Cyanocobalamin

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Cyanocobalamin
Cyanocobalamin-b12.png
Skeletal formula
Cyanocobalamin-from-xtal-3D-st-noH.png
Stick model of cyanocobalamin based on the crystal structure [1]
Clinical data
Pronunciationsye AN oh koe BAL a min [2]
Trade names Cobolin-M, [2] Depo-Cobolin, [2] others [3]
AHFS/Drugs.com Professional Drug Facts
MedlinePlus a604029
License data
Pregnancy
category
Routes of
administration 		By mouth, intramuscular, nasal spray [5] [6]
ATC code
Legal status
Legal status
  • US: OTC / Rx-only
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.000.618 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C63H88CoN14O14P
Molar mass 1355.388 g·mol−1
3D model (JSmol)
Melting point 300 °C (572 °F) +
Boiling point 300 °C (572 °F) +
Solubility in water 1/80g/ml
  • CC1=CC2=C(C=C1C)N(C=N2)C3C(C(C(O3)CO)OP(=O)([O-])OC(C)CNC(=O)CCC4(C(C5C6(C(C(C(=C(C7=NC(=CC8=NC(=C(C4=N5)C)C(C8(C)C)CCC(=O)N)C(C7(C)CC(=O)N)CCC(=O)N)C)[N-]6)CCC(=O)N)(C)CC(=O)N)C)CC(=O)N)C)O.[C-]#N.[Co+3]
  • InChI=1S/C62H90N13O14P.CN.Co/c1-29-20-39-40(21-30(29)2)75(28-70-39)57-52(84)53(41(27-76)87-57)89-90(85,86)88-31(3)26-69-49(83)18-19-59(8)37(22-46(66)80)56-62(11)61(10,25-48(68)82)36(14-17-45(65)79)51(74-62)33(5)55-60(9,24-47(67)81)34(12-15-43(63)77)38(71-55)23-42-58(6,7)35(13-16-44(64)78)50(72-42)32(4)54(59)73-56;1-2;/h20-21,23,28,31,34-37,41,52-53,56-57,76,84H,12-19,22,24-27H2,1-11H3,(H15,63,64,65,66,67,68,69,71,72,73,74,77,78,79,80,81,82,83,85,86);;/q;-1;+3/p-2/t31-,34-,35-,36-,37+,41-,52-,53-,56-,57?,59-,60+,61+,62+;;/m1../s1
  • Key:FDJOLVPMNUYSCM-QJRSUKKJSA-L

Cyanocobalamin is a form of vitamin B
12 used to treat and prevent vitamin B
12 deficiency except in the presence of cyanide toxicity. [7] [8] [2] The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. [9] [5] It is used by mouth, by injection into a muscle, or as a nasal spray. [5] [6]

Contents

Cyanocobalamin is generally well tolerated. [10] Minor side effects may include diarrhea, nausea, upset stomach, and itchiness. [11] Serious side effects may include anaphylaxis, and low blood potassium resulting in heart failure. [11] Use is not recommended in those who are allergic to cobalt or have Leber's disease. [9] No overdosage or toxicity has been reported. [11] It is less preferred than hydroxocobalamin for treating vitamin B
12 deficiency because it has slightly lower bioavailability. Some study have shown that it has an antihypotensive effect. [5] Vitamin B
12 is an essential nutrient meaning that it cannot be made by the body but is required for life. [12] [10]

Cyanocobalamin was first manufactured in the 1940s. [13] It is available as a generic medication and over the counter. [5] [10] In 2021, it was the 110th most commonly prescribed medication in the United States, with more than 5 million prescriptions. [14] [15]

Medical use

Cyanocobalamin is usually prescribed after surgical removal of part or all of the stomach or intestine to ensure adequate serum levels of vitamin B
12. It is also used to treat pernicious anemia, vitamin B
12 deficiency (due to low intake from food or inability to absorb due to genetic or other factors), thyrotoxicosis, hemorrhage, malignancy, liver disease and kidney disease. Cyanocobalamin injections are often prescribed to gastric bypass patients who have had part of their small intestine bypassed, making it difficult for B
12 to be acquired via food or vitamins. Cyanocobalamin is also used to perform the Schilling test to check ability to absorb vitamin B
12. [16]

Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous hydroxycobalamin is used to treat cyanide poisoning. [17]

Side effects

Possible side effects of cyanocobalamin injection include allergic reactions such as hives, difficult breathing; redness of the face; swelling of the arms, hands, feet, ankles or lower legs; extreme thirst; and diarrhea. Less-serious side effects may include headache, dizziness, leg pain, itching, or rash. [18]

Treatment of megaloblastic anemia with concurrent vitamin B
12 deficiency using B
12 vitamers (including cyanocobalamin), creates the possibility of hypokalemia due to increased erythropoiesis (red blood cell production) and consequent cellular uptake of potassium upon anemia resolution. [19] When treated with cyanocobalamin, patients with Leber's disease may develop serious optic atrophy, possibly leading to blindness. [20]

Chemistry

Vitamin B
12 is the "generic descriptor" name for any vitamers of vitamin B
12. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin B
12 compounds. [21]

Cyanocobalamin is one of the most widely manufactured vitamers in the vitamin B
12 family (the family of chemicals that function as B
12 when put into the body), because cyanocobalamin is the most air-stable of the B
12 forms. [22] It is the easiest [23] to crystallize and therefore easiest [24] to purify after it is produced by bacterial fermentation. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is hygroscopic in the anhydrous form, and sparingly soluble in water (1:80). [25] It is stable to autoclaving for short periods at 121 °C (250 °F). The vitamin B
12 coenzymes are unstable in light. After consumption the cyanide ligand is replaced by other groups (adenosyl, methyl) to produce the biologically active forms. The cyanide is converted to thiocyanate and excreted by the kidney. [26]

Chemical reactions

Reduced forms of Cyanocobalamin, with a Co(I) (top), Co(II) (middle), and Co(III) (bottom) Various reduced forms of Cyanocobalamin.jpg
Reduced forms of Cyanocobalamin, with a Co(I) (top), Co(II) (middle), and Co(III) (bottom)

In the cobalamins, cobalt normally exists in the trivalent state, Co(III). However, under reducing conditions, the cobalt center is reduced to Co(II) or even Co(I), which are usually denoted as B
12r and B
12s, for reduced and super reduced, respectively.

B
12r and B
12s can be prepared from cyanocobalamin by controlled potential reduction, or chemical reduction using sodium borohydride in alkaline solution, zinc in acetic acid, or by the action of thiols. Both B
12r and B
12s are stable indefinitely under oxygen-free conditions. B
12r appears orange-brown in solution, while B
12s appears bluish-green under natural daylight, and purple under artificial light. [27]

B
12s is one of the most nucleophilic species known in aqueous solution. [27] This property allows the convenient preparation of cobalamin analogs with different substituents, via nucleophilic attack on alkyl halides and vinyl halides. [27]

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to B
12s, followed by the addition of the corresponding alkyl halides, acyl halides, alkene or alkyne. Steric hindrance is the major limiting factor in the synthesis of the B
12 coenzyme analogs. For example, no reaction occurs between neopentyl chloride and B
12s, whereas the secondary alkyl halide analogs are too unstable to be isolated. [27] This effect may be due to the strong coordination between benzimidazole and the central cobalt atom, pulling it down into the plane of the corrin ring. The trans effect determines the polarizability of the Co–C bond so formed. However, once the benzimidazole is detached from cobalt by quaternization with methyl iodide, it is replaced by H
2O or hydroxyl ions. Various secondary alkyl halides are then readily attacked by the modified B
12s to give the corresponding stable cobalamin analogs. [28] The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography. [27]

Cobalamin analogs prepared by this method include the naturally occurring coenzymes methylcobalamin and cobamamide, and other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin. [27] This reaction is under review for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst systems. [29]

Production

Cyanocobalamin is commercially prepared by bacterial fermentation. Fermentation by a variety of microorganisms yields a mixture of methylcobalamin, hydroxocobalamin and adenosylcobalamin. These compounds are converted to cyanocobalamin by addition of potassium cyanide in the presence of sodium nitrite and heat. Since multiple species of Propionibacterium produce no exotoxins or endotoxins and have been granted GRAS status (generally regarded as safe) by the United States Food and Drug Administration, they are the preferred bacterial fermentation organisms for vitamin B
12 production. [30]

Historically, the physiological form was initially thought to be cyanocobalamin. This was because hydroxocobalamin produced by bacteria was changed to cyanocobalamin during purification in activated charcoal columns after separation from the bacterial cultures (because cyanide is naturally present in activated charcoal). [31] Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule. [32]

The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes. [33]

Metabolism

The two bioactive forms of vitamin B
12 are methylcobalamin in cytosol and adenosylcobalamin in mitochondria. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. The MMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin. [34] This function has also been attributed to cobalamin reductases. [35] The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins. [36]

Cyanocobalamin is added to fortify [37] nutrition, including baby milk powder, breakfast cereals and energy drinks for humans, also animal feed for poultry, swine and fish. Vitamin B
12 becomes inactive due to hydrogen cyanide and nitric oxide in cigarette smoke. Vitamin B
12 also becomes inactive due to nitrous oxide N
2O commonly known as laughing gas, used for anaesthesia and as a recreational drug. [38] Vitamin B
12 becomes inactive due to microwaving or other forms of heating. [39]

In the cytosol

Methylcobalamin and 5-methyltetrahydrofolate are needed by methionine synthase in the methionine cycle to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine, which is used to make SAMe. SAMe is the universal methyl donor and is used for DNA methylation and to make phospholipid membranes, choline, sphingomyelin, acetylcholine, and other neurotransmitters.

In mitochondria

Vitamin B 12 adenosylcobalamin in mitochondrion--cholesterol and protein metabolism Odd-chain FA oxydation.png
Vitamin B
12 adenosylcobalamin in mitochondrion—cholesterol and protein metabolism

The enzymes that use B
12 as a built-in cofactor are methylmalonyl-CoA mutase (PDB 4REQ [40] ) and methionine synthase (PDB 1Q8J). [41]

The metabolism of propionyl-CoA occurs in the mitochondria and requires Vitamin B
12 (as adenosylcobalamin) to make succinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin B
12 deficiency, elevated blood levels of methylmalonic acid (MMA) occur. Thus, elevated blood levels of homocysteine and MMA may both be indicators of vitamin B
12 deficiency.

Adenosylcobalamin is needed as cofactor in methylmalonyl-CoA mutase—MUT enzyme. Processing of cholesterol and protein gives propionyl-CoA that is converted to methylmalonyl-CoA, which is used by MUT enzyme to make succinyl-CoA. Vitamin B
12 is needed to prevent anemia, since making porphyrin and heme in mitochondria for producing hemoglobin in red blood cells depends on succinyl-CoA made by vitamin B
12.

Absorption and transport

Inadequate absorption of vitamin B
12 may be related to coeliac disease. Intestinal absorption of vitamin B
12 requires successively three different protein molecules: haptocorrin, intrinsic factor and transcobalamin II.

See also

Related Research Articles

<span class="mw-page-title-main">Pernicious anemia</span> Anemia caused by vitamin B12 deficiency

Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are feeling tired and weak. Other symptoms may include shortness of breath, feeling faint, a smooth red tongue, pale skin, chest pain, nausea and vomiting, loss of appetite, heartburn, numbness in the hands and feet, difficulty walking, memory loss, muscle weakness, poor reflexes, blurred vision, clumsiness, depression, and confusion. Without treatment, some of these problems may become permanent.

<span class="mw-page-title-main">Methylmalonic acidemia</span> Medical condition

Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

<span class="mw-page-title-main">Megaloblastic anemia</span> Medical condition

Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis. Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Loss of micronutrients may also be a cause.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase deficiency</span> Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

<span class="mw-page-title-main">Methylcobalamin</span> Form of vitamin B12

Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin, a form of vitamin B12. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and can be obtained as bright red crystals. From the perspective of coordination chemistry, methylcobalamin is notable as a rare example of a compound that contains metal–alkyl bonds. Nickel–methyl intermediates have been proposed for the final step of methanogenesis.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase</span> Mammalian protein found in Homo sapiens

Methylmalonyl-CoA mutase (EC 5.4.99.2, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

<span class="mw-page-title-main">Methylmalonic acid</span> Chemical compound

Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.

<span class="mw-page-title-main">Hydroxocobalamin</span> Form of vitamin B12

Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment for cyanide poisoning, Leber's optic atrophy, and toxic amblyopia. It is given by injection into a muscle or vein.

<span class="mw-page-title-main">Methylmalonyl-CoA</span> Chemical compound

Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle. The compound is sometimes referred to as "methylmalyl-CoA".

<span class="mw-page-title-main">Adenosylcobalamin</span> Biologically active form of vitamin B12

Adenosylcobalamin (AdoCbl), also known as coenzyme B12, cobamamide, and dibencozide, is, along with methylcobalamin (MeCbl), one of the biologically active forms of vitamin B12.

<span class="mw-page-title-main">Cobalamin riboswitch</span>

Cobalamin riboswitch is a cis-regulatory element which is widely distributed in 5' untranslated regions of vitamin B12 (Cobalamin) related genes in bacteria.

Vitamin B<sub>12</sub> deficiency Disorder resulting from low blood levels of vitamin B12

Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. Symptoms can vary from none to severe. Mild deficiency may have few or absent symptoms. In moderate deficiency, feeling tired, headaches, soreness of the tongue, mouth ulcers, breathlessness, feeling faint, rapid heartbeat, low blood pressure, pallor, hair loss, decreased ability to think and severe joint pain and the beginning of neurological symptoms, including abnormal sensations such as pins and needles, numbness and tinnitus may occur. Severe deficiency may include symptoms of reduced heart function as well as more severe neurological symptoms, including changes in reflexes, poor muscle function, memory problems, blurred vision, irritability, ataxia, decreased smell and taste, decreased level of consciousness, depression, anxiety, guilt and psychosis. If left untreated, some of these changes can become permanent. Temporary infertility, reversible with treatment, may occur. A late finding type of anemia known as megaloblastic anemia is often but not always present. In exclusively breastfed infants of vegan mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement.

Vitamin B<sub><small>12</small></sub> Vitamin used in animal cells metabolism

Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. It is important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the circulatory system in the maturation of red blood cells in the bone marrow. Plants do not need cobalamin and carry out the reactions with enzymes that are not dependent on it.

<span class="mw-page-title-main">MMAA</span> Protein-coding gene in the species Homo sapiens

Methylmalonic aciduria type A protein, mitochondrial also known as MMAA is a protein that in humans is encoded by the MMAA gene.

<span class="mw-page-title-main">MMACHC</span> Protein-coding gene in the species Homo sapiens

Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is a protein that in humans is encoded by the MMACHC gene.

<span class="mw-page-title-main">Imerslund–Gräsbeck syndrome</span> Medical condition

Imerslund–Gräsbeck syndrome is a rare autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the "Cubam" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.

<span class="mw-page-title-main">Vitamin B12-binding domain</span> Type of protein domain

In molecular biology, the vitamin B12-binding domain is a protein domain which binds to cobalamin. It can bind two different forms of the cobalamin cofactor, with cobalt bonded either to a methyl group (methylcobalamin) or to 5'-deoxyadenosine (adenosylcobalamin). Cobalamin-binding domains are mainly found in two families of enzymes present in animals and prokaryotes, which perform distinct kinds of reactions at the cobalt-carbon bond. Enzymes that require methylcobalamin carry out methyl transfer reactions. Enzymes that require adenosylcobalamin catalyse reactions in which the first step is the cleavage of adenosylcobalamin to form cob(II)alamin and the 5'-deoxyadenosyl radical, and thus act as radical generators. In both types of enzymes the B12-binding domain uses a histidine to bind the cobalt atom of cobalamin cofactors. This histidine is embedded in a DXHXXG sequence, the most conserved primary sequence motif of the domain. Proteins containing the cobalamin-binding domain include:

<span class="mw-page-title-main">Cobalamin biosynthesis</span>

Cobalamin biosynthesis is the process by which bacteria and archea make cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it is used by enzymes in both the producing organisms and other species, including humans who acquire it through their diet.

<span class="mw-page-title-main">Cobalt in biology</span> Use of Cobalt by organisms

Cobalt is essential to the metabolism of all animals. It is a key constituent of cobalamin, also known as vitamin B12, the primary biological reservoir of cobalt as an ultratrace element. Bacteria in the stomachs of ruminant animals convert cobalt salts into vitamin B12, a compound which can only be produced by bacteria or archaea. A minimal presence of cobalt in soils therefore markedly improves the health of grazing animals, and an uptake of 0.20 mg/kg a day is recommended because they have no other source of vitamin B12.

References

  1. ↑ Prieto L, Neuburger M, Spingler B, Zelder F (October 2016). "Inorganic Cyanide as Protecting Group in the Stereospecific Reconstitution of Vitamin B12 from an Artificial Green Secocorrinoid" (PDF). Organic Letters. 18 (20): 5292–5295. doi:10.1021/acs.orglett.6b02611. PMID   27726382.
  2. 1 2 3 4 "Vitamin B12 Injection: Side Effects, Uses & Dosage". Drugs.com. Retrieved 19 April 2019.
  3. ↑ "Cyanocobalamin – Drug Usage Statistics, United States, 2006–2016". ClinCalc.com. Retrieved 9 November 2019.
  4. ↑ https://www.tga.gov.au/therapeutic-goods-exempted-pregnancy-categorisation [ bare URL ]
  5. 1 2 3 4 5 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 993–994. ISBN   9780857113382.
  6. 1 2 "Cyanocobalamin Side Effects in Detail". Drugs.com. Retrieved 19 April 2019.
  7. ↑ Linnell JC, Matthews DM, England JM (November 1978). "Therapeutic misuse of cyanocobalamin". Lancet. 2 (8098): 1053–1054. doi:10.1016/s0140-6736(78)92379-6. PMID   82069. S2CID   29703726.
  8. ↑ Herbert V (September 1988). "Vitamin B-12: plant sources, requirements, and assay". The American Journal of Clinical Nutrition. 48 (3 Suppl): 852–858. doi:10.1093/ajcn/48.3.852. PMID   3046314.
  9. 1 2 "DailyMed – cyanocobalamin, isopropyl alcohol". dailymed.nlm.nih.gov. Retrieved 19 April 2019.
  10. 1 2 3 Lilley LL, Collins SR, Snyder JS (2019). Pharmacology and the Nursing Process E-Book. Elsevier Health Sciences. p. 83. ISBN   9780323550468.
  11. 1 2 3 "Cyanocobalamin - FDA prescribing information, side effects and uses". Drugs.com. Retrieved 19 April 2019.
  12. ↑ Markle HV (1996). "Cobalamin". Critical Reviews in Clinical Laboratory Sciences. 33 (4): 247–356. doi:10.3109/10408369609081009. PMID   8875026.
  13. ↑ Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux S (2014). Nathan and Oski's Hematology and Oncology of Infancy and Childhood E-Book. Elsevier Health Sciences. p. 309. ISBN   9780323291774.
  14. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  15. ↑ "Cyanocobalamin - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  16. ↑ Cyanocobalamin. University of Maryland Medical Center
  17. ↑ MacLennan L, Moiemen N (February 2015). "Management of cyanide toxicity in patients with burns". Burns. 41 (1): 18–24. doi:10.1016/j.burns.2014.06.001. PMID   24994676.
  18. ↑ "Cyanocobalamin Injection". MedlinePlus. Archived from the original on 19 April 2015. Retrieved 4 July 2015.
  19. ↑ "Clinical Vitamin B12 Deficiency. Managing Patients". Centers for Disease Control and Prevention. Archived from the original on 26 April 2015. Retrieved 4 July 2015.
  20. ↑ "Vitamin B12". MedlinePlus. Archived from the original on 5 April 2015. Retrieved 4 July 2015.
  21. ↑ Quadros EV (January 2010). "Advances in the understanding of cobalamin assimilation and metabolism". British Journal of Haematology. 148 (2): 195–204. doi:10.1111/j.1365-2141.2009.07937.x. PMC   2809139 . PMID   19832808.
  22. ↑ "Cyanocobalamin Injection". Empower Pharmacy. Retrieved 2 April 2021.
  23. ↑ "Vitamin B12 (Cyanocobalamin)". +Medicine LibreTexts. 12 May 2017. Retrieved 2 April 2021.
  24. ↑ "TERMIUM Plus®". Canada.ca. Government of Canada. 8 October 2009. Retrieved 2 April 2021.
  25. ↑ "Nascobal® (Cyanocobalamin, USP) Nasal Spray 500 mcg/spray 0.125 mL Rx only" (PDF). Access Data FDA. Retrieved 2 April 2021.
  26. ↑ Pimenta E, Calhoun DA, Oparil S (2010). "Chapter 28: Hypertensive emergencies". In Jeremias A, Brown DL (eds.). Cardiac Intensive Care (2nd ed.). Philadelphia, PA: Saunders/Elsevier. ISBN   978-1-4160-3773-6.
  27. 1 2 3 4 5 6 Dolphin D (January 1971). "[205] Preparation of the reduced forms of vitamin B12 and of some analogs of the vitamin B12 coenzyme containing a cobalt-carbon bond". In McCormick DB, Wright LD (eds.). [205] Preparation of the reduced forms of vitamin B12 and of some analogs of the vitamin B12 coenzyme containing a cobalt-carbon bond. Methods in Enzymology. Vol. 18. Academic Press. pp. 34–52. doi:10.1016/S0076-6879(71)18006-8. ISBN   9780121818821.
  28. ↑ Brodie JD (February 1969). "On the mechanism of catalysis by vitamin B12". Proceedings of the National Academy of Sciences of the United States of America. 62 (2): 461–467. Bibcode:1969PNAS...62..461B. doi: 10.1073/pnas.62.2.461 . PMC   277821 . PMID   5256224.
  29. ↑ Shimakoshi H, Hisaeda Y. "Environmental-friendly catalysts learned from Vitamin B
    12    -dependent enzymes"     (PDF). Tcimail. 128: 2.    [ permanent dead link ]
  30. ↑ Riaz M, Ansari ZA, Iqbal F, Akram M (2007). "Microbial production of vitamin B12 by methanol utilizing strain of Pseudomonas specie". Pak J. Biochem. Mol. Biol. 40: 5–10. Archived from the original on 25 April 2012. Retrieved 31 October 2017.
  31. ↑ Linnell JC, Matthews DM (February 1984). "Cobalamin metabolism and its clinical aspects". Clinical Science. 66 (2): 113–121. doi:10.1042/cs0660113. PMID   6420106.
  32. ↑ Herbert V (September 1988). "Vitamin B-12: plant sources, requirements, and assay". The American Journal of Clinical Nutrition. 48 (3 Suppl): 852–858. doi:10.1093/ajcn/48.3.852. PMID   3046314.
  33. ↑ Zhang Y (26 January 2009). "New round of price slashing in vitamin B12 sector (Fine and Specialty)". China Chemical Reporter. Archived from the original on 13 May 2013.
  34. ↑ Hannibal L, Kim J, Brasch NE, Wang S, Rosenblatt DS, Banerjee R, et al. (August 2009). "Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product". Molecular Genetics and Metabolism. 97 (4): 260–266. doi:10.1016/j.ymgme.2009.04.005. PMC   2709701 . PMID   19447654.
  35. ↑ Watanabe F, Nakano Y (1997). "Purification and characterization of aquacobalamin reductases from mammals". Vitamins and Coenzymes Part K. Methods in Enzymology. Vol. 281. pp. 295–305. doi:10.1016/S0076-6879(97)81036-1. ISBN   9780121821821. PMID   9250994.
  36. ↑ Quadros EV, Jackson B, Hoffbrand AV, Linnell JC (8 October 2019). "Interconversion of cobalamins in human lymphocytes in vitro and the influence of nitrous oxide on synthesis of cobalamin coenzymes". Vitamin B12, Proceedings of the Third European Symposium on Vitamin B12 and Intrinsic Factor. De Gruyter. pp. 1045–1054. doi:10.1515/9783111510828-118. ISBN   978-3-11-151082-8.
  37. ↑ "DSM in Food, Beverages & Dietary Supplements". DSM. Retrieved 2 March 2015.
  38. ↑ Thompson AG, Leite MI, Lunn MP, Bennett DL (June 2015). "Whippits, nitrous oxide and the dangers of legal highs". Practical Neurology. 15 (3): 207–209. doi:10.1136/practneurol-2014-001071. PMC   4453489 . PMID   25977272.
  39. ↑ Watanabe F, Abe K, Fujita T, Goto M, Hiemori M, Nakano Y (January 1998). "Effects of Microwave Heating on the Loss of Vitamin B(12) in Foods". Journal of Agricultural and Food Chemistry. 46 (1): 206–210. doi:10.1021/jf970670x. PMID   10554220. S2CID   23096987.
  40. ↑ Mancia F, Evans PR (June 1998). "Conformational changes on substrate binding to methylmalonyl CoA mutase and new insights into the free radical mechanism". Structure. 6 (6): 711–720. doi: 10.1016/S0969-2126(98)00073-2 . PMID   9655823.
  41. ↑ Evans JC, Huddler DP, Hilgers MT, Romanchuk G, Matthews RG, Ludwig ML (March 2004). "Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase". Proceedings of the National Academy of Sciences of the United States of America. 101 (11): 3729–3736. Bibcode:2004PNAS..101.3729E. doi: 10.1073/pnas.0308082100 . PMC   374312 . PMID   14752199.
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