Nutrition Guide

Niacin was first described by Hugo Weidel in 1873 in his studies of nicotine.[4] The original preparation remains useful: the oxidation of nicotine using nitric acid.[5] Niacin was extracted from livers by Conrad Elvehjem who later identified the active ingredient, then referred to as the “pellagra-preventing factor” and the “anti-blacktongue factor.”[6] When the biological significance of nicotinic acid was realized, it was thought appropriate to choose a name to dissociate it from nicotine, in order to avoid the perception that vitamins or niacin-rich food contains nicotine. The resulting name ‘niacin’ was derived from nicotinic acid + vitamin.

Carpenter found in 1951 that niacin in corn is biologically unavailable and can only be released in very alkali lime water of pH 11.[7] This process is known as nixtamalization.[8]

Niacin is referred to as Vitamin B3 because it was the third of the B vitamins to be discovered. It has historically been referred to as “vitamin PP.”

Niacin, also known as vitamin B3, is a water-soluble vitamin which prevents the deficiency disease pellagra. It is an organic compound with the molecular formula C6H5NO2. It is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amide, nicotinamide (”niacinamide”), where the carboxyl group has been replaced by an amide group (CONH2), as well as more complex amides and a variety of esters. The terms niacin, nicotinamide, and vitamin B3 are often used interchangeably to refer to any one of this family of molecules, since they have a common biochemical activity.

Niacin is converted to nicotinamide and then to NAD and NADP in vivo. Although the two are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects of niacin, which occur as side-effects of niacin’s conversion. Thus nicotinamide does not reduce cholesterol or cause flushing,[1] although nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.[2] Niacin is a precursor to NADH, NAD, NAD+, NADP and NADPH, which play essential metabolic roles in living cells.[3] Niacin is involved in both DNA repair, and the production of steroid hormones in the adrenal gland.

Niacin is one of five vitamins associated with a pandemic deficiency disease: these are niacin (pellagra), vitamin C (scurvy), thiamin (beriberi), vitamin D (rickets), and vitamin A (no common name, but one of the most common symptomatic deficiencies worldwide).

Methylcobalamin is a cobalamin (MeB12) used in peripheral neuropathy, diabetic neuropathy etc. It is a form of vitamin B12. It has been studied in conjunction with sleep-wake rhythm disorders, where it appears to yield benefits, but at a low or inconsistent level.[1]

It is used in treating diseases of vitamin B12 deficiency (such as pernicious anemia), or diseases of effective B12 deficiency, such as vitamin B12 metabMethylcobalamin is a cobalamin (MeB12) used in peripheral neuropathy, diabetic neuropathy etc. It is a form of vitamin B12. It has been studied in conjunction with sleep-wake rhythm disorders, where it appears to yield benefits, but at a low or inconsistent level.[1]

It is used in treating diseases of vitamin B12 deficiency (such as pernicious anemia), or diseases of effective B12 deficiency, such as vitamin B12 metabolic pathway pathologies.

One study suggests that once absorbed, methylcobalamin may be retained in the body better than cyanocobalamin.[2]
olic pathway pathologies.

One study suggests that once absorbed, methylcobalamin may be retained in the body better than cyanocobalamin.[2]

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.

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.

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.

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 ?g (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.

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.)

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)

Hydroxocobalamin (OHCbl) is a natural analog of vitamin B-12, a basic member of the cobalamin family of compounds. Iit 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).