Niacinamide - Monograph

Alternative Medicine Review, Dec, 2002

Introduction

Niacinamide, also known as nicotinamide, is a water-soluble amide of nicotinic acid. Niacinamide is one of two principal forms of the B-complex vitamin, B3. Niacin was first isolated from rice bran in 1911. Niacinamide, the amide of niacin, was later isolated in 1934 by Warburg and Christian when coenzyme II, NADP, was extracted from horse erythrocytes. (1) While niacinamide and niacin have identical vitamin activities (i.e., they both prevent development of the vitamin B3-deficiency condition, pellagra), they have very different pharmacological activities.

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Biochemistry

The structure of niacinamide consists of a pyridine ring with an amide group in position three. Niacinamide is a component of nicotinamide adenine dinucleotide (NAD), also known as coenzyme I, and nicotinamide adenine dinucleotide phosphate (NADP), also known as coenzyme II. These coenzymes are involved in many intracellular oxidation-reduction reactions. They participate in hydrogen transfer reactions, functioning as hydride ion carriers of biological systems.

Pharmacokinetics

The pharmacokinetics of niacinamide depend on dose, species, gender, and route of administration. (2) Niacinamide is readily absorbed from all parts of the gastrointestinal tract. (3) A negligible portion of niacinamide is metabolized to niacin, mostly due to bacterial activity. (4) Peak serum concentrations are reached in humans within one hour of oral ingestion of standard preparations. (5) Niacinamide is rapidly cleared from the circulation and distributed in all tissues. It has a high hepatic excretion ratio and plasma clearance can be reduced in patients with hepatic insufficiency. (6)

Mechanisms of Action

Niacinamide acts as an antioxidant by preventing NAD depletion during DNA repair by inhibiting poly (ADP-ribose) polymerase (PARP), which also modulates major histocompatibility complex (MHC) class II expression. Niacinamide inhibits free radical formation and facilitates beta-cell regeneration in vivo and in vitro. (7,8) Additional protection from macrophage toxins may be involved in prevention of type 1 diabetes. (9) Specifically, niacinamide has been shown, via PARP inhibition, to protect pancreatic islet-cell lysis alter exposure to oxygen free radicals (10) and nitric oxide. (11,12) Niacinamide has also been found to stimulate GABA receptors, without binding to the receptor sites, thus creating a benzodiazepine-like effect. (13)

Anti-inflammatory action affecting neutrophil chemotaxis has been reported for niacinamide. (14) Additionally, due to its inhibition of ADP-ribosylation, niacinamide has been shown to suppress cytokine-mediated induction of nitric oxide synthase in a number of cells, thus effecting interleukin-1-exposed chondrocytes, resulting in decreased inflammation. (15)

Deficiency States

Pellagra, a disease consisting of bilaterally symmetrical lesions on both sides of the body and hands, occurs as a result of a niacin deficiency. The disease is characterized by hyperpigmentation and thickening of the skin, inflammation of the tongue and mouth, and digestive disturbances including indigestion, anorexia, and diarrhea. In late stages of the disease, irritability, amnesia, and delirium occur.

Clinical Indications

Diabetes

The time of diagnosis of type 1 diabetes is crucial for the potential success of any intervention. Early diagnosis is associated with higher residual C-peptide secretion and a better chance of clinical remission. (16) Treatment with high-dose niacinamide has been shown to exert protective effects on beta-cell function in humans. In a recent meta-analysis, 10 randomized, controlled trials were analyzed. A combined analysis of 158 niacinamide-treated and 129 control patients with recent-onset type 1 diabetes revealed significantly better preservation of basal C-peptide secretion in the niacinamide-receiving cohort after one year. Sub-analysis of the five placebo-controlled trials yielded the same result. (17)

There are studies that show no beneficial effect of niacinamide in terms of clinical remission of type 1 diabetes. The patients enrolled in negative studies were diagnosed with diabetes between the ages of 10 and 15, suggesting increased insulin resistance, occurring during and around the time of puberty, may be the reason for a lack of positive outcome using niacinamide in this population. (18-20)

Niacinamide has been used successfully to prevent or delay the onset of type 1 diabetes among high-risk individuals, defined by high islet-cell antibodies and family history of type 1 diabetes. In a New Zealand study of 80,000 children, 5-7 years old, 20,000 were screened for islet-cell antibodies. (21) The 150 children with positive islet-cell antibodies received niacinamide therapy. The incidence of type 1 diabetes in the treated group was eight per 100,000/year, well below the rate of 15-20 per 100,000/year observed among the 60,000 children who were not screened or subsequently treated.