prior alkylation with N-ethylmaleimide or iodoacetamide, fibronectin did not form disulfide-bonded multimers in guanidine-containing solutions. The patterns of altered tryptic susceptibility and cyanide cleavage suggested that multimer formation is mediated by both sulfhydryls of fibronectin. The transition from dimeric to multimeric fibronectin can serve as a model for the formation of disulfide-bonded fibronectin multimers in the extracellular matrix.
Topics: Disulfides; Electrophoresis, Polyacrylamide Gel; Factor XIII; Fibronectins; Fluorescent Antibody Technique; Guanidine; Guanidines; Humans; Macromolecular Substances; Potassium Cyanide; Solubility; Sulfhydryl Compounds; Transglutaminases; Trypsin
PubMed: 6133865
DOI: No ID Found -
The Journal of Biophysical and... May 1959Nitrosophenylhydroxylamine-ammonium (cupferron), potassium cyanide, sodium azide, ethylenediaminetetraacetate (EDTA), alpha,alpha'-dipyridyl, and o-phenanthroline were...
Nitrosophenylhydroxylamine-ammonium (cupferron), potassium cyanide, sodium azide, ethylenediaminetetraacetate (EDTA), alpha,alpha'-dipyridyl, and o-phenanthroline were tested (1) for their ability to enhance the frequencies of chromosomal aberrations produced by x-rays in the root tip cells of the broad bean, Vicia faba, and (2) for their ability to inhibit oxygen consumption of excised roots of the same plant. In all cases a close correlation was found between the inhibitory effect on respiration and the enhancement of the sensitivity to x-rays at low oxygen pressures. EDTA, dipyridyl, and o-phenanthroline did not affect respiration to any greater extent, and they were without influence on the radiosensitivity. Cyanide, azide, and cupferron, which strongly inhibited respiration, also increased the frequencies of chromosome aberrations produced by x-rays at low oxygen pressures. The relation between oxygen concentration and radiosensitivity was determined both in the presence and the absence of the respiratory inhibitor cupferron. When cupferron was present, the radiosensitivity was influenced by oxygen concentrations 30 times lower than those effective in the absence of the inhibitor. In an atmosphere of pure oxygen, an increase of radiosensitivity of about 20 per cent was obtained with cupferron, EDTA, and potassium cyanide.
Topics: Chelating Agents; Chromosome Aberrations; Chromosome Disorders; Chromosomes; Fabaceae; Metabolism; Vicia; Vicia faba; X-Rays
PubMed: 13664689
DOI: 10.1083/jcb.5.3.479 -
Biological & Pharmaceutical Bulletin Mar 2007We previously demonstrated that tenuifoliside B and 3,6'-disinapoylsucrose in Polygalae Radix, the root of Polygala tenuifolia WILLDENOW, inhibited potassium cyanide...
We previously demonstrated that tenuifoliside B and 3,6'-disinapoylsucrose in Polygalae Radix, the root of Polygala tenuifolia WILLDENOW, inhibited potassium cyanide (KCN)-induced hypoxia and scopolamine-induced memory impairment in mice. Because both ingredients have a common sinapoyl moiety in their structure, we inferred that the sinapoyl moiety could inhibit hypoxia and memory impairment. In the present study to clarify the hypothesis, sinapic acid inhibited KCN-induced hypoxia and scopolamine-induced memory impairment as well as tenuifoliside B and 3,6'-disinapoylsucrose did. In addition, sinapic acid inhibited decompression- or bilateral carotid artery ligation-induced hypoxia (or mortality) and CO2-induced impairment in mice, and basal forebrain lesion-induced cerebral cholinergic dysfunction (decreases in acetylcholine concentration and choline acetyltransferase activity) in rats. These results, taken together, suggest the possibilities that sinapic acid is not only a very important moiety in the pharmacological activities of tenuifoliside B and 3,6'-disinapoylsucrose but also a candidate for a cerebral protective and cognition-improving medicine.
Topics: Acetylcholine; Amnesia; Animals; Carbon Dioxide; Cognition; Coma; Coumaric Acids; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Frontal Lobe; Hypoxia; Ibotenic Acid; Male; Medicine, Kampo; Memory Disorders; Mice; Mice, Inbred ICR; Neuroprotective Agents; Parietal Lobe; Potassium Cyanide; Rats; Rats, Wistar; Scopolamine; Survival Rate
PubMed: 17329848
DOI: 10.1248/bpb.30.514 -
Emergency Medicine Journal : EMJ Mar 2007To clarify the cardiovascular mechanisms of cyanide poisoning by evaluating oxygen transport characteristics using a canine model.
OBJECTIVE
To clarify the cardiovascular mechanisms of cyanide poisoning by evaluating oxygen transport characteristics using a canine model.
METHODS
A prospective controlled experiment was performed at a hospital-based animal laboratory. Five male beagle (17 (2) kg) dogs were anesthetised with alpha-chloralose, paralysed with pancuronium bromide and mechanically ventilated. Potassium cyanide was infused at 0.045 mg/kg/min for 110 min. Heart rate, blood pressure, cardiac output, oxygen delivery (DO2), oxygen consumption (VO2) and oxygen extraction ratio (OER) were measured every 10 min for 140 min. DO2 was measured by an indirect calorimeter.
RESULTS
Cyanide and lactate levels peaked at 1.52 (0.25) mg/l and 9.1 (1.5) mmol/l, respectively. Systolic blood pressure remained relatively constant whereas diastolic blood pressure decreased by 19%. Cardiac output, heart rate and DO2 increased to a maximum of 6%, 10% and 10%, respectively, at 40 min, after which they declined to a low of 32%, 28% and 30% below baseline, respectively. Stroke volume remained constant. Oxygen consumption initially increased by 5%, then decreased to 24% below baseline. The OER initially declined to 35% below baseline, then increased throughout the rest of the study.
CONCLUSION
Cyanide poisoning in the canine model showed two phases of injury. The first (compensated) phase had a mechanism consistent with a traditional global oxygen consumption defect. The second (decompensated) phase had a mechanism consistent with heart failure. This heart failure was due to bradycardia. These data suggest chronotropy as an avenue of further study in the temporary treatment of cyanide poisoning.
Topics: Animals; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Heart Rate; Male; Oxygen Consumption; Potassium Cyanide; Pulmonary Wedge Pressure; Respiratory Transport
PubMed: 17351216
DOI: 10.1136/emj.2006.038927 -
Applied and Environmental Microbiology Mar 2000The oxidation of either ferrous iron or sulfur by Thiobacillus ferrooxidans was selectively inhibited or controlled by various anions, inhibitors, and osmotic pressure....
The oxidation of either ferrous iron or sulfur by Thiobacillus ferrooxidans was selectively inhibited or controlled by various anions, inhibitors, and osmotic pressure. Iron oxidation was more sensitive than sulfur oxidation to inhibition by chloride, phosphate, and nitrate at low concentrations (below 0.1 M) and also to inhibition by azide and cyanide. Sulfur oxidation was more sensitive than iron oxidation to the inhibitory effect of high osmotic pressure. These differences were evident not only between iron oxidation by iron-grown cells and sulfur oxidation by sulfur-grown cells but also between the iron and sulfur oxidation activities of the same iron-grown cells. Growth experiments with ferrous iron or sulfur as an oxidizable substrate confirmed the higher sensitivity of iron oxidation to inhibition by phosphate, chloride, azide, and cyanide. Sulfur oxidation was actually stimulated by 50 mM phosphate or chloride. Leaching of Fe and Zn from pyrite (FeS(2)) and sphalerite (ZnS) by T. ferrooxidans was differentially affected by phosphate and chloride, which inhibited the solubilization of Fe without significantly affecting the solubilization of Zn.
Topics: Anions; Chlorides; Environmental Microbiology; Ferrous Compounds; Iron; Oxidation-Reduction; Phosphates; Potassium Cyanide; Sodium Azide; Sulfides; Sulfur; Thiobacillus; Zinc; Zinc Compounds
PubMed: 10698768
DOI: 10.1128/AEM.66.3.1031-1037.2000 -
Plant Physiology Jul 1973Potassium cyanide at 3 mum to 10 mm promotes germination of Amaranthus albus, Lactuca sativa, and Lepidium virginicum seeds. l-Cysteine hydrogen sulfide lyase, which...
Potassium cyanide at 3 mum to 10 mm promotes germination of Amaranthus albus, Lactuca sativa, and Lepidium virginicum seeds. l-Cysteine hydrogen sulfide lyase, which catalyzes the reaction of HCN with l-cysteine to form beta-l cyanoalanine, is active in the seeds. beta-l-Cyanoalanine is the most effective of the 23 alpha-amino acids tested for promoting germination of A. albus seeds. Aspartate, which is produced by enzymatic hydrolysis of asparagine formed by hydrolysis from beta-cyanoalanine, is the second most effective of the 23 amino acids. Uptake of aspartate-4-(14)C is much lower than of cyanide.Radioactive tracer in K(14)CN shows uptake of about 1.5 mumoles of HCN per gram of A. albus and L. sativa seeds after 20 hours of imbibition. Extracts of the seeds gave high (14)C activity in beta-cyanoalanine, asparagine, and aspartate. The acid-hydrolyzed protein extract gave high activity only in aspartate. Tests were negative for free cyanide in the seed. Respiration of the seed is inhibited more than 75% by KCN and by KN(3) at 10 mm. Azide at greater than 1.0 mm inhibits the promotion of germination by cyanides. Neither 0.1 mm KCN nor KN(3) inhibit O(2) consumption, whereas lower concentrations promote germination. It is concluded that the high rate of utilization of cyanide in the reaction to form beta-l-cyanoalanine and the subsequent incorporation into protein limit any inhibition of oxygen consumption. The promotion of seed germination is substrate-limited by asparagine-aspartate, which is required for protein synthesis.
PubMed: 16658492
DOI: 10.1104/pp.52.1.23 -
Scientific Reports Feb 2017Fluorescence lifetime imaging microscopy (FLIM) can measure and discriminate endogenous fluorophores present in biological samples. This study seeks to identify FLIM as...
Fluorescence lifetime imaging microscopy (FLIM) can measure and discriminate endogenous fluorophores present in biological samples. This study seeks to identify FLIM as a suitable method to non-invasively detect a shift in cellular metabolic activity towards glycolysis or oxidative phosphorylation in 3D Caco-2 models of colorectal carcinoma. These models were treated with potassium cyanide or hydrogen peroxide as controls, and epidermal growth factor (EGF) as a physiologically-relevant influencer of cell metabolic behaviour. Autofluorescence, attributed to nicotinamide adenine dinucleotide (NADH), was induced by two-photon laser excitation and its lifetime decay was analysed using a standard multi-exponential decay approach and also a novel custom-written code for phasor-based analysis. While both methods enabled detection of a statistically significant shift of metabolic activity towards glycolysis using potassium cyanide, and oxidative phosphorylation using hydrogen peroxide, employing the phasor approach required fewer initial assumptions to quantify the lifetimes of contributing fluorophores. 3D Caco-2 models treated with EGF had increased glucose consumption, production of lactate, and presence of ATP. FLIM analyses of these cultures revealed a significant shift in the contribution of protein-bound NADH towards free NADH, indicating increased glycolysis-mediated metabolic activity. This data demonstrate that FLIM is suitable to interpret metabolic changes in 3D in vitro models.
Topics: Algorithms; Caco-2 Cells; Cell Culture Techniques; Glycolysis; Humans; Metabolomics; Microscopy, Fluorescence; Oxidative Phosphorylation
PubMed: 28211922
DOI: 10.1038/srep42730 -
Clinical Toxicology (Philadelphia, Pa.) 2016The objective of this study is to measure mitochondrial respiration using intact cells from whole blood exposed to cyanide as a new biomarker for mitochondrial...
OBJECTIVES
The objective of this study is to measure mitochondrial respiration using intact cells from whole blood exposed to cyanide as a new biomarker for mitochondrial inhibition.
METHODS
A single nontourniqueted venous blood sample was collected from 10 healthy volunteers after informed consent. Venous lactate was measured immediately following blood collection. Half of the remaining blood sample was then incubated with 100 mM of potassium cyanide (KCN) for 5 min, and half of the sample remained unexposed. Repeat lactate measurements were performed from blood exposed and not exposed to KCN. Measurement of mitochondrial respiration: intact PBMCs were placed in a 2-mL chamber at a final concentration of 2-3 × 10(6) cells/mL. Measurements of oxygen consumption were performed at 37°C in a high-resolution oxygraph (Oxygraph-2k Oroboros Instruments, Innsbruck, Austria). Oxygen flux (in pmol O2/s/10(6) cells), which is directly proportional to oxygen consumption, was recorded continuously using DatLab software 6 (Oroboros Instruments).
RESULTS
There were significance differences in the relevant key parameters of mitochondrial respiration: Of the parameters measuring mitochondrial respiration, four of the six demonstrated a statistically significant mean difference between control and cyanide: for routine respiration (mean difference [control-cyanide]: 8.9 pmol O2/s/10(6) cells; 95% CI: 5.6-12.2, p < 0.0001); Proton Leak (mean difference: 0.73 pmol O2/s/10(6) cells; 95% CI: -0.33-1.79, p = 0.157); Maximal respiration (mean difference: 21.7 pmol O2/s/10(6) cells; 95% CI: 16.0-27.6, p < 0.0001); Residual oxygen consumption (mean difference 0.25 pmol O2/s/10(6) cells; 95% CI: -0.68-1.18, p = 0.557). There was a significant difference in spare respiratory capacity (SRC) and adenosine triphosphate (ATP)-linked respiration with the control samples demonstrating a higher SRC and ATP-linked respiration. Finally, there is a statistically significant difference in lactate (mean difference -0.32, 95% CI: -0.41 to -0.23, p < 0.0001), though clinically similar level, with a higher lactate concentration in the cyanide samples.
CONCLUSIONS
In this ex vivo model, the measurements of key parameters in mitochondrial respiration may be a more sensitive measure of cellular function when compared to lactate.
Topics: Adult; Female; Humans; Leukocytes, Mononuclear; Male; Mitochondria; Oxygen Consumption; Potassium Cyanide
PubMed: 26846815
DOI: 10.3109/15563650.2016.1139712