hydroxocobalamin

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Standard therapy for treatment of vitamin B₁₂ deficiency has been intramuscular (IM) or intravenous (IV) injections of hydroxocobalamin (OHCbl), since the majority of cases are due to malabsorption by the enteral route (gut).{{cite journal | vauthors = Thakkar K, Billa G | title = Treatment of vitamin B12 deficiency – Methylcobalamine? Cyancobalamine? Hydroxocobalamin? – clearing the confusion | journal = European Journal of Clinical Nutrition | volume = 69 | issue = 1 | pages = 1–2 | date = January 2015 | pmid = 25117994 | doi = 10.1038/ejcn.2014.165 | doi-access = free }} It is used in 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.{{cite journal | vauthors = Carethers M | title = Diagnosing vitamin B12 deficiency, a common geriatric disorder | journal = Geriatrics | volume = 43 | issue = 3 | pages = 89–94, 105–107, 111–112 | date = March 1988 | pmid = 3277892 }}

In a newly diagnosed vitamin B₁₂-deficient patient, normally defined as when serum levels are less than 200 pg/ml, daily IM injections of hydroxocobalamin 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 six months before initiating monthly IM injections. Once clinical improvement is confirmed, maintenance supplementation of B₁₂ will generally be needed for life.{{citation needed|date=April 2020}}

Although less common in this form than cyanocobalamine and methylcobalamine, hydroxocobalamine is also available as pills for oral or sublingual administration. However, one study on the treatment of children with methylmalonic acidemia and homocystinuria found oral hydroxocobalamine at 1 mg daily to be ineffective in reducing levels of homocysteine. In a trial on adult volunteers, this dose did not lead to a significant increase in serum vitamin B₁₂ levels when given thrice daily for one week. In addition, once-daily administration of 1 mg oral hydroxocobalamine caused the studied children's levels of homocysteine to increase and their levels of methionine to decrease, while the reverse happened when hydroxocobalamine was given intramuscularly.{{cite journal | vauthors = Bartholomew DW, Batshaw ML, Allen RH, Roe CR, Rosenblatt D, Valle DL, Francomano CA | title = Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria | journal = The Journal of Pediatrics | volume = 112 | issue = 1 | pages = 32–39 | date = January 1988 | pmid = 3257264 | doi = 10.1016/s0022-3476(88)80114-8 | publisher = Elsevier BV }}

In 2006 the FDA approved hydroxocobalamin for treating smoke inhalation, which can cause cyanide poisoning.{{cite web |title=Bronx Firefighter Who Collapsed in Burning Home Likely Saved by Smoke Inhalation Drug | date = 20 May 2024 |url=https://www.insurancejournal.com/news/east/2024/05/20/775014.htm |website=Insurance Journal |access-date=20 May 2024}} Hydroxocobalamin is first line therapy for people with cyanide poisoning. Hydroxocobalamin converts cyanide to the much less toxic cyanocobalamin. Cyanocobalamin is renally cleared. The use of hydroxocobalamin became first line due to its low adverse risk profile, rapid onset of action, and ease of use in the prehospital setting.{{cite journal | vauthors = Shepherd G, Velez LI | title = Role of hydroxocobalamin in acute cyanide poisoning | journal = The Annals of Pharmacotherapy | volume = 42 | issue = 5 | pages = 661–669 | date = May 2008 | pmid = 18397973 | doi = 10.1345/aph.1K559 | s2cid = 24097516 | url = https://nootropicsfrontline.com/wp-content/uploads/2021/07/wiki_hydroxycobalamin-acute-cyanide-poisoning_removed.pdf | access-date = 23 July 2021 | archive-date = 7 November 2022 | archive-url = https://web.archive.org/web/20221107064416/https://nootropicsfrontline.com/wp-content/uploads/2021/07/wiki_hydroxycobalamin-acute-cyanide-poisoning_removed.pdf | url-status = dead }}

Injection of hydroxocobalamin is 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)

• 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 damage to the stomach, where intrinsic factor is secreted, or damage to the ileum, where intrinsic factor facilitates vitamin B₁₂ absorption. These conditions include tropical sprue and nontropical sprue (celiac disease).
• Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric mucosa (which can be caused by ingestion of corrosives, extensive tumors, and conditions associated with gastric atrophy, such as multiple sclerosis, certain endocrine disorders, iron deficiency, and subtotal gastrectomy)
• Structural lesions leading to vitamin B₁₂ deficiency, including regional ileitis, ileal reactions, and malignancies
• Competition for vitamin B₁₂ by intestinal parasites or bacteria. The tapeworm from undercooked fish (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 use of vitamin B₁₂, which may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia

Pernicious anemia is the most common cause of vitamin B₁₂ deficiency.{{cite book | vauthors = Qudsiya Z, De Jesus O | chapter = Subacute Combined Degeneration of the Spinal Cord | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK559316/ | title = StatPearls |publisher=StatPearls Publishing |date=2022|pmid=32644742 }} While it technically refers to anemia caused specifically by autoimmune deficiency of intrinsic factor, it is commonly used to refer to B₁₂-deficient anemia as a whole, regardless of cause.

The literature data on the acute toxicity profile of hydroxocobalamin show it is generally regarded as safe with local and systemic exposure. The ability of hydroxocobalamin to rapidly scavenge and detoxify cyanide by chelation has resulted in several acute animal and human studies using systemic hydroxocobalamin doses at suprapharmacological doses as high as 140 mg/kg to support its use as an intravenous (IV) treatment for cyanide exposure.{{cite journal | vauthors = Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH | title = Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers | journal = Journal of Toxicology. Clinical Toxicology | volume = 31 | issue = 2 | pages = 277–294 | date = 1993 | pmid = 8492341 | doi = 10.3109/15563659309000395}}{{cite journal | vauthors = Riou B, Berdeaux A, Pussard E, Giudicelli JF | title = Comparison of the hemodynamic effects of hydroxocobalamin and cobalt edetate at equipotent cyanide antidotal doses in conscious dogs | journal = Intensive Care Medicine | volume = 19 | issue = 1 | pages = 26–32 | date = 1993 | pmid = 8440794 | doi = 10.1007/BF01709274| s2cid = 19462753 }} The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning.

The drug causes a reddish discoloration of the urine (chromaturia), which can look like blood in the urine.{{cite journal | vauthors = Koratala A, Chamarthi G, Segal MS | title = Not all that is red is blood: a curious case of chromaturia | journal = Clinical Case Reports | volume = 6 | issue = 6 | pages = 1179–1180 | date = June 2018 | pmid = 29881591 | pmc = 5986001 | doi = 10.1002/ccr3.1514 }}

Hydroxocobalamin acetate occurs as odorless, dark-red orthorhombic crystals. The injection formulations appear as clear, dark-red solutions. It has a distribution coefficient of {{gaps|1.133|e=-5}} and a pKa of 7.65.{{citation needed|date=October 2023}}

Vitamin B₁₂ refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folate, 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:

• the mitochondrial methylmalonyl-CoA mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and
• the activation of methionine synthase, which is the rate-limiting step in the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate.{{cite book | vauthors = Katzung BG |title=Clinical Pharmacology |date=1989 |publisher=Appleton & Lange |location=Connecticut |isbn=978-0-8385-1301-9}}

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: cyanocobalamin (CNCbl), methylcobalamin (MeCbl), adenosylcobalamin (AdCbl, also known as cobamamide or 5-deoxyadenosylcobalamin), and hydroxocobalamin (OHCbl). In the serum, hydroxocobalamin and cyanocobalamin are believed to function as storage or transport forms of the molecule, whereas methylcobalamin and adenosylcobalamin are the active forms of the coenzyme required for cell growth and replication. Cyanocobalamin is usually converted to hydroxocobalamin in the serum, whereas hydroxocobalamin is converted to either methylcobalamin or adenosylcobalamin. Cobalamins circulate bound to serum proteins called transcobalamins (TC) and haptocorrins. Hydroxocobalamin has a higher affinity to the TC II transport protein than cyanocobalamin, or adenosylcobalamin. From a biochemical point of view, two essential enzymatic reactions require vitamin B₁₂ (cobalamin).{{cite book | vauthors = Hardman JG, Limbird LE, Gilman AG |title=Goodman & Gilman's The pharmacological basis of therapeutics |date=2001 |publisher=McGraw-Hill Medical Publications |location=New York, NY |isbn=978-0-07-135469-1 |edition=10th}}

Intracellular vitamin B₁₂ is maintained in two active coenzymes, methylcobalamin and adenosylcobalamin. 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 and 350 pg/mL.{{cite journal | vauthors = Savage DG, Lindenbaum J, Stabler SP, Allen RH | title = Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies | journal = The American Journal of Medicine | volume = 96 | issue = 3 | pages = 239–46 | date = March 1994 | pmid = 8154512 | doi = 10.1016/0002-9343(94)90149-x }} 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 adenosylcobalamin.

• Methylcobalamin
• Cyanocobalamin
• Vitamin B12
• Cobalamin biosynthesis

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