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Cyanocobalamin

2007 Schools Wikipedia Selection. Related subjects: Chemical compounds

                                         Cyanocobalamin chemical structure

   Cyanocobalamin

                                                  Systematic ( IUPAC) name
                                                                         ?
                                                               Identifiers
                                                        CAS number 68-19-9
                                                         ATC code B03 BB01
                                                           PubChem 5479203
                                                        DrugBank APRD00326
                                                             Chemical data
                                          Formula C[63]H[88]CoN[14]O[14]P^
                                                 Mol. weight 1355.37 g/mol
                                                      Pharmacokinetic data
                      Bioavailability readily absorbed in lower half ileum
     Protein binding Very high to specific transcobalamins plasma proteins
       Binding of hydroxocobalamin is slightly higher than cyanocobalamin.
                                                        Metabolism hepatic
                                            Half life Approximately 6 days
                                                   (400 days in the liver)
                                                           Excretion renal
                                                Therapeutic considerations
                                                            Pregnancy cat.

                                                                         ?
                                                              Legal status

                                                                   POM(UK)
                                                           Routes oral, iv

   Cyanocobalamin is a vitamin commonly known as vitamin B[12] (or B[12]
   for short).

   The name vitamin B[12] is used in two different ways. In a broad sense
   it refers to a group of cobalt-containing compounds known as cobalamins
   - cyanocobalamin (an artifact formed as a result of the use of cyanide
   in the purification procedures), hydroxocobalamin and the two coenzyme
   forms of B[12], methylcobalamin (MeB[12]) and 5-deoxyadenosylcobalamin
   ( adenosylcobalamin - AdoB[12]). In a more specific way, the term B[12]
   is used to refer to only one of these forms, cyanocobalamin, which is
   the principal B[12] form used for foods and in nutritional supplements.

   Pseudo-B[12] refers to B[12]-like substances which are found in certain
   organisms; however, these substances do not have B[12] biological
   activity for humans.

Structure

   B[12] is the most chemically complex of all the vitamins. The structure
   of B[12] is based on a corrin ring, which is similar to the porphyrin
   ring found in heme, chlorophyll, and cytochrome. The central metal ion
   is Co (cobalt). Four of the six coordination sites are provided by the
   corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth
   coordination site, the centre of reactivity, is variable, being a cyano
   group (-CN), a hydroxyl group (-OH), a methyl group (-CH[3]) or a
   5'-deoxy adenosyl group (here the C5' atom of the deoxyribose forms the
   covalent bond with Co), respectively, to yield the four B[12] forms
   mentioned above. The covalent C-Co bond is the only carbon-metal bond
   known in biology.

Synthesis

   B[12] cannot be made by plants or by animals, as the only type of
   organisms that have the enzymes required for the synthesis of B[12] are
   bacteria and archaea. The total synthesis of B[12] was reported in 1973
   by Robert Burns Woodward, and remains one of the classic feats of total
   synthesis.

Functions

   Coenzyme B[12]'s reactive C-Co bond participates in two types of
   enzyme-catalyzed reactions.
    1. Rearrangements in which a hydrogen atom is directly transferred
       between two adjacent atoms with concomitant exchange of the second
       substituent, X, which may be a carbon atom with substituents, an
       oxygen atom of an alcochol, or an amine.
    2. Methyl (-CH[3]) group transfers between two molecules.

   In humans there are only two coenzyme B[12]-dependent enzymes:
    1. MUT which uses the AdoB[12] form and reaction type 1 to catalyze a
       carbon skeleton rearrangement (the X group is -COSCoA). MUT's
       reaction converts MMl-CoA to Su-CoA, an important step in the
       extraction of energy from proteins and fats (for more see MUT's
       reaction mechanism)
    2. MTR, a methyl transfer enzyme, which uses the MeB[12] and reaction
       type 2 to catalyzes the conversion of the amino acid Hcy into Met
       (for more see MTR's reaction mechanism).

History as a treatment for anaemia

   B[12] deficiency is the cause of several forms of anaemia. The
   treatment for this disease was first devised by William Murphy who bled
   dogs to make them anaemia and then fed them various substances to see
   what (if anything) would make them healthy again. He discovered that
   ingesting large amounts of liver seemed to cure the disease. George
   Minot and George Whipple then set about to chemically isolate the
   curative substance and ultimately were able to isolate vitamin B[12]
   from the liver. For this, all three shared the 1934 Nobel Prize in
   Medicine.

   The chemical structure of the molecule was determined by Dorothy
   Crowfoot Hodgkin and her team in 1956, based on crystallographic data.

Other medical uses

   Hydroxycobalamin is used in Europe as a treatment for cyanide
   poisoning, with a large amount (5-10 g) given intravenously, in
   combination with sodium thiosulfate. The treatment is marketed under
   the tradename Cyanokit . The mechanism of action is straightforward,
   the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide
   ion, and the resulting harmless B[12] is excreted in urine.

Deficiency

   The usual daily intake in the Western diet is 5–7 µg ( Food and Drug
   Administration (FDA) Daily Value ); the daily requirement is 1–2 µg.
   B[12] is mostly absorbed in the terminal ileum. The production of
   intrinsic factor in the stomach is vital to absorption of this vitamin.
   Megaloblastic anaemia can result from inadequate intake of B[12],
   inadequate production of intrinsic factor (pernicious anaemia),
   disorders of the terminal ileum resulting in malabsorption, or by
   competition for available B[12] (such as fish tapeworms or bacteria
   present in blind loop syndrome).

   Hematological deficiency is manifested primarily by anaemia and
   macrocytosis; other cell lines such as white blood cells and platelets
   are often also low. Bone marrow examination may show megaloblastic
   hemopoiesis. Serum homocysteine and methylmalonic acid levels are also
   high in B[12] deficiency and can be helpful if the diagnosis is
   unclear.

   Neurological signs of B[12] deficiency, which can occur without
   accompanying hematologic abnormalities, include demyelination and
   irreversible nerve cell death. Symptoms include numbness or tingling of
   the extremities and an ataxic gait, a syndrome known as subacute
   combined degeneration of the cord.

   The American Psychiatric Association's American Journal of Psychiatry
   has published studies showing a relationship between depression levels
   and deficient B[12] blood levels in elderly people in 2000 and 2002 .

Diagnosis of B[12] deficiency

   Serum B[12] levels are often low in B[12] deficiency, but there does
   not exist a robust assay, and if other features of B12 deficiency are
   present then the diagnosis must not be discounted. One possible
   explanation for normal B[12] levels in B[12] deficiency is antibody
   interference in people with high titres of intrinsic factor antibody.
   Bone marrow aspiration, serum homocysteine and methylmalonic acid
   levels can also be helpful.

Treatment of B12 deficiency

   Traditionally, treatment for B[12] deficiency was through intramuscular
   injections of cyanocobalamin. However, it has recently been appreciated
   that deficiency can be treated with oral B[12] supplements when given
   in sufficient doses. When given in oral doses ranging from 0.1–2 mg
   daily, B[12] can be absorbed in a pathway that does not require an
   intact ileum or intrinsic factor. The Schilling test can determine
   whether symptoms of B[12] deficiency are caused by lack of intrinsic
   factor, though this is being performed less often due to the lack of
   availability of reagent for the test.

Allergies

   Vitamin B12 supplements should be avoided in people sensitive or
   allergic to cobalamin, cobalt or any other product ingredients.

Side effects, contraindications, and warnings

     * Cardiovascular: Caution should be used in patients undergoing
       angioplasty since an intravenous loading dose of folic acid,
       vitamin B6 and vitamin B12 followed by oral administration of folic
       acid 1.2mg plus vitamin B6 48mg and vitamin B12 60mcg taken daily
       after coronary stenting might actually increase restenosis rates.
       Due to the potential for harm this combination of vitamins should
       not be recommended for patients receiving coronary stents.
     * Dermatologic: Itching, rash, transitory exanthema, and urticaria
       have been reported. Vitamin B12 (20 micrograms/day) and pyridoxine
       (80mg/day) has been associated with cases of rosacea fulminans,
       characterized by intense erythema with nodules, papules, and
       pustules. Symptoms may persist for up to 4 months after the
       supplement is stopped, and may require treatment with systemic
       corticosteroids and topical therapy.

     * Gastrointestinal: Diarrhea has been reported.
     * Hematologic: Peripheral vascular thrombosis has been reported.
       Treatment of vitamin B12 deficiency can unmask polycythemia vera,
       which is characterized by an increase in blood volume and the
       number of red blood cells. The correction of megaloblastic anaemia
       with vitamin B12 can result in fatal hypokalemia and gout in
       susceptible individuals, and it can obscure folate deficiency in
       megaloblastic anaemia. Caution is warranted.

     * Leber's disease: Vitamin B12 is contraindicated in early Leber's
       disease, which is hereditary optic nerve atrophy. Vitamin B12 can
       cause severe and swift optic atrophy.

Pregnancy and breastfeeding

   Vitamin B12 is likely safe when used orally in amounts that do not
   exceed the recommended dietary allowance (RDA). The RDA for vitamin B12
   in pregnant women is 2.6mcg per day and 2.8mcg during lactation
   periods.

   There is insufficient reliable information available about the safety
   of consuming greater amounts of Vitamin B12 during pregnancy.

Interactions

Interactions with drugs

     * Alcohol (ethanol): Excessive alcohol intake lasting longer than two
       weeks can decrease vitamin B12 absorption from the gastrointestinal
       tract.
     * Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser):
       Aminosalicylic acid can reduce oral vitamin B12 absorption,
       possibly by as much as 55%, as part of a general malabsorption
       syndrome. Megaloblastic changes, and occasional cases of
       symptomatic anaemia have occurred, usually after doses of 8 to 12
       grams/day for several months. Vitamin B12 levels should be
       monitored in people taking aminosalicylic acid for more than one
       month.
     * Antibiotics: An increased bacterial load can bind significant
       amounts of vitamin B12 in the gut, preventing its absorption. In
       people with bacterial overgrowth of the small bowel, antibiotics
       such as metronidazole (Flagyl®) can actually improve vitamin B12
       status. The effects of most antibiotics on gastrointestinal
       bacteria are unlikely to have clinically significant effects on
       vitamin B12 levels.
     * Birth control pills: The data regarding the effects of oral
       contraceptives on vitamin B12 serum levels are conflicting. Some
       studies have found reduced serum levels in oral contraceptive
       users, but others have found no effect despite use of oral
       contraceptives for up to 6 months. When oral contraceptive use is
       stopped, normalization of vitamin B12 levels usually occurs. Lower
       vitamin B12 serum levels seen with oral contraceptives probably are
       not clinically significant.
     * Chloramphenicol (Chloromycetin®): Limited case reports suggest that
       chloramphenicol can delay or interrupt the reticulocyte response to
       supplemental vitamin B12 in some patients. Blood counts should be
       monitored closely if this combination cannot be avoided.
     * Cobalt irradiation: Cobalt irradiation of the small bowel can
       decrease gastrointestinal (GI) absorption of vitamin B12.
     * Colchicine: Colchicine in doses of 1.9 to 3.9mg/day can disrupt
       normal intestinal mucosal function, leading to malabsorption of
       several nutrients, including vitamin B12. Lower doses do not seem
       to have a significant effect on vitamin B12 absorption after 3
       years of colchicine therapy. The significance of this interaction
       is unclear. Vitamin B12 levels should be monitored in people taking
       large doses of colchicine for prolonged periods.
     * Colestipol (Colestid®), Cholestyramine (Questran®): These resins
       used for sequestering bile acids in order to decrease cholesterol,
       can decrease gastrointestinal (GI) absorption of vitamin B12. It is
       unlikely that this interaction will deplete body stores of vitamin
       B12 unless there are other factors contributing to deficiency. In a
       group of children treated with cholestyramine for up to 2.5 years
       there was not any change in serum vitamin B12 levels. Routine
       supplements are not necessary.
     * H[2] blockers: include cimetidine (Tagamet®), famotidine (Pepcid®),
       nizatidine (Axid®), and ranitidine (Zantac®). Reduced secretion of
       gastric acid and pepsin produced by H[2] blockers can reduce
       absorption of protein-bound (dietary) vitamin B12, but not of
       supplemental vitamin B12. Gastric acid is needed to release vitamin
       B12 from protein for absorption. Clinically significant vitamin B12
       deficiency and megaloblastic anaemia are unlikely, unless H[2]
       blocker therapy is prolonged (2 years or more), or the person's
       diet is poor. It is also more likely if the person is rendered
       achlorhydric (with complete absence of gastric acid secretion),
       which occurs more frequently with proton pump inhibitors than H[2]
       blockers. Vitamin B12 levels should be monitored in people taking
       high doses of H[2] blockers for prolonged periods.
     * Metformin (Glucophage®): Metformin may reduce serum folic acid and
       vitamin B12 levels. These changes can lead to hyperhomocysteinemia,
       adding to the risk of cardiovascular disease in people with
       diabetes. There are also rare reports of megaloblastic anaemia in
       people who have taken metformin for 5 years or more. Reduced serum
       levels of vitamin B12 occur in up to 30% of people taking metformin
       chronically. However, clinically significant deficiency is not
       likely to develop if dietary intake of vitamin B12 is adequate.
       Deficiency can be corrected with vitamin B12 supplements even if
       metformin is continued. The metformin-induced malabsorption of
       vitamin B12 is reversible by oral calcium supplementation. The
       general clinical significance of Metformin upon B12 levels is as
       yet unknown.
     * Neomycin: Absorption of vitamin B12 can be reduced by neomycin, but
       prolonged use of large doses is needed to induce pernicious
       anaemia. Supplements are not usually needed with normal doses.
     * Nicotine: Nicotine can reduce serum vitamin B12 levels. The need
       for vitamin B12 supplementation has not been adequately studied.
     * Nitrous oxide: Nitrous oxide inactivates the cobalamin form of
       vitamin B12 by oxidation. Symptoms of vitamin B12 deficiency,
       including sensory neuropathy, myelopathy, and encephalopathy, can
       occur within days or weeks of exposure to nitrous oxide anesthesia
       in people with subclinical vitamin B12 deficiency. Symptoms are
       treated with high doses of vitamin B12, but recovery can be slow
       and incomplete. People with normal vitamin B12 levels have
       sufficient vitamin B12 stores to make the effects of nitrous oxide
       insignificant, unless exposure is repeated and prolonged (nitrous
       oxide abuse). Vitamin B12 levels should be checked in people with
       risk factors for vitamin B12 deficiency prior to using nitrous
       oxide anesthesia.
     * Phenytoin (Dilantin®), phenobarbital, primidone (Mysoline®): These
       anticonvulsants have been associated with reduced vitamin B12
       absorption, and reduced serum and cerebrospinal fluid levels in
       some patients. This may contribute to the megaloblastic anemia,
       primarily caused by folate deficiency, associated with these drugs.
       It's also suggested that reduced vitamin B12 levels may contribute
       to the neuropsychiatric side effects of these drugs. Patients
       should be encouraged to maintain adequate dietary vitamin B12
       intake. Folate and vitamin B12 status should be checked if symptoms
       of anaemia develop.
     * Proton pump inhibitors (PPIs): The PPIs include omeprazole
       (Prilosec®, Losec®), lansoprazole (Prevacid®), rabeprazole
       (Aciphex®), pantoprazole (Protonix®, Pantoloc®), and esomeprazole
       (Nexium®). The reduced secretion of gastric acid and pepsin
       produced by PPIs can reduce absorption of protein-bound (dietary)
       vitamin B12, but not supplemental vitamin B12. Gastric acid is
       needed to release vitamin B12 from protein for absorption. Reduced
       vitamin B12 levels may be more common with PPIs than with
       H2-blockers, because they are more likely to produce achlorhydria
       (complete absence of gastric acid secretion). However, clinically
       significant vitamin B12 deficiency is unlikely, unless PPI therapy
       is prolonged (2 years or more) or dietary vitamin intake is low.
       Vitamin B12 levels should be monitored in people taking high doses
       of PPIs for prolonged periods.
     * Zidovudine (AZT, Combivir®, Retrovir®): Reduced serum vitamin B12
       levels may occur when zidovudine therapy is started. This adds to
       other factors that cause low vitamin B12 levels in people with HIV,
       and might contribute to the hematological toxicity associated with
       zidovudine. However, data suggests vitamin B12 supplements are not
       helpful for people taking zidovudine.

Interactions with herbs and dietary supplements

     * Folic acid: Folic acid, particularly in large doses, can mask
       vitamin B12 deficiency. In vitamin B12 deficiency, folic acid can
       produce hematologic improvement in megaloblastic anaemia, while
       allowing potentially irreversible neurological damage to progress.
       Vitamin B12 status should be determined before folic acid is given
       as monotherapy.
     * Potassium: Potassium supplements can reduce absorption of vitamin
       B12 in some people. This effect has been reported with potassium
       chloride and, to a lesser extent, with potassium citrate. Potassium
       might contribute to vitamin B12 deficiency in some people with
       other risk factors, but routine supplements are not necessary.
     * Vitamin C: Preliminary evidence suggests that vitamin C supplements
       can destroy dietary vitamin B12. However, other components of food,
       such as iron and nitrates, might counteract this effect. Clinical
       significance is unknown, and it can likely be avoided if vitamin C
       supplements are taken at least 2 hours after meals.

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