... CYANIDE ION IS CONJUGATED WITH SULFUR TO FORM THIOCYANATE. ... CONJUGATION IS CATALYZED BY ... RHODANESE WHICH IS WIDELY DISTRIBUTED IN MOST ANIMAL TISSUES ... /LIVER/ PARTICULARLY ACTIVE. ... RHODANESE MECHANISM IS CAPABLE OF DETOXICATING ONLY LIMITED AMT OF CYANIDE, SUCH AS ARE FORMED DURING NORMAL METAB. /ANOTHER SULFUR DONOR IS 3-MERCAPTOPYRUVATE. THE ENZYME, MERCAPTOSULFUR TRANSFERASE IS LOCALIZED IN CYTOSOL./ /CYANIDE/
THE EXCRETION OF THIOCYANATE FOLLOWING THE ADMINISTRATION OF EQUITOXIC DOSES OF CYANIDE TO UNPROTECTED MICE AND TO ANIMALS PRETREATED WITH VARIOUS CYANIDE ANTIDOTES WAS STUDIED. CYANIDE GIVEN ALONE OR TO ANIMALS PRETREATED WITH THIOSULFATE IS EXTENSIVELY CONVERTED TO THIOCYANATE. THE CYANIDE IS EXCRETED IN THE URINE, AS DEMONSTRATED BY DETECTION OF HIGH AMOUNTS OF COBALT IONS AND STRONGLY COMPLEX-BOUND CYANIDE IN THE URINE. A METHOD FOR THE DETERMINATION OF CYANIDE PRESENT AS COBALT CYANIDE COMPLEXES IS DESCRIBED AND ITS FORENSIC APPLICATION IS PROPOSED.
Aliphatic nitriles have been postulated to manifest their toxicity through cyanide (CN) liberation. The signs of toxicity and effect of equitoxic LD50 doses of saturated and unsaturated aliphatic mono- and dinitriles on tissue and blood CN levels, tissue glutathione levels and cytochrome c oxidase activities were studied in rats. Signs of toxicity were classified into cholinomimetic effects observed with unsaturated nitriles and CNS effects observed with saturated potassium cyanide. Hepatic and blood CN levels 1 hr after treatment were highest following malononitrile and decreased in the order of propionitrile > potassium cyanide > butyronitrile > acrylonitrile > allylcyanide > fumaronitrile > acetonitrile. The order differed in brain where potassium cyanide preceded malononitrile and PCN. Hepatic and cytochrome c oxidase were significantly inhibited and corresponded to their CN levels. No significant inhibition of cytochrome c oxidase was observed in vitro. Acrylonitrile was the only nitrile which significantly reduced tissue GSH levels. Toxic expression of aliphatic nitriles depended on CN release and their degree of unsaturation. With unsaturated aliphatic nitriles CN release played a minimal role in their toxicity. /Cyanides/
Rhizopus oryzae, a mucoraceous fungus associated with the postharvest spoilage of cassava was found to effectively metabolize cyanide. Degradation of cyanogenic glycosides of cassava by R oryzae was studied by growing the organism in potato dextrose broth with and without linarmarin and potassium cyanide. The influence of adaptation of the organism to low and high cyanide concentrations on both growth and the release of extracellular rhodanese into cyanide containing media was studied. Nonadapted cultures of R oryzae grow poorly when compared with the cyanide adapted cultures. However non-adapted R oryzae cultures released large quantities of rhodanese when compared with the adapted ones. Potassium cyanide (1.0 mM) was found to be an efficient inducer of rhodanese whereas potassium cyanide (5.0 mM) repressed the release of rhodanese. A significant inductive effect was produced by thiosulphate and thiocyanate.
Organic nitriles are converted into cyanide ions through the action of cytochrome P450 enzymes in the liver. Cyanide is rapidly absorbed and distributed throughout the body. Cyanide is mainly metabolized into thiocyanate by either rhodanese or 3-mercaptopyruvate sulfur transferase. Cyanide metabolites are excreted in the urine. (L96)
IDENTIFICATION: Other cyanides, such as sodium and potassium cyanide, are solid or crystalline hygroscopic salts widely used in ore extracting processes for the recovery of gold and silver, electroplating, case-hardening of steel, base metal flotation, metal degreasing, dyeing, printing, and photography. They are also widely used in the synthesis of organic and inorganic chemicals (e.g., nitriles, carboxylic acids, amides, esters, and amines; heavy metal cyanides) and in the production of chelating agents. HUMAN EXPOSURE: Cyanides are well absorbed via the gastrointestinal tract or skin and rapidly absorbed via the respiratory tract. Once absorbed, cyanide is rapidly and ubiquitously distributed throughout the body, although the highest levels are typically found in the liver, lungs, blood, and brain. There is no accumulation of cyanide in the blood or tissues following chronic or repeated exposure. Approximately 80% of absorbed cyanide is metabolized to thiocyanate in the liver by the mitochondrial sulfur transferase enzyme rhodanese and other sulfur transferases. Thiocyanate is excreted in the urine. Minor pathways for cyanide detoxification involve reaction with cystine to produce aminothiazoline- and iminothiazolidinecarboxylic acids and combination with hydroxycobalamin (vitamin B12a) to form cyanocobalamin (vitamin B12); these end-products are also excreted in the urine. The principal features of the toxicity profile for cyanide are its high acute toxicity by all routes of administration, with a very steep and rate-dependent dose-effect curve, and chronic toxicity, probably mediated through the main metabolite and detoxification product, thiocyanate. The toxic effects of cyanide ion in humans and animals are generally similar and are believed to result from inactivation of cytochrome oxidase and inhibition of cellular respiration and consequent histotoxic anoxia. The primary targets of cyanide toxicity in humans are the cardiovascular, respiratory, and central nervous systems. The endocrine system is also a potential target for long-term toxicity, as a function of continued exposure to thiocyanate, which prevents the uptake of iodine in the thyroid and acts as a goitrogenic agent. Sequele after severe acute intoxications may include neuropsychiatric manifestations and Parkinson-type disease. Cyanide from tobacco smoke has been implicated as a contributing factor in tobacco-alcohol amblyopia. Long-term exposure to lower concentrations of cyanide in occupational settings can result in a variety of symptoms related to central nervous system effects. Cyanides are weakly irritating to the skin and eye; alkali salts have not been identified. ANIMAL/PLANT STUDIES: The principal features of the toxicity profile for cyanide are its high acute toxicity by all routes of administration, with a very steep and rate-dependent dose-effect curve, and chronic toxicity, probably mediated through the main metabolite and detoxification product, thiocyanate. The toxic effects of cyanide ion in humans and animals are generally similar and are believed to result from inactivation of cytochrome oxidase and inhibition of cellular respiration and consequent histotoxic anoxia. The primary targets of cyanide toxicity in animals are the cardiovascular, respiratory, and central nervous systems. The endocrine system is also a potential target for long-term toxicity, as a function of continued exposure to thiocyanate, which prevents the uptake of iodine in the thyroid and acts as a goitrogenic agent. In a 13-week repeated-dose toxicity study in which cyanide was administered in drinking-water, there were no clinical signs associated with central nervous system effects or histopathological effects in the brain or thyroid of rats or mice. There were slight changes in the reproductive tract in male rats, which, although they apparently would not affect fertility in rats. The examination of neurotoxicity in this study was limited to clinical observation and optical microscopy in autopsy. The few available studies specifically intended to investigate neurotoxicity, while reporting adverse effects at exposure levels of 1.2 mg cyanide/kg body weight per day in rats and 0.48 mg cyanide/kg body weight per day in goats, suffer from weaknesses that preclude their quantitative assessment. In relation to characterization of concentration-response for repeated-dose toxicity for inhalation (relevant principally to the occupational environment), in three separate studies in rats, there were no adverse systemic effects in rats exposed to acetone cyanohydrin, which is rapidly hydrolysed to hydrogen cyanide at physiological pH, at concentrations up to 211 mg/m3 (corresponding to a concentration of 67 mg hydrogen cyanide/m3). The steepness of the dose-effect curve is illustrated by the observation of 30% mortality among rats exposed part of the day to 225 mg acetone cyanohydrin/m3 (71 mg hydrogen cyanide/m3). Adverse effects of exposure to the low concentrations of cyanide that are generally present in the general environment (<1 ug/m3 in ambient air; <10 ug/litre in water) are unlikely. /Cyanide/
Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
Exposure to high levels of cyanide for a short time harms the brain and heart and can even cause coma, seizures, apnea, cardiac arrest and death. Chronic inhalation of cyanide causes breathing difficulties, chest pain, vomiting, blood changes, headaches, and enlargement of the thyroid gland. Skin contact with cyanide salts can irritate and produce sores. (L96, L97)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
暴露途径
这种物质可以通过吸入、皮肤接触和摄入被身体吸收。
The substance can be absorbed into the body by inhalation, through the skin and by ingestion.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
IN 30 DAYS, 72% OF (14)C FROM IP DOSE OF (14)C-CYANIDE TO MICE WAS EXCRETED IN URINE & FECES, 25% IN EXPIRED AIR, & 3% WAS RETAINED ... PEAK EXCRETION OCCURRED WITHIN 10 MIN IN EXPIRED AIR & WITHIN 6-24 HR IN URINE & FECES. /CYANIDE/
CYANIDE ION IS READILY ABSORBED AFTER ORAL OR PARENTERAL ADMIN. PROLONGED LOCAL CONTACT WITH CYANIDE SOLN ... MAY RESULT IN ABSORPTION OF TOXIC AMT THROUGH SKIN. PART OF ABSORBED CYANIDE IS EXCRETED UNCHANGED BY THE LUNG. LARGER PORTION ... CONVERTED BY SULFURTRANSFERASE TO RELATIVELY NONTOXIC THIOCYANATE ION. /CYANIDE/
AFTER IM INJECTION OF POTASSIUM CYANIDE AT 10 MG(CN)/KG IN SHEEP, THE CN CONCN IN WHOLE BLOOD WAS 2-3 TIMES AS HIGH AS IN PLASMA, SERUM, CEREBROSPINAL FLUID, CAUDATE NUCLEUS & WHITE MATTER.
The excretion of (14)C-labeled cyanide in rats exposed to chronic intake of potassium cyanide was studied in rats exposed to daily intake of labeled potassium cyanide in the diet for 6 weeks. Urinary excretion was the main route of elimination of cyanide carbon in these rats, accounting for 83% of the total excreted radioactivity in 12 hr and 89% of the total excreted radioactivity in 24 hr. The major excretion metabolite of cyanide in urine was thiocyanate, and this metabolite accounted for 71 and 79% of the total urinary activity in 12 hr and 24 hr, respectively. When these results were compared with those observed for control rats, it was clear that the mode of elimination of cyanide carbon in both urine and breath was not altered by the chronic intake of cyanide.
PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
申请人：Arora Nidhi
公开号：US20120015962A1
公开（公告）日：2012-01-19
Compounds of the formula I or II:
wherein X, m, Ar, R
1
and R
2
are as defined herein. The subject compounds are useful for treatment of IRAK-mediated conditions.
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
This application relates to novel compounds of formula (I) (and their pharmaceutically acceptable salts), as defined herein, processes and intermediates for their preparation, pharmaceutical formulations comprising the novel compounds of formula (I), and the use of the compounds of formula (I) as thrombin inhibitors.
[EN] THIOPHENE DERIVATIVES FOR THE TREATMENT OF DISORDERS CAUSED BY IGE<br/>[FR] DÉRIVÉS DE THIOPHÈNE POUR LE TRAITEMENT DE TROUBLES PROVOQUÉS PAR IGE
申请人：UCB BIOPHARMA SRL
公开号：WO2019243550A1
公开（公告）日：2019-12-26
Thiophene derivatives of formula (I) and a pharmaceutically acceptable salt thereof are provided. These compounds have utility for the treatment or prevention of disorders caused by IgE, such as allergy, type 1 hypersensitivity or familiar sinus inflammation.
A NEW PEPTIDE DEFORMYLASE INHIBITOR COMPOUND AND MANUFACTURING PROCESS THEREOF
申请人：KANG Jae Hoon
公开号：US20100168421A1
公开（公告）日：2010-07-01
The present invention relates to the novel antibacterial compounds having potent antibacterial activity as inhibitors of peptide deformylase. This invention further relates to pharmaceutically acceptable salts thereof, to processes for their preparation, and to pharmaceutical compositions containing them as an active ingredient.
