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Principles of Heart Failure Pharmacotherapy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Erika L. Hellenbart, Stephanie Dwyer Kaluzna, Robert J. DiDomenico
The onset of action for nitroglycerin and nitroprusside is virtually immediate (Table 5.5).38,104,105 Both drugs are rapidly metabolized, resulting in short half-lives and brief durations of action (less than 10 min). Therefore, both nitroglycerin and nitroprusside are administered as continuous infusions and require titration to the desired hemodynamic response. Each molecule of nitroprusside contains five anions of cyanide which are released when nitroprusside reacts with oxyhemoglobin in vivo.38,104,105,107 Hepatic detoxification of cyanide, via rhodanese, produces thiocyanate, which is slowly excreted by the kidneys (half-life ~3 days) and may lead to toxicity (Table 5.5).38,105
The Modification of Cysteine
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
The formation of 2-mercapto-5-nitrobenzoic acid, which occurs with the reaction of 2-nitrothiocyanobenzoic acid with thiols to form S-cyano derivatives, can be used for the quantitative determination of sulfhydryl groups. 2-Mercapto-5-nitrobenzoic acid has an absorbance maximum at 412 nm with a molar extinction coefficient of 13,600 M−1 cm−1.65 Pecci and co-workers66 have characterized the reaction of rhodanese with 2-nitrothiocyanobenzoic acid. These investigators used a 1.3 molar excess of reagent in 0.050 M phosphate buffer, pH 8.0 at 18°C. The reaction was followed spectrophotometrically by the release of 2-mercapto-5-nitrobenzoic acid and was complete after 6 h.
Hazard Characterization and Dose–Response Assessment
Published in Ted W. Simon, Environmental Risk Assessment, 2019
Dose addition assumes a common mode of action, and if the MOA is not known, EPA recommends separating chemicals by the affected target organ. This recommendation falls short: hydrogen sulfide and cyanide both form methemoglobin adducts, and both prevent oxygen transport by red blood cells. Does this respiratory inhibition represent a common mode of action? Hydrogen sulfide is detoxified by sulfide oxidase, an enzyme that produces thiosulfate from hydrogen sulfide. Cyanide is detoxified by rhodanese, an enzyme that uses thiosulfate to convert cyanide to thiocyanate, which is also found in cruciferous vegetables like broccoli. The increased levels of thiosulfate accelerate detoxification of cyanide. Cyanide antidote kits used by poison control centers contain injectable thiosulfate, and here is an instance where two chemicals with a common MOA fail to be dose-additive and act as antagonists as defined below.24
Methyl mercaptan gas: mechanisms of toxicity and demonstration of the effectiveness of cobinamide as an antidote in mice and rabbits
Published in Clinical Toxicology, 2022
George P. Philipopoulos, John Tat, Adriano Chan, Jingjing Jiang, David Mukai, Tanya Burney, Melody Doosty, Sari Mahon, Hemal H. Patel, Carl W. White, Matthew Brenner, Jangwoen Lee, Gerry R. Boss
Sodium nitrite, sodium thiosulfate, and hydroxocobalamin are effective in treating cyanide poisoning in animals and humans, and some studies suggest hydroxocobalamin is effective against hydrogen sulfide poisoning [4,19–26]. However, it is unknown whether these drugs could be used against CH3SH poisoning. Sodium nitrite generates methemoglobin, which scavenges cyanide, but methemoglobinemia reduces oxygen carrying capacity of blood and nitrite can cause hypotension [27–29]. Sodium thiosulfate acts against cyanide by serving as a substrate for rhodanese to convert cyanide into thiocyanate [30], but thiosulfate would unlikely be helpful against CH3SH poisoning. Hydroxocobalamin binds cyanide and hydrogen sulfide [31,32], but it is unknown if it also binds CH3SH, and it must be administered in large volumes via intravenous infusion.
Intramuscular sodium tetrathionate as an antidote in a clinically relevant swine model of acute cyanide toxicity
Published in Clinical Toxicology, 2020
Tara B. Hendry-Hofer, Alyssa E. Witeof, Patrick C. Ng, Sari B. Mahon, Matthew Brenner, Gerry R. Boss, Vikhyat S. Bebarta
Either of the two sulfane sulfurs of sodium tetrathionate, Na2S4O6, can react directly with cyanide, yielding thiocyanate, sulfate, and sodium thiosulfate. Thiosulfate, in turn, acts as a substrate for the enzyme rhodanese, again generating thiocyanate. Tetrathionate thereby neutralizes two moles of cyanide, compared to thiosulfate (Figure 1) [16–18]. Sodium tetrathionate was first examined in 1910 in a study indicating efficacy in a rabbit model of cyanide toxicity [19]. It was later shown to be 1.5–3.3 fold more potent then thiosulfate in treating mice, rats, and dogs with cyanide poisoning. These studies lacked proper controls and were done in animal models not clinically relevant by today’s standards [20–22]. Thus, these early studies indicate sodium tetrathionate is minimally toxic and efficacious against cyanide toxicity [20–22]. Based on these data and tetrathionate’s ability to neutralize two cyanide molecules, we hypothesized it would be efficacious against cyanide poisoning when delivered intramuscularly (IM) following cyanide exposure. The objective of our study was to evaluate the efficacy of IM sodium tetrathionate compared to saline control on survival and clinical outcomes in swine after acute systemic cyanide poisoning.
Molecular mechanism of amygdalin action in vitro: review of the latest research
Published in Immunopharmacology and Immunotoxicology, 2018
Przemysław Liczbiński, Bożena Bukowska
The first theories on anticancer properties of amygdalin and laetrile concerned the role of β-glucosidase in cancer cells5. This enzyme is responsible for conversion of amygdalin, it hydrolyzes glycosidic bonds, and thus mediates generation of HCN. Krebs Jr. based this thesis on the fact that β-glucosidase content is significantly higher in cancer tissues than in physiologically unchanged tissues, which leads to a greater HCN release. In addition, in physiologically unchanged cells, such as hepatocytes and nephrocytes, the rhodanese enzyme responsible for the removal of HCN from the organism is present. Cancer cells also contain the rhodanese enzyme and its amount is comparable to that found in normal cells in the liver and kidneys, making it hard to be attacked by cyanide6. The mechanism proposed Dr. Krebs and Krebs Jr. suggesting that glucosidase activity concerns only cancer cells has also occurred to be wrong because this enzyme has been found (but in lower amounts) in physiologically unchanged tissues7,8. Naming the vitamin B-17 in 1970 created a new concept, which aimed to circumvent the ban on the use of medicines. The ban did not include the use of vitamins, including vitamin B-179. To date, in 1977, The U.S. Food and Drug Administration (FDA) banned shipping amygdalin and laetrile in 23 states of the USA10.