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Hydroxocobalamin (OHCbl) is a natural analog of vitamin B-12, a basic member of the cobalamin family of compounds. Once described as the most beautiful compound in the world since it has an intense red color. 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 tetrahydrofolate (Katzung, 1989).
Additional recommended knowledge
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 B12 deficiency (list taken from the drug prescription label published by the FDA:
a. Pernicious anemia, whether uncomplicated or accompanied by nervous system involvement
b. Dietary deficiency of vitamin B12 occurring in strict vegetarians and in their breastfed infants. (Isolated vitamin B12 deficiency is very rare.)
c. 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.)
d. 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.)
e. Structural lesions leading to vitamin B12 deficiency include regional ileitis, ileal reactions, malignancies, etc.
f. Competition for vitamin B12 by intestinal parasites or bacteria
g. 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.
h. Inadequate utilization of vitamin B12 (This may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia.)
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 (1mg) 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 (1mg) 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 IM injections of OHCbl or CNCbl must be given for life.
Recent regulatory approval for use for cyanide poisoning at doses from 2.5 to 10 gm per injection. Hydroxocobalamin will bind circulating and cellular cyanide molecules to form cyanocobalamin which is excreted in the urine.
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 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 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 synthetase 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.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Hydroxocobalamin". A list of authors is available in Wikipedia.|