Chemistry:Nicotinic acid

From HandWiki
Short description: Organic compound and a form of vitamin B3
"Niacin" redirects here. For the vitamin group, see Vitamin B3. For other uses, see Niacin (disambiguation).

Nicotinic acid
Kekulé, skeletal formula of nicotinic acid
Kekulé, skeletal formula of nicotinic acid
Ball and stick model of nicotinic acid
Ball and stick model of nicotinic acid
Names
Pronunciation /ˈnaɪəsɪn/
Preferred IUPAC name
Pyridine-3-carboxylic acid[2]
Other names
  • Niacin (USAN US)[1]
  • Bionic
  • Vitamin B3
  • Vitamin PP
Identifiers
3D model (JSmol)
3DMet
109591
ChEBI
ChEMBL
ChemSpider
DrugBank
EC Number
  • 200-441-0
3340
KEGG
MeSH Niacin
RTECS number
  • QT0525000
UNII
Properties
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
18 g L−1
log P 0.219
Acidity (pKa) 2.0, 4.85
Isoelectric point 4.75
1.4936
Thermochemistry
−344.9 kJ mol−1
−2.73083 MJ mol−1
Pharmacology
1=ATC code }} C04AC01 (WHO) C10BA01 (WHO) C10AD02 (WHO) C10AD52 (WHO)
License data
Intramuscular, by mouth
Pharmacokinetics:
20–45 min
Hazards
GHS pictograms GHS07: Harmful
GHS Signal word Warning
H319
P264, P280, P305+351+338, P337+313, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondFlammability 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)
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).
checkY verify (what is checkY☒N ?)
Infobox references
Nicotinic acid
INN: Nicotinic acid
Clinical data
Trade namesNiacor, Niaspan, others
AHFS/Drugs.comMonograph
MedlinePlusa682518
License data
Pregnancy
category
Routes of
administration		Intramuscular, by mouth
Legal status
Legal status
  • US: OTC / Rx-only
Identifiers
PDB ligand

Template:Infobox drug/maintenance categories/container only

Space-filling model of nicotinic acid

Nicotinic acid,[lower-alpha 1] or niacin,[lower-alpha 2] is an organic compound and a vitamer of vitamin B3, an essential human nutrient.[4][5] It is produced by plants and animals from the amino acid tryptophan.[6]

Nicotinic acid is also a prescription medication.[7] Amounts far in excess of the recommended dietary intake for vitamin functions will lower blood triglycerides and low density lipoprotein cholesterol (LDL-C), and raise blood high density lipoprotein cholesterol (HDL-C, often referred to as "good" cholesterol). There are two forms: immediate-release and sustained-release nicotinic acid. Initial prescription amounts are 500 mg/day, increased over time until a therapeutic effect is achieved. Immediate-release doses can be as high as 3,000 mg/day; sustained-release as high as 2,000 mg/day.[7] Despite the proven lipid changes, nicotinic acid has not been found useful for decreasing the risk of cardiovascular disease in those already prescribed a statin drug.[8] A 2010 review had concluded that nicotinic acid was effective as a mono-therapy,[9] but a 2017 review incorporating twice as many trials concluded that prescription nicotinic acid, while affecting lipid levels, did not reduce all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes.[10] Prescription nicotinic acid was shown to cause hepatotoxicity[11] and increase risk of type 2 diabetes.[12][13] Nicotinic acid prescriptions in the United States had peaked in 2009 at 9.4 million,[14] declining to 800 thousand by 2020.[14] In 2023, it was the 288th most commonly prescribed medication in the US, with more than 500,000 prescriptions.[15][16]

Nicotinic acid has the formula C6H5NO2 and belongs to the group of the pyridinecarboxylic acids.[5] As the precursor for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, it is involved in DNA repair.[17]

Extra-terrestrial nicotinic acid has been found in carbonaceous chondrite meteorites[18] and in sample-returns from the asteroids 162173 Ryugu[19] and 101955 Bennu.[20]


Definition

The term "niacin" was originally coined from "nicotinic acid vitamin", with the goal of distancing the nutrient B3 from the drug nicotine in tobacco. As a result, it originally referred to the nutritional entity of vitamin B3.[21] However, in American English, the term has also come to mean "nicotinic acid" in the context of high-dose use as a prescription medicine.[22] In other varieties of English, the medicine is only ever called "nicotinic acid".[23] The term "nicotinic acid" unambiguously refers to the substance and the prescription medicine containing it, which treats elevated cholesterol and triglycerides. When used as a drug, daily doses range from 500 to 3,000 mg/day.[24][22] High-dose nicotinamide does not have this medicinal effect.[25]

Biological functions

Vitamin B3 has several vitamers that can act in place of each other, including nicotinic acid and nicotinamide. It is precursor of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These compounds are coenzymes for many dehydrogenases, participating in many hydrogen transfer processes. 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.[25] Vitamin intake recommendations made by several countries are that intakes of 14–18 mg/day are sufficient to meet the needs of healthy adults.[6][26] [27] Nicotinic acid and nicotinamide are both used for prevention and treatment of pellagra, a disease caused by lack of the vitamin.[28][25]

As a dietary supplement

In the United States, nicotinic acid is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim[29] allowed by the US Food & Drug Administration (FDA). An example would be "Supports a healthy blood lipid profile." The American Heart Association strongly advises against the substitution of dietary supplement nicotinic acid for prescription nicotinic acid because of potentially serious side effects, which means that nicotinic acid should only be used under the supervision of a health care professional, and because manufacture of dietary supplement nicotinic acid is not as well-regulated by the FDA as prescription nicotinic acid.[30] More than 30 mg nicotinic acid consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic.[4]

As lipid-modifying medication

Prescription nicotinic acid, commonly labeled as niacin in the United States, is available in immediate-release and slow-release formulations. It is used to treat primary hyperlipidemia and hypertriglyceridemia.[24][22] It is used either as a monotherapy or in combination with other lipid-modifying drugs. Dosages start at 500 mg/day and are often gradually increased to as high as 3000 mg/day for immediate release or 2000 mg/day for slow release (also referred to as sustained release) to achieve the targeted lipid changes (lower LDL-C and triglycerides, and higher HDL-C).[24][22] Prescriptions in the US peaked in 2009, at 9.4 million[14] and had declined to 800 thousand by 2020.[14] In 2023, it was the 288th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.[15][16]

Systematic reviews found no effect of prescription nicotinic acid on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes despite raising HDL cholesterol in patients already taking statins.[8][31] Reported side effects include an increased risk of new-onset type 2 diabetes.[10][12][13][32]

Mechanisms

Nicotinic acid reduces synthesis of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), lipoprotein(a) and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C).[33] The lipid-therapeutic effects of nicotinic acid are partly mediated through the activation of G protein-coupled receptors, including hydroxycarboxylic acid receptor 2 (HCA2)and hydroxycarboxylic acid receptor 3 (HCA3), which are highly expressed in body fat.[34][35] HCA2 and HCA3 inhibit cyclic adenosine monophosphate (cAMP) production and thus suppress the release of free fatty acids (FFAs) from body fat, reducing their availability to the liver to synthesize the blood-circulating lipids in question.[36][37][38] A decrease in free fatty acids also suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus increasing VLDL-C turnover and reducing its production.[39] Nicotinic acid also directly inhibits the action of diacylglycerol O-acyltransferase 2 (DGAT2) a key enzyme for triglyceride synthesis.[38]

The mechanism behind nicotinic acid increasing HDL-C is not totally understood, but seems to occur in various ways. Nicotinic acid increases apolipoprotein A1 levels by inhibiting the breakdown of this protein, which is a component of HDL particles.[40][41] It also inhibits HDL-C hepatic uptake by suppressing production of the cholesterol ester transfer protein (CETP) gene.[33] It stimulates the ABCA1 transporter in monocytes and macrophages and upregulates peroxisome proliferator-activated receptor gamma, resulting in reverse cholesterol transport.[42]

Combined with statins

Extended release nicotinic acid was combined with lovastatin (Advicor), and with simvastatin (Simcor), as prescription drug combinations. The combination niacin/lovastatin was approved by the US Food and Drug Administration (FDA) in 2001.[43] The combination niacin/simvastatin was approved by the FDA in 2008.[44][45] Subsequently, large outcome trials using these nicotinic acid and statin therapies were unable to demonstrate incremental benefit of nicotinic acid beyond statin therapy alone.[46] The FDA withdrew approval of both drugs in 2016. The reason given: "Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." The drug company discontinued the drugs.[47]

Contraindications

Prescription immediate release (Niacor) and extended release (Niaspan) nicotinic acid are contraindicated for people with either active or a history of liver disease because both, but especially Niaspan, have been associated with instances of serious, on occasion fatal, liver failure.[22][48] Both products are contraindicated for people with existing peptic ulcer disease, or other bleeding problems because nicotinic acid lowers platelet count and interferes with blood clotting.[24][22][48] Both products are also contraindicated for women who are pregnant or expecting to become pregnant because safety during pregnancy has not been evaluated in human trials. These products are contraindicated for women who are lactating because it is known that nicotinic acid is excreted into human milk, but the amount and potential for adverse effects in the nursing infant are not known. Women are advised to either not nurse their child or discontinue the drug. High-dose nicotinic acid has not been tested or approved for use in children under 16 years.[24][22][48]

Adverse effects

The most common adverse effects of medicinal nicotinic acid (500–3000 mg) are flushing (e.g., warmth, redness, itching or tingling) of the face, neck and chest, headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash.[5][4][48] These can be minimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach.[48]

The acute adverse effects of high-dose nicotinic acid therapy (1–3 grams per day) – which is commonly used in the treatment of hyperlipidemias – can further include hypotension, fatigue, glucose intolerance and insulin resistance, heartburn, blurred or impaired vision, and macular edema.[5][4] With long-term use, the adverse effects of high-dose nicotinic acid therapy (750 mg per day) also include liver failure (associated with fatigue, nausea, and loss of appetite), hepatitis, and acute liver failure;[5][4] these hepatotoxic effects of nicotinic acid occur more often when extended-release dosage forms are used.[5][4] The long-term use of nicotinic acid at greater than or equal to 2 grams per day also significantly increases the risk of cerebral hemorrhage, ischemic stroke, gastrointestinal ulceration and bleeding, diabetes, dyspepsia, and diarrhea.[4]

Flushing

Flushing – a short-term dilatation of skin arterioles, causing reddish skin color – usually lasts for about 15 to 30 minutes, although sometimes can persist for weeks. Typically, the face is affected, but the reaction can extend to neck and upper chest. The cause is blood vessel dilation[5][4] due to elevation in prostaglandin GD2 (PGD2) and serotonin.[49][50][51][52] Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction.[49] Flushing is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing.[4]

Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway.[4][53] Aspirin taken half an hour before the nicotinic acid prevents flushing, as does ibuprofen. Taking nicotinic acid with meals also helps reduce this side effect.[4] Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing.[4] Slow- or "sustained"-release forms of nicotinic acid have been developed to lessen these side effects.[54][55] Nicotinamide and inositol nicotinate can be used as no-flush forms of vitamin B3, however the efficacy of the latter is dubious.[56]

Liver damage

Nicotinic acid in medicinal doses can cause modest elevations in serum transaminase and unconjugated bilirubin, both biomarkers of liver injury. The increases usually resolve even when drug intake is continued.[11][57][58] However, less commonly, the sustained release form of the drug can lead to serious hepatotoxicity, with onset in days to weeks. Early symptoms of serious liver damage include nausea, vomiting and abdominal pain, followed by jaundice and pruritus. The mechanism is thought to be a direct toxicity of elevated serum niacin. Lowering dose or switching to the immediate release form can resolve symptoms. In rare instances the injury is severe, and progresses to liver failure.[11]

Diabetes

The high doses of nicotinic acid used to treat hyperlipidemia have been shown to elevate fasting blood glucose in people with type 2 diabetes.[12] Long-term nicotinic acid therapy was also associated with an increase in the risk of new-onset type 2 diabetes.[12][13]

Other adverse effects

High doses of nicotinic acid 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.[59] Niaspan, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time.[22]

Pharmacology

Pharmacodynamics

Nicotinic acid activates the HCA2 receptor, which has effects in addition to lowering serum cholesterol and triglyceride concentrations: antioxidative, anti-inflammatory, antithrombotic, improved endothelial function and plaque stability, all of which counter development and progression of atherosclerosis.[60][61]

Nicotinic acid inhibits cytochrome P450 enzymes CYP2E1, CYP2D6 and CYP3A4.[62] Niacin produces a rise in serum unconjugated bilirubin in normal individuals and in those with Gilbert's Syndrome. However, in the Gilbert's Syndrome, the rise in bilirubin is higher and clearance is delayed longer than in normal people.[63] One test used to aid in diagnosing Gilbert's Syndrome involves intravenous administration of nicotinic acid (niacin) in a dose of 50 mg over a period of 30 seconds.[57][58]

Pharmacokinetics

Both nicotinic acid and nicotinamide are rapidly absorbed from the stomach and small intestine.[64] Absorption is facilitated by sodium-dependent diffusion, and at higher intakes, via passive diffusion. Unlike some other vitamins, the percent absorbed does not decrease with increasing dose, so that even at amounts of 3-4 grams, absorption is nearly complete.[25] With a one gram dose, peak plasma concentrations of 15 to 30 μg/mL are reached within 30 to 60 minutes. Approximately 88% of an oral pharmacologic dose is eliminated by the kidneys as unchanged nicotinic acid or nicotinuric acid, its primary metabolite. The plasma elimination half-life of nicotinic acid ranges from 20 to 45 minutes.[24]

Nicotinic acid and nicotinamide are both converted into the coenzyme NAD.[65] NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency.[66] In the liver, nicotinamide is converted to storage nicotinamide adenine dinucleotide (NAD). As needed, liver NAD is hydrolyzed to nicotinamide and nicotinic acid for transport to tissues, there reconverted to NAD to serve as an enzyme cofactor.[25] Excess nicotinic acid is methylated in the liver to N1-methylnicotinamide (NMN) and excreted in urine as such or as the oxidized metabolites N1-methyl-2-pyridone-5-carboxamide and N1-Methyl-4-pyridone-3-carboxamide (2PY and 4PY). Decreased urinary content of these metabolites is a measure of niacin deficiency.[25]

Production

Biosynthesis

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

In addition to absorbing niacin from diet, nicotinic acid can be synthesized from the essential amino acid tryptophan, a five-step process with the penultimate compound being quinolinic acid (see figure). Some bacteria and plants utilize aspartic acid in a pathway that also goes to quinolinic acid.[67] For humans, the efficiency of conversion is estimated as requiring 60 mg of tryptophan to make 1 mg of niacin. Riboflavin, vitamin B6 and iron are required for the process.[25] Pellagra is a consequence of a corn-dominant diet because the niacin in corn is poorly bioavailable and corn proteins are low in tryptophan compared to wheat and rice proteins.[68]

Industrial synthesis

Nicotinic acid was first synthesized in 1867 by oxidative degradation of nicotine with potassium chromate and sulfuric acid[69] — this is the origin of the name.[21] Nicotinic acid is prepared by hydrolysis of nicotinonitrile, which, as described above, is generated by oxidation of 3-picoline. Oxidation can be effected by air, but ammoxidation is more efficient. In the latter process, nicotinonitrile is produced by ammoxidation of 3-methylpyridine. Nitrile hydratase is then used to catalyze nicotinonitrile to nicotinamide, which can be sold directly or converted to nicotinic acid.[70] Alternatively, ammonia, acetic acid and paraldehyde are used to make 5-ethyl-2-methyl-pyridine, which is then oxidized to nicotinic acid.[71] New "greener" catalysts are being tested using manganese-substituted aluminophosphates that use acetyl peroxyborate as non-corrosive oxidant, avoiding producing nitrogen oxides as do traditional ammoxidations.[72]

The demand for commercial production includes for animal feed and for food fortification meant for human consumption. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 2014.[69]

Climate impact

The production of nicotinic acid creates nitrous oxide as a by-product, which is a potent greenhouse gas. In 2018, it was discovered that a nicotinic acid factory in Visp, Switzerland, was responsible for around one percent of the country's greenhouse gas emissions.[73][74] Eventually, catalytic scrubbing technology that eliminates most of the emissions was installed in 2021.[75]

Chemistry

This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position.[25] Other forms of vitamin B3 include the corresponding amide nicotinamide, where the carboxyl group has been replaced by a carboxamide group (CONH2).[25]

Preparations

Prescription products can be immediate release (Niacor, 500 mg tablets) or extended release (Niaspan, 500 and 1000 mg tablets). Niaspan has a film coating that delays release of the nicotinic acid, resulting in an absorption over a period of 8–12 hours. This reduces vasodilation and flushing side effects, but increases the risk of hepatotoxicity compared to the immediate release drug.[76][77]

Prescription nicotinic acid preparations in combination with statin drugs (discontinued) are described above. A combination of niacin and laropiprant had been approved for use in Europe and marketed as Tredaptive. Laropiprant is a prostaglandin D2 binding drug shown to reduce niacin-induced vasodilation and flushing side effects.[33][78][79] A clinical trial 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.[80] The study resulted in the withdrawal of Tredaptive from the international market.[81][82]

History

Niacin as a chemical compound was first described by chemist Hugo Weidel in 1873 in his studies of nicotine,[83] but that predated by many years the concept of food components other than protein, fat and carbohydrates that were essential for life. Vitamin nomenclature was initially alphabetical, with Elmer McCollum calling these fat-soluble A and water-soluble B.[84] Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with niacin as vitamin B3.[84]

Corn (maize) became a staple food in the southeast United States and in parts of Europe. A disease that was characterized by dermatitis of sunlight-exposed skin was described in Spain in 1735 by Gaspar Casal. He attributed the cause to poor diet.[85] In northern Italy it was named "pellagra" from the Lombard language (agra = holly-like or serum-like; pell = skin).[86][87] In time, the disease was more closely linked specifically to corn.[88] In the US, Joseph Goldberger was assigned to study pellagra by the Surgeon General of the United States. His studies confirmed a corn-based diet as the culprit, but he did not identify the root cause.[89][90]

Nicotinic acid was extracted from liver by biochemist Conrad Elvehjem in 1937. He later identified the active ingredient, referring to it as "pellagra-preventing factor" and the "anti-blacktongue factor."[91] It was also referred to as "vitamin PP", "vitamin P-P" and "PP-factor", all derived from the term "pellagra-preventive factor".[92] In the late 1930s, studies by Tom Douglas Spies, Marion Blankenhorn, and Clark Cooper confirmed that nicotinic acid cured pellagra in humans.[93] The prevalence of the disease was greatly reduced as a result.[94] Nicotinic acid was initially synthesized by oxidizing nicotine with potassium chromate and sulfuric acid.[21] Hence, in 1942, when flour enrichment with nicotinic acid began, a headline in the popular press said "Tobacco in Your Bread." In response, 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 nicotinic acid from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. The resulting name niacin was derived from nicotinic acid + vitamin.[95][21]

Carpenter found in 1951, that niacin in corn is biologically unavailable, and can be released only in very alkaline lime water of pH 11. This explains why a Latin-American culture that used alkali-treated cornmeal to make tortilla was not at risk for niacin deficiency.[96] The modern explanation is that alkali treatment enhances the bioavailability of tryptophan, not directly for any form of the vitamin.[97]: §5.2 

In 1955, Altschul and colleagues described large amounts of nicotinic acid as having a lipid-lowering property.[98] As such, niacin is the oldest known lipid-lowering drug.[99] Lovastatin, the first 'statin' drug, was first marketed in 1987.[100]

Extra-terrestrial occurrence

Extra-terrestrial nicotinic acid has been found in carbonaceous chondrite meteorites and in sample-returns from the asteroids 162173 Ryugu and 101955 Bennu.

Vitamin B3 vitamers from extra-terrestrial sources
Asteroid Nicotinic acid Nicotinamide
101955 Bennu[20] 0.43 nmol/g not reported
162173 Ryugu 0.40 nmol/g,[20] 99ppb[19] not detected[19]
Meteorite Nicotinic acid Nicotinamide
Orgueil[19] 715ppb 214ppb
Murray[18] 626ppb 65ppb
Murchison 2.4 nmol/g,[20] 190ppb[18] 16ppb[18]
Tagish Lake[18] 108ppb 5ppb

Notes

  1. ↑ International nonproprietary name
  2. ↑ Common name in the United States (USAN)

References

  1. ↑ (in en) Martindale: the complete drug reference (37 ed.). London: Pharmaceutical press. 2011. p. 2117. ISBN 978-0-85369-933-0. OCLC 1256529676. https://archive.org/details/martindalecomple0000unse_37ed/page/2116/mode/2up?q=niacin. 
  2. ↑ "Chapter P-6. Applications to Specific Classes of Compounds". Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: Royal Society of Chemistry. 2014. pp. 648–1047. doi:10.1039/9781849733069-00648. ISBN 978-0-85404-182-4. 
  3. ↑ "Niacin Use During Pregnancy". 29 July 2019. https://www.drugs.com/pregnancy/niacin.html. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 "Niacin Fact Sheet for Health Professionals". Office of Dietary Supplements, US National Institutes of Health. 18 November 2022. https://ods.od.nih.gov/factsheets/Niacin-HealthProfessional/. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Niacin". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 8 October 2018. https://lpi.oregonstate.edu/mic/vitamins/niacin. 
  6. ↑ 6.0 6.1 Institute of Medicine (1998). "Niacin". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. pp. 123–149. ISBN 978-0-309-06554-2. https://www.nap.edu/read/6015/chapter/8. Retrieved 29 August 2018. 
  7. ↑ 7.0 7.1 "Niacin". 16 March 2019. https://www.drugs.com/niacin.html. 
  8. ↑ 8.0 8.1 "Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients". BMJ 349. July 2014. doi:10.1136/bmj.g4379. PMID 25038074. 
  9. ↑ "Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis". Atherosclerosis 210 (2): 353–61. June 2010. doi:10.1016/j.atherosclerosis.2009.12.023. PMID 20079494. 
  10. ↑ 10.0 10.1 "Niacin for primary and secondary prevention of cardiovascular events". The Cochrane Database of Systematic Reviews 2017 (6). June 2017. doi:10.1002/14651858.CD009744.pub2. PMID 28616955. 
  11. ↑ 11.0 11.1 11.2 "Niacin". IN: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (Internet). Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. February 2014. 
  12. ↑ 12.0 12.1 12.2 12.3 "Cardiovascular drugs that increase the risk of new-onset diabetes". Am. Heart J. 167 (4): 421–8. April 2014. doi:10.1016/j.ahj.2013.12.025. PMID 24655688. http://www.escholarship.org/uc/item/6gd606b1. Retrieved 27 June 2020. 
  13. ↑ 13.0 13.1 13.2 "Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials". Heart 102 (3): 198–203. February 2016. doi:10.1136/heartjnl-2015-308055. PMID 26370223. 
  14. ↑ 14.0 14.1 14.2 14.3 "Niacin - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Niacin. 
  15. ↑ 15.0 15.1 "The Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  16. ↑ 16.0 16.1 "Niacin Drug Usage Statistics, United States, 2014 - 2023". https://clincalc.com/DrugStats/Drugs/Niacin. 
  17. ↑ "B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review". Nutrients 8 (2): 68. January 2016. doi:10.3390/nu8020068. PMID 26828517. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "Identifying the wide diversity of extraterrestrial purine and pyrimidine nucleobases in carbonaceous meteorites". Nature Communications 13 (1). April 2022. doi:10.1038/s41467-022-29612-x. PMID 35473908. Bibcode: 2022NatCo..13.2008O. 
  19. ↑ 19.0 19.1 19.2 19.3 "Uracil in the carbonaceous asteroid (162173) Ryugu" (in en). Nature Communications 14 (1). 21 March 2023. doi:10.1038/s41467-023-36904-3. ISSN 2041-1723. PMID 36944653. Bibcode: 2023NatCo..14.1292O. 
  20. ↑ 20.0 20.1 20.2 20.3 "Abundant ammonia and nitrogen-rich soluble organic matter in samples from asteroid (101955) Bennu". Nature Astronomy 9 (2): 199–210. 2025. doi:10.1038/s41550-024-02472-9. PMID 39990238. Bibcode: 2025NatAs...9..199G. 
  21. ↑ 21.0 21.1 21.2 21.3 "Niacin and Nicotinic Acid". Journal of the American Medical Association 118 (10): 823. 7 March 1942. doi:10.1001/jama.1942.02830100053014. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 "Niaspan Patient Package and Product Information (PPPI)". December 2018. http://www.rxabbott.com/pdf/niaspan.pdf. 
  23. ↑ "Substances related to nicotinic acid - referral | European Medicines Agency (EMA)" (in en). 13 March 2014. https://www.ema.europa.eu/en/medicines/human/referrals/substances-related-nicotinic-acid. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 "NIACOR-niacin tablet". March 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce739d68-d89c-437c-90fb-3c0c45140f22. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8 "Niacin". Present Knowledge in Nutrition (Eleventh ed.). London, United Kingdom: Academic Press (Elsevier). 2020. pp. 209–24. ISBN 978-0-323-66162-1. 
  26. ↑ "Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies". 2017. https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf. 
  27. ↑ "Nutrient reference values for Australia and New Zealand". National Health and Medical Research Council. 9 September 2005. http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/n35.pdf. 
  28. ↑ "Pellagra: dermatitis, dementia, and diarrhea". International Journal of Dermatology 43 (1): 1–5. January 2004. doi:10.1111/j.1365-4632.2004.01959.x. PMID 14693013. 
  29. ↑ "Structure/Function Claims". December 2017. https://www.fda.gov/food/food-labeling-nutrition/structurefunction-claims. 
  30. ↑ "Cholesterol Medications". 10 November 2018. https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/cholesterol-medications. 
  31. ↑ "Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct?". Curr Atheroscler Rep 17 (8). August 2015. doi:10.1007/s11883-015-0521-x. PMID 26048725. 
  32. ↑ "Role of Niacin in Current Clinical Practice: A Systematic Review". The American Journal of Medicine 130 (2): 173–187. February 2017. doi:10.1016/j.amjmed.2016.07.038. PMID 27793642. 
  33. ↑ 33.0 33.1 33.2 "Niacin: the evidence, clinical use, and future directions". Current Atherosclerosis Reports 14 (1): 49–59. February 2012. doi:10.1007/s11883-011-0212-1. PMID 22037771. 
  34. ↑ "Molecular identification of nicotinic acid receptor". Biochemical and Biophysical Research Communications 303 (1): 364–9. March 2003. doi:10.1016/S0006-291X(03)00342-5. PMID 12646212. Bibcode: 2003BBRC..303..364S. 
  35. ↑ "Molecular identification of high and low affinity receptors for nicotinic acid". The Journal of Biological Chemistry 278 (11): 9869–74. March 2003. doi:10.1074/jbc.M210695200. PMID 12522134. 
  36. ↑ "Nicotinic acid: pharmacological effects and mechanisms of action". Annual Review of Pharmacology and Toxicology 48 (1): 79–106. 2008. doi:10.1146/annurev.pharmtox.48.113006.094746. PMID 17705685. 
  37. ↑ "Future of GPR109A agonists in the treatment of dyslipidaemia". Diabetes, Obesity & Metabolism 13 (8): 685–91. August 2011. doi:10.1111/j.1463-1326.2011.01400.x. PMID 21418500. 
  38. ↑ 38.0 38.1 "Molecular pathways and agents for lowering LDL-cholesterol in addition to statins". Pharmacol Ther 126 (3): 263–78. June 2010. doi:10.1016/j.pharmthera.2010.02.006. PMID 20227438. 
  39. ↑ "Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid". Cell Metabolism 12 (4): 411–9. October 2010. doi:10.1016/j.cmet.2010.09.001. PMID 20889132. 
  40. ↑ "Niacin, lipids, and heart disease". Curr Cardiol Rep 5 (6): 470–6. November 2003. doi:10.1007/s11886-003-0109-x. PMID 14558989. 
  41. ↑ "Niacin: another look at an underutilized lipid-lowering medication". Nature Reviews. Endocrinology 8 (9): 517–28. September 2012. doi:10.1038/nrendo.2012.22. PMID 22349076. 
  42. ↑ "Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin". Biochemical Pharmacology 67 (3): 411–9. February 2004. doi:10.1016/j.bcp.2003.09.014. PMID 15037193. 
  43. ↑ "Drug Approval Package: Advicor (Niacin Extended-Release & Lovastatin) NDA #21-249". 13 September 2002. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-249_Advicor.cfm. 
  44. ↑ "Drug Approval Package: Simcor (Niacin/Simvastatin) NDA #022078". 31 July 2008. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022078s000TOC.cfm. 
  45. ↑ "Abbott Receives FDA Approval for Simcor (Niaspan / simvastatin), a Novel Combination Medicine for Comprehensive Cholesterol Management". Drugs.com (Press release). Archived from the original on 5 August 2020. Retrieved 15 March 2008.
  46. ↑ "Is HPS2-THRIVE the death knell for niacin?". J Clin Lipidol 9 (3): 343–50. 2015. doi:10.1016/j.jacl.2015.01.008. PMID 26073392. 
  47. ↑ "AbbVie Inc.; Withdrawal of Approval of New Drug Applications for Advicor and Simcor". 18 April 2016. https://www.federalregister.gov/documents/2016/04/18/2016-08894/abbvie-inc-withdrawal-of-approval-of-new-drug-applications-for-advicor-and-simcor. 
  48. ↑ 48.0 48.1 48.2 48.3 48.4 "Niaspan- niacin tablet, film coated, extended release". 20 August 2013. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dd18020-c211-423d-b3d8-a926ae626e14. 
  49. ↑ 49.0 49.1 "Niacin-induced "flush" involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model". The Journal of Pharmacology and Experimental Therapeutics 327 (3): 665–72. December 2008. doi:10.1124/jpet.108.141333. PMID 18784348. 
  50. ↑ "GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing". The Journal of Clinical Investigation 115 (12): 3634–40. December 2005. doi:10.1172/JCI23626. PMID 16322797. 
  51. ↑ "Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells". Molecular Pharmacology 70 (6): 1844–9. December 2006. doi:10.1124/mol.106.030833. PMID 17008386. 
  52. ↑ "Langerhans cells release prostaglandin D2 in response to nicotinic acid". The Journal of Investigative Dermatology 126 (12): 2637–46. December 2006. doi:10.1038/sj.jid.5700586. PMID 17008871. 
  53. ↑ "Mechanism of action of niacin". The American Journal of Cardiology 101 (8A): 20B–26B. April 2008. doi:10.1016/j.amjcard.2008.02.029. PMID 18375237. 
  54. ↑ Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical Publishing Division. ISBN 978-0-07-145153-6. 
  55. ↑ "Options for therapeutic intervention: How effective are the different agents?". European Heart Journal Supplements 8 (F): F47–F53. October 2006. doi:10.1093/eurheartj/sul041. 
  56. ↑ "Niacin: The facts on flushing". http://www.dpic.org/article/professional/niacin-facts-flushing. 
  57. ↑ 57.0 57.1 "The Nicotinic Acid Provocation Test and Unconjugated Hyperbilirubinaemia". The Ulster Medical Journal 60 (1): 49–52. April 1991. PMID 1853497. 
  58. ↑ 58.0 58.1 "Nicotinic Acid Test in the Diagnosis of Gilbert's Syndrome: Correlation With Bilirubin Clearance". Gut 22 (8): 663–668. August 1981. doi:10.1136/gut.22.8.663. PMID 7286783. 
  59. ↑ "Ocular Effects of Niacin: A Review of the Literature". Med Hypothesis Discov Innov Ophthalmol 4 (2): 64–71. 2015. PMID 26060832. 
  60. ↑ "Niacin in the Treatment of Hyperlipidemias in Light of New Clinical Trials: Has Niacin Lost its Place?". Med. Sci. Monit. 21: 2156–62. July 2015. doi:10.12659/MSM.893619. PMID 26210594. 
  61. ↑ "Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids". Arteriosclerosis, Thrombosis, and Vascular Biology 30 (5): 968–75. May 2010. doi:10.1161/ATVBAHA.109.201129. PMID 20167660. 
  62. ↑ "Inhibition of human P450 enzymes by nicotinic acid and nicotinamide". Biochemical and Biophysical Research Communications 317 (3): 950–6. May 2004. doi:10.1016/j.bbrc.2004.03.137. PMID 15081432. Bibcode: 2004BBRC..317..950G. 
  63. ↑ Nathan and Oski's Hematology of Infancy and Childhood. Elsevier Health Sciences. January 2009. pp. 118–119. ISBN 978-1-4160-3430-8. 
  64. ↑ "Intestinal absorption of water-soluble vitamins in health and disease". The Biochemical Journal 437 (3): 357–372. August 2011. doi:10.1042/BJ20110326. PMID 21749321. 
  65. ↑ Lehninger principles of biochemistry. New York: Worth Publishers. 2000. ISBN 978-1-57259-153-0. https://archive.org/details/lehningerprincip01lehn. 
  66. ↑ "Pellagra among chronic alcoholics: clinical and pathological study of 20 necropsy cases". Journal of Neurology, Neurosurgery, and Psychiatry 44 (3): 209–15. March 1981. doi:10.1136/jnnp.44.3.209. PMID 7229643. 
  67. ↑ "Nicotinamide adenine dinucleotide biosynthesis and pyridine nucleotide cycle metabolism in microbial systems". Microbiol. Rev. 44 (1): 83–105. 1 March 1980. doi:10.1128/MMBR.44.1.83-105.1980. PMID 6997723. 
  68. ↑ "The Relationship of Pellagra to Corn and the Low Availability of Niacin in Cereals". Nutritional Adequacy, Nutrient Availability and Needs. Experientia Supplementum. 44. 1983. pp. 197–222. doi:10.1007/978-3-0348-6540-1_12. ISBN 978-3-0348-6542-5. 
  69. ↑ 69.0 69.1 "Vitamins, 11. Niacin (Nicotinic Acid, Nicotinamide". Ullmann's Encyclopedia of Industrial Chemistry (6th ed.). Weinheim: Wiley-VCH. 2015. pp. 1–9. doi:10.1002/14356007.o27_o14.pub2. ISBN 978-3-527-30385-4. 
  70. ↑ "Ullmann's Encyclopedia of Industrial Chemistry". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. 2007. doi:10.1002/14356007.a22_399. 
  71. ↑ "100 Years of Progress with LONZA". CHIMIA 51 (6): 259–69. June 1997. doi:10.2533/chimia.1997.259. 
  72. ↑ Sarah Everts (2008). "Clean Catalysis: Environmentally friendly synthesis of niacin generates less inorganic waste". Chemical & Engineering News. ISSN 0009-2347. 
  73. ↑ "The climate disgrace of Visp". 2021. https://www.europeanpressprize.com/article/the-climate-disgrace-of-visp/. 
  74. ↑ "Application of Enzymes and Microbes for the Industrial Production of Vitamins and Vitamin-Like Compounds" (in en). Comprehensive Biotechnology. Elsevier. 2011. p. 620. doi:10.1016/b978-0-444-64046-8.00188-9. ISBN 978-0-444-64047-5. "Lonza AG of Switzerland produces nicotinic acid in their Swiss production site in Visp, whereas the manufacturing site for the amide is in China, Guangdong Province." 
  75. ↑ "Urgent abatement of industrial sources of nitrous oxide". Nature Climate Change 13 (7): 599–601. July 2023. doi:10.1038/s41558-023-01723-3. Bibcode: 2023NatCC..13..599D. 
  76. ↑ "A case for immediate-release niacin". Heart & Lung 41 (1): 95–8. 2012. doi:10.1016/j.hrtlng.2010.07.019. PMID 21414665. 
  77. ↑ "Pharmacokinetics and dose recommendations of Niaspan in chronic kidney disease and dialysis patients". Nephrology, Dialysis, Transplantation 26 (1): 276–82. January 2011. doi:10.1093/ndt/gfq344. PMID 20562093. 
  78. ↑ "Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1". Clinical Pharmacology and Therapeutics 81 (6): 849–57. June 2007. doi:10.1038/sj.clpt.6100180. PMID 17392721. 
  79. ↑ "Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors". Cardiology Clinics 26 (4): 547–60. November 2008. doi:10.1016/j.ccl.2008.06.007. PMID 19031552. 
  80. ↑ "Effects of extended-release niacin with laropiprant in high-risk patients". N. Engl. J. Med. 371 (3): 203–12. July 2014. doi:10.1056/NEJMoa1300955. PMID 25014686. 
  81. ↑ "Niacin/Laropiprant Products to Be Suspended Worldwide". 11 January 2013. http://www.medscape.com/viewarticle/777519. 
  82. ↑ "Merck begins overseas recall of HDL cholesterol drug". Reuters. 11 January 2013. https://www.reuters.com/article/us-merck-cholesteroldrug-withdrawal-idUSBRE90A0MB20130111?feedType=RSS&feedName=healthNews. 
  83. ↑ "Zur Kenntniss des Nicotins". Justus Liebigs Annalen der Chemie und Pharmacie 165 (2): 330–49. 1873. doi:10.1002/jlac.18731650212. https://zenodo.org/record/1427317. Retrieved 3 July 2019. 
  84. ↑ 84.0 84.1 The Vitamins: Fundamental Aspects in Nutrition and Health (3rd ed.). Elsevier, Boston, MA. 2007. pp. 7–33. ISBN 978-0-080-56130-1. https://books.google.com/books?id=1CMHiWum0Y4C&pg=PA16. Retrieved 30 June 2020. 
  85. ↑ "The natural and medical history of the principality of the Asturias". Classic Descriptions of Disease (3rd ed.). Springfield: Charles C Thomas. 1945. pp. 607–12. 
  86. ↑ F. Cherubini, Vocabolario Milanese-Italiano, Imp. Regia Stamperia, 1840-43, vol. I, III.
  87. ↑ "Definition of Pellagra". MedicineNet.com. http://www.medterms.com/script/main/art.asp?articlekey=4821. 
  88. ↑ Cesare Lombroso, Studi clinici ed esperimentali sulla natura, causa e terapia delle pellagra (Bologna: Fava e Garagnani, 1869)
  89. ↑ "Joseph Goldberger: an unsung hero of American clinical epidemiology". Ann Intern Med 121 (5): 372–75. September 1994. doi:10.7326/0003-4819-121-5-199409010-00010. PMID 8042827. 
  90. ↑ "Dr. Joseph Goldberger and the War on Pellagra | Ashes on the Potomac". https://history.nih.gov/pages/viewpage.action?pageId=8883184. 
  91. ↑ "The isolation and identification of the anti-blacktongue factor J". J. Biol. Chem. 123 (1): 137–49. 1938. doi:10.1016/S0021-9258(18)74164-1. http://www.jbc.org/content/123/1/137.full.pdf. 
  92. ↑ Pellagra And Its Prevention And Control In Major Emergencies (Report). World Health Organization. 2000. WHO/NHD/00.10. 
  93. ↑ "The use of nicotinic acid in the treatment of pellagra". Journal of the American Medical Association 110 (9): 622–627. 26 February 1938. doi:10.1001/jama.1938.02790090004002. ISSN 0002-9955. 
  94. ↑ White Rose History. I. Exclamation! Publishers. 2003. p. Appendix D, p. 2. ISBN 978-0-9710541-9-6. https://books.google.com/books?id=WOPfM-0hz1AC&dq=%22pellagra%3A+Drs.+Tom+Douglas%22&pg=PA630. "Men of the Year, outstanding in comprehensive science were three medical researchers who discovered that nicotinic acid was a cure for human pellagra: Drs. Tom Douglas Spies of Cincinnati General Hospital, Marion Arthur Blankenhorn of the University of Cincinnati, Clark Niel Cooper of Waterloo, Iowa." 
  95. ↑ "Niacin and Niacin Amide". Journal of the American Medical Association 118 (10): 819. 7 March 1942. doi:10.1001/jama.1942.02830100049011. 
  96. ↑ "Raw versus processed corn in niacin-deficient diets". The Journal of Nutrition 45 (1): 21–8. September 1951. doi:10.1093/jn/45.1.21. PMID 14880960. 
  97. ↑ Maize in human nutrition. Rome: Food and Agriculture Organization of the United Nations. 1992. ISBN 978-92-5-103013-4. https://www.fao.org/3/T0395E/T0395E00.htm.  – Section 5.2 "Lime-treated maize (part II)", Section 8 "Improvement of maize diets"
  98. ↑ "Influence of nicotinic acid on serum cholesterol in man". Archives of Biochemistry and Biophysics 54 (2): 558–9. February 1955. doi:10.1016/0003-9861(55)90070-9. PMID 14350806. 
  99. ↑ "Niacin: an old lipid drug in a new NAD+ dress". J. Lipid Res. 60 (4): 741–6. April 2019. doi:10.1194/jlr.S092007. PMID 30782960. 
  100. ↑ "The $10 billion pill". Fortune 147 (1): 58–62, 66, 68. January 2003. PMID 12602122. https://money.cnn.com/magazines/fortune/fortune_archive/2003/01/20/335643/index.htm. 



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