Niacin

Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient.[2] It has the formula C
6
H
5
NO
2
and belongs to the group of the pyridinecarboxylic acid.[2]

Niacin
Kekulé, skeletal formula of niacin
Ball and stick model of niacin
Names
Pronunciation /ˈnəsɪn/
Preferred IUPAC name
Pyridine-3-carboxylic acid[1]
Other names
  • Nicotinic acid (INN)
  • Bionic
  • Vitamin B3
  • Vitamin PP
Identifiers
CAS Number
3D model (JSmol)
3DMet
Beilstein Reference
109591
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.401
EC Number
  • 200-441-0
Gmelin Reference
3340
KEGG
MeSH Niacin
PubChem CID
RTECS number
  • QT0525000
UNII
Properties
Chemical formula
C6H5NO2
Molar mass 123.111 g·mol−1
Appearance White, translucent crystals
Density 1.473 g cm−3
Melting point 237 °C; 458 °F; 510 K
Solubility in water
18 g L−1
log P 0.219
Acidity (pKa) 2.0, 4.85
Isoelectric point 4.75
Refractive index (nD)
1.4936
Dipole moment
0.1271305813 D
Thermochemistry
Std enthalpy of
formation fH298)
−344.9 kJ mol−1
Std enthalpy of
combustion cH298)
−2.73083 MJ mol−1
Pharmacology
C04AC01 (WHO) C10AD02 (WHO)
License data
Intramuscular, by mouth
Pharmacokinetics:
20–45 min
Hazards
GHS pictograms
GHS Signal word Warning
GHS hazard statements
H319
GHS precautionary statements
P264, P280, P305+351+338, P337+313, P501
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
1
0
Flash point 193 °C (379 °F; 466 K)
Autoignition
temperature
365 °C (689 °F; 638 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

Niacin is obtained in the diet from a variety of whole and processed foods, with highest contents in fortified packaged foods, tuna, salmon, some vegetable and other animal sources.[2] Some countries require its addition to grains.[2][3] Supplemental niacin is primarily used to treat high blood cholesterol and pellagra (niacin deficiency). Insufficient amounts of niacin can cause nausea, skin and mouth lesions, anemia, headaches, and tiredness. This lack of niacin may also be observed in pandemic deficiency diseases, which are caused by a lack of five crucial vitamins (niacin, vitamin C, thiamin, vitamin D, and vitamin A) and are usually found in areas of widespread poverty and malnutrition.[2]

Niacin supplementation has not been found useful for decreasing the risk of cardiovascular disease in those already on a statin,[4] but appears to be effective in those not taking a statin.[5] Although niacin and nicotinamide (niacinamide) are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects (lipid-modifying effects) as niacin. When niacin takes on the -amide group, it does not reduce cholesterol or cause flushing.[6] As the precursor for NAD and NADP, niacin is also involved in DNA repair.[7][8] In 2016 it was the 277th most prescribed medication in the United States with more than a million prescriptions.[9] It has the European food additive series E number of E375.

Medical uses

Treatment of deficiency

Niacin and niacinamide are used for prevention and treatment of pellagra.[10]

Abnormal lipids

Niacin has sometimes been used in addition to other lipid-lowering medications.[11] Systematic reviews found no effect of niacin on cardiovascular disease or death, in spite of raising HDL cholesterol, and reported side effects including an increased risk of diabetes.[4][12][13]

Contraindications

Niacin is contraindicated with active liver disease, persistent elevated serum transaminases, active peptic ulcer disease, or arterial bleeding.[14]

Adverse effects

The most common adverse effects of niacin at relatively low doses (50–500 mg) are flushing (e.g., warmth, redness, itching or tingling), headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash.[14][15] These can be minimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach.[14]

The acute adverse effects of high-dose niacin therapy (1–3 grams/day) – which is commonly used in the treatment of hyperlipidemias – further include hypotension, fatigue, glucose intolerance and insulin resistance, heartburn, blurred or impaired vision, and macular edema.[15] With long-term use, the adverse effects of high-dose niacin therapy also include hepatic dysfunction (associated with fatigue, nausea, and loss of appetite), hepatitis, and acute liver failure;[15] these hepatotoxic effects of niacin occur more often when extended-release dosage forms are used.[15] The long-term use of niacin at high doses (2 grams/day) also significantly increases the risk of cerebral hemorrhage, ischemic stroke, gastrointestinal ulceration and bleeding, diabetes, dyspepsia, and diarrhea.[15]

Facial flushing

Flushing usually lasts for about 15 to 30 minutes, though it can sometimes last up to two hours. It is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing. Flushing can be blocked by taking 300 mg of aspirin half an hour before taking niacin, by taking one tablet of ibuprofen per day or by co-administering the prostaglandin receptor antagonist laropiprant. Taking niacin with meals also helps reduce this side effect. Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most patients no longer experience flushing.[16] Reduction of flushing focuses on altering or blocking the prostaglandin-mediated pathway.[17] Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects.[18][19]

Prostaglandin (PGD2) is the primary cause of the flushing reaction, with serotonin appearing to have a secondary role in this reaction.[20] The effect is mediated by prostaglandin E2 and D2 due to GPR109A activation of epidermal Langerhans cells and keratinocytes.[21][22] Langerhans cells use cyclooxygenase type 1 (COX-1) for PGE2 production and are more responsible for acute flushing, while keratinocytes are COX-2 dependent and are in active continued vasodilation.[23][24] Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction.[20]

Gastrointestinal and hepatic

Hepatotoxicity is possibly related to metabolism via amidation resulting in NAD production.[25] The time-release form has a lower therapeutic index for lowering serum lipids relative to this form of toxicity.[26]

Diabetes

The high doses of niacin used to improve the lipid profile have been shown to elevate blood sugar by 5-10%, thereby worsening existing diabetes mellitus.[27]

One review found that niacin therapy was associated with an increase in the risk of new-onset diabetes over 3.6 years from 4.9% to 5.5%.[28]

Other

Side effects of heart arrhythmias have also been reported.[27] Increased prothrombin time and decreased platelet count have been reported; therefore, these should be monitored closely in patients who are also taking anticoagulants.[14]

Particularly the time-release variety, at extremely high doses, can cause acute toxic reactions.[29] Extremely high doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases.[30]

Pregnancy

Niacin in doses used to lower cholesterol levels has been associated with birth defects in laboratory animals, with possible consequences for infant development in pregnant women.[27]

Deficiency

A man with pellagra, which is caused by a chronic lack of vitamin B3 in the diet

Between 1906 and 1940 more than 3 million Americans were affected by pellagra, with more than 100,000 deaths. Joseph Goldberger was assigned to study pellagra by the Surgeon General of the United States and produced good results. In the late 1930s, studies by Tom Spies, Marion Blankenhorn, and Clark Cooper established that niacin cured pellagra in humans. The disease was greatly reduced as a result.

At present, niacin deficiency is sometimes seen in developed countries, and it is usually apparent in conditions of poverty, malnutrition, and chronic alcoholism.[31] It also tends to occur in less developed areas where people eat maize (corn) as a staple food, as maize is the only grain low in digestible niacin. A cooking technique called nixtamalization i.e., pretreating with alkali ingredients, increases the bioavailability of niacin during maize meal/flour production. For this reason, people who consume corn as tortillas or hominy are not at risk of niacin deficiency.

Mild niacin deficiency has been shown to slow metabolism, causing decreased tolerance to cold.

Severe deficiency of niacin in the diet causes the disease pellagra, which is characterized by diarrhea, dermatitis, and dementia, as well as Casal's necklace lesions on the lower neck, hyperpigmentation, thickening of the skin, inflammation of the mouth and tongue, digestive disturbances, amnesia, delirium, and eventually death, if left untreated.[32] Common psychiatric symptoms of niacin deficiency include irritability, poor concentration, anxiety, fatigue, restlessness, apathy, and depression.[32] Studies have indicated that, in patients with alcoholic pellagra, niacin deficiency may be an important factor influencing both the onset and severity of this condition. Patients with alcoholism typically experience increased intestinal permeability, leading to negative health outcomes.

Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency.[32] This condition was first identified in the 1950s by the Hartnup family in London. It is due to a deficit in the intestines and kidneys, making it difficult for the body to break down and absorb dietary tryptophan (an essential amino acid that is utilized to synthesize niacin). The resulting condition is similar to pellagra, including symptoms of red, scaly rash, and sensitivity to sunlight. Oral niacin is given as a treatment for this condition in doses ranging from 40–200 mg, with a good prognosis if identified and treated early.[32] Niacin synthesis is also deficient in carcinoid syndrome, because of metabolic diversion of its precursor tryptophan to form serotonin.

Dietary recommendations

Dietary recommendations
Australia and New Zealand
Age group RDI for niacin (mg NE/day)[33] Upper level of intake[33]
Infants 0–6 months2 mg/d preformed niacin*ND
Infants 7–12 months4 mg/d NE*
1–3610
4–8815
9–131220
14–1830
19+35
Females 14+14
Males 14+16
Pregnant females 14–5018
Pregnant females 14–1830
Pregnant females 19–5035
Lactating females 14–5017
Lactating females 14–1830
Lactating females 19–5035
* Adequate Intake for infants[34]
Canada
Age group (years) RDA of niacin (mg NE/d)[35] Tolerable upper intake level[35]
0–6 months2 mg/d preformed niacin*ND
7–12 months4 mg/d NE*
1–3610
4–8815
9–131220
Females 14–181430
Males 14–1816
Females 19+1435
Males 19+16
Pregnant females <181830
Pregnant females 18–501835
Lactating females <181730
Lactating females 18–501735
European Food Safety Authority
Gender Adequate Intake (mg NE/MJ)[36]
Females1.3
Males1.6
Age (years) Tolerable upper limit of Nicotinic acid (mg/day)[36] Tolerable upper limit of Nicotinamide (mg/day)[36]
1–32150
4–63220
7–104350
11–146500
15–178700
United States
Age group RDA for niacin (mg NE/day) Tolerable upper intake level[34]
Infants 0–6 months2*ND**
Infants 6–12 months4*
1–3610
4–8815
9–131220
Females 14–181430
Males 14–181630
Females 19+1435
Males 19+1635
Pregnant females 14–181830
Pregnant females 19–501835
Lactating females 14–181730
Lactating females 19–501735
* Adequate intake for infants, as an RDA has yet to be established
** Not possible to establish; source of intake should be formula and food only[34]

The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for niacin in 1998.[34] The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values (DRV), with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women (including those pregnant or lactating), men and children the PRI is 1.6 mg niacin per megajoule (MJ) of energy consumed. As the conversion is 1 MJ = 238.8 kcal, an adult consuming 2388 calories should be consuming 16 mg niacin. This is comparable to U.S. RDAs.[37] The niacin UL is set at 10 mg/day, which is much less than the U.S. value. The UL applies to niacin as a supplement consumed as one dose, and in intended to avoid the skin flush reaction. This explains why the PRI can be higher than the UL.[38]

Both the DRI and DRV describe amounts needed as niacin equivalents (NE), calculated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid is utilized to synthesize the vitamin.[34][37]

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For niacin labeling purposes 100% of the Daily Value was 20 mg, but as of 27 May 2016 it was revised to 16 mg to bring it into agreement with the RDA.[39] A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was 28 July 2018, but on 29 September 2017 the FDA released a proposed rule that extended the deadline to 1 January 2020 for large companies and 1 January 2021 for small companies.[40]

Food sources

Niacin is found in a variety of whole and processed foods, including fortified packaged foods, meat from various animal sources, seafoods, and spices.[2][41]

Among whole food sources with the highest niacin content per 100 grams:

Meats

  • cooked skipjack tuna, 18.8 mg
  • cooked light meat turkey, 11.8 mg
  • cooked, lean ground pork, 11.1 mg
  • cooked venison, 10.8 mg
  • cooked, lean veal, 8.0 mg

Plant foods and spices

  • sesame seed flour, 12.5 mg
  • ground ginger, 9.6 mg
  • dried tarragon, 9.0 mg
  • dried, green sweet peppers, 7.4 mg
  • grilled portobello mushrooms, 6.2 mg
  • roasted sunflower seeds, 4.1 mg
  • dehydrated apricots, 3.6 mg
  • baked potato, 3.1 mg

Fortified breakfast cereals have among the highest niacin contents (more than 20 mg per 100 grams).[41] Whole grain flours, such as from wheat, rice, barley or corn, and pasta have niacin contents in a range of 3–10 mg per 100 grams.[41]

Pharmacology

Pharmacodynamics

Niacin and nicotinamide are both precursors of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in vivo.[42] NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. NADP and NAD are coenzymes for many dehydrogenases, participating in many hydrogen transfer processes.[43] NAD is important in catabolism of fat, carbohydrate, protein, and alcohol, as well as cell signaling and DNA repair, and NADP mostly in anabolism reactions such as fatty acid and cholesterol synthesis.[43] High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency.[44]

The therapeutic effects of niacin are partly mediated through the activation of G protein-coupled receptors, including niacin receptor 1 (NIACR1) and niacin receptor 2 (NIACR2) which are highly expressed in adipose tissue, spleen, immune cells, and keratinocytes, but not in other expected organs such as liver, kidney, heart or intestine.[45][46] NIACR1 and NIACR2 inhibit cyclic adenosine monophosphate (cAMP) production and thus fat breakdown in adipose tissue and free fatty acids available for liver to produce triglycerides and very-low-density lipoproteins (VLDL) and consequently low-density lipoprotein (LDL).[25][47] A decrease in free fatty acids also suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus increasing VLDL turnover and reducing its production.[48]

The mechanism behind niacin increasing HDL is not totally understood, but seems to occur in various ways. Niacin increases apolipoprotein A1 levels due to anticatabolic effects resulting in higher reverse cholesterol transport. It also inhibits HDL hepatic uptake, down-regulating production of the cholesterol ester transfer protein (CETP) gene.[49] Finally, it stimulates the ABCA1 transporter in monocytes and macrophages and upregulates peroxisome proliferator-activated receptor gamma, resulting in reverse cholesterol transport.[50]

Niacin reduces secondary outcomes associated with atherosclerosis, such as low-density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG), but increases high-density lipoprotein cholesterol (HDL).[49] Despite the importance of other cardiovascular risk factors, high HDL was associated with fewer cardiovascular events independent of LDL reduction.[51][52] Other effects include anti-thrombotic and vascular inflammation, improving endothelial function, and plaque stability.[53] As mediators produced from adipocytes, adipokines, such as tumor necrosis factor (TNF)-a, interleukins and chemokines, have pro-inflammatory effects, while others, such as adiponectin, have anti-inflammatory effects that influence the onset of atherosclerosis.[54] Niacin also appears to upregulate brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) expression.[55]

Research has been able to show the function of niacin in the pathway lipid metabolism. It is seen that this vitamin can decrease the synthesis of apoB-containing lipoproteins such as VLDL, LDL, IDL and lipoprotein (a) via several mechanisms: (1) directly inhibiting the action of DGAT2, a key enzyme for triglyceride synthesis; (2) influencing binding to the receptor HCAR2 thereby decreasing lipolysis and FFA flux to the liver for triglyceride synthesis; and (3) increasing apoB catabolism. HDL cholesterol levels are increased by niacin through direct and indirect pathways, such as by decreasing cholesterylester transfer protein activity and triglyceride levels, while increasing HDL cholesterol levels.[56]

Pharmacokinetics

Niacin, serotonin (5-hydroxytryptamine), and melatonin biosynthesis from tryptophan

Biosynthesis

The liver can synthesize niacin from the essential amino acid tryptophan, requiring 60 mg of tryptophan to make 1 mg of niacin. Riboflavin, vitamin B6 and iron are required for the process.[34]

Physical and chemical properties

This colorless, water-soluble solid 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 a carboxamide group (CONH
2
), as well as more complex amides and a variety of esters.

Laboratory synthesis

Several thousand tons of niacin are manufactured each year, starting from 3-methylpyridine.

Preparations

Niacin is available as a prescription product, and in the United States as a dietary supplement. Prescription products can be immediate release (Niacor, 500 mg tablets) or extended release (Niaspan, 500 and 1000 mg tablets). Dietary supplement products can be immediate or slow release, the latter including inositol hexanicotinate.[57][58] The last has questionable clinical efficacy in reducing cholesterol levels.[59]

Nicotinamide

Nicotinamide may be obtained from the diet where it is present primarily as NAD+ and NADP+. These are hydrolysed in the intestine and the resulting nicotinamide is absorbed either as such, or following its hydrolysis to nicotinic acid. Nicotinamide is present in nature in only small amounts, however it is the main form of vitamin B3 in plasma. In unprepared foods, niacin is present mainly in the form of the cellular pyridine nucleotides NAD and NADP. Enzymatic hydrolysis of the co-enzymes can occur during the course of food preparation. Boiling releases most of the total niacin present in sweet corn as nicotinamide (up to 55 mg/kg).

Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.[60]

Extended release

A prescription extended release niacin, Niaspan, has a film coating that delays release of the niacin, resulting in an absorption over a period of 8–12 hours. The extended release formulations generally reduce vasodilation and flushing side effects, but increase the risk of hepatotoxicity compared to the immediate release forms.[61][62]

A formulation of laropiprant (Merck & Co., Inc.) and niacin had previously been approved for use in Europe and marketed as Tredaptive. Laropiprant is a prostaglandin D2 binding drug shown to reduce vasodilatation and flushing up to 73%.[49][63][64][65] The HPS2-THRIVE study,[66] a study sponsored by Merck, showed no additional efficacy of Tredaptive in lowering cholesterol when used together with other statin drugs, but did show an increase in other side effects. The study resulted in the complete withdrawal of Tredaptive from the international market.[67][68][69]

Inositol hexanicotinate

Inositol hexanicotinate

One form of dietary supplement is inositol hexanicotinate (IHN), also called inositol nicotinate, which is inositol that has been esterified with niacin on all six of inositol's alcohol groups.[70] IHN is usually sold as "flush-free" or "no-flush" niacin in units of 250, 500, or 1000 mg/tablets or capsules. It is sold as an over-the-counter formulation, and often is marketed and labeled as niacin, thus misleading consumers into thinking they are getting the active form of the medication. While this form of niacin does not cause the flushing associated with the immediate-release products, the evidence that it has lipid-modifying functions is disputed. As the clinical trials date from the early 1960s (Dorner, Welsh) or the late 1970s (Ziliotto, Kruse, Agusti), it is difficult to assess them by today's standards.[71] One of the last of those studies affirmed the superiority of inositol and xantinol esters of nicotinic acid for reducing serum free fatty acid,[72] but other studies conducted during the same period found no benefit.[73] Studies explain that this is primarily because "flush-free" preparations do not contain any free nicotinic acid. A more recent placebo-controlled trial was small (n=11/group), but results after three months at 1500 mg/day showed no trend for improvements in total cholesterol, LDL-C, HDL-C or triglycerides.[74] Thus, so far there is not enough evidence to recommend IHN to treat dyslipidemia.

Rename

In 1942, when flour enrichment with nicotinic acid began, a headline in the popular press said "Tobacco in Your Bread." So the Council on Foods and Nutrition of the American Medical Association approved of the Food and Nutrition Board's new names niacin and niacin amide for use primarily by non-scientists. It was thought appropriate to choose a name to dissociate it from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins.[75] The resulting name niacin was derived from nicotinic acid + vitamin.[76][77]

History

Niacin was first described by chemist Hugo Weidel in 1873 in his studies of nicotine.[78] The original preparation remains useful: the oxidation of nicotine using nitric acid.[79] For the first time, niacin was extracted by Casimir Funk, but he thought that it was thiamine and due to the discovered amine group he coined the term "vitamine". Niacin was extracted from livers by biochemist Conrad Elvehjem in 1937, who later identified the active ingredient, then referred to as the "pellagra-preventing factor" and the "anti-blacktongue factor."[80] Soon after, in studies conducted in Alabama and Cincinnati, Dr. Tom Spies found that nicotinic acid cured the sufferers of pellagra.[81]

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", "vitamin P-P" and "PP-factor", that are derived from the term "pellagra-preventive factor".[76] Carpenter found in 1951 that niacin in corn is biologically unavailable, and can be released only in very alkaline lime water of pH 11.[82] In 1955, Altschul and colleagues described niacin as having a lipid-lowering property.[83] As such, niacin is the oldest known lipid-lowering drug.

Research

In animal models and in vitro, niacin produces marked anti-inflammatory effects in a variety of tissues – including the brain, gastrointestinal tract, skin, and vascular tissue – through the activation of NIACR1.[84][85][86][87] Niacin has been shown to attenuate neuroinflammation and may have efficacy in treating neuroimmune disorders such as multiple sclerosis and Parkinson's disease.[84][87] Unlike niacin, nicotinamide does not activate NIACR1; however, both niacin and nicotinamide activate the G protein-coupled estrogen receptor (GPER) in vitro.[88]

In 2014, concurring with earlier work in 2001 by Arizona State University, researchers from Pennsylvania State University working with NASA found niacin, pyridine carboxylic acids and pyridine dicarboxylic acids inside meteorites.[89]

References

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    When taken in pharmacologic doses of 1,000 to 3,000 mg/day, nicotinic acid can also cause more serious adverse effects [2,4,14,37]. Many of these effects have occurred in patients taking high-dose nicotinic acid supplements to treat hyperlipidemias. These adverse effects can include hypotension severe enough to increase the risk of falls; fatigue; impaired glucose tolerance and insulin resistance; gastrointestinal effects, such as nausea, heartburn, and abdominal pain; and ocular effects, such as blurred or impaired vision and macular edema (a buildup of fluid at the center of the retina). High doses of nicotinic acid taken over months or years can also be hepatotoxic; effects can include increased levels of liver enzymes; hepatic dysfunction resulting in fatigue, nausea, and anorexia; hepatitis; and acute liver failure [2,14,30,38]. Hepatotoxicity is more likely to occur with the use of extended-release forms of nicotinic acid [14,39,40].
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