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British Journal of Anaesthesia Jul 1976Twenty-six patients, receiving an infusion of sodium nitroprusside (SNP) during surgery, had considerable increases in both red cell and plasma cyanide concentration,... (Clinical Trial)
Clinical Trial
Twenty-six patients, receiving an infusion of sodium nitroprusside (SNP) during surgery, had considerable increases in both red cell and plasma cyanide concentration, but only small changes in plasma thiocyanate concentration. There was a linear relationship between both plasma and RBC cyanide concentrations and the total dose of SNP. The expired cyanide concentration followed the changes in the plasma. We believe that the development of metabolic acidosis, and the recent fatalities involving SNP, are attributable to histotoxic hypoxia as a result of excessive plasma concentrations of cyanide. On the basis of our results, we recommend that the total dose of SNP should not exceed 1.5 mg/kg during short-term infusions and that the plasma cyanide should not exceed 300 nmol%. Plasma thiocyanate concentrations are, in general, an unreliable indication of extent of exposure to cyanide, although they may become important during long-term infusions.
Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Cyanides; Female; Ferricyanides; Humans; Infusions, Parenteral; Male; Middle Aged; Nitroprusside; Respiration; Thiocyanates; Time Factors
PubMed: 797397
DOI: 10.1093/bja/48.7.651 -
British Journal of Anaesthesia Feb 1979Blood cyanide (HCN) and thiocyanate (SCN) concentrations were measured at intervals in anaesthetized dogs given bolus doses of sodium nitroprusside (SNP) 1 mg kg-1 or...
Blood cyanide (HCN) and thiocyanate (SCN) concentrations were measured at intervals in anaesthetized dogs given bolus doses of sodium nitroprusside (SNP) 1 mg kg-1 or potassium cyanide 1.07 mg kg-1 and in animals infused with SNP 1.5 mg kg-1 for 1 h. Cyanide appeared rapidly in the red cells to give peak concentrations which accounted for more than 90% of the total blood HCN. A delay between the peak plasma and red cell HCN concentrations confirmed that some of the SNP was degraded in the plasma. Comparison of HCN and SCN concentrations with those measured previously in patients receiving an infusion of SNP suggests that the degradation of SNP and detoxication of HCN may be more rapid in the dog. The various pathways of HCN detoxication are discussed in relation to the reduced formation of SCN in dogs receiving SNP compared with those receiving KCN.
Topics: Animals; Cyanides; Dogs; Erythrocytes; Ferricyanides; Nitroprusside; Potassium Cyanide; Thiocyanates; Time Factors
PubMed: 426998
DOI: 10.1093/bja/51.2.89 -
Journal of Applied Physiology... May 2018In adult left ventricular mouse myocytes, exposure to sodium cyanide (NaCN) in the presence of glucose dose-dependently reduced contraction amplitude, with ~80% of...
In adult left ventricular mouse myocytes, exposure to sodium cyanide (NaCN) in the presence of glucose dose-dependently reduced contraction amplitude, with ~80% of maximal inhibitory effect attained at 100 µM. NaCN (100 µM) exposure for 10 min significantly decreased contraction and intracellular Ca concentration ([Ca]) transient amplitudes, systolic but not diastolic [Ca], and maximal L-type Ca current ( I) amplitude, indicating acute alteration of [Ca] homeostasis largely accounted for the observed excitation-contraction abnormalities. In addition, NaCN depolarized resting membrane potential ( E), reduced action potential (AP) amplitude, prolonged AP duration at 50% (APD) and 90% repolarization (APD), and suppressed depolarization-activated K currents but had no effect on Na-Ca exchange current ( I). NaCN did not affect cellular adenosine triphosphate levels but depolarized mitochondrial membrane potential (ΔΨ) and increased superoxide (O) levels. Methylene blue (MB; 20 µg/ml) added 3 min after NaCN restored contraction and [Ca] transient amplitudes, systolic [Ca], E, AP amplitude, APD, APD, I, depolarization-activated K currents, ΔΨ, and O levels toward normal. We conclude that MB reversed NaCN-induced cardiotoxicity by preserving intracellular Ca homeostasis and excitation-contraction coupling ( I), minimizing risks of arrhythmias ( E, AP configuration, and depolarization-activated K currents), and reducing O levels. NEW & NOTEWORTHY Cyanide poisoning due to industrial exposure, smoke inhalation, and bioterrorism manifests as cardiogenic shock and requires rapidly effective antidote. In the early stage of cyanide exposure, adenosine triphosphate levels are normal but myocyte contractility is reduced, largely due to alterations in Ca homeostasis because of changes in oxidation-reduction environment of ion channels. Methylene blue, a drug approved by the U.S. Food and Drug Administration, ameliorates cyanide toxicity by normalizing oxidation-reduction state and Ca channel function.
Topics: Action Potentials; Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channels, L-Type; Calcium Signaling; Cardiotoxicity; Cyanides; Excitation Contraction Coupling; Heart Ventricles; Ion Channels; Membrane Potentials; Methylene Blue; Mice; Myocardial Contraction; Myocytes, Cardiac; Sodium-Calcium Exchanger
PubMed: 29420146
DOI: 10.1152/japplphysiol.00967.2017 -
Molecules (Basel, Switzerland) Jun 2023This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a...
This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).
Topics: Cyanides; Carboxylic Acids; Alcohols; Sodium
PubMed: 37446749
DOI: 10.3390/molecules28135087 -
JHEP Reports : Innovation in Hepatology Aug 2022In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal...
BACKGROUND & AIMS
In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging.
METHODS
To primary cocultures of astrocytes and neurons, low concentrations (1 and 5 μM) of NHCl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy.
RESULTS
Neuronal cultures treated with NHCl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both <0.0001). BDL led to increased cerebral LP ( = 0.0003) and cytosolic ROS generation ( <0.0001), which was restored by OP (both <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP.
CONCLUSIONS
Our results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development.
LAY SUMMARY
The impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.
PubMed: 35845295
DOI: 10.1016/j.jhepr.2022.100510 -
Archives of Razi Institute Jul 2021The present study aimed to assess the effect of tissue hypoxia induced by sodium cyanide (NaCN) on male mice fertility and the protective role of ethyl pyruvate (EP). A...
The present study aimed to assess the effect of tissue hypoxia induced by sodium cyanide (NaCN) on male mice fertility and the protective role of ethyl pyruvate (EP). A number of 30 adult mice were assigned to three groups: 1) a control group, 2) a treatment group treated with 2 mg/kg of NaCN, and 3) a treatment group treated with 2 mg/kg of NaCN, along with 40 mg/kg EP (NaCN+EP). After 35 days, animals were anesthetized and serum, sperm, and tissue samples were taken. The results demonstrated a significant decrease in sperm quality, reproduction potency, and anti-oxidant potential, as well as an increase in lipid peroxidation in the NaCN group (p <0.05). Moreover, the use of EP effectively restrained the disastrous effects of tissue hypoxia. It can be concluded that EP can moderate the complications resulting from tissue-hypoxia that is related to testes parameters.
Topics: Animals; Male; Mice; Hypoxia; Pyruvates; Reproduction; Sodium Cyanide
PubMed: 34223731
DOI: 10.22092/ari.2020.126806.1362 -
Military Medical Research Mar 2019Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide,... (Review)
Review
Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide, hydrogen cyanide, and irritants. In the case of an incident at a nuclear power plant or recycling facility associated with fire, smoke may also contain radioactive material. Medical treatments may vary in different countries, and in this paper, we discuss the similarities and differences in the treatments between China and Germany. Carbon monoxide poisoning is treated by 100% oxygen administration and, if available, hyperbaric oxygenation in China as well as in Germany. In addition, antidotes binding the cyanide ions and relieving the respiratory chain are important. Methemoglobin-forming agents (e.g., nitrites, dimethylaminophenol) or hydroxocobalamin (Vitamin B12) are options. The metabolic elimination of cyanide may be enhanced by sodium thiosulfate. In China, sodium nitrite with sodium thiosulfate is the most common combination. The use of dimethylaminophenol instead of sodium nitrite is typical for Germany, and hydroxocobalamin is considered the antidote of choice if available in cases of cyanide intoxications by fire smoke inhalation as it does not further reduce oxygen transport capacity. Systematic prophylactic use of corticosteroids to prevent toxic pulmonary edema is not recommended in China or Germany. Stable iodine is indicated in the case of radioiodine exposure and must be administered within several hours to be effective. The decorporation of metal radionuclides is possible with Ca (DTPA) or Prussian blue that should be given as soon as possible. These medications are used in both countries, but it seems that Ca (DTPA) is administered at lower dosages in China. Although the details of the treatment of inhalation injury and radionuclide(s) decorporation may vary, the general therapeutic strategy is very similar in China and Germany.
Topics: Antidotes; Carbon Monoxide; China; Germany; Humans; Hydrogen Cyanide; Hydroxocobalamin; Hyperbaric Oxygenation; Inhalation Exposure; Radiation Exposure; Radiography; Radioisotopes; Smoke Inhalation Injury; Sodium Nitrite; Thiosulfates
PubMed: 30961671
DOI: 10.1186/s40779-019-0200-2 -
Chemical Research in Toxicology May 2013Isoamyl nitrite has previously been considered acceptable as an inhaled cyanide antidote; therefore, the antidotal utility of this organic nitrite compared with sodium... (Comparative Study)
Comparative Study
Comparison of the relative propensities of isoamyl nitrite and sodium nitrite to ameliorate acute cyanide poisoning in mice and a novel antidotal effect arising from anesthetics.
Isoamyl nitrite has previously been considered acceptable as an inhaled cyanide antidote; therefore, the antidotal utility of this organic nitrite compared with sodium nitrite was investigated. To facilitate a quantitative comparison, doses of both sodium nitrite and isoamyl nitrite were given intraperitoneally in equimolar amounts to sublethally cyanide-challenged mice. Righting recovery from the knockdown state was clearly compromised in the isoamyl nitrite-treated animals, the effect being attributable to the toxicity of the isoamyl alchol produced during hydrolysis of the isoamyl nitrite to release nitrite anion. Subsequently, inhaled aqueous sodium nitrite aerosol was demonstrated to ameliorate sublethal cyanide toxicity, when provided to mice after the toxic dose, by the more rapid recovery of righting ability compared to that of the control animals given only the toxicant. Aerosolized sodium nitrite has thus been shown by these experiments to have promise as a better alternative to organic nitrites for development as an inhaled cyanide antidote. The inhaled sodium nitrite led to the production of NO in the bloodstream as determined by the appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. The aerosol delivery was performed in an unmetered inhalation chamber, and in this study, no attempt was made to optimize the procedure. It is argued that administration of an effective inhaled aqueous sodium nitrite dose in humans is possible, though just beyond the capability of current individual metered-dose inhaler designs, such as those used for asthma. Finally, working at slightly greater than LD50 NaCN doses, it was fortuitously discovered that (i) anesthesia leads to significantly prolonged survival compared to that of unanesthetized animals and that (ii) the antidotal activity of nitrite anion was completely abolished under anesthesia. Plausible explanations for these effects in mice and their practical consequences in relation to testing putative cyanide antidotes are discussed.
Topics: Amyl Nitrite; Anesthetics; Animals; Antidotes; Cyanides; Electron Spin Resonance Spectroscopy; Male; Mice; Sodium Nitrite
PubMed: 23536974
DOI: 10.1021/tx400103k -
Basic & Clinical Pharmacology &... Sep 2015Hydroxocobalamin is an effective first-line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination...
Hydroxocobalamin is an effective first-line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58-year-old male committed a suicide attempt by ingesting of 1200-1500 mg of potassium cyanide; he was unconscious for 1-1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO3 14.0 mmol/L, base excess -12.7 mmol/L, saturation O2 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 mL/hr/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased to 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO3 27.2 mmol/L, base excess 2.2 mmol/L, saturation O2 0.994). The follow-up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibres layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease in amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long-term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time-points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate.
Topics: Antidotes; Drug Therapy, Combination; Humans; Hydroxocobalamin; Male; Middle Aged; Potassium Cyanide; Suicide, Attempted; Thiosulfates
PubMed: 25645744
DOI: 10.1111/bcpt.12387