Hydroxocobalamin

Hydroxocobalamin

Systematic (IUPAC) name
Coα-[α-(5,6-dimethylbenzimidazolyl)]- Coβ-hydroxocobamide
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a605007
Pregnancy cat.	?
Legal status	Prescription injectable in U.S. Not DEA-controlled
Routes	Injectable (IM, intravenous, or subcutaneous)
Pharmacokinetic data
Protein binding	Very high (90%)
Metabolism	Primarily hepatic. Cobalamins are absorbed in the ileum and stored in the liver.
Half-life	~6 days
Identifiers
CAS number	13422-51-0 Y
ATC code	B03BA03 V03AB33
PubChem	CID 6433575
DrugBank	APRD01022
ChemSpider	21160115 Y
UNII	Q40X8H422O Y
KEGG	D01027 Y
ChEMBL	CHEMBL1200742 N
Chemical data
Formula	C62H89CoN13O15P
Mol. mass	1346.37 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C62H90N13O14P.Co.H2O/c1-29-20-40-41(21-30(29)2)75(28-70-40)56-52(84)53(42(27-76)87-56)89-90(85,86)88-31(3)26-69-49(83)19-15-36-50-32(4)54-58(6,7)34(12-16-43(63)77)38(71-54)22-39-35(13-17-44(64)78)59(8,23-46(66)80)55(72-39)33(5)51-37(14-18-45(65)79)61(10,25-48(68)82)62(11,74-51)57(73-50)60(36,9)24-47(67)81;;/h20-22,28,31,34-37,42,52-53,56-57,76,84H,12-19,23-27H2,1-11H3,(H15,63,64,65,66,67,68,69,71,72,73,74,77,78,79,80,81,82,83,85,86);;1H2/q;+3;/p-3 Y Key:GTSMWDDKWYUXGH-UHFFFAOYSA-K Y
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Hydroxocobalamin (OHCbl, or B_12a) is a natural form, or vitamer, of vitamin B₁₂, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B₁₂ produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B₁₂, hydroxocobalamin has an intense red color. It is not a form normally found in the human body, but is easily converted in the body to usable coenzyme forms of vitamin B₁₂. Pharmaceutically, hydroxycobalamin is usually produced as a sterile injectable solution, and is used for treatment of the vitamin deficiency, and also (because of its afinity for cyanide ion) as a treatment for cyanide poisoning.^[1] Experimentally, it has been tested as a scavenger of nitric oxide.

Vitamin B₁₂ is a term that refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions: (1) the mitochondrial methylmalonylcoenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and (2) activation of methionine synthase, which is the rate limiting step in the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate.

Chemical characteristics

Description: OHCbl acetate occurs as an odorless, dark-red orthorhombic needles. The injection formulations appear as a clear, dark-red solution. Distribution Coefficient: 1.133 × 10-5 (octanol:acetate buffer pH 7.4) pKa: 7.65 Systematic Name: Cobinamide, Co-hydroxy-, dihydrogen phosphate (ester), inner salt, 3'- ester with (5,6-dimethyl-1-alpha-D-ribofuranosyl-1H-benzimidazole- kappaN3)

Causes of deficiency

Hydroxocobalamin Injection USP, are used to rectify the following causes of vitamin B₁₂ deficiency (list taken from the drug prescription label published by the U.S. Food and Drug Administration (FDA):

• Pernicious anemia, whether uncomplicated or accompanied by nervous system involvement
• Dietary deficiency of vitamin B₁₂ occurring in strict vegetarians and in their breastfed infants. (Isolated vitamin B₁₂ deficiency is very rare.)
• Malabsorption of vitamin B₁₂ resulting from structural or functional damage to the stomach where intrinsic factor is secreted or to the ileum where intrinsic factor facilitates vitamin B₁₂ absorption (These conditions include tropical sprue and nontropical sprue [idiopathic steatorrhea, gluten-induced enteropathy]. Folate deficiency in these patients is usually more severe than vitamin B₁₂ deficiency.)
• Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric mucosa (ingestion of corrosives, extensive neoplasia, and a number of conditions associated with a variable degree of gastric atrophy, such as multiple sclerosis, certain endocrine disorders, iron deficiency, and subtotal gastrectomy). (Total gastrectomy always produces vitamin B₁₂ deficiency.)
• Structural lesions leading to vitamin B₁₂ deficiency include regional ileitis, ileal reactions, malignancies, etc.
• Competition for vitamin B₁₂ by intestinal parasites or bacteria
• The fish tapeworm (Diphyllobothrium latum) absorbs huge quantities of vitamin B₁₂ and infested patients often have associated gastric atrophy. The blind loop syndrome may produce deficiency of vitamin B₁₂ or folate.
• Inadequate utilization of vitamin B₁₂ (This may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia.)

Indications

Vitamin B₁₂ deficiency

Vitamin B₁₂ compounds are used as prescription medicine (injection) for vitamin B₁₂ replacement therapy, usually at 100 mcg/dose. In the UK 1,000mcg (1 mg) per dose is generally used. Damage that results from vitamin B₁₂ deficiency can be prevented with early diagnosis and adequate treatment.

For most, the standard therapy for treatment of vitamin B₁₂ deficiency has been intramuscular (IM) injections of vitamin B₁₂ in the form of cyanocobalamin (CNCbl) or hydroxocobalamin (OHCbl). CNCbl is traditionally prescribed in the United States. Outside of the United States, OHCbl is most generally used for vitamin B₁₂ replacement therapy and is considered the “drug of choice” for vitamin B₁₂ deficiency by the Martindale Extra Pharmacopoeia (Sweetman, 2002) and the World Health Organization (WHO) Model List of Essential Drugs. This preference for OHCbl in many countries is due to its long retention in the body and the need for less frequent IM injections in restoring vitamin B₁₂ (cobalamin) serum levels. Furthermore, IM administration of OHCbl is also the preferred treatment for pediatric patients with intrinsic cobalamin metabolic diseases; vitamin B₁₂ deficient patients with tobacco amblyopia due to cyanide poisoning; and patients with pernicious anemia who have optic neuropathy (Carethers, 1988; Chisholm et al., 1967; Freeman, 1992; Markle, 1996).

In a newly-diagnosed vitamin B₁₂-deficient patient, normally defined as when serum cobalamin (vitamin B₁₂) levels are less than 200 pg/mL, daily IM injections of OHCbl up to 1,000 μg (1 mg) per day are given to replenish the body’s depleted cobalamin stores. In the presence of neurological symptoms, following daily treatment, injections up to weekly or biweekly are indicated for 6 months before initiating monthly IM injections. Once clinical improvement is confirmed, maintenance supplementation of B₁₂ will generally be needed for life.

Cyanide poisoning

Hydroxocobalamin has also been used in the treatment of cyanide poisoning.^[2][3][4]

Hydoxyocobalamin is marketed under the trade name Cyanokit for cyanide toxicity.^[5] The standard dose is 5 gm IV infused over 15 minutes. A second 5 gm dose can be given in patients with severe toxicity. Hydroxocobalamin will bind circulating and cellular cyanide molecules to form cyanocobalamin which is excreted in the urine.^[3]

Experimental uses as nitric oxide scavenger and antiinflammatory

Hydroxycobalamin is a scavenger of nitric oxide as well as cyanide, and has been used experimentally to modifify nitric oxide mediated inflammation. For example, a hydoxocobalamin skin creme was found to reduce chronic skin inflammation.^[6]

Hydroxycobalamin has also been used in a pilot-study treatment of migraines, as an inhibitor of nitric oxide induced vasodilation.^[7]

Toxicity

The literature data on the acute toxicity profile of OHCbl show that it is generally regarded as safe with local and systemic exposure. The ability of OHCbl to rapidly scavenge and detoxify cyanide by chelation has resulted in several acute animal and human studies using systemic OHCbl doses at suprapharmacological doses as high as 140 mg/kg to support its use as an intravenous (IV) treatment for cyanide exposure (Forsyth et al., 1993; Riou et al., 1993). The US FDA at the end of 2006 approved the use OHCbl as an injection for the treatment of cyanide poisoning.

Vitamin B₁₂ group

Vitamin B₁₂ is a term that refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions: (1) the mitochondrial methylmalonyl coenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and (2) activation of methionine synthase, which is the rate limiting step in the synthesis of methionine from homocysteine and tetrahydrofolate (Katzung, 1989). Cobalamins are characterized by a porphyrin-like corrin nucleus that contains a single cobalt atom bound to a benzimidazolyl nucleotide and a variable residue (R) group. The variable R group gives rise to the four most commonly known cobalamins: CNCbl, methylcobalamin, 5-deoxyadenosylcobalamin, and OHCbl. In the serum, OHCbl and CNCbl are believed to function as storage or transport forms of the molecule; whereas, methylcobalamin and 5¢ deoxyadenosylcobalamin are the active forms of the coenzyme required for cell growth and replication (Katzung, 1989). CNCbl is usually converted to OHCbl in the serum, whereas OHCbl is converted to either methylcobalamin or 5¢ deoxyadenosyl cobalamin. Cobalamins circulate bound to serum proteins called transcobalamins (TC) and haptocorrins. OHCbl has a higher affinity to the TC II transport protein than CNCbl, or 5- deoxyadenosylcobalamin. From a biochemical point of view, two essential enzymatic reactions require vitamin B₁₂ (cobalamin) (Katzung, 1989, Hardman, 2001). Intracellular vitamin B₁₂ is maintained in two active coenzymes, methylcobalamin and 5¢ deoxyadenosylcobalamin, which are both involved in specific enzymatic reactions. In the face of vitamin B₁₂ deficiency, conversion of methylmalonyl-CoA to succinyl-CoA cannot take place, which results in accumulation of methylmalonyl CoA and aberrant fatty acid synthesis. In the other enzymatic reaction, methylcobalamin supports the methionine synthase reaction, which is essential for normal metabolism of folate. The folate-cobalamin interaction is pivotal for normal synthesis of purines and pyrimidines and the transfer of the methyl group to cobalamin is essential for the adequate supply of tetrahydrofolate, the substrate for metabolic steps that require folate. In a state of vitamin B₁₂ deficiency, the cell responds by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate. The resulting elevated concentrations of homocysteine and MMA are often found in patients with low serum vitamin B₁₂ and can usually be lowered with successful vitamin B₁₂ replacement therapy. However, elevated MMA and homocysteine concentrations may persist in patients with cobalamin concentrations between 200 to 350 pg/mL (Lindenbaum et al. 1994). Supplementation with vitamin B₁₂ during conditions of deficiency restores the intracellular level of cobalamin and maintains a sufficient level of the two active coenzymes: methylcobalamin and deoxyadenosylcobalamin.

See also

• Cobamamide
• Methylcobalamin
• Nitric oxide
• Vitamin B12

References

1. ^ Dart, Richard C., "Hydroxocobalamin for Acute Cyanide Poisoning", Clinical Toxicology, 2006, Vol. 44, No. s1, Pages 1-3, Retrieved (2010-02-14)
2. ^ Hall AH, Dart R, Bogdan G (June 2007). "Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide poisoning?". Ann Emerg Med 49 (6): 806–13. doi:10.1016/j.annemergmed.2006.09.021. PMID 17098327. http://linkinghub.elsevier.com/retrieve/pii/S0196-0644(06)02276-1. 
3. ^ ^{a b} Shepherd G, Velez LI (May 2008). "Role of hydroxocobalamin in acute cyanide poisoning". Ann Pharmacother 42 (5): 661–9. doi:10.1345/aph.1K559. PMID 18397973. http://www.theannals.com/cgi/pmidlookup?view=long&pmid=18397973. 
4. ^ Borron SW, Baud FJ, Mégarbane B, Bismuth C (June 2007). "Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation". Am J Emerg Med 25 (5): 551–8. doi:10.1016/j.ajem.2006.10.010. PMID 17543660. http://linkinghub.elsevier.com/retrieve/pii/S0735-6757(06)00436-0. 
5. ^ CYANOKIT.com
6. ^ [1] Topical vitamin B12—a new therapeutic approach in atopic dermatitis—evaluation of efficacy and tolerability in a randomized placebo-controlled multicentre clinical trial.British Journal of Dermatology Volume 150, Issue 5, pages 977–983, May 2004
7. ^ [2] An open study of hydroxocobalamin in migraine.

External links

• Hydroxocobalamin in the ChEBI database