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Annals of Emergency Medicine Jun 2017The 2 antidotes for acute cyanide poisoning in the United States must be administered by intravenous injection. In the out-of-hospital setting, intravenous injection is...
STUDY OBJECTIVE
The 2 antidotes for acute cyanide poisoning in the United States must be administered by intravenous injection. In the out-of-hospital setting, intravenous injection is not practical, particularly for mass casualties, and intramuscular injection would be preferred. The purpose of this study is to determine whether sodium nitrite and sodium thiosulfate are effective cyanide antidotes when administered by intramuscular injection.
METHODS
We used a randomized, nonblinded, parallel-group study design in 3 mammalian models: cyanide gas inhalation in mice, with treatment postexposure; intravenous sodium cyanide infusion in rabbits, with severe hypotension as the trigger for treatment; and intravenous potassium cyanide infusion in pigs, with apnea as the trigger for treatment. The drugs were administered by intramuscular injection, and all 3 models were lethal in the absence of therapy.
RESULTS
We found that sodium nitrite and sodium thiosulfate individually rescued 100% of the mice, and that the combination of the 2 drugs rescued 73% of the rabbits and 80% of the pigs. In all 3 species, survival in treated animals was significantly better than in control animals (log rank test, P<.05). In the pigs, the drugs attenuated an increase in the plasma lactate concentration within 5 minutes postantidote injection (difference: plasma lactate, saline solution-treated versus nitrite- or thiosulfate-treated 1.76 [95% confidence interval 1.25 to 2.27]).
CONCLUSION
We conclude that sodium nitrite and sodium thiosulfate administered by intramuscular injection are effective against severe cyanide poisoning in 3 clinically relevant animal models of out-of-hospital emergency care.
Topics: Animals; Antidotes; Cyanides; Disease Models, Animal; Injections, Intramuscular; Male; Mice; Rabbits; Random Allocation; Sodium Nitrite; Sus scrofa; Thiosulfates
PubMed: 28041825
DOI: 10.1016/j.annemergmed.2016.09.034 -
Clinical Toxicology (Philadelphia, Pa.) Jan 2022Cyanide is a rapid acting, lethal, metabolic poison and remains a significant threat. Current FDA-approved antidotes are not amenable or efficient enough for a mass...
BACKGROUND
Cyanide is a rapid acting, lethal, metabolic poison and remains a significant threat. Current FDA-approved antidotes are not amenable or efficient enough for a mass casualty incident.
OBJECTIVE
The objective of this study is to evaluate short and long-term efficacy of intramuscular aqueous dimethyl trisulfide (DMTS) on survival and clinical outcomes in a swine model of cyanide exposure.
METHODS
Anesthetized swine were instrumented and acclimated until breathing spontaneously. Potassium cyanide infusion was initiated and continued until 5 min after the onset of apnea. Subsequently, animals were treated with intramuscular DMTS ( = 11) or saline control ( = 10). Laboratory values and DMTS blood concentrations were assessed at various time points and physiological parameters were monitored continuously until the end of the experiment unless death occurred. A subset of animals treated with DMTS ( = 5) were survived for 7 days to evaluate muscle integrity by repeat biopsy and neurobehavioral outcomes.
RESULTS
Physiological parameters and time to apnea were similar in both groups at baseline and at time of treatment. Survival in the DMTS-treated group was 90% and 30% in saline controls ( = 0.0034). DMTS-treated animals returned to breathing at 12.0 ± 10.4 min (mean ± SD) compared to 22.9 ± 7.0 min (mean ± SD) in the 3 surviving controls. Blood collected prior to euthanasia showed improved blood lactate concentrations in the DMTS treatment group; 5.47 ± 2.65 mmol/L vs. 9.39 ± 4.51 mmol/L (mean ± SD) in controls ( = 0.0310). Low concentrations of DMTS were detected in the blood, gradually increasing over time with no elimination phase observed. There was no mortality, histological evidence of muscle trauma, or observed adverse neurobehavioral outcomes, in DMTS-treated animals survived to 7 days.
CONCLUSION
Intramuscular administration of aqueous DMTS improves survival following cyanide poisoning with no observed long-term effects on muscle integrity at the injection site or adverse neurobehavioral outcomes.
Topics: Animals; Antidotes; Cyanides; Humans; Potassium Cyanide; Sulfides; Swine
PubMed: 34142637
DOI: 10.1080/15563650.2021.1935992 -
Biochemistry. Biokhimiia Oct 2017In this work, it was found that the ability of common uncouplers - carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol (DNP) - to reduce...
In this work, it was found that the ability of common uncouplers - carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol (DNP) - to reduce membrane potential of isolated rat liver mitochondria was diminished in the presence of millimolar concentrations of the known cytochrome c oxidase inhibitor - cyanide. In the experiments, mitochondria were energized by addition of ATP in the presence of rotenone, inhibiting oxidation of endogenous substrates via respiratory complex I. Cyanide also reduced the uncoupling effect of FCCP and DNP on mitochondria energized by succinate in the presence of ferricyanide. Importantly, cyanide did not alter the protonophoric activity of FCCP and DNP in artificial bilayer lipid membranes. The causes of the effect of cyanide on the efficiency of protonophoric uncouplers in mitochondria are considered in the framework of the suggestion that conformational changes of membrane proteins could affect the state of lipids in their vicinity. In particular, changes in local microviscosity and vacuum permittivity could change the efficiency of protonophore-mediated translocation.
Topics: 2,4-Dinitrophenol; Adenosine Triphosphate; Animals; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Electron Transport Complex I; Membrane Potential, Mitochondrial; Mitochondria, Liver; Mitochondrial Membranes; Potassium Cyanide; Rats; Rotenone; Uncoupling Agents
PubMed: 29037134
DOI: 10.1134/S0006297917100066 -
Heliyon Jun 2023Spebrutinib is a new Bruton tyrosine kinase inhibitor developed by Avila Therapeutics and Celgene. Spebrutinib (SPB) is currently in phase Ib clinical trials for the...
Spebrutinib is a new Bruton tyrosine kinase inhibitor developed by Avila Therapeutics and Celgene. Spebrutinib (SPB) is currently in phase Ib clinical trials for the treatment of lymphoma in the United States. Preliminary studies were first performed to predict susceptible sites of metabolism, reactivity pathways and structural alerts for toxicities by StarDrop WhichP450™ module, Xenosite web predictor tool and DEREK software; respectively. SPB metabolites and adducts were characterized from rat liver microsomes (RLM) using LC-MS/MS. Formation of reactive intermediates was investigated using potassium cyanide (KCN), glutathione (GSH) and methoxylamine as trapping nucleophiles for the unstable and reactive iminium, iminoquinone and aldehyde intermediates, respectively, with the aim to produce stable adducts that can be detected and characterized using mass spectrometry. Fourteen phase I metabolites, four cyanide adducts, six GSH adducts and three methoxylamine adducts of SPB were identified and characterized. The proposed metabolic pathways involved in generation of phase I metabolites of SPB are oxidation, hydroxylation, -dealkylation, epoxidation, defluorination and reduction. Several reactive intermediates were identified and characterized, the formation of which can aid in explaining the adverse drug reactions of SPB. Several iminium, 2-iminopyrimidin-5()-one and aldehyde intermediates of SPB were revealed. Acrylamide is identified as a structural alert for toxicity by DEREK report and was found to be involved in the formation of several glycidamide and aldehyde reactive intermediates.
PubMed: 37484253
DOI: 10.1016/j.heliyon.2023.e17058 -
Clinical Toxicology (Philadelphia, Pa.) Jan 2020Cyanide is a metabolic poison used in multiple industries and is a high threat chemical agent. Current antidotes require intravenous administration, limiting their...
Cyanide is a metabolic poison used in multiple industries and is a high threat chemical agent. Current antidotes require intravenous administration, limiting their usefulness in a mass casualty scenario. Sodium tetrathionate reacts directly with cyanide yielding thiosulfate and the non-toxic compound thiocyanate. Thiosulfate, in turn, neutralizes a second molecule of cyanide, thus, per mole, sodium tetrathionate neutralizes two moles of cyanide. Historical studies examined its efficacy as a cyanide antidote, but it has not been evaluated in a clinically relevant, large animal model, nor has it previously been administered by intramuscular injection. The objective of this study is to evaluate the efficacy of intramuscular sodium tetrathionate on survival and clinical outcomes in a large, swine model of severe cyanide toxicity. Anesthetized swine were instrumented for continuous monitoring of hemodynamics, then acclimated and breathing spontaneously prior to potassium cyanide infusion (0.17 mg/kg/min). At 6-min post-apnea (no breaths for 20 s), the cyanide infusion was terminated, and animals were treated with sodium tetrathionate (∼18 mg/kg) or normal saline control. Clinical parameters and laboratory values were evaluated at various time points until death or termination of the experiment (90 min post-treatment). Laboratory values, vital signs, and time to apnea were similar in both groups at baseline and treatment. Survival in the sodium tetrathionate treated group was 100% and 17% in controls ( = 0.0043). All animals treated with sodium tetrathionate returned to breathing at a mean time of 10.85 min after antidote, and all but one control remained apneic through end of the experiment. Animals treated with tetrathionate showed improvement in blood lactate ( ≤ 0.002) starting at 30 min post-treatment. The average time to death in the control group is 63.3 ± 23.2 min. No systemic or localized adverse effects of intramuscular administration of sodium tetrathionate were observed. Sodium tetrathionate significantly improves survival and clinical outcomes in a large, swine model of acute cyanide poisoning.
Topics: Animals; Antidotes; Cyanides; Disease Models, Animal; Female; Injections, Intramuscular; Swine; Tetrathionic Acid
PubMed: 31008657
DOI: 10.1080/15563650.2019.1602272 -
Environmental Science and Pollution... Mar 2023Endophytic bacteria inhabit plant tissues such as roots, stems, leaves, fruits, and seeds and can multiply inside plant tissue without damaging them. This study involves...
Endophytic bacteria inhabit plant tissues such as roots, stems, leaves, fruits, and seeds and can multiply inside plant tissue without damaging them. This study involves the isolation, characterization, metabolic profiling, and effect of endophytic bacteria isolated from the roots of Scots pine (Pinus sylvestris), on the growth of sunflower. In the current study, fifteen isolates of endophytic bacteria were obtained from the roots of Scots pine, and their molecular characterization was performed using 16 s rRNA ribotyping. The molecular characterization revealed that the strains belonged to Bacillus spp., Pseudomonas spp., Micrococcus sp., Serratia sp., Enterobacter sp., Pantoea sp., Staphylococcus sp., and Microbacterium sp. Among the isolated strains, 9 strains showed positive results for ammonium production, 12 strains for calcium solubilization, 11 strains for magnesium solubilization, 5 strains for zinc solubilization, 12 strains for phosphate solubilization, 8 strains for potassium solubilization, 10 strains for indole acetic acid (IAA) production, 9 strains for siderophore, and 6 strains for hydrogen cyanide (HCN) production. The greenhouse experiment results demonstrated that all isolated endophytic bacteria improved the shoot length, dry weight, and chlorophyll content of sunflower, whereas a significant increase was observed by PS-3 (Bacillus cereus), PS-6 (Serratia marcescens), and PS-8 (Pseudomonas putida). Besides, the concentration of nitrogen, phosphorus, and potassium were also measured in sunflower shoots, and results asserted that bacterial inoculation increased the bioavailability of these essential nutrients to plants compared to uninoculated control. Thus, these endophytic bacteria could be used as an encouraging option to improve plant growth and performance.
Topics: Helianthus; Pinus sylvestris; Endophytes; Bacteria; Asteraceae; Metabolome; Plant Roots
PubMed: 36607575
DOI: 10.1007/s11356-022-25118-7 -
Ecotoxicology and Environmental Safety Oct 2022Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to...
Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to investigate the role of high mobility group A2 (HMGA2) in Cr (VI)-induced metabolism reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in A549 and HELF cells. First, knockdown of HMGA2 by siHMGA2 significantly attenuated Cr (VI)-reduced expression of OXPHOS-related proteins (COX IV and ND1) and mitochondrial mass, indicating that HMGA2 was involved in Cr (VI)-reduced OXPHOS. Overexpression of HMGA2 by transfection of HMGA2-DNA plasmids reduced the expression of COX IV, ND1 and mitochondrial mass, suggesting the negative role of HMGA2 in OXPHOS. Secondly, both CCCP, the inhibitor of mitochondrial function, and the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), decreased the level of HMGA2, indicating that the interaction of mitochondrial dysfunction and ER stress resulted in Cr (VI)-induced HMGA2 expression. Further study demonstrated that ER stress/HMGA2 axis mediated the metabolism rewiring from OXPHOS to aerobic glycolysis. Notably, Cr (VI) induced the accumulation of HMGA2 proteins in mitochondria and ChIP assay demonstrated that HMGA2 proteins could bind to D-loop region of mitochondrial DNA (mtDNA), which provided the proof for HMGA2-modulating OXPHOS. Taken together, our results suggested that the interaction of mitochondria and ER stress-enhanced HMGA2 played an important role in Cr (VI)-induced metabolic reprogramming from OXPHOS to glycolysis by binding directly to D-loop region of mtDNA. This work informs on the potential mode of action for Cr (VI)-induced tumors and builds on growing evidence regarding the contribution of cellular metabolic disruption contributing to carcinogenicity.
Topics: Carbonyl Cyanide m-Chlorophenyl Hydrazone; Chromium; DNA, Mitochondrial; Glycolysis; Mitochondria
PubMed: 36116352
DOI: 10.1016/j.ecoenv.2022.114085 -
Chemical Communications (Cambridge,... Jan 2022We report two methods that use either NMR spectroscopy or direct magnetic susceptibility measurements for (strictly ) determination of the state of charge of redox flow...
We report two methods that use either NMR spectroscopy or direct magnetic susceptibility measurements for (strictly ) determination of the state of charge of redox flow batteries. These methods are demonstrated on the inorganic, redox-active potassium ferro/ferri cyanide catholyte cycled against 2,6-dihydroxyanthraquinone as the anolyte in a full cell, and should be applicable to a wide range of redox couples, provided that the magnetization of the electrolyte solution depends on its oxidation state.
PubMed: 34986212
DOI: 10.1039/d1cc01895g -
ACS Applied Materials & Interfaces Aug 2022Potassium ferricyanide in an aqueous solution is easily decomposed into highly toxic substances (potassium cyanide and hydrogen cyanide) by light or alkaline action,...
Potassium ferricyanide in an aqueous solution is easily decomposed into highly toxic substances (potassium cyanide and hydrogen cyanide) by light or alkaline action, which poses a major hazard to environmental and human health. Here, a reticulated aggregation-induced emission (AIE) supramolecular polymer material (TPAP-Mb@Q[14]) was prepared by the supramolecular self-assembly of twisted cucurbit[14]uril (Q[14]) and a triphenylamine derivative (TPAP-Mb). TPAP-Mb@Q[14] not only recognizes Fe(CN) with sensitive specificity with a limit of detection (LOD) of 1.64 × 10 M but can also effectively remove and adsorb Fe(CN) from an aqueous solution with a removal rate as high as 97.38%. Meanwhile, an important component of the supramolecular polymer material (Q[14]) can be reused. Thus, the Q[14]-based supramolecular assembly has the potential to be used for applications addressing toxic anionic contaminants present in aqueous environments.
PubMed: 35926157
DOI: 10.1021/acsami.2c10866 -
International Journal of Biological... Jan 2018Two extracellular peroxidases from Bjerkandera adusta strain CX-9, namely a lignin peroxidase (called LiP BA45) and manganese peroxidase (called MnP BA30), were purified...
Two extracellular peroxidases from Bjerkandera adusta strain CX-9, namely a lignin peroxidase (called LiP BA45) and manganese peroxidase (called MnP BA30), were purified simultaneously by applying successively, ammonium sulfate precipitation-dialysis, Mono-S Sepharose anion-exchange and Sephacryl S-200 gel filtration and biochemically characterized. The sequence of their NH-terminal amino acid residues showed high homology with those of fungi peroxidases. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis revealed that the purified enzymes MnP BA30 and LiP BA45 were a monomers with a molecular masses 30125.16 and 45221.10Da, respectively. While MnP BA30 was optimally active at pH 3 and 70°C, LiP BA45 showed optimum activity at pH 4 and 50°C. The two enzymes were inhibited by sodium azide and potassium cyanide, suggesting the presence of heme-components in their tertiary structures. The K and V for LiP BA45 toward 2,4-Dichlorolphenol (2,4-DCP) were 0.099mM and 9.12U/mg, respectively and for MnP BA30 toward 2,6-Dimethylphenol (2,6-DMP), they were 0.151mM and 18.60U/mg, respectively. Interestingly, MnP BA30 and LiP BA45 demonstrated higher catalytic efficiency than that of other tested peroxidases (MnP, LiP, HaP4, and LiP-SN) and marked organic solvent-stability and dye-decolorization efficiency. Data suggest that these peroxidases may be considered as potential candidates for future applications in distaining synthetic-dyes.
Topics: Amino Acid Sequence; Chlorophenols; Cloning, Molecular; Coloring Agents; Coriolaceae; Enzyme Assays; Enzyme Stability; Fungal Proteins; Gene Expression; Hot Temperature; Hydrogen-Ion Concentration; Kinetics; Lignin; Molecular Weight; Peroxidases; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Substrate Specificity; Xylenes
PubMed: 28813685
DOI: 10.1016/j.ijbiomac.2017.08.061