WIKIPEDIA Niacin Niacin, also known as nicotinie acid, is an organic compound and a form of vitamin By, an essential human nutrient] Tt ean be manufactured by plants and animals from the amino acid ‘uyptophan.{ Niacin is obtained in the diet from a varity of whole and processed foods, with highest contents in fortified packaged foods, meat, poultry, red fish such as tuna and salmon, lesser amounts in nuts, legumes and seeds {S] Nigein as a dietary supplement is used to treat pellagra, a disease caused by niacin deficiency. Signs and symptoms of pellagra include skin and ‘mouth lesions, anemia, headaches, and tiredness. (©! Many countries mandate its addition to wheat flour or other food grains, thereby reducing the risk of pellage. 371 ‘The amide derivative nicotinamide (niacinamide) is a component of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP+).. Although niacin and nicotinamide are identical in their vitamin activity, nicotinamide does not have the same pharmacological, lipid-modifying effects or side effects as niacin, ie., when niacin, takes on the -amide group, it does not reduce cholesterol nor cause flushing 1191 Nicotinamide is. recommended as a treatment for niacin deficiency because it can be administered in remedial amounts without causing the flushing, considered an adverse effect. ‘Niacin is also a prescription medication.{#) 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 niacin. 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. Despite the proven lipid changes, niacin has not been found useful for decreasing the risk of cardiovascular disease in those already on a statin.21 A 2o1o review had concluded that niacin was effective as a mono-therapy,(*] but a 2017 review incorporating twice ‘as many trials concluded that prescription niacin, while affecting lipid levels, did not reduce all- ‘cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes] Prescription niacin was shown to cause hepatotoxicty!'S) and increase risk of type 2 diabetes.#61271 Niacin prescriptions in the U.S. had peaked in 2009, at 9.4 million, declining to 43 million by 2017.{'8) Pronunciation cin Trarosin Preferred IUPAC name Pyridine 3 Other names carorylic acl! [Nicotinic acid (NN) Bionic Vitamin By Vitamin PP 2D model smal) Identifiers 5967-6 (htpsicom rmonchemisty.cas.or sldota?eas_m=59.6 1.8) Interactive image (ht psllchemapps staat edujmoljmol php?m odel=00%428%30 (0%428e%ecenet)‘Niacin has the formala C,Hi,NO, and belongs tothe group of the pyridinecarborglic acids. As ‘the precursor for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide Phosphate, niacin is involved in DNA repair!" Contents Definition Vitamin deficioncy Measuring vitamin status Dietary recommendations Sources Food preparation Food fortification ‘As a dietary supplement As lipid-modifying medication Mechanisms Combined with statins Contraindications Adi fects Pharmacology Pharmacodynamics Pharmacokinetics Production Biosynthesis. Industrial synthesis Chomistry Preparations History Research Referencs External inks 30Met 1300073 (itp. 3 met cna afrego,pfe ‘ilshow_daia.php?ac 800073 109591 (CHEBI15940 (tio sJiwwe| ac uklehe busearchid.do?chebit =15940)/ (ChEMBL DrugBank ECHA Infocars EC Number CCHEMBLSTS (tps! web aesuklenem Ddbindexphpfeomp cundinspecChEMB 13734 213 (htiesiwwn.che ‘spidercomvChemic a Structure, 913m) 7 1200527 (ntpssiww wdrugbank.calérugs! 1p00827) “ +100.000.401 (itp ‘2ha.europa eulsubst ‘ance nformatlon/su betancenfo/100.000, 401)¢ 200-464-0 M0 IUPHARIBPS: 1588 (np. guid ‘etopharmacology.og!Definition ‘Niacin is both a vitamin, ie. an essential nutrient, marketed as a dietary supplement, and in the US, a prescription medicine. As a vitamin, itis precursor of the coenzymes nicotinamide adenine Ginucleotide (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.2°1 Vitamin intake recommendations made by several countries are that intakes of 14-18 mg/day are suflicient to meet the needs of healthy adults,“ll2ll221 Niacin or nicotinamide (niacinamide) are used for prevention and treatment of pellagra, a disease caused by lack of the vitamin.!®1!29] When niacin is used as a medicine to trest elevated cholesterol and triglycerides, daily doses range from 500 to 3,000 mg/day/*31l24] High-dose nicotinamide does not have this medicinal effect.!2°1 Vitamin deficiency Severe deficiency of niacin in the diet causes the disease pellagra, characterized by diarrhea, sun- sensitive dermatitis involving byperpigmentation and thickening of the skin (see image), inflammation of the mouth and tongue, delirium, dementia, and if left untreated, death I Common psychiatric symptoms include iritability, poor concentration, anxiety, fatigue, Ioss of memory, restlessness, apathy, and depression/2°) ‘The biochemical mechanism(s) for the observed deficieney-caused neurodegeneration are not well understood, but may rest on: A) the requirement for nicotinamide adenine dinucleotide (NAD+) to suppress the creation of neurotoxic typtophan metabolites, B) inhibition of mitochondrial ATP generation, resulting in cell damage; ©), activation of the poly (ADP-ribose) polymerase (PARP) pathway, as PARP is a nuclear enzyme involved in DNA repair, but in the absence of NAD+ can lead to cell death; D) reduced synthesis of neuro-protective brain-derived neurotrophic factor or its. receptor tropomyosin receptor kinase B; or E) changes to genome expression directly due to the niacin deficiency. Niacin deficiency is rarely seen in developed countries, and it is more typieally associated with poverty, malnutrition or malnutrition secondary to chronie aleobolism.28 1 also tends to occur in less developed areas where people eat maize (corn) as a staple food, a8 maize isthe only grain low in digestible niacin. A cooking technique called nixtamalization ie, pretreating with alkali GRAGMLigandDisplay ‘yAligandid=1588) KEGG ‘Do0049 (tps. egg jplentry00004 9” (600255 (htps:vaw. egg jplentryiC0025 af MesH [Niacin (tips two muningoviegimeshi2 014/MB,_og/?modo=8 leam=Niacin) PubChem CID | 936 htps:ipubche m.nebinim nih.govle cempoundi938) RTECS (210525000 umber NII 2679MFEBTA (htos fdasis.nim.nin.gov'st slorediectepregno sTOMFOBTA)“ Comprex | prxsi01020032 ne ashiboar eomptox.opa.90 psillcomptox.epa g ‘idashboardichemica eta TXSI01020 932) [SICBHENODICE-H9)5-24-3-7-4 ih -AH,(48,9)4 Koy: PUNIIMVLHYAWGP-UHFFFAOYS ANSingredients, increases the bioavailability of niacin during maize meal/flour production.) For this reason, people who consume corn as tortillas or hominy are at less risk of niacin deficiency. For treating deficiency, the World Health Organization (WHO) recommends administering niacinamide(ie. nicotinamide) instead of niacin, to avoid the flushing side effect commonly ‘caused by the latter. Guidelines suggest using 300 mg/day for three to four weeks.("©! Dementia and dermatitis show improvement within a week. Because deficiencies of other B-vitamins may be present, the WHO recommends a multi-vitamin in addition to the niaeinamide.(°1 Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency. 28! It is named after an English family with a genetic disorder that resulted in a failure to absorb the essential ‘amino acid tryptophan, tryptophan being a precursor for niacin synthesis. The symptoms are similar to pellagra, including red, scaly rash and sensitivity to sunlight. Oral niacin or niacinamide is given as a treatment for this condition in doses ranging from 50 to 100 mg twice a day, with a good prognosis if identified and treated early.28) Niacin synthesis is also deficient in carcinoid syndrome, because of metabolic diversion of its precursor tryptophan to form serotonin [3] Measuring vitamin status Plasma concentrations of niacin and niacin metabolites are not useful markers of niacin status [4] Urinary exeretion of the methylated metabolite Ni-methyl-nicotinamide is considered reliable and sensitive. The measurement requires a 24-hour urine collection. For adults, a value of less than 5.8 jmol/day represent deficient niacin status and 5.8 to 17.5 jumol/day represents low 4) According to the World Health Organization, an alternative mean of expressing urinary Ni- ‘methyl-nicotinamide is as mg/g creatinine in a 24-hour urine collection, with deficient defined as, <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3{! Niacin deficiency occurs before the signs and symptoms of pellagra appear.!*) Erythrocyte nicotinamide adenine dinucleotide (NAD) concentrations potentially provide another sensitive indicator of niacin depletion, although definitions of deficient, low and adequate have not been established. Lastly, plasma tryptophan, deereases on a low niacin diet because tryptophan converts to niacin, However, low tryptophan, could also be caused by a diet low in this essential amino acid, soit is not specific to confirming, vitamin status 4) Dietary recommendations nChItICBHENOZe8.6(0)5-2.°-3-74 ‘Sint-4H (4.89) Koy: PVNIIMVLHYAWGP-UHFFFAOYA & SMILES Oc{-O}etecenet Properties Chemical | CeHsNOz formula Molar mass 123.111 g-mar* Appearance | White, anslucent crystals Density 1.473 g om Mating point 287 °C: 458 °F; 510k Scuubiliyin 18 gL" water log P 0219 Acidity (pKa) 2.0, 4.85, Isoelectric 4.75 point Refractive 1.4936 index (99) Dipole moment |0,1271305813 D Thermochemistry ‘Sid enthalpy of | 344.9 kd mot formation (AH? 298) ‘Sid enthalpy of 2.73089 Nd mot" combustion (AH 298) Pharmacology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, also Tolerable upper intake levels (ULs). In lieu of an RDA, Adequate Intakes (Als) are identified for popalations for which there is not sufficient evidence to identify a dietary intake level that is suficient to meet the nutrient requirements of most people. [3 (see table). ‘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. For the BU, Als and ULs have the same definition as in the US, except that units are milligrams per megajoule (MJ) of energy consumed rather than mg/day. For ‘women (including those pregnant or lactating), men and children the PRI is 1.6 mg per megajoule. As the conversion is 1 MJ = 239 keal, an adult consuming 2390 kilocalories should be consuming 16 mg niacin. This is comparable to US RDAs (14 mg/day for adult women, 16 mg/day for adult men) 21 JLs are established by identifying amounts of vitamins and minerals that cause adverse effects, ‘and then selecting as an upper limit amounts that are the "maximum daily intake unlikely to ‘cause adverse health effects."3"! Regulatory agencies from different countries do not always agree. For the US, 30 or 35 mg for teenagers and adults, less for children.[4] The EFSA UL for adults is set at 10 mg/day - about one-third of the US value. For all of the government ULs, the term applies to niacin as a supplement consumed as one dose, and is intended as a limit to avoid the skin flush reaetion. This explains why for EFSA, the recommended daily intake can be higher than the UL.{32) Both the DRI and DRV describe amounts needed as niacin equivalents (NE), caleulated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid isutilized to synthesize the vitamin. 4124) 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 is 16 mg. Prior to 27 May 2016 it was 20 mg, revised to bring it into agreement with the RDA. #lL3#] Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$i0 million or more in annual food sales, and by 1 January 2021 for ‘manufacturers with lower volume food sales.{251[36) 4 table of the old and new adult daily values isprovided at Reference Daily Intake. Sources ATC code License data (COsACOA (WHO (htt psulwww.whoce.notat ddd index ?eod cosacot)) C19BA01 (WHO (tpstiwvra hoce:nolate_ded_ind ed ?c0de=C10BA01)) (C10AD02 (WHO (hit sulmwwnhoce natat © ded index/?00d! Gi0AD02)) C10AD52 (WHO (tps twwrw 7 hoce:nolate_ded_ Ind ex/?e0de=Ci0AD52)) EV EMA: by Nicotinic acid (htpsvww.ema. ‘europa.eulemavind xjsp?eurl=42F page h2Fmedicines%2F1 anging’k2Fepar_sear chjep&mi¢=AsearchT archB ykey ale eadyLoaded=tuskis NewQuery=truesstat thorisedstats s=Withdrawnéstatus =Suspendedéstatus= RefusecskeywordSe areh=Submi&search Typeinn&taxonomy Pal searchGenericType eresBkeywor Nicotinic+acis) NumberNiacin is found in a variety of whole and processed foods, including fortified packaged foods, ‘meat from various animal sources, seafoods, and s "In general, animal-sourced foods provide about 5-10 mg niacin per serving, although dairy foods and eggs have little, Some plant- sourced foods such as nuts and grains provide about 2-5 mg niacin per serving, although this naturally present niacin is largely bound to polysaccharides and giycopeptides, making it only about 30% bioavailable, Fortified food ingredients such as wheat flour have niacin added, which is bioavailable 5] Among whole food sources with the highest niacin content per 100 grams: Intramuscular, by mouth Biological | 20-48 min hatte Hazards (GHS labeling Pictograms > Signalword | Warning Hazard Hate statements NEPA 704 (fre diamond) Flash point 183°C (379 °F 468K) Autoignition 365°C (689 °F: temperature 98 K) Excopt where otherwise note, data are given for materials in the ard sat (at 25°C [77 "Fy, ‘00KPS) vost (what is 2) Info NN: Ni er Niacin icotinic acidClinical data ‘Trade names Niacor, Niaspan, others ‘AHFS/Drugs.com Monograph (htps/ License data ups comimo ogeaphiacin.tim D 2682518 htpsdime dlineps. goverusi formedsia682518.n mi SEMA by Nicotine aid (tpi? nema europa emavindexjsp?eur s4aFpages%i2Fm dices 2Flandin 42Fepar search sNewQuery=trusdst satus=Authorseddst itndrown8st‘CompTox Dashboard (EPA) ECHA Infoc: US DallyMed: Niacin psdaiyrned ‘munih gowldalymed! seareh.clm?labellyp wweb.2c.ukipdbe -stviPDBeXolorelig ‘and’igand=NIO), RCSB POB (itp! +100.000,40% (ht ‘lecha.ouropa ou! substance informal ‘on“isunstanceinfot 0.000.401) ¢Dietary recommendations os eae vom [age | a a Aang eo tri Unper eet "ake aie als ‘Aman wit pallagra, which Is caused by a chrosic lack of vain By inthe detOA traci ng nei mgd Genser es ears)hee orup onze ng Tome upene Fate 1218 oo “nog so" sh ar oS Source!) (nat t905) Source) weutiece) J 60 ‘Beet depending on wha part how cooked | «8 Top (189) contains S69 Park depending on what par, how cooked | «8 Tuna yelowin Bs ees Peanuts “a “Tuna, wht, canned 38 Peanut butr at i a 104 Mushrooms, wits a8 08 cos isn 35 100 : “Turey depending on what pa, how cooked | 7-12 na - Chicken depending en what par, how cooked | 7-12 eeeAmount (mg? 1008) ‘Avocado 7 sour Potato, baked wth skin 14 comm (maize) 10 Rice, white 06 Kate oa Eogs a4 Mik 04 Cheese a4 Tot a4 Vegetarian and vegan diets can provide adequate amounts if produets such as nutritional yeast, peanuts, peanut butter, tahini, brown, rice, mushrooms, avocado and sunflower seeds are included. Fortified foods and dietary supplements can also be consumed to ensure adequate intake. 511801 Food preparation ‘Niacin naturally found in food is susceptible to destruction from high hest cooking, especially in the presence of acidic foods and sauces, It s soluble in water, and so may also be lost from foods boiled in water. |##) Food fortifi ation Countries fortify foods with nutrients to address known deficiencies 7! As of 2020, 54 countries required food fortification of wheat flour with niacin oF niacinamide; 14 also mandate fortification of maize flour, and 6 mandate fortification of riee$#l From country to ‘country, niacin fortification ranges from 1.3 to 6.0 mg/100 g,##1 As a dietary supplement{In the United States, niacin is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving, These products, ten have a Structure/Function health claim!) 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 niacin for prescription niacin because of potentially serious side effects, which means that niacin should only be used under the supervision of a health care professional, and because manufacture of dietary supplement niacin is not as well-regulated by the FDA as, prescription niacin,(*4] More than 30 mg niacin consumed as a dietary supplement ean 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 toxie.(51 As lipid-modifying medication In the United States, prescription niacin, in immediate-release and slow-release forms, is used to treat primary hyperlipidemia and hypertrilyeeridemia 23124 1 js used either as @ monotherapy or in combination with other lipid-modifying drugs. Dosages start at {500 mg/day and are often gradually inereased to as high as 3000 mg/day for immediate release or 2000 ma/day for slow release (also referred to as sustained release) to achieve the targeted lipid changes (lower LDL-C and triglycerides, and higher HDI-C). 29124] Prescriptions in the US peaked in 2009, at 9.4 million and had declined to 1.9 million by 2017, In late 2037, Avondale, having ‘acquired the rights to Niacor from Upsher Smith, raised the price of the drug by more than 800%.'451 ystematie reviews found no effeet of prescription niacin on all-cause mortality, cardiovascular mortality, myocardial infaretions, nor fatal or non-fatal strokes despite raising HDL cholesterol.!1/49) Reported side effects include an increased risk of new-onset type 2 diabetes /4lasli7Ila71 Mecha Niacin reduces synthesis of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDI-C), lipoprotein(a) and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C).48) The lipid-therapeutic effects of niacin are partly mediated through the activation of G protein-coupled receptors, including hydroxyearboxylic acid receptor 2 (HCA,)and hydroxyearboxylie acid receptor 3 (HCA,), which are highly expressed in body fat'9I(50) HCA, and HCA, 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 [55255] q decrease in free fatty acids also suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus increasing VLDI-C turnover and reducing its production.(1 Niacin also directly inhibits the action of diacyiglycerol O-acyitransferase 2 (DGAT2) a key enzyme for triglyceride synthesis 58) ‘The mechanism behind niacin increasing HDL-C is not totally understood, but seems to occur in various ways. Niacin increases apolipoprotein Ax levels by inhibiting the breakdown of this protein, which is a component of HDL-C551561 1, also inhibits HDL-C hepatic uptake by suppressing production of the cholesterol ester transfer protein (CBTP) gene 48] t stimulates the ABCA1 transporterin monocytes and macrophages and upregulates peroxisome proliferator-activated receptor gamma, resulting in reverse cholesterol transport.'97 Combined with statins Extended release niacin was combined with the lovastatin trade-named Advicor, and wit prescription drug combinations. Advicor was approved by the U.S. Food and Drug Administration (FDA) in 200154) simeor was approved in 20081159) Subsequently, large outcome trials using these niacin and statin therapies were unable to demonstrate eremental benefit of niacin beyond statin therapy alone.®°l 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 thatthe totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels andor inerease in HDL~ cholesterol levels in statin-treated patients results in a reduction inthe risk of cardiovascular events.” The drug company discontinued the drugs.6! simvastatin, trade-named Simeor as Contraindications Prescription immediate release (Nincor) and extended release (Niaspan) niacin 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 24161 Both products are contraindicated for people wit existing peptic uler disease, or other bleeding problems because niacin lowers platelet count and interferes with blood clotting.!*8!!241l62! 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 product are ontraindicated for women who are lactating because itis known that niacin i excreted into human milk, bt the amount and potential for adverse effects in the nursing infant are not known, Women are advised to either not nurse ther child or discontinue the drug. High dose niacin has not been tested or approved for use in children under 16 years.(28I(24lI62) Adverse effects The most common adverse effects of medicinal niacin (500-3000 mg) are flushing (e.g., warmth, redness, itching or tingling) of the face, nck and chest, headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash SII] These can be rinimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach, 62] ‘The acute adverse effects of high-dose niacin therapy (13 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/I3] With long-term use, the adverse effects of high-dose niacin therapy (750 mg per day) also include liver failure (associated with fatigue, nausea, and loss of appetite), hepatitis, and acute liver failure;I/) these hepatotoxic effects of niacin‘occur more often when extended-release dosage forms are used.{2II5] The long-term use of niacin at greater than or equal to 2 grams per ay also significantly increases the risk of cerebral hemorrhage, ischemic stroke, gastrointestinal ulceration and bleeding, diabetes, dyspepsia, and diarrhea! 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! 351 due to elevation in prostaglandin GD, (PGD2) and serotonin,|@s164l(sI'6s1 Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction.(°3) Flushing is sometimes accompanied by a prickly or itching sensation, n particular, in areas covered by clothing,!5! Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway.{51l71 Aspirin taken half an hour before the niacin prevents flushing, as does ibuprofen. Taking niacin with meals also helps reduce this side effeet'51 Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing.!®! Slow- or "sustained”-release forms of niacin have been developed to lessen these side effects 1°81 Liver damage ‘icin in medicinal doses can cause modest elevations in serum transaminase and unconjugated bilirubin, both biomarkers of liver injury. The increases usually resolves even when drug intake is continued. '5I'70l(711 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 inelude 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. Diabetes ‘The high doses of niacin used to treat hyperlipidemia have been shown to elevate fasting blood glucose in people with type 2 diabetes.) Long-term niacin therapy was also associated with an inerease in the risk of new-onset type 2 diabetes, 26127) Other adverse effects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 eeases.(74I Niaspan, the slow-release product, has been associated with a reduction in platelet content and @ modest inerease in prothrombin time 24) Pharmacology Pharmacodynamics ‘Niacin and nicotinamide are both converted into the coenzyme NAD7S1 NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase, NAD and NADP are coenzymes for many dehydrogenases, participating in many hydrogen transfer processes.\74I 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 synthesis74) High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency.-5) Activating HCA, has effects other than lowering serum cholesterol and triglyeeride concentrations: antioxidative, anti-inflammatory, antithrombotic, improved endothelial function and plaque stability, all of which counter development and progression of atherosclerosis. 126177 ‘Niacin inhibits cytochrome P450 enzymes CYP2E1, CYPaD6 and CYP3A4.7*I 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 79! One test used to aid in diagnosing Gilbert's Syndrome involves intravenous ‘administration of nieotinic acid (niacin) in a dose of 50 mg over a period of 30 seconds.71I741 Pharmacokinetics Both niacin and niacinamide are rapidly absorbed from the stomach and small intestine/®l 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.(#°) With a one gram dose, peak plasma concentrations of 15 to 30 jig/ml. are reached within 3o to 60 minutes. Approximately 88% of an oral pharmacologic dose is eliminated. by the kidneys as unchanged niacin or nicotinuric acd, its primary metabolite. The plasma elimination half-life of niacin ranges from 20 to 45 minutes.23) “iacinamide is the major form in the bloodstream. In the liver, niacinamide is converted to storage nicotinamide adenine dinucleotide (NAD), As needed, liver NAD is hydrolyzed to niacinamide and niacin for transport to tissues, there reconverted to NAD to serve as an ‘enzyme cofactor. (2°) Excess niacin is methylated in the liver to N*-methyinicotinamide (NMN) and excreted in urine as such or as theoxidized metabolite N'-methyl-2-pyridor niacin deficiency,(29] e-5-carboxamide (2-pyridone). Decreased urinary content of these metabolites is a measure of Production Biosynthesis {In addition to absorbing niacin from diet, niacin 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 quinolinie acid.(* For humans, the efficiency of conversion is estimated as requiring 60 mg of tryptophan to make 1 mg of niacin. Riboflavin, vitamin Bg and iron are required for the process.) Pellagra is a consequence of a corn-dominant diet because the niaein in corn is poorly bioavailable and eorn proteins are low in tryptophan compared to wheat and rice proteins.(82) Industrial synthesis Nicotinonitrile is produced by ammoxidation of g-methylpyridine. Nitrile hydratase is then used to catalyze nicotinonitrile to nicotinamide, which can be converted to niacin, alternatively, ammonia, acetic acid and paraldehyde are used to make 5-ethyl+ 2-methyl-pyridine, which is then oxidized to niacin, [841 ‘The demand for commercial production includes for animal feed and for food fortification meant for human consumption. According to Ullmann's Eneyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 201485 roma Chemistry ‘This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) atthe 3-position 29] Other forms of vitamin B, include the corresponding amide nicotinamide (niacinamide), where the carboxyl group has been replaced by a carboxamide group (CONH,).221 Preparations‘Niacin is incorporated into multi-vitamin and sold as a single-ingredient dietary supplement. The latter can be immediate or slow release [8 icotinamide (niacinamide) is used to treat niacin deficiency because it does not cause the flushing adverse reaction seen with niacin, Nicotinamide may be toxie to the liver at doses exceeding 3 g/day for adults.(871 Prescription products can be immediate release (Niacor, 500 mg tablets) or extended release (Niaspan, 500 and 1000 mg tablets). Siaspan has a film coating that delays release of the niacin, 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,(*1[89 Prescription niacin in combination with statin drugs (discontinued) is described above. A combination of niacin and laropiprant had been approved for use in Europe and marketed as Tredaptive. Laropiprant is a prostaglandin Da binding drug shown to reduce niacin- induced vasodilation and flushing side effects.(4810010") 4 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 effects5#! The study resulted in the ‘withdrawal of Tredaptive from the international market. 21194) ‘One form of dietary supplement sold in the US is inositol hexanicotinate (IHN), also called inositol nicotinate. This is inositol that has been esterified with niacin on all six of inositol’s aleohol ‘groups.95] THN is usually sold as "flush-free" or "no-flush" niacin in units of 250, 500, oF 1000 mg/tablets or capsules. In the US, itis sold as an over-the-counter formulation, and often is ‘marketed and labeled as niacin, thus misleading consumers into thinking they are getting an active form of the medication, While this form of niacin does not cause the flushing associated with the jimmediate-release products, there is not enough evidence to recommend IHN to treat byperlipidemia 261 History ‘Niacin as a chemical compound was first deseribed by chemist Hugo Weidel in 1873 in his studies of nicotine (°7 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 MeCollum calling these fat= soluble A and water-soluble B, ‘981 Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with niacin as vitamin By. 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! In northern Italy it *pellagra” from the Lombard language (agra = holly-like or serum-lke; pelt = skin).9901 tn time, the disease was moreclosely linked specifically to corn.(®41 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 eause,(103L:04] ‘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."!®5) 1t was also referred to as “vitamin PP", "vitamin P-P" and "PP- factor’, all derived from the term "pellagra-preventive factor"! In the late 1930s, studies by Tom Douglas Spies, Marion Blankenhorn, ‘and Clark Cooper confirmed that niacin cured pellagra in humans. The prevalence of the disease was greatly reduced as a result.1061 In 1942, when flour enrichment with nicotine acid began, a headline inthe popular press said "Tobacco in Your Bread.” In response, the Council on Foods and Nutrition ofthe American Medical Association approved of the Food and Nutrition Board's new names niacin and niacin amide for use primarily by non-scientists. I was thought appropriate to choose a name to dissociate nicotinic acid from nicotine, to avoid the perception that vitamins or niacinrich food contains nicotine, or that cigarettes contain vitamins 22 The resulting name niacin was derived from nicotinic acid + vitamin.191l+8) Carpenter found in 1951, that niacin in corn is biologically tnavalable, and can be released only in very alkaline lime water of pHi 1. This explains why a Latin-American culture that used alkali treated cornmeal to make tortilla was not at risk for niacin deficiency.) In 1955, Altschul and colleagues described large amounts of niacin as having a lipid-lowering property.{©l As such, niacin is the oldest ‘known lipid-lowering drug") Lovastatin, the first 'statin’ drug, was first marketed in 1987/41 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 hydroxycarboxylic acid receptor 2 (HHCA2), also known as niacin receptor 1 (NIACR:).“4I34145I36) Yplike niacin, nicotinamide does not activate NIACR1; however, both niacin and nicotinamide activate the G protein-coupled estrogen receptor (GPER) in vitro.|!"7) References 1 ‘Chapter P-6. Applications to Specific Classes of Compounds". Nomenclature of Organic Chemistry : {PAC Recommendations and Preferred Names 2013 (Blue Book). 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Appendix D, p. 2 ISBN 978-0-9710541-9-6 "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, lowe.” 4107. "Niacin and Nicotinic Acid”, Joumal of the American Medical Association. 148 (10): 823. 7 March 1942. doi 10.1001 jama.1942.02830100053014 (hitps:/doi.org/10.1001%42Fjama. 1942,02830100053014) jiacin and Niacin Amide", Journal of the American Medical Association. 118 (10): 819. 7 March 1942. dol 10,1001 ama, 1942,02830100049011 (hitps://dol.org/10,1001%2Fjama,1942,02830 10004901} 108, Laguna J, Carpenter KJ (September 1951). "Raw versus processed corn in niacin-deficient diets”. The Journal of Nutrition. 45 (1) 21-8, dot 10,1093/jv45.1.21 (https:fldol,org/10,1093%2Fn%2F45,1.21). PMID 14880960 (https://pubmed,ncbisnlm.nih.gov/148809 60). 110. Altschul R, Hoffer A, Stephen JD (February 1955). "Influence of nicotinic acid on serum cholesterol in man". Archives of Biochemisiry and Biophysics. 54 (2): 558-8, doi 10.1016/0003-9861(55)90070-9 (https:lidoi.org/10.1016%2F0003-98619%2855%29 9070-9), PMID 14350806 (https://pubmed,ncbi.nim.nih.gov/ 14350806) “11. Romani M, Hofer DC, Katsyuba E, Auwerx J (April 2019). "Niacin: an old lipid drug in a new NAD+ dress" (https:/www.nebi.nim nih. govlpmcfarticles/PMCB446705). J. Lipid Res. 60 (4): 7416. doi 10.1194/.S092007 (htips//doi.org/10.1194%2F jr $092007) PMC 6446705 (htips:/hwww.ncbi.nlm.nih.govipmelartcles/PMC8446705). PMID 30782960 (https://pubmed.ncb .nlm.nih.govi307829 60). 112. Simons J (January 2003). "The $10 billion pl” (http://archive fortune. com/magazines/fortune/fortune_archive/2003/01/20/335643/n dex him). Fortune. 147 (1) 58-82, 88, 68. PMID 12602122 (htips:/pubmed.ncbi nlm nin. gow/12602 422113. Offermanns S, Schwaninger M (April 2015). "Nutritional or pharmacological activation of HCA(2) ameliorates neuroinammation’ Trends in Molecular Medicine. 21 (4): 245-55. dot 10.1016/.molmed.2015,02.002 (htips:lidoi.org/10.1016%2F}.molmed 2015.02.00 2), PMID 25766751 (https://oubmed.nebi.nim,nih.govi25766751| 114, Chai JT, Dighy JE, Choushury RP (May 2013). "GPR109A and vascular inflammation” (hitps://wvwncbi.nim.nih.govipmetarticles/P MC3631117). Current Athorosciorosis Reports. 15 (5). 325. doi 10.1007/s11883-013-0325.9 (hlips:/doi.org/10.1007%42Fs11883-013 -0325-9). PMC 3631117 (hitpss/wwww.ncbi.nim.nih govipmelarticles/PMC3631117). PMID 23526298 (hitps://pubmed.ncoi.nim.nin.go ¥i23526298) 115. Graff EC, Fang H, Wanders D, Judd RL (February 2016). “Antt.iflammatory effects of the hydroxycarboxylc acid receptor 2" ‘Metabolism. 65 (2): 102~13. doi 10.1016/] metabol.2016.10.001 (hitps://dol.org/10.1016%2F] metabol.2015.10.001 PMID 26773933 (htips:/pubmod.ncbi.nlm.nin.gov!26773933) 118, Wakade C, Chong R (December 2014). "A novel treatment target for Parkinson's disease", Journal of the Neurological Sciences, 347 (1-2): 34-8, doi 10.1016) jns.2014,10,024 (hitps:sidoi.org/10.1016%2F},ins.2014.10.024), PMID 25456298 (hitps:lipubmed.ncb i.nim.nih.gov'25455298). S2CID 23760853 (hitps.//api.semanticscholar.org/CorpusiD 29760853) 117. Santolla MF, De Francesco EM, Lappano R, Rosano C, Abonante S, Maggialini M (July 2014). “Niacin activates the G protein estrogen receptor (GPER}mediated signalling’. Cellular Signalling. 26 (7). 1466-75. doi 10.1016), cellsig.2014.03.011 (httpsil/doi.or .g/10.1016%42F}.celsig.2014.03.011). PMID 24662263 (https:!/pubmed.ncbi.nlm.nih.gow/24662263). External links 1 *Niacin" (htipss/druginfo.nim.nih.govidrugportaliname/niacin). Drug Information Portal. U.S. National Library of Medicine. Rotriovad trom *lpsion wikipeia orgiwlindox ohple=Niacndcki= 1066849687" ‘This page ws st edited on 20 January 2022, at 12:31 (UTC). ‘ext is avalabio under the Creative Commons Atibuton ShareAlike License adsitonal terms may apply. By using this se, you agree to the Terms of Use and Privacy Paley. Wipedia® isa registered vademark ofthe Wikimesla Foundation, Ine, a non-pratt organization.