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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__62051505357217__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__62051505357217__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:15940","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__62051505357217__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"62051505357217","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__62051505357217__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol Marvin 10180716063D starting HoverWatcher_5 Time for openFile( Marvin 10180716063D 14 14 0 0 1 0 999 V2000 -1.8995 1.3340 0.0396 C 0 0 0 0 0 0 0 0 0 6 0 0 -1.8995 -0.0710 0.0328 C 0 0 0 0 0 0 0 0 0 5 0 0 -0.6649 -0.7448 0.0300 C 0 0 0 0 0 0 0 0 0 4 0 0 0.4823 1.3762 0.0519 C 0 0 0 0 0 0 0 0 0 2 0 0 -0.7211 2.0030 0.0487 N 0 0 0 0 0 0 0 0 0 1 0 0 0.5646 -0.0386 0.0404 C 0 0 0 0 0 0 0 0 0 3 0 0 1.7847 -0.6988 0.0342 C 0 0 0 0 0 0 0 0 0 0 0 0 2.7973 -0.2018 0.5064 O 0 0 0 0 0 0 0 0 0 0 0 0 1.9084 -1.8180 -0.4554 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.7774 1.8557 0.0383 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.7792 -0.5918 0.0314 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.6818 -1.7681 0.0294 H 0 0 0 0 0 0 0 0 0 0 0 0 1.3191 1.9634 0.0514 H 0 0 0 0 0 0 0 0 0 0 0 0 2.6889 -2.2240 -0.4790 H 0 0 0 0 0 0 0 0 0 0 0 0 2 1 4 0 0 0 0 3 2 4 0 0 0 0 1 5 4 0 0 0 0 5 4 4 0 0 0 0 4 6 4 0 0 0 0 3 6 4 0 0 0 0 6 7 1 0 0 0 0 7 9 1 0 0 0 0 7 8 2 0 0 0 0 1 10 1 0 0 0 0 2 11 1 0 0 0 0 3 12 1 0 0 0 0 4 13 1 0 0 0 0 9 14 1 0 0 0 0 M END): 16 ms reading 14 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 14 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan.
Nicotinic acid 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 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. 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. A 2010 review had concluded that nicotinic acid was effective as a mono-therapy, 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. Prescription nicotinic acid was shown to cause hepatotoxicity and increase risk of type 2 diabetes. Nicotinic acid prescriptions in the U.S. had peaked in 2009 at 9.4 million, declining to 800 thousand by 2020.
Nicotinic acid has the formula C6H5NO2 and belongs to the group of the pyridinecarboxylic acids. As the precursor for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, it is involved in DNA repair.
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Read full article at Wikipedia
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| InChI=1S/C6H5NO2/c8-6(9)5-2-1-3-7-4-5/h1-4H,(H,8,9) |
| PVNIIMVLHYAWGP-UHFFFAOYSA-N |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Bacillus subtilis
(NCBI:txid1423)
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of strain
29784
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Cordyceps sinensis
(NCBI:txid72228)
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Found in
mycelium
(BTO:0001436).
Ethanolic extract of dried mycelia
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
cerebrospinal fluid
(UBERON:0001359).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 165-177. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp., Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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Found in
faeces
(UBERON:0001988).
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
|
Found in
blood
(UBERON:0000178).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 165-177. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp., Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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Found in
saliva
(UBERON:0001836).
See:
Sugimoto et al. (2013) Physiological and environmental parameters associated with mass spectrometry-based salivary metabolomic profiles.
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Homo sapiens
(NCBI:txid9606)
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Found in
urine
(BTO:0001419).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 130. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp. Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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From MetaboLights
See:
MetaboLights Study
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Homo sapiens
(NCBI:txid9606)
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From MetaboLights
See:
MetaboLights Study
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Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
EC 3.5.1.19 (nicotinamidase) inhibitor
An EC 3.5.1.* (non-peptide linear amide C-N hydrolase) inhibitor that interferes with the action of nicotinamidase (EC 3.5.1.19).
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via alkaloid )
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
human urinary metabolite
Any metabolite (endogenous or exogenous) found in human urine samples.
plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
water-soluble vitamin (role)
Any vitamin that dissolves in water and readily absorbed into tissues for immediate use. Unlike the fat-soluble vitamins, they are not stored in the body and need to be replenished regularly in the diet and will rarely accumulate to toxic levels since they are quickly excreted from the body via urine.
(via B vitamin )
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vasodilator agent
A drug used to cause dilation of the blood vessels.
antidote
Any protective agent counteracting or neutralizing the action of poisons.
antilipemic drug
A substance used to treat hyperlipidemia (an excess of lipids in the blood).
nutraceutical
A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance.
(via B vitamin )
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View more via ChEBI Ontology
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nicotinic acid
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pyridine-3-carboxylic acid
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acide nicotinique
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WHO MedNet
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ácido nicotínico
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WHO MedNet
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acidum nicotinicum
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WHO MedNet
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nicotinic acid
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WHO MedNet
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3-carboxylpyridine
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ChemIDplus
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3-carboxypyridine
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NIST Chemistry WebBook
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3-pyridinecarboxylic acid
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KEGG COMPOUND
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3-Pyridylcarboxylic acid
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HMDB
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anti-pellagra vitamin
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NIST Chemistry WebBook
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β-pyridinecarboxylic acid
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ChEBI
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m-pyridinecarboxylic acid
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NIST Chemistry WebBook
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Niacin
 Note: (2015-01-13) Note that the term 'niacin' has also been used as a synonym for nicotinamide, as well as other molecules that exhibit the biological activity of nicotinic acid. |
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KEGG COMPOUND
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Nicotinic acid
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KEGG COMPOUND
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NICOTINIC ACID
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PDBeChem
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Nicotinsaure
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ChemIDplus
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Nikotinsäure
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ChEBI
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P.P. factor
| Note: (2015-01-13) Note that the term 'P.P. factor' has also been used as a synonym for nicotinamide. |
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NIST Chemistry WebBook
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pellagra preventive factor
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NIST Chemistry WebBook
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PP factor
| Note: (2015-01-13) Note that the term 'PP factor' has also been used as a synonym for nicotinamide. |
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NIST Chemistry WebBook
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pyridine-β-carboxylic acid
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NIST Chemistry WebBook
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pyridine-carboxylique-3
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ChemIDplus
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vitamin B3
| Note: (2015-01-13) Note that the term 'vitamin B3' has been used as a synonym for nicotinamide, as well as other molecules that exhibit the biological activity of nicotinic acid. |
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ChEBI
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Niacor
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KEGG DRUG
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Niaspan
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KEGG DRUG
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2835
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DrugCentral
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913
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ChemSpider
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C00000208
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KNApSAcK
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C00253
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KEGG COMPOUND
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D00049
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KEGG DRUG
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DB00627
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DrugBank
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FDB001014
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FooDB
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HMDB0001488
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HMDB
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LSM-4676
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LINCS
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Niacin
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Wikipedia
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NIACINE
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MetaCyc
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NIO
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PDBeChem
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| View more database links |
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109591
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Reaxys Registry Number
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Reaxys
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3340
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Gmelin Registry Number
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Gmelin
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59-67-6
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CAS Registry Number
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KEGG COMPOUND
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59-67-6
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CAS Registry Number
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ChemIDplus
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59-67-6
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CAS Registry Number
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NIST Chemistry WebBook
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Choi P, Rhayat L, Pinloche E, Devillard E, De Paepe E, Vanhaecke L, Haesebrouck F, Ducatelle R, Van Immerseel F, Goossens E (2021)
Bacillus Subtilis 29784 as a Feed Additive for Broilers Shifts the Intestinal Microbial Composition and Supports the Production of Hypoxanthine and Nicotinic Acid.
Animals : an open access journal from MDPI 11, 1335 [PubMed:34066686]
[show Abstract]
The probiotic Bacillus subtilis strain 29784 (Bs29784) has been shown to improve performance in broilers. In this study, we used a metabolomic and 16S rRNA gene sequencing approach to evaluate effects of Bs29874 in the broiler intestine. Nicotinic acid and hypoxanthine were key metabolites that were produced by the strain in vitro and were also found in vivo to be increased in small intestinal content of broilers fed Bs29784 as dietary additive. Both metabolites have well-described anti-inflammatory effects in the intestine. Furthermore, Bs29784 supplementation to the feed significantly altered the ileal microbiome of 13-day-old broilers, thereby increasing the abundance of genus Bacillus, while decreasing genera and OTUs belonging to the Lactobacillaceae and Enterobacteriacae families. Moreover, Bs29784 did not change the cecal microbial community structure, but specifically enriched members of the family Clostridiales VadinBB60, as well as the butyrate-producing families Ruminococcaceae and Lachnospiraceae. The abundance of various OTUs and genera belonging to these families was significantly associated with nicotinic acid levels in the cecum, suggesting a possible cross-feeding between B. subtilis strain 29784 and these beneficial microbes. Taken together, the data indicate that Bs29784 exerts its described probiotic effects through a combined action of its metabolites on both the host and its microbiome. | Yu CS, Wang Q, Bajsa-Hirschel J, Cantrell CL, Duke SO, Liu XH (2021)
Synthesis, Crystal Structure, Herbicidal Activity, and SAR Study of Novel N-(Arylmethoxy)-2-chloronicotinamides Derived from Nicotinic Acid.
Journal of agricultural and food chemistry 69, 6423-6430 [PubMed:34085526]
[show Abstract]
Nicotinic acid, also known as niacin, is a natural product, which is widely found in plants and animals. To discover novel natural-product-based herbicides, a series of N-(arylmethoxy)-2-chloronicotinamides were designed and synthesized. Some of the new N-(arylmethoxy)-2-chloronicotinamides exhibited excellent herbicidal activity against Agrostis stolonifera (bentgrass) at 100 μM. Compound 5f (2-chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide) possessed excellent herbicidal activity against Lemna paucicostata (duckweed), with an IC50 value of 7.8 μM, whereas the commercial herbicides clomazone and propanil had values of 125 and 2 μM, respectively. The structure-activity relationships reported in this paper could be used for the development of new herbicides against monocotyledonous weeds. | Pollard CL, Gibb Z, Swegen A, Lawson EF, Grupen CG (2021)
Nicotinic acid supplementation at a supraphysiological dose increases the bioavailability of NAD+ precursors in mares.
Journal of animal physiology and animal nutrition 105, 1154-1164 [PubMed:34117670]
[show Abstract]
NAD+ deficiency has recently been linked with increased occurrences of congenital abnormalities and embryonic death in human and animal subjects. Early embryonic death is a major component of pregnancy loss in mares and very little is known regarding the requirement for NAD+ in horses. The aim of this study was to quantify NAD+ and its metabolites in the plasma and urine of mares after orally administering an acute dose of nicotinic acid and determine the absorption, metabolism and excretion of this essential precursor for NAD+ biosynthesis. Nicotinic acid (5 g per os) was administered to four mares via a dosing syringe. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6 and 22 h, and urine samples were collected at 0, 3, 6 and 22 h. The samples were processed and analysed by mass spectrometry. A general additive model was applied to all metabolite concentration values followed by a post-hoc multiple comparisons test. Nicotinic acid was rapidly absorbed into peripheral blood within 15 min of administration and the concentrations of nicotinic acid, nicotinamide (NAM), nicotinuric acid, nicotinic acid mononucleotide and nicotinic acid adenine dinucleotide (NaAD) increased significantly in plasma at 30 min. The concentrations of NAM, nicotinic acid riboside and NaAD increased significantly in urine at 3 h. The levels of NAM and NaAD remained significantly elevated in plasma at 22 h, sixfold and ninefold greater, respectively, than the basal levels at 0 h. While the extracellular levels of NAD+ in the samples remained undetected, the large, sustained elevation of NaAD levels in plasma indicates that the NAD+ levels were boosted within the cellular compartments. The results show that nicotinic acid supplementation increases the bioavailability of NAD+ precursors in mares, which is proposed to be beneficial during periods of peak NAD+ demand, such as during early embryo development. | Almubarak AM, Kim E, Yu IJ, Jeon Y (2021)
Supplementation with Niacin during in vitro maturation improves the quality of porcine embryos.
Theriogenology 169, 36-46 [PubMed:33932650]
[show Abstract]
Niacin, also known as vitamin B3, has a pivotal role in energy metabolism, cellular signaling cascades regulating gene expression, and apoptosis. However, the effect of Niacin on porcine early embryo developmental competence remains to be elucidated. The present study aimed to assess the effects of Niacin treatment during in vitro maturation (IVM) on the nuclear maturation of porcine oocytes and subsequent development of in vitro embryos. In addition, the expression profiles of selected genes related to lipid metabolism, oxidative stress, and apoptosis were assessed. The IVM medium was supplemented with different concentrations of Niacin (0, 300, 600, and 900 μM). The results showed that a high concentration of Niacin (900 μM) significantly decreased cumulus expansion compared to the other groups (p < 0.05). No significant difference was observed among the experimental groups for nuclear maturation rate. Niacin treatments (300, 600, and 900 μM) during IVM significantly (p < 0.05) enhanced glutathione levels. Treatment with 300 and 600 μM significantly (p < 0.05) lowered the reactive oxygen species levels compared to treatment with 900 μM and the control group. Niacin supplementation to the IVM media significantly improved the cleavage and blastocyst rates compared to the control group. Supplementation with 300 and 600 μM of Niacin significantly increased the total cell number of blastocysts compared to supplementation with 900 μM or the control groups. Cytoplasmic lipid droplets were significantly reduced after 600 μM treatment. Supplementation of Niacin to IVM media positively affected the relative expression of genes related to energy and oxidative status (SIRT1), pro-apoptosis (BAX), anti-apoptosis (BCL2), and lipid metabolism (ACACA and PNPLA2) in cumulus cells and oocytes. Taken together, Niacin supplementation to porcine IVM media improved the developmental competence of early embryos mainly through protection against oxidative stress and its influence on energy metabolism and apoptosis pathways. | Watson WD, Timm KN, Lewis AJ, Miller JJJ, Emmanuel Y, Clarke K, Neubauer S, Tyler DJ, Rider OJ (2020)
Nicotinic acid receptor agonists impair myocardial contractility by energy starvation.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34, 14878-14891 [PubMed:32954525]
[show Abstract]
Nicotinic acid receptor agonists have previously been shown to cause acute reductions in cardiac contractility. We sought to uncover the changes in cardiac metabolism underlying these alterations in function. In nine humans, we recorded cardiac energetics and function before and after a single oral dose of nicotinic acid using cardiac MRI to demonstrate contractile function and Phosphorus-31 (31 P) magnetic resonance spectroscopy to demonstrate myocardial energetics. Nicotinic Acid 400 mg lowered ejection fraction by 4% (64 ± 8% to 60 ± 7%, P = .03), and was accompanied by a fall in phosphocreatine/ATP ratio by 0.4 (2.2 ± 0.4 to 1.8 ± 0.1, P = .04). In four groups of eight Wistar rats, we used pyruvate dehydrogenase (PDH) flux studies to demonstrate changes in carbohydrate metabolism induced by the nicotinic acid receptor agonist, Acipimox, using hyperpolarized Carbon-13 (13 C) magnetic resonance spectroscopy. In rats which had been starved overnight, Acipimox caused a fall in ejection fraction by 7.8% (67.5 ± 8.9 to 60 ± 3.1, P = .03) and a nearly threefold rise in flux through PDH (from 0.182 ± 0.114 to 0.486 ± 0.139, P = .002), though this rise did not match pyruvate dehydrogenase flux observed in rats fed carbohydrate rich chow (0.726 ± 0.201). In fed rats, Acipimox decreased pyruvate dehydrogenase flux (to 0.512 ± 0.13, P = .04). Concentration of plasma insulin fell by two-thirds in fed rats administered Acipimox (from 1695 ± 891 ng/L to 550 ± 222 ng/L, P = .005) in spite of glucose concentrations remaining the same. In conclusion, we demonstrate that nicotinic acid receptor agonists impair cardiac contractility associated with a decline in cardiac energetics and show that the mechanism is likely a combination of reduced fatty acid availability and a failure to upregulate carbohydrate metabolism, essentially starving the heart of fuel. | Bahrami A, Divar MR, Azari M, Kafi M (2020)
Nicotinic Acid (Niacin) Supplementation in Cooling and Freezing Extenders Enhances Stallion Semen Characteristics
Journal of Equine Veterinary Science. 94, Not Available [Agricola:IND607088605]
[show Abstract]
In the present study, we aimed to evaluate the possible protective effects of the nicotinic acid (NA) at three concentrations (10, 20, and 40 mM) on the equine cooled and frozen-thawed spermatozoa quality markers including viability, plasma membrane or acrosome integrity, DNA fragmentation, lipid peroxidation, and total oxidant levels. We also evaluated the effects of NA on preservation of the post-thaw sperm quality after 6 hours of cold storage before freezing. Five stallions were used for semen collections. The current experiment was repeated six times using pooled semen samples from two stallions, each time. We showed that NA at 20 and 40 mM concentrations could significantly improve the stallion sperm quality markers during cold storage. However, the protective effects were not different between 20 mM and 40 mM concentrations in most measures. Nicotinic acid could also improve the post-thaw stallion sperm quality at 10, 20, and 40 mM concentrations. However, the 40 mM concentration showed a negative impact on some post-thaw kinematic sperm parameters. Nicotinic acid at 10 and 20 mM concentrations could preserve the sperm cryo-tolerance to be frozen up to 8 hours after collection without a significant decline in most of the post-thaw sperm quality measures. Nicotinic acid could also decrease the level of the lipid peroxidation and total reactive oxygen/nitrogen species in the cooled and frozen-thawed spermatozoa, in a dose-dependent manner. Therefore, NA at 20 mM concentration could preserve most of the stallion sperm quality measures during cold storage (42 hours, 5°C) and enabled storage of cooled stallion semen for 6 hours before freezing without significant deterioration of the post-thaw sperm quality. | Lee DW, Park YW, Lee MY, Jeong KH, Lee JY (2020)
Structural analysis and insight into effector binding of the niacin-responsive repressor NiaR from Bacillus halodurans.
Scientific reports 10, 21039 [PubMed:33273654]
[show Abstract]
The niacin-responsive repressor, NiaR, is transcriptional repressor of certain nicotinamide adenine dinucleotide (NAD) biosynthetic genes in response to an increase in niacin levels. NAD is a vital molecule involved in various cellular redox reactions as an electron donor or electron acceptor. The NiaR family is conserved broadly in the Bacillus/Clostridium group, as well as in the Fusobacteria and Thermotogales lineages. The NiaR structure consists of two domains: an N-terminal DNA-binding domain, and a C-terminal regulation domain containing a metal-binding site. In this paper, we report the crystal structures of apo and niacin-bound forms of NiaR from Bacillus halodurans (BhNiaR). The analysis of metal-binding and niacin-binding sites through the apo and niacin-bound structures is described. Each N- and C-terminal domain structure of BhNiaR is almost identical with NiaR from Thermotoga maritima, but the overall domain arrangement is quite different. A zinc ion is fully occupied in each subunit with well-conserved residues in the C-terminal domain. Niacin is also located at a hydrophobic pocket near the zinc ion in the C-terminal domain. | Liu D, Wang X, Kong L, Chen Z (2015)
Nicotinic acid regulates glucose and lipid metabolism through lipid independent pathways.
Current pharmaceutical biotechnology 16, 3-10 [PubMed:25429652]
[show Abstract]
Nicotinic acid (NA) decreases low density lipoprotein (LDL) cholesterol and increases highdensity lipoprotein (HDL) cholesterol at pharmacological doses 500-2000 mg/day, which further inhibits the progression of atherosclerosis and cardiovascular morbidity. However, some effects of NA may be mediated through lipid-independent pathways. NA participates in the regulation of glucose metabolism and the NAD-sirtuin pathway, which may relate to the altered mitochondrial biogenesis. NA exerts its anti-atherosclerotic or side effects via binding to GPR109A and receptor TRPV1. NA may regulate lipid metabolism via adipokines, especially TNFα and adiponectin. NA participates in several cellular pathways, including forkhead transcription factors, sirtuins, and protein kinase B. Though much progress on the regulatory effect of NA has been obtained, much remains to be determined about the exact cellular signal pathways on the regulatory mechanism. To reveal the mechanisms of excessive fatty deposition diseases, it is necessary to investigate the signaling pathways in the muscle, liver, and adipose tissue by which NA controls lipid metabolism. In this paper, we will review recent data on the pharmacological effects of NA and discuss how NA might be harnessed to regulate glucose and lipid metabolism through lipid-independent pathways. | Li Q, Xie G, Zhang W, Zhong W, Sun X, Tan X, Sun X, Jia W, Zhou Z (2014)
Dietary nicotinic acid supplementation ameliorates chronic alcohol-induced fatty liver in rats.
Alcoholism, clinical and experimental research 38, 1982-1992 [PubMed:24848081]
[show Abstract]
BackgroundAlcohol abuse frequently causes niacin deficiency in association with the development of alcoholic liver disease. The objective of the present study was to determine whether dietary nicotinic acid (NA) deficiency exaggerates and whether dietary NA supplementation alleviates alcohol-induced fatty liver.MethodsMale Sprague-Dawley rats were pair-fed with 4 isocaloric liquid diets: control, ethanol (EtOH), EtOH with dietary NA deficiency, and EtOH with dietary NA supplementation, respectively, for 8 weeks. The control and EtOH diets contained normal levels of NA (7.5 mg/l). Dietary NA deficiency (0 mg NA/l) was achieved by removing NA from the vitamin mix, while NA was added to the liquid diet at 750 mg/l for dietary NA supplementation.ResultsChronic EtOH feeding induced significant lipid accumulation in the liver, which was not worsened by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Liver total NAD, NAD(+) , and NADH levels were remarkably higher in the NA supplemented group than the NA deficient or EtOH alone groups. Dietary NA supplementation to EtOH-fed rats increased the protein levels of hepatic cytochrome P450 4A1 (CYP4A1) and acyl-coenzyme A oxidase 1 without affecting their mRNA levels. Interestingly, we found dietary NA supplementation reduced the ubiquitination level of CYP4A1. In addition, hepatic fatty acid synthase expression was reduced, while the serum β-hydroxybutyrate and adiponectin concentrations were significantly elevated by dietary NA supplementation. Moreover, dietary NA supplementation modulated EtOH-perturbed liver and serum metabolite profiles.ConclusionsThese results demonstrate that alcoholic fatty liver was not exaggerated by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Increased hepatic fatty acid oxidation and decreased hepatic de novo lipogenesis contribute to the effects of dietary NA supplementation. | Kharbanda KK (2014)
Nicotinic acid supplementation in the context of alcoholic liver injury: friend or foe?
Alcoholism, clinical and experimental research 38, 1829-1831 [PubMed:25040591]
[show Abstract]
Li and colleagues (2014) in this issue report that dietary nicotinic acid (NA) supplementation ameliorates ethanol-induced hepatic steatosis, but a deficiency does not worsen injury induced by alcohol alone. The authors further present some mechanistic insights into the protective role of NA supplementation. Results of this and other previous studies in the context of alcoholic liver injury raise one important question as to what should be an adequate dose of NA that will provide the maximum benefit to hepatic and extrahepatic tissues and with minimum adverse effects. | Ma L, Lee BH, Mao R, Cai A, Jia Y, Clifton H, Schaefer S, Xu L, Zheng J (2014)
Nicotinic acid activates the capsaicin receptor TRPV1: Potential mechanism for cutaneous flushing.
Arteriosclerosis, thrombosis, and vascular biology 34, 1272-1280 [PubMed:24675661]
[show Abstract]
ObjectiveNicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food.Approach and resultsWe observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1(-/-) knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1.ConclusionsDirect activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance. | Zhou PP, Sun XB, Qiu WY (2014)
Nicotinic acid and its derivatives: synthetic routes, crystal forms and polymorphs.
Current drug discovery technologies 11, 97-108 [PubMed:24568240]
[show Abstract]
Nicotinic acid is a well-known pharmaceutical in the vitamin B group that has attracted great interest in the past decades due to its significant importance in the treatment of the human diseases like pellagra. Also, nicotinic acid derivatives have been devoted to much attention due to their different pharmaceutical effects in the treatment of diseases. In view of this, the developments of nicotinic acid and its derivatives including their synthetic methods by using different substrates, and their structural modifications (e.g., substitution of one or more positions of pyridyl ring or acid) were reviewed in details. Drug molecules like nicotinic acid and its derivatives may exist in more than one crystal form in its solid state, known as polymorphs. Different polymorphs have different dissolution rates and aqueous solubility. Therefore, we reviewed structures of different crystal forms of nicotinic acid and its derivatives. | Shibata K, Fukuwatari T, Suzuki C (2014)
Pharmacological doses of nicotinic acid and nicotinamide are independently metabolized in rats.
Journal of nutritional science and vitaminology 60, 86-93 [PubMed:24975217]
[show Abstract]
Two compounds are known as the vitamin niacIn: nicotinic acid (NiA) and nicotinamide (Nam). The physiological functions and metabolic fates of NiA and Nam are identical, but differ when pharmacological doses are administered. Our study aimed to investigate the metabolic interactions between NiA and Nam when their pharmacological doses were administered together. We measured seven major niacin catabolites, including NiA, Nam, N(1)-methylnicotinamide (MNA), N(1)-methyl-2-pyridone-5-carboxamide (2-Py), N(1)-methyl-4-pyridone-3-carboxamide (4-Py), Nam N-oxide, and nicotinuric acid (NuA). Under physiological conditions, niacin is chiefly catabolized to 4-Py via MNA. However, this was not the primary pathway when rats were fed a diet containing excess niacin. When rats were fed a diet containing excess NiA, NuA was the major catabolite, and on being fed a diet containing excess Nam, MNA was the major catabolite. When rats were fed a diet containing an excess of both NiA and Nam, MNA and NuA were the major catabolites. The metabolic fates of excess NiA and Nam did not mutually interfere. Therefore, the administration of NiA and Nam together may be better than the administration of NiA or Nam alone because different pharmacological effects are expected. | Li J, Li Y, Zhang P, Niu H, Shi Y (2014)
Nicotinic acid modulates intracellular calcium concentration and disassembles the cytoskeleton.
Molecular medicine reports 10, 2805-2810 [PubMed:25241762]
[show Abstract]
Nicotinic acid (NA), a member of the vitamin B family, is well known for its functions in the treatment and prevention of atherosclerosis due to decreasing plasma levels of low-density lipoprotein cholesterol. In recent years, the major side effect of NA, cutaneous flushing, has also attracted extensive attention. However, the effects of NA in other aspects of physiology or cell biology have remained elusive. The present study provided evidence that high concentrations of NA were able to first reduce and later elevate intracellular [Ca2+] in the NIH3T3 cell line. The reduction of the intracellular Ca2+ concentration was achieved within the initial 10 sec, and was preceded by a gradual elevation of intracellular [Ca2+]. Notably, marked accumulation of opaque materials in the perinuclear region was observed in NIH3T3 cells treated with 70 mM NA. Further analysis revealed that treatment with 70 mM NA for 1 h disassembled the microtubule and F‑actin cytoskeleton systems and resulted in β‑tubulin degradation in an ubiquitin‑proteasome-dependent manner. These data indicated that high concentrations of NA disrupted cytoskeleton structures, which may have contributed to minus end (nucleus region) to plus end (cell membrane region)-directed transport processes and resulted in the deposition of material in the perinuclear region. Artificially increasing [Ca2+] adding CaCl2 to the culture media effected the disassembly of F‑actin, while it had no apparent effect on microtubules. These results suggested that the disruption of the cytoskeleton systems was not entirely due to the NA-induced elevation of [Ca2+]. Finally, microinjection of NA into xenopus embryos blocked the transport of melanosomes to the peripheral cellular area. In conclusion, the present study indicated that NA disassembles F‑actin and microtubule systems, thereby blocking cytoskeleton-dependent intracellular transport. | Trechot P, Petitpain N, Guy C, Pinzano A, Javot L, Schmutz JL, Marie B, Barbaud A (2013)
Nicorandil: from ulcer to fistula into adjacent organs.
International wound journal 10, 210-213 [PubMed:22458880]
[show Abstract]
Nicorandil is an original vasodilatator used to control angina by decreasing cardiac preload and afterload. Since 1997, many reports of single or multiple nicorandil-induced ulcerations have been published. To date, eight cases of nicorandil-induced fistula into adjacent organs have been described. The pathogeneses of nicorandil-induced ulceration and fistula into adjacent organs are not yet elucidated. The two main hepatic biotransformation pathways of nicorandil are denitration and reduction of the alkyl chain leading to nicotinamide and niconitic acid which merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate. This merging which is known as saturable, may contribute to a slow and abnormal distribution of nicotinamide and nicotinic acid out of the endogenous pool. Under these special conditions, providing these two molecules in situ, nicotinic acid associated with nicotinamide may ulcerate rather recent or maintained trauma. Ulcers and fistulae induced by nicorandil heal after withdrawal. Surgical intervention is unnecessary and inappropriate as it is ineffective and exacerbates morbidity. All practitioners should be correctly informed about these serious but preventable nicorandil side effects, which mostly occur in the elderly and fragile population. In the absence of corrective measures, withdrawal of this original and active drug should be considered. | Phua LC, Koh PK, Cheah PY, Ho HK, Chan EC (2013)
Global gas chromatography/time-of-flight mass spectrometry (GC/TOFMS)-based metabonomic profiling of lyophilized human feces.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 937, 103-113 [PubMed:24029555]
[show Abstract]
Gas chromatography mass spectrometry (GC/MS)-based fecal metabonomics represents a powerful systems biology approach for elucidating metabolic biomarkers of lower gastrointestinal tract (GIT) diseases. Unlike metabolic profiling of fecal water, the profiling of complete fecal material remains under-explored. Here, a gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) method was developed and validated for the global metabonomic profiling of human feces. Fecal and fecal water metabotypes were also profiled and compared. Additionally, the unclear influence of blood in stool on the fecal metabotype was investigated unprecedentedly. Eighty milligram of lyophilized feces was ultrasonicated with 1mL of methanol:water (8:2) for 30min, followed by centrifugation, drying of supernatant, oximation and trimethylsilylation for 45min. Lyophilized feces demonstrated a more comprehensive metabolic coverage than fecal water, based on the number of chromatographic peaks. Principal component analysis (PCA) indicated occult blood (1mgHb/g feces) exerted a negligible effect on the fecal metabotype. Conversely, a unique metabotype related to feces spiked with gross blood (100mgHb/g feces) was revealed (PCA, R(2)X=0.837, Q(2)=0.794), confirming the potential confounding effect of gross GIT bleeding on the fecal metabotype. This pertinent finding highlights the importance of prudent interpretation of fecal metabonomic data, particularly in GIT diseases where bleeding is prevalent. | Roux A, Xu Y, Heilier JF, Olivier MF, Ezan E, Tabet JC, Junot C (2012)
Annotation of the human adult urinary metabolome and metabolite identification using ultra high performance liquid chromatography coupled to a linear quadrupole ion trap-Orbitrap mass spectrometer.
Analytical chemistry 84, 6429-6437 [PubMed:22770225]
[show Abstract]
Metabolic profiles of biofluids obtained by atmospheric pressure ionization mass spectrometry-based technologies contain hundreds to thousands of features, most of them remaining unknown or at least not characterized in analytical systems. We report here on the annotation of the human adult urinary metabolome and metabolite identification from electrospray ionization mass spectrometry (ESI-MS)-based metabolomics data sets. Features of biological interest were first of all annotated using the ESI-MS database of the laboratory. They were also grouped, thanks to software tools, and annotated using public databases. Metabolite identification was achieved using two complementary approaches: (i) formal identification by matching chromatographic retention times, mass spectra, and also product ion spectra (if required) of metabolites to be characterized in biological data sets to those of reference compounds and (ii) putative identification from biological data thanks to MS/MS experiments for metabolites not available in our chemical library. By these means, 384 metabolites corresponding to 1484 annotated features (659 in negative ion mode and 825 in positive ion mode) were characterized in human urine samples. Of these metabolites, 192 and 66 were formally and putatively identified, respectively, and 54 are reported in human urine for the first time. These lists of features could be used by other laboratories to annotate their ESI-MS metabolomics data sets. | Smith BC, Anderson MA, Hoadley KA, Keck JL, Cleland WW, Denu JM (2012)
Structural and kinetic isotope effect studies of nicotinamidase (Pnc1) from Saccharomyces cerevisiae.
Biochemistry 51, 243-256 [PubMed:22229411]
[show Abstract]
Nicotinamidases catalyze the hydrolysis of nicotinamide to nicotinic acid and ammonia. Nicotinamidases are absent in mammals but function in NAD(+) salvage in many bacteria, yeast, plants, protozoa, and metazoans. We have performed structural and kinetic investigations of the nicotinamidase from Saccharomyces cerevisiae (Pnc1). Steady-state product inhibitor analysis revealed an irreversible reaction in which ammonia is the first product released, followed by nicotinic acid. A series of nicotinamide analogues acting as inhibitors or substrates were examined, revealing that the nicotinamide carbonyl oxygen and ring nitrogen are critical for binding and reactivity. X-ray structural analysis revealed a covalent adduct between nicotinaldehyde and Cys167 of Pnc1 and coordination of the nicotinamide ring nitrogen to the active-site zinc ion. Using this structure as a guide, the function of several residues was probed via mutagenesis and primary (15)N and (13)C kinetic isotope effects (KIEs) on V/K for amide bond hydrolysis. The KIE values of almost all variants were increased, indicating that C-N bond cleavage is at least partially rate limiting; however, a decreased KIE for D51N was indicative of a stronger commitment to catalysis. In addition, KIE values using slower alternate substrates indicated that C-N bond cleavage is at least partially rate limiting with nicotinamide to highly rate limiting with thionicotinamide. A detailed mechanism involving nucleophilic attack of Cys167, followed by elimination of ammonia and then hydrolysis to liberate nicotinic acid, is discussed. These results will aid in the design of mechanism-based inhibitors to target pathogens that rely on nicotinamidase activity. | Stach K, Zaddach F, Nguyen XD, Elmas E, Kralev S, Weiss C, Borggrefe M, Kälsch T (2012)
Effects of nicotinic acid on endothelial cells and platelets.
Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 21, 89-95 [PubMed:21632263]
[show Abstract]
BackgroundInteractions between platelets and endothelial cells under inflammatory conditions lead to an increased expression of various activity markers of atherosclerosis in the vessel wall. The purpose of this study was to investigate possible protective effects of nicotinic acid in an in vitro endothelial cell model.MethodsAfter a 24-hour incubation period with nicotinic acid (1 mmol/l), human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide and were then incubated in direct contact with activated platelets. Following this incubation, the expression of CD40L and CD62P on platelets and the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, uPAR, and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analyzed by ELISA for soluble MCP-1 and MMP-1.ResultsThe increased expression of VCAM-1 on endothelial cells by proinflammatory stimulation with activated platelets was significantly reduced through preincubation with nicotinic acid (P<.05). Furthermore, platelets in direct contact with preincubated endothelial cells showed a significant reduction in their CD62P and CD40L expression when compared to platelets incubated with untreated endothelial cells (P<.05). Treatment with nicotinic acid did not have a significant effect on ICAM-1, uPAR, and MT1-MMP expression on endothelial cells. Levels of soluble MCP-1 and MMP-1 in supernatants were lower after preincubation with nicotinic acid.ConclusionNicotinic acid inhibits platelet activation after platelets contacted nicotinic acid treated endothelial cells and inhibits VCAM-1 expression on human endothelial cells under inflammatory conditions. These findings suggest a possible pleiotropic therapeutic relevance of nicotinic acid in atherosclerosis. | Suksiriworapong J, Sripha K, Kreuter J, Junyaprasert VB (2012)
Functionalized (poly(ɛ-caprolactone))₂-poly(ethylene glycol) nanoparticles with grafting nicotinic acid as drug carriers.
International journal of pharmaceutics 423, 562-570 [PubMed:22155410]
[show Abstract]
Nicotinic acid was grafted on (poly(ɛ-caprolactone))(2)-poly(ethylene glycol) copolymers that were used for the preparation of nanoparticles with the objectives to monitor particle size and to optimize the drug loading capacity as well as the release profile of the particles. Increasing amounts of grafting nicotinic acid increased the particle size as a result of an enhanced hydrophobicity of the copolymer. Ibuprofen and indomethacin with two different molecular characteristics were selected as model drugs to be bound to the nanoparticles. The presence of grafting nicotinic acid enhanced the loading capacity for both drugs compared to the nanoparticles without nicotinic acid. However, no correlation between amount of grafting nicotinic acid and loading capacity was observed. The release characteristic of both drugs was fitted to the Higuchi model indicating Fickian diffusion. The release characteristic of indomethacin mainly depended on the crystalline property of the copolymer whereas that of ibuprofen was additionally influenced by the hydrogen bonding between drug and grafted copolymer. | Godin AM, Ferreira WC, Rocha LT, Ferreira RG, Paiva AL, Merlo LA, Nascimento EB, Bastos LF, Coelho MM (2012)
Nicotinic acid induces antinociceptive and anti-inflammatory effects in different experimental models.
Pharmacology, biochemistry, and behavior 101, 493-498 [PubMed:22366213]
[show Abstract]
Although in vitro studies have shown that nicotinic acid inhibits some aspects of the inflammatory response, a reduced number of in vivo studies have investigated this activity. To the best of our knowledge, the effects induced by nicotinic acid in models of nociceptive and inflammatory pain are not known. Per os (p.o.) administration of nicotinic acid (250, 500 or 1000 mg/kg, -1 h) inhibited the first and the second phases of the nociceptive response induced by formalin in mice. Nicotinic acid (250 or 500 mg/kg, -1 and 3 h) also inhibited the mechanical allodynia induced by carrageenan in rats, a model of inflammatory pain. However, in a model of nociceptive pain, exposure of mice to a hot-plate, nicotinic acid was devoid of activity. In addition to inhibiting the nociceptive response in models of inflammatory pain, nicotinic acid (250 or 500 mg/kg, p.o., -1 and 3 h) inhibited paw edema induced by carrageenan in mice and rats. Picolinic acid (62.5 or 125 mg/kg, p.o., -1 h), a nicotinic acid isomer, inhibited both phases of the nociceptive response induced by formalin, but not paw edema induced by carrageenan in mice. The other nicotinic acid isomer, isonicotinic acid, was devoid of activity in these two models. In conclusion, our results represent the first demonstration of the activity of nicotinic acid in experimental models of nociceptive and inflammatory pain and also provide further support to its anti-inflammatory activity. It is unlikely that conversion to nicotinamide represents an important mechanism to explain the antinociceptive and anti-inflammatory activities of nicotinic acid. The demonstration of new activities of nicotinic acid, a drug that has already been approved for clinical use and presents a positive safety record, may contribute to raise the interest in conducting clinical trials to investigate its usefulness in the treatment of painful and inflammatory diseases. | Jacobson EL, Kim H, Kim M, Jacobson MK (2012)
Niacin: vitamin and antidyslipidemic drug.
Sub-cellular biochemistry 56, 37-47 [PubMed:22116693]
[show Abstract]
Niacin is defined collectively as nicotinamide and nicotinic acid, both of which fulfill the vitamin functions of niacin carried out by the bioactive forms NAD(P). In the last few decades numerous new enzymes that consume NAD(P) as substrates have been identified. The functions of these enzymes are emerging as exciting paradigm shifts, even though they are in early stages of discovery. The recent identification of the nicotinic acid receptor has allowed distinction of the drug-like roles of nicotinic acid from its vitamin functions, specifically in modulating blood lipid levels and undesirable side effects such as skin vasodilation and the more rare hepatic toxicities. This information has led to a new strategy for drug delivery for niacin, which, if successful, could have a major impact on human health through decreasing risk for cardiovascular disease. Understanding the many other effects of niacin has much broader potential for disease intervention and treatment in numerous diseases including cancer. | French JB, Cen Y, Vrablik TL, Xu P, Allen E, Hanna-Rose W, Sauve AA (2010)
Characterization of nicotinamidases: steady state kinetic parameters, classwide inhibition by nicotinaldehydes, and catalytic mechanism.
Biochemistry 49, 10421-10439 [PubMed:20979384]
[show Abstract]
Nicotinamidases are metabolic enzymes that hydrolyze nicotinamide to nicotinic acid. These enzymes are widely distributed across biology, with examples found encoded in the genomes of Mycobacteria, Archaea, Eubacteria, Protozoa, yeast, and invertebrates, but there are none found in mammals. Although recent structural work has improved our understanding of these enzymes, their catalytic mechanism is still not well understood. Recent data show that nicotinamidases are required for the growth and virulence of several pathogenic microbes. The enzymes of Saccharomyces cerevisiae, Drosophila melanogaster, and Caenorhabditis elegans regulate life span in their respective organisms, consistent with proposed roles in the regulation of NAD(+) metabolism and organismal aging. In this work, the steady state kinetic parameters of nicotinamidase enzymes from C. elegans, Sa. cerevisiae, Streptococcus pneumoniae (a pathogen responsible for human pneumonia), Borrelia burgdorferi (the pathogen that causes Lyme disease), and Plasmodium falciparum (responsible for most human malaria) are reported. Nicotinamidases are generally efficient catalysts with steady state k(cat) values typically exceeding 1 s(-1). The K(m) values for nicotinamide are low and in the range of 2 -110 μM. Nicotinaldehyde was determined to be a potent competitive inhibitor of these enzymes, binding in the low micromolar to low nanomolar range for all nicotinamidases tested. A variety of nicotinaldehyde derivatives were synthesized and evaluated as inhibitors in kinetic assays. Inhibitions are consistent with reaction of the universally conserved catalytic Cys on each enzyme with the aldehyde carbonyl carbon to form a thiohemiacetal complex that is stabilized by a conserved oxyanion hole. The S. pneumoniae nicotinamidase can catalyze exchange of (18)O into the carboxy oxygens of nicotinic acid with H(2)(18)O. The collected data, along with kinetic analysis of several mutants, allowed us to propose a catalytic mechanism that explains nicotinamidase and nicotinic acid (18)O exchange chemistry for the S. pneumoniae enzyme involving key catalytic residues, a catalytic transition metal ion, and the intermediacy of a thioester intermediate. | Beauparlant P, Bédard D, Bernier C, Chan H, Gilbert K, Goulet D, Gratton MO, Lavoie M, Roulston A, Turcotte E, Watson M (2009)
Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777.
Anti-cancer drugs 20, 346-354 [PubMed:19369827]
[show Abstract]
GMX1778 was recently shown to function as a potent inhibitor of nicotinamide phosphoribosyl transferase. To translate the discovery of GMX1778 mechanism of action into optimal clinical use of its intravenously administered prodrug, GMX1777, the efficacy of GMX1777 was evaluated in xenograft models and the pharmacokinetic profile of GMX1778 and its effect on nicotinamide adenine dinucleotide cellular levels was measured by liquid chromatography/mass spectrometry. Consistent with the requirement for a prolonged exposure for cytotoxicity in vitro, a dose of 75 mg/kg of GMX1777 administered as two bolus intravenous injections in 1 day were not effective at reducing the growth of multiple myeloma (IM-9) tumors, whereas the same dose of GMX1777 administered over a 24 h intravenous infusion caused tumor regression in the IM-9 model, a small-cell lung cancer (SHP-77) model, and a colon carcinoma (HCT-116) model. A 72 h continuous intravenous infusion of GMX1777 was also effective in the IM-9 model, but was associated with a smaller therapeutic index. GMX1777 at a dose of 75 mg/kg administered over a 24 h intravenous infusion produced GMX1778 steady-state plasma levels of approximately 1 microg/ml and caused nicotinamide adenine dinucleotide levels to decrease significantly in tumors. Consistent with the GMX1778 mechanism of action, nicotinic acid protected mice treated with a lethal dose of GMX1777. These data support the design of an open-label, dose-escalation trial, in which patients with refractory solid tumors and lymphomas receive 24 h infusions of GMX1777 as a single agent in 3-week cycles. Furthermore, these results indicate that nicotinic acid is a potent antidote to treat GMX1777 overdose. | Riederer M, Erwa W, Zimmermann R, Frank S, Zechner R (2009)
Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine.
Atherosclerosis 204, 412-417 [PubMed:18996527]
[show Abstract]
Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active NNMT. NNMT mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the NNMT inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced NNMT enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue NNMT contributes to the increased plasma homocysteine levels in patients treated with NA. | Schmidt D, Smenton A, Raghavan S, Carballo-Jane E, Lubell S, Ciecko T, Holt TG, Wolff M, Taggart A, Wilsie L, Krsmanovic M, Ren N, Blom D, Cheng K, McCann PE, Gerard Waters M, Tata J, Colletti S (2009)
Pyrazole acids as niacin receptor agonists for the treatment of dyslipidemia.
Bioorganic & medicinal chemistry letters 19, 4768-4772 [PubMed:19592242]
[show Abstract]
Niacin is an effective drug for raising HDL cholesterol and reducing coronary risks, but patients show low compliance with treatment due to severe facial flushing upon taking the drug. A series of bicyclic pyrazole carboxylic acids were synthesized and tested for their ability to activate the niacin receptor. One analog, 23, showed improved potency and lacked flushing at doses that effectively altered the lipid profile of rats. | Bays HE, Ballantyne C (2009)
What's the deal with niacin development: is laropiprant add-on therapy a winning strategy to beat a straight flush?
Current opinion in lipidology 20, 467-476 [PubMed:19779335]
[show Abstract]
Purpose of reviewNiacin is a B-complex vitamin used as a lipid-altering drug since the 1950s. Niacin improves multiple lipid parameters. Atherosclerotic coronary heart disease outcome studies support niacin's efficacy in reducing coronary heart disease events, either as monotherapy or when used in combination with other lipid-altering drugs. The most commonly reported reason for the lack of its more widespread clinical use is niacin-induced flushing.Recent findingsLaropiprant is a highly selective prostaglandin D2 receptor 1 antagonist that mitigates niacin-induced flushing.SummaryThis review examines the history and provides a perspective regarding the extended-release niacin/laropiprant development program, which was designed to better allow patients to achieve a more therapeutic niacin dose of 2 g/day, without the need for titration. Ongoing coronary heart disease outcome studies will provide better insight as to the benefits of niacin in general, and the safety and efficacy of extended-release niacin/laropiprant specifically. | Perry CM (2009)
Extended-release niacin (nicotinic acid)/laropiprant.
Drugs 69, 1665-1679 [PubMed:19678716]
[show Abstract]
Extended-release (ER) niacin (nicotinic acid)/laropiprant is a once-daily fixed-dose combination tablet that has been evaluated (with or without an HMG-CoA reductase inhibitor [statin]) in the treatment of adults with dyslipidaemia or primary hypercholesterolaemia. Niacin (vitamin B3) is a lipid-modifying drug and laropiprant is an anti-flushing agent, which reduces flushing induced by niacin. In a randomized, double-blind, placebo-controlled, multicentre, 24-week trial, a significant (p < 0.001) reduction (18.4%) in plasma low-density lipoprotein cholesterol (LDL-C) levels (primary endpoint) was achieved with ER niacin/laropiprant 2000 mg/40 mg once daily (after an initial 4-week 1000 mg/20 mg once-daily regimen) compared with placebo (weeks 12-24) in adults with primary hypercholesterolaemia or mixed dyslipidaemia. ER niacin/laropiprant 2000 mg/40 mg plus simvastatin 20 mg or 40 mg once daily (after an initial 4-week lower-dose regimen) produced significant (p < 0.05) improvements, from baseline, in LDL-C levels (primary endpoint) compared with once-daily ER niacin/laropiprant 2000 mg/40 mg or simvastatin alone at week 12 in a randomized, double-blind, multicentre, factorial trial in adults with primary hypercholesterolaemia or mixed dyslipidaemia. The incidence and intensity of flushing (an efficacy endpoint) were significantly (p < 0.05) reduced with ER niacin/laropiprant compared with ER niacin in randomized trials. ER niacin/laropiprant, alone or in combination with a statin, was generally well tolerated for up to 24 weeks by adults with dyslipidaemia or primary hyercholesterolaemia. | Bodor ET, Offermanns S (2008)
Nicotinic acid: an old drug with a promising future.
British journal of pharmacology 153 Suppl 1, S68-75 [PubMed:18037924]
[show Abstract]
Nicotinic acid has been used for decades to treat dyslipidaemic states. In particular its ability to raise the plasma HDL cholesterol concentration has led to an increased interest in its pharmacological potential. The clinical use of nicotinic acid is somewhat limited due to several harmless but unpleasant side effects, most notably a cutaneous flushing phenomenon. With the recent discovery of a nicotinic acid receptor, it has become possible to better understand the mechanisms underlying the metabolic and vascular effects of nicotinic acid. Based on these new insights into the action of nicotinic acid, novel strategies are currently under development to maximize the pharmacological potential of this drug. The generation of both flush-reducing co-medications of nicotinic acid and novel drugs targeting the nicotinic acid receptor will provide future therapeutic options for the treatment of dyslipidaemic disorders. | Alrasadi K, Awan Z, Alwaili K, Ruel I, Hafiane A, Krimbou L, Genest J (2008)
Comparison of treatment of severe high-density lipoprotein cholesterol deficiency in men with daily atorvastatin (20 mg) versus fenofibrate (200 mg) versus extended-release niacin (2 g).
The American journal of cardiology 102, 1341-1347 [PubMed:18993152]
[show Abstract]
To determine whether available lipid-modifying medication can increase high-density lipoprotein (HDL) cholesterol in well-defined genetic or familial HDL-deficiency states, we studied 19 men with HDL deficiency (HDL cholesterol <5th percentile for age and gender) 55 +/- 10 years of age. Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had coronary artery disease. Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene. Patients were assigned to sequentially receive atorvastatin 20 mg/day, fenofibrate 200 mg/day, and extended-release niacin 2 g/day for 8 weeks, with a 4-week washout period between each treatment. Patients in whom a statin was required, according to current treatment guidelines, were kept on atorvastatin throughout the study. Baseline HDL cholesterol level was 0.63 +/- 0.12 mmol/L (24 +/- 5 mg/dl), triglycerides 2.01 +/- 0.98 mmol/L (180 +/- 86 mg/dl), and low-density lipoprotein (LDL) cholesterol 2.29 +/- 0.95 mmol/L (94 +/- 39 mg/dl). Mean percent changes in HDL cholesterol on atorvastatin, fenofibrate, and niacin were -6% (p = NS), +6% (p = NS), and +22% (p <0.05), respectively. Furthermore, niacin significantly increased the large alpha-1 apolipoprotein A-I-containing HDL subspecies (12 to 17 nm). In conclusion, niacin was the only effective drug to increase HDL cholesterol. The absolute increase in HDL cholesterol, approximately 0.10 mmol/L (3.9 mg/dl), is of uncertain clinical significance. Biomarkers of HDL-mediated cellular cholesterol efflux were not changed by niacin therapy. Atorvastatin or fenofibrate had little effect on HDL cholesterol; atorvastatin decreased the total cholesterol/HDL cholesterol ratio by 26%. Fenofibrate did not change HDL cholesterol levels and caused an increase in LDL cholesterol. Aggressive LDL cholesterol lowering may be the strategy of choice in such patients. | Meyers CD, Liu P, Kamanna VS, Kashyap ML (2007)
Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: an in vitro model of the niacin flush.
Atherosclerosis 192, 253-258 [PubMed:16945375]
[show Abstract]
Nicotinic acid is a safe, broad-spectrum lipid agent shown to prevent cardiovascular disease, yet its widespread use is limited by the prostaglandin D2 (PGD2) mediated niacin flush. Previous research suggests that nicotinic acid-induced PGD2 secretion is mediated by the skin, but the exact cell type remains unclear. We hypothesized that macrophages are a source of nicotinic acid-induced PGD2 secretion and performed a series of experiments to confirm this. Nicotinic acid (0.1-3 mM) induced PGD2 secretion in cultured human macrophages, but not monocytes or endothelial cells. The PGD2 secretion was dependent on the concentration of nicotinic acid and the time of exposure. Nicotinuric acid, but not nicotinamide, also induced PGD2 secretion. Pre-incubation of the cells with aspirin (100 microM) entirely prevented the nicotinic acid effects on PGD2 secretion. The PGD2 secreting effects of nicotinic acid were additive to the effects of the calcium ionophore A23187 (6 microM), but were independent of extra cellular calcium. These findings, combined with recent in vivo work, provide evidence that macrophages play a significant role in mediating the niacin flush and may lead to better strategies to eliminate this limiting side effect. | Schulz I (2006)
[Treatment of dyslipidemia: how and when to combine lipid lowering drugs].
Arquivos brasileiros de endocrinologia e metabologia 50, 344-359 [PubMed:16767301]
[show Abstract]
Familial combined hyperlipidemia (FCH) is a frequent familial lipid disorder associated with insulin resistance, low HDL cholesterol, high triglycerides and cholesterol levels with variable phenotypes within the same family. FCH is linked to a high risk for cardiovascular diseases. Treatment goals for lipid abnormalities are changing in recent years. Lowering elevated levels of LDL e Non HDL-cholesterol levels are primary targets of therapy. Lower LDL-C than 70 mg/dL seems to be useful to lower cardiovascular risk in patients with very high risk. Many statins are available, with different potencies and drug interactions. Combination therapy of statins and bile acid sequestrants or ezitimibe may be necessary to further decrease LDL cholesterol levels in order to meet guideline goals. High triglycerides and low HDL cholesterol are also important goals in the treatment of these patients, and frequently statins alone are insufficient to normalize the lipid profile. Combination therapy with fibrates will further lower triglycerides and increase HDL cholesterol levels; this combination is also associated with higher incidence of myopathy and liver toxicity; appropriate evaluation of patients' risk and benefits is necessary. Association of statin/niacin seems be very useful in patients with FCH, especially as niacin is the best drug to increase HDL cholesterol; this association is not linked to a higher frequency of myopathy. Niacin causes flushing, that can in part be managed with use of aspirin and extended release forms (Niaspan); niacin also may increase plasma glucose and uric acid levels. Evaluation of risks and benefits for each patient is needed. | Barakat MR, Metelitsina TI, DuPont JC, Grunwald JE (2006)
Effect of niacin on retinal vascular diameter in patients with age-related macular degeneration.
Current eye research 31, 629-634 [PubMed:16877271]
[show Abstract]
PurposeNiacin is a B vitamin well-known for causing vasodilation and flushing. The purpose of this study was to investigate its effect on the retinal vasculature of patients with age-related macular degeneration (AMD).MethodsTwelve patients with AMD were enrolled in a double-blind, randomized, placebo-controlled, crossover trial. Fundus photographs of the posterior pole were taken at baseline, 30 min, and 90 min after a single dose of niacin or placebo. The protocol was repeated after a washout period using the alternate study drug. The diameters of two veins and one artery on each image were measured.ResultsAn analysis of variance for repeated measures comparing the effects of niacin with those of placebo demonstrated a significant increase in the inferior temporal retinal artery diameter (p = 0.01), with a 5.3 +/- 7.7% increase at 30 min (p = 0.05) and 5.8 +/- 5.0% increase at 90 min (p = 0.003). No significant changes were observed in the temporal retinal veins.ConclusionsOur results suggest that niacin produces vasodilatation of retinal arterioles. Further studies are needed to ascertain whether niacin treatment may be beneficial in retinal ischemic diseases. | Santos RD (2005)
[Pharmacology of niacin or nicotinic acid].
Arquivos brasileiros de cardiologia 85 Suppl 5, 17-19 [PubMed:16400392]
[show Abstract]
Niacin or nicotinic acid is a soluble vitamin with hypolipidemic properties. Niacin reduces triglycerides (20 50%), LDL-c (5-25%), and raises HDL-c (15-35%). The Coronary Drug Project study showed that the use of niacin was associated with reduction on coronary events and total mortality, and more recently it has been demonstrated that niacin combined with other hypolipidemic drugs can attenuate the progression of coronary atherosclerosis. Niacin appears to reduce the mobilization of free fatty acids from the adipocytes, acting on specific receptors, diminishing the liver formation of triglyceride-rich lipoproteins. There are two forms of niacin, one of rapid absorption (crystalline), more commonly associated with flushing, and another of extended release, recently reported to be better tolerated. The use of niacin can be associated with dyspepsia, increased plasma levels of liver enzymes and also with a modest elevation in glucose and uric acid plasma levels, at least using the extended-release preparation up to 2 g/d. | Carlson LA (2005)
Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review.
Journal of internal medicine 258, 94-114 [PubMed:16018787]
[show Abstract]
Nicotinic acid has, like the Roman God Janus, two faces. One is the vitamin. The other is the broad-spectrum lipid drug. The Canadian pathologist Rudolf Altschul discovered 50 years ago that nicotinic acid in gram doses lowered plasma levels of cholesterol. From the point of view of treatment of the dyslipidaemias that are risk factors for clinical atherosclerosis nicotinic acid is a miracle drug. It lowers the levels of all atherogenic lipoproteins--VLDL and LDL with subclasses as well as Lp(a)--and in addition it raises more than any other drug the levels of the protective HDL lipoproteins. Trials have shown that treatment with nicotinic acid reduces progression of atherosclerosis, and clinical events and mortality from coronary heart disease. The new combination treatment with statin-lowering LDL and nicotinic acid-raising HDL is reviewed. A basic effect of nicotinic acid is the inhibition of fat-mobilizing lipolysis in adipose tissue leading to a lowering of plasma free fatty acids, which has many metabolic implications which are reviewed. The very recent discovery of a nicotinic acid receptor and the finding that the drug stimulates the expression of the ABCA 1 membrane cholesterol transporter have paved the way for exciting and promising new 50 years in the history of nicotinic acid. | Pradhan B, Neopane A, Karki S, Karki DB (2005)
Effectiveness of nicotinic acid and bezafibrate alone and in combination for reducing serum triglyceride level.
Kathmandu University medical journal (KUMJ) 3, 411-414 [PubMed:16449845]
[show Abstract]
ObjectiveTo study the effectiveness of nicotinic acid and Bezafibrate alone and in combination for reducing triglyceride level.DesignIt was a randomised, prospective, longitudinal study.SettingPatients attending a private clinic, and medical department of Kathmandu Medical College, Sinamangal.MethodsThis study included 83 consecutive patients, 19 females and 64 males with hypertriglyceridaemia (defined as serum triglyceride >200mg/dl) attending the department of medicine, Kathmandu Medical College, Sinamangal and private clinic.Main outcome measuresStatistically significant reduction of serum triglyceride level.Result51 out of 83 patients completed the study in which Nicotinic acid alone reduced the serum trygleceride level from 320.62 +/- 104.23 to 182.55 +/- 46.21, which is a reduction of 138.07 +/- 85.69 (P. value = 001). Bezafibrate when given alone also reduced triglyceride level significantly from 345.25 +/- 181.03 to 203.30+/-93.59 which is a reduction of 141.95 +/- 121.130 (P value= .001). When a combination of both drugs was given the reduction of 472.73+/-247.53 (P value =.002) was achieved.ConclusionsNicotinic acid is a very effective drug in reducing serum triglyceride level and its effectiveness is similar to Bezafibrate. There is no added benefit of giving a combination of nicotinic acid and Bezafibrate in reducing serum triglyceride level. | Lenard NR, Dunn AJ (2005)
Potential role for nonesterified fatty acids in beta-adrenoceptor-induced increases in brain tryptophan.
Neurochemistry international 46, 179-187 [PubMed:15627518]
[show Abstract]
We tested the hypothesis that beta2- and beta3-adrenergic receptor-mediated increases in brain tryptophan are due to the liberation of fatty acids, which in turn displace tryptophan from its albumin-binding site and thus facilitate its entry into the brain. Male CD-1 mice were injected with subtype-selective beta-adrenergic agonists 1h before brain samples were collected for analysis of tryptophan content by HPLC with electrochemical detection, and blood samples were collected for analysis of total and free tryptophan and nonesterified fatty acid (NEFA) concentrations. The beta2-selective agonist, clenbuterol (0.1 mg/kg), increased concentrations of tryptophan in all brain regions studied and decreased plasma total tryptophan, but had no effect on plasma free tryptophan or NEFAs. The beta3-selective agonists, BRL 37344 (0.2 mg/kg) or CL 316243 (0.01 mg/kg), increased brain tryptophan, plasma NEFAs and free tryptophan. Pretreatment with nicotinic acid (500 mg/kg), an inhibitor of lipolysis, almost completely prevented the increase in plasma free tryptophan and NEFAs, and attenuated the increase in brain tryptophan induced by CL 316243. These results suggest that beta2- and beta3-adrenergic agonists increase brain tryptophan by a mechanism other than the liberation of NEFAs. Nonetheless, beta3-adrenergic agonists appear to increase brain tryptophan by a mechanism that may depend partially on elevations of plasma NEFAs. | Tavintharan S, Lim SC, Sum CF (2005)
Patients with low levels of high-density lipoprotein cholesterol: to treat or not to treat?
Singapore medical journal 46, 519-528 [PubMed:16172771]
[show Abstract]
Clinical evidence indicates that a low level of high-density lipoprotein cholesterol (HDL-C) is a major risk of atherosclerosis. Raising HDL-C reduces this risk significantly, making HDL-C levels an important target of treatment for dyslipidaemia, especially in pre-existent atherosclerosis. HDL-C is protective against atherosclerosis, largely due to its function of reverse cholesterol transport. Additionally, some important roles include fibrinolysis, antioxidant functions, and reduction of platelet aggregability. A number of agents potentially modify HDL favourably. Niacin is the most potent HDL-C raising agent currently available in clinical practice, followed by fibrates. CETP inhibitors show greater HDL-C rising, but are still used in trial settings only. HDL mimetic agents are another group of agents that offer much promise. Clinical outcome data are awaited for these newer therapeutic agents. | Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V (2005)
Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family.
The Biochemical journal 388, 309-316 [PubMed:15651982]
[show Abstract]
SMCT (sodium-coupled monocarboxylate transporter; slc5a8) is a Na+-coupled transporter for lactate, pyruvate and short-chain fatty acids. Similar to these already known substrates of SMCT, the water-soluble B-complex vitamin nicotinic acid also exists as a monocarboxylate anion (nicotinate) under physiological conditions. Therefore we evaluated the ability of SMCT to mediate the uptake of nicotinate. In mammalian cells, the cloned mouse SMCT (slc5a8) induced the uptake of nicotinate. The SMCT-induced uptake was Na+-dependent. The Michaelis constant for the uptake process was 296+/-88 microM. The Na+-activation kinetics indicated that at least two Na+ ions are involved in the process. Among the various structural analogues tested, nicotinate was the most effective substrate. Nicotinamide and methylnicotinate were not recognized by the transporter. 2-pyrazine carboxylate and isonicotinate interacted with the transporter to a moderate extent. SMCT-mediated uptake of nicotinate was inhibited by lactate and pyruvate. In the Xenopus laevis oocyte expression system, SMCT-mediated nicotinate transport was electrogenic, as evident from the nicotinate-induced inward currents under voltage-clamp conditions. Substrate-induced currents in this expression system corroborated the substrate specificity determined in the mammalian cell expression system. The kinetic parameters with regard to the affinity of the transporter for nicotinate and the Hill coefficient for Na+ activation, determined by using the oocyte expression system, were also similar to those obtained from the mammalian cell expression system. We conclude that SMCT functions not only as a Na+-coupled transporter for short-chain fatty acids and lactate but also as a Na+-coupled transporter for the water-soluble vitamin nicotinic acid. | Pike NB (2005)
Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid.
The Journal of clinical investigation 115, 3400-3403 [PubMed:16322787]
[show Abstract]
The recent discovery of the G(i) protein-coupled receptor GPR109A (HM74A in humans; PUMA-G in mice) as a receptor for nicotinic acid has provided the opportunity to gain greater understanding of the underlying biology contributing to the clinical efficacy (increases in HDL, decreases in VLDL, LDL, and triglycerides) and the characteristic side-effect profile of nicotinic acid. GPR109A has been proven to be the molecular target for the actions of nicotinic acid on adipose tissue, and in this issue of the JCI, Benyó et al. have confirmed the involvement of GPR109A in the nicotinic acid-induced flushing response, a common side effect. The involvement of GPR109A in both the desirable and undesirable clinical actions of nicotinic acid raises interesting questions regarding the function of this receptor. | Rubic T, Trottmann M, Lorenz RL (2004)
Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin.
Biochemical pharmacology 67, 411-419 [PubMed:15037193]
[show Abstract]
Niacin, the first lipid lowering drug shown to improve survival after myocardial infarction, decreases LDL and increases HDL cholesterol levels. These effects cannot fully be explained by its suspected mechanism of action, inhibition of lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate prostaglandin D2 (PGD2) formation. The major metabolite of PGD2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), was recently identified as the most potent endogenous PPARgamma activator. We, therefore, studied the effects of niacin on the PPARgamma- and cAMP-dependent expression of receptors promoting reverse cholesterol transport. The transcription of PPARgamma-, HDL-, LDL- and scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative RT-PCR and cellular cholesterol efflux and PPARgamma activation studied in macrophage and hepatocyte models. Niacin stimulated the translocation of PPARgamma and the transcription of PPARgamma, CD36 and ABCA1 in monocytoid cells, whereas the LDL-receptor (LDL-R) was unchanged. Thereby niacin enhanced HDL-mediated cholesterol efflux from the cells resulting in a reduced cellular cholesterol content. The niacin effect on CD36 but not on ABCA1 was prevented by cyclooxygenase inhibition, whereas the niacin effect on ABCA1 but not on CD36 was prevented by PKA inhibition, suggesting mediation by the 15d-PGJ2/PPARgamma and the cAMP/PKA pathways, respectively. These new actions of niacin on several key effectors of reverse cholesterol transport out of the vessel wall provide a rational to expect regression of atherosclerosis and test the combination of niacin with statins for an overadditive clinical benefit. | Carlson LA (2004)
Niaspan, the prolonged release preparation of nicotinic acid (niacin), the broad-spectrum lipid drug.
International journal of clinical practice 58, 706-713 [PubMed:15311728]
[show Abstract]
Niacin (nicotinic acid) is the broad-spectrum lipid drug, which lowers the concentration of all atherogenic plasma lipids/lipoproteins and at the same time raises the levels of the protective HDL (high-density lipoprotein). Niaspan is a prolonged release (PR) formulation of niacin, which has considerable advantages over both immediate release (IR) and slow release (SR) formulations of this drug. The major early side effect of IR niacin, the flush, is reduced with Niaspan. The hepatotoxic effects with SR niacin are not present with Niaspan. It is suitable for once daily prescription at bedtime. Niaspan is effective as monotherapy and in combination with other lipid-lowering drugs such as statins and fibrates. It is particularly useful for treatment of the dyslipidaemia of type 2 diabetes, where IR but not PR niacin may deteriorate the diabetic condition. Overall, niacin, now available as the well-tolerable drug formulation Niaspan, is the unique broad-spectrum lipid drug for the prevention and treatment of clinical atherosclerosis. | Colombié S, Sablayrolles JM (2004)
Nicotinic acid controls lactate production by K1-LDH: a Saccharomyces cerevisiae strain expressing a bacterial LDH gene.
Journal of industrial microbiology & biotechnology 31, 209-215 [PubMed:15205990]
[show Abstract]
Industrial applications for lactate, such as the production of chemicals, has led to interest in producing this organic acid by metabolically engineered a yeast such as Saccharomyces cerevisiae, which is more acid tolerant than lactic acid bacteria. This paper deals with lactate production by S. cerevisiae K1-LDH, in which the Lactobacillus plantarum lactate dehydrogenase (LDH) gene is integrated into the genome of the wine yeast strain K1. We show that a vitamin, nicotinic acid (NiA), was the limiting factor for lactate production during fermentation with the K1-LDH strain. Increasing the NiA concentration in batch conditions or in the medium used to feed chemostats affected the lactate yield. Moreover, the addition of pulses of NiA or the exponential addition of NiA made it possible to control the lactate production kinetics throughout the fermentation process. The results point to the role of NiA in the regulation of metabolic pathways, but the physiological mechanisms remain poorly understood. | Karpe F, Frayn KN (2004)
The nicotinic acid receptor--a new mechanism for an old drug.
Lancet (London, England) 363, 1892-1894 [PubMed:15183629]
[show Abstract]
ContextNon-esterified fatty acids in plasma originate from adipose tissue. Delivery of fatty acids to the liver provides the substrate for VLDL triglycerides. Insulin-sensitive organs, overburdened by high concentrations of non-esterified fatty acids, may develop resistance to insulin action. In addition, insulin secretion from pancreatic beta-cells may be impaired by long-standing elevation of concentrations of non-esterified fatty acid in plasma. Normally, such concentrations fluctuate over the day depending on the transient suppression of lipolysis from adipose tissue by insulin released after meals. Diurnal concentrations of non-esterified fatty acid are often elevated in obesity, in particular in male-pattern upper-body fat accumulation. Nicotinic acid is the only drug that primarily lowers concentrations of non-esterified fatty acids and thereby lowers VLDL triglycerides. Nicotinic acid, or its analogues, seems to alleviate insulin resistance in the short-term whereas, paradoxically, the long-term effect is often the opposite. Suppression of lipolysis by nicotinic acid gives rise to a prominent rebound and the degree to which this occurs might explain this paradox.Starting pointThe exact cellular mechanism by which nicotinic acid exerts its antilipolytic effects has not been known until the recent discovery of a distinct G-protein coupled receptor. Nicotinic acid is a high affinity ligand, but the endogenous ligand is still unknown. Recently, Tina Rubic and colleagues (Biochem Pharmacol 2004; 67: 411-19) proposed a mechanism in which nicotinic acid stimulates cholesterol mobilisation from macrophages, thereby providing a potential link between regression of atherosclerosis and use of nicotinic acid.Where nextResearch on signalling through the nicotinic acid receptor might give rise to novel and more effective methods to interfere with fatty-acid metabolism, with insulin resistance, hyperlipidaemia, and atherosclerosis as target diseases. | McKenney J (2003)
Niacin for dyslipidemia: considerations in product selection.
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 60, 995-1005 [PubMed:12789870]
[show Abstract]
The efficacy and safety profiles of various forms of niacin for treating dyslipidemia are described. Niacin is well recognized for treating dyslipidemia in adults and has been shown to be effective in reducing coronary events. It has a broad range of effects on serum lipids and lipoproteins, including lowering total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides. Niacin is the most effective lipid-modifying drug for raising high-density-lipoprotein (HDL) cholesterol levels and has been shown to lower Lp(a) lipoprotein. Niacin reduces triglycerides and very-low-density-lipoprotein and LDL cholesterol synthesis, primarily by decreasing fatty acid mobilization from adipose tissue. Niacin appears to raise HDL cholesterol by reducing hepatic apolipoprotein A-l clearance and enhancing reverse cholesterol transport. Niacin is metabolized through a conjugation or nicotinamide pathway. Standard immediate-release niacin is metabolized primarily through the conjugation pathway, which results in a high frequency of flushing. Long-acting niacin is metabolized through the nicotinamide pathway, which results in less flushing but increases the risk of hepatotoxicity. Extended-release niacin has a more balanced metabolism and causes fewer of both types of adverse effects. Improved serum lipid levels during niacin therapy have been associated with clinical and angiographic evidence of reduced coronary artery disease, especially when combined with statins. Niacin is particularly useful for managing high triglyceride and low HDL cholesterol levels as well as the lipid abnormalities associated with metabolic syndrome, including those commonly encountered in patients with diabetes. Several niacin products are available with significant differences in their safety and efficacy profiles. Health care providers must consider the differences between agents when recommending niacin for dyslipidemia treatment. | Müller B, Kasper M, Surber C, Imanidis G (2003)
Permeation, metabolism and site of action concentration of nicotinic acid derivatives in human skin. Correlation with topical pharmacological effect.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 20, 181-195 [PubMed:14550884]
[show Abstract]
A novel methodology for establishing a pharmacological dose-effect relationship of methyl nicotinate, hexyl nicotinate and nicotinic acid acting as peripheral vasodilators in the skin following topical application is investigated. This methodology involves the estimation of the unbound drug concentration in the aqueous compartment at the site of action in tissue, termed C(*), which was evaluated as the pertinent concentration responsible for the pharmacological effect. Blood capillaries next to the epidermis-dermis boundary were postulated to be the relevant site of action. C(*) was estimated from drug transport parameters for different layers of human cadaver skin determined in vitro. Immunohistochemical studies showed that the plane of separation of skin achieved by heat treatment was between the basal cells of the epidermis and the lamina lucida, confirming the integrity of the epidermis and the dermis used in the experiments. The permeation rate for epidermis increased drastically with increasing lipophilicity of the drug. Dermis permeability was roughly the same for all three compounds. The epidermis represented the major transport barrier in vitro for methyl nicotinate and nicotinic acid but not for hexyl nicotinate. The esters were metabolised to nicotinic acid during tissue permeation to an extent that was rather limited for the epidermis but very pronounced for the dermis. Nonspecific alpha-naphthylacetate-esterase activity was predominantly located in the dermis, which was in agreement with the metabolism results. The drugs were applied each at three different concentrations in vivo to the ventral forearm of healthy human volunteers and vasodilation was evaluated based on skin erythema which was quantified by measuring colour change of reflected light. Area under the curve of the change of colour co-ordinates as a function of time was used as a measure of pharmacological effect. The pharmacological effect of all three drugs was comparable when similar C(*) values were considered, even though the concentrations applied to the skin differed by orders of magnitude. The effect showed a strong positive dependence on C(*). Methyl and hexyl nicotinate showed identical, nearly sigmoidal effect/C(*)-profiles, while the profile for nicotinic acid was linear, suggesting a possible difference in the intrinsic pharmacological potency between the esters and the acid. These results demonstrate the validity of C(*) as the relevant drug concentration for the cutaneous pharmacological effect of the topically applied drugs and underline the usefulness of the presented methodology for establishing dose-response relationships in dermal therapy and expressing bioavailability. | Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S (2003)
PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.
Nature medicine 9, 352-355 [PubMed:12563315]
[show Abstract]
Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia. | Kobayashi M, Shimizu S (1999)
[Nicotinic acid and nicotinamide].
Nihon rinsho. Japanese journal of clinical medicine 57, 2211-2217 [PubMed:10540864]
[show Abstract]
Nicotinic acid and nicotinamide are called niacin. They are the antipellagra vitamin essential to many animals for growth and health. In human being, niacin is believed necessary together with other vitamins for the prevention and cure of pellagra. Niacin is widely distributed in nature; appreciable amounts are found in liver, fish, yeast and cereal grains. Nicotinamide is a precursor of the coenzyme NAD and NADP. Some of the most understood metabolic processes that involve niacin are glycolysis, fatty acid synthesis and respiration. Niacin is also related to the following diseases: Hartnup disease; blue diaper syndrome; tryptophanuria; hydroxykynureninuria; xanthurenic aciduria; Huntington's disease. | Salvi A, Carrupt PA, Mayer JM, Testa B (1997)
Esterase-like activity of human serum albumin toward prodrug esters of nicotinic acid.
Drug metabolism and disposition: the biological fate of chemicals 25, 395-398 [PubMed:9107536]
[show Abstract]
The esterase-like activity of human serum albumin (HSA) toward esters of nicotinic acid was investigated under a variety of conditions such as protein concentration, temperature, pH, ionic strength, nature of buffers, and presence of organic solvents. Initial rate constants of hydrolysis of 18 nicotinates in the presence of 50 microM HSA were measured at pH 7.4 and 37 degrees C. The substrates displayed half-lifes ranging from less than 15 min (2-butoxyethyl nicotinate) to more than 95 hr (methyl nicotinate). The hydrolysis of tert-butyl nicotinate was too slow to be measurable, whereas 1-carbamoylethyl nicotinate was stabilized against hydrolysis by the presence of HSA. The rate constants of HSA-catalyzed hydrolysis were well correlated (r2 = 0.85; N = 12) with previously published data obtained in human plasma, indicating similar substrate specificities in the two biological preparations. All evidence points to serum albumin as the possible major catalyst of hydrolysis of nicotinate esters in human plasma. | Stratford MR, Dennis MF, Hoskin P, Phillips H, Hodgkiss RJ, Rojas A (1996)
Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring.
British journal of cancer 74, 16-21 [PubMed:8679452]
[show Abstract]
The effect of inhibiting gastric acid secretion on nicotinamide pharmacokinetics was studied in five volunteers with the intent of reducing the large variations observed previously in the time to and magnitude of peak plasma concentrations. Plasma levels were determined using a standard high-performance liquid chromatography (HPLC) method after an oral dose of 3 g of nicotinamide either alone or preceded by pretreatment with omeprazole. Suppression of gastric acid production had no significant effect on the rate of uptake or on the peak levels achieved. To bypass gastric acidity, the rectal route was also assessed using a suppository in four volunteers and one patient undergoing radiotherapy. Absorption was slow and variable and much lower plasma levels were observed than after oral dosing. Thus, no improvement in the pharmacokinetics of nicotinamide was observed using either of these two approaches. Parallel estimations were made using a novel and non-invasive method for monitoring nicotinamide pharmacokinetics in saliva. A large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. The time to peak levels of nicotinamide or of nicotinamide plus nicotinic acid in saliva correlated well with that in plasma. However, peak concentrations for nicotinamide alone were significantly lower than in plasma, and very variable, whereas for nicotinamide plus nicotinic acid saliva levels were 20-30% higher, but more consistent. Although there are some practical difficulties in quantitatively handling saliva, the method is very useful for monitoring nicotinamide pharmacokinetics and for assessment of compliance with nicotinamide treatment. | Zarzycki PK, Kowalski P, Nowakowska J, Lamparczyk H (1995)
High-performance liquid chromatographic and capillary electrophoretic determination of free nicotinic acid in human plasma and separation of its metabolites by capillary electrophoresis.
Journal of chromatography. A 709, 203-208 [PubMed:7581845]
[show Abstract]
Two methods are described based on high-performance liquid chromatography and capillary electrophoresis that provide the selective and sensitive determination of nicotinic acid in human plasma. Moreover, the capillary electrophoresis system was used for the separation of nicotinic acid, nicotinamide, nicotinamide N-oxide, N'-methylnicotinamide, 6-hydroxynicontinic acid, nicotinuric acid and barbital (internal standard). The extraction procedure is simple; no gradient elution or derivatization is required. Both methods can be useful for clinical and biomedical investigations. | Martínez-Piñeiro L, Mateos F, Martínez ME, Martínez I, Martínez-Piñeiro JA (1993)
Changes in acid-base balance and calcium metabolism after urinary diversion through ileal segments. II. Treatment with nicotinic acid.
British journal of urology 72, 858-867 [PubMed:8306147]
[show Abstract]
Investigations in animals have shown that nicotinic acid, an intestinal cyclic-AMP inhibitor, partially corrects the metabolic changes associated with urinary diversion through intestinal segments. Blood and serum chemistry were studied in patients before and 3 to 5 months after undergoing urinary diversion through ileal segments, both with and without nicotinic acid treatment. It was found that diverted patients had metabolic acidosis, an increased anion gap and increased levels of serum alkaline phosphatase; there were no significant changes in serum PTH and vitamin D levels, calcaemia and phosphoraemia. There was a tendency towards dehydration, hypernatraemia, hyperchloraemia and secondary hyperaldosteronism produced by ileal secretion of a hypotonic fluid. Nicotinic acid 3 g/day significantly reduced the chloraemia but did not correct the metabolic acidosis, although it reduced its severity, since blood pH decreased when treatment was suspended. Nicotinic acid cannot be recommended for routine use in the management of metabolic acidosis after urinary diversion, and patients with a marginal renal reserve should not be considered for trans-intestinal urinary diversion. | Patterson MC, Di Bisceglie AM, Higgins JJ, Abel RB, Schiffmann R, Parker CC, Argoff CE, Grewal RP, Yu K, Pentchev PG (1993)
The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C.
Neurology 43, 61-64 [PubMed:8423912]
[show Abstract]
Niemann-Pick disease type C (NP-C) is a neurovisceral lipidosis characterized by defective intracellular trafficking of cholesterol and lysosomal accumulation of unesterified cholesterol, believed to be an offending metabolite. We studied the effect of cholesterol-lowering agents on hepatic and plasma cholesterol levels in NP-C by randomly assigning 25 patients with NP-C to one of five treatment regimens containing different combinations of cholestyramine, lovastatin, nicotinic acid, or dimethyl sulfoxide (DMSO). Unesterified cholesterol content was measured in liver biopsies before and after 4 months' treatment. All drug regimens except DMSO alone reduced hepatic and plasma cholesterol levels. Toxicity was limited and did not prevent any patient from completing the study. The combination of cholestyramine, lovastatin, and nicotinic acid lowered cholesterol levels in liver and blood with minimal side effects. A controlled clinical study will be necessary to determine if this regimen influences the rate of neurologic progression. | Chekalina SI, Guseva LI, Bardyechev MS (1985)
[Use of nicotinic acid and midocalm for correcting blood coagulation in patients with radiation edema of the extremities].
Meditsinskaia radiologiia 30, 28-30 [PubMed:4033386]
[show Abstract]
A study was made of the functional activity of platelets, plasmatic coagulation and fibrinolysis in patients with late radiation disorders of the blood and lymph flow during treatment with vasodilative drugs: nicotinic acid and midocalm. These drugs tend to decrease the functional activity of platelets and to raise the blood fibrinolytic activity. Their use is indicated to this group of patients to better their intravascular status. | Grundy SM, Mok HY, Zech L, Berman M (1981)
Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man.
Journal of lipid research 22, 24-36 [PubMed:7217784]
[show Abstract]
The mechanisms for the hypolipidemic action of nicotinic acid were examined in 12 patients with hyperlipidemia. Most patients were studied in the hospital on a metabolic ward. The first month was a control period followed by 1 month on nicotinic acid. During treatment with nicotinic acid, the triglycerides (TG) decreased in total plasma by an average of 52% and in very low density lipoproteins (VLDL) by 36%. Transport rates of VLDL-TG were determined by multicompartmental analysis following injection of [3H]glycerol as a precursor. Nicotinic acid decreased transport (synthesis) of VLDL-TG by an average of 21%. Kinetic modeling of the VLDL-TG data suggested that the TG reduction was due to a decrease in TG content of VLDL and hence a reduction in lipoprotein size more than number. For the whole group, plasma cholesterol fell during nicotinic acid therapy by a mean of 22%. The drug produced no detectable changes in fecal excretions of cholesterol (neutral steroids) or bile acids. However, it induced a small but significant increment in hepatic secretion of biliary cholesterol that might have led to a net loss of cholesterol from the body even though this loss could not be detected by sterol balance. Despite this increase in outputs of biliary cholesterol, there was not a significant increase in molar % cholesterol or in % saturation of gallbladder bile. Therefore, it is doubtful that nicotinic acid enhances the risk for cholesterol gallstones. | Hertle H, Kiese M, Renner G (1979)
Absorption in rats, dogs, pigs, and humans of nicotinic acid after oral administration of phosphatidyl inositol pentanicotinate hydrochloride (PIN).
Arzneimittel-Forschung 29, 114-116 [PubMed:582105]
[show Abstract]
Bound nicotinic acid in feces after oral administration of phosphatidyl inositol pentanicotinate (PIN) was determined by chromatographical isolation from acid hydrolysate and UV absorbance of the eluted nicotinic acid. With all species tested, the absorption of nicotinic acid after administration of PIN was found to be incomplete, proportions from 5 to 25% of the amount of nicotinic acid administered with PIN being recovered from feces. Humans absorbed about 75% of the nicotinic acid administered with 700 mg PIN, i.e. 230 mg. It is concluded that the presence of bound nicotinic acid in feces is due to slow absorption of the PIN or slow hydrolysis of the nicotinic acid ester. Rabbit liver homogenate, human blood plasma, and human duodenal juice were found to liberate nicotinic acid from PIN. | Angelin B, Einarsson K, Leijd B (1979)
Biliary lipid composition during treatment with different hypolipidaemic drugs.
European journal of clinical investigation 9, 185-190 [PubMed:113218]
[show Abstract]
In an attempt to clarify the possible lithogenic effects of commonly used hypolipidaemic drugs, gallbladder bile was obtained from patients with primary hyperlipoproteinaemia before and during treatment with nicotinic acid (n = 13), cholestyramine (n = 19), clofibrate (n = 11), and a combination of cholestyramine and clofibrate (n = 11). Each treatment period was minimum 6 weeks, and standardized dietary conditions were obtained. Both nicotinic acid and clofibrate treatment caused an increase in biliary cholesterol concentration relative to biliary total lipids (bile acids, phospholipids, and cholesterol). During cholestyramine medication the relative cholesterol concentration fell. A combination of cholestyramine with clofibrate medication led to a decrease of bile saturation to pretreatment levels in nine of the eleven subjects. In the other two a further increase in the cholesterol saturation of the bile occurred. Treatment with nicotinic acid and clofibrate but not with cholestyramine is thus probably associated with an increased risk for development of cholesterol gallstones. It is suggested that addition of cholestyramine may be a possible way to prevent the lithogenic effect of clofibrate in patients with hyperlipoproteinaemia when not only hypocholesterolaemic but also hypotriglyceridaemic effects are wanted. | Hengen N, Seiberth V, Hengen M (1978)
High-performance liquid-chromatographic determination of free nicotinic acid and its metabolite, nicotinuric acid, in plasma and urine.
Clinical chemistry 24, 1740-1743 [PubMed:699281]
[show Abstract]
We report a liquid-chromatographic procedure for determining free nicotinic acid and a metabolite, nicotinuric acid, in plasma and urine. Five-tenths milliliter of urine or deproteinized plasma is evaporated and the residue analyzed isocratically by reversed-phase ion-pair chromatography, with measurement of the eluted nicotinic acid and nicotinuric acid at 254 nm. Nicotinic acid, nicotinuric acid, and the internal standard (isonicotinic acid) have retention times of 7.8, 8.4, and 6.8 min, respectively, in plasma, and 12.3, 13.1, and 10.8 min in urine, because of double column length. Day-to-day reproducibilities (CV) for nicotinic acid and nicotinuric acid within 7.5% are attainable for the concentration ranges 0.1--20 mg/liter, equivalent to 0.81--162 micromol of nicotinic acid and 0.55--11 micromol of nicotinuric acid per liter for plasma; in urine for the range 0.5--100 mg/liter, equivalent to 4--810 micromol of nicotinic acid and 2.8--555 micromol of nicotinuric acid per liter. Metabolites of nicotinic acid such as nicotinamide, N-methylnicotinamide, 2-hydroxypyridine-5-carboxylic acid, and other structurally related substances do not interfere. | Sutherland WH, Larking PW, Nye ER (1976)
Modification of nicotinic acid and prostaglandin E1 antilipolytic action in vitro.
Atherosclerosis 25, 45-53 [PubMed:186078]
[show Abstract]
In epididymal adipose tissue from rats, human serum antagonizes inhibition of basal lipolysis by nicotinic acid in vitro. Under similar conditions caffeine-stimulated lipolysis was unaffected by the presence of human serum. Very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins were all found to antagonize the action of nicotinic acid on basal lipolysis. VLDL also antagonized prostaglandin E1 (PGE1)-inhibition of basal lipolysis in vitro. The fat cell membrane was suggested as the site at which human serum lipoproteins antagonize nicotinic acid or PGE1 antilipolytic action on basal lipolysis in vitro. | Mrochek JE, Jolley RL, Young DS, Turner WJ (1976)
Metabolic response of humans to ingestion of nicotinic acid and nicotinamide.
Clinical chemistry 22, 1821-1827 [PubMed:135660]
[show Abstract]
The identification of nicotinamide-N1-oxide as a metabolite in the urine of a schizophrenic patient prompted a study of the relative metabolism of nicotinic acid and nicotinamide in mental patients and healthy volunteers. Metabolites quantified included N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide, N1-methylnicotinamide, nicotinuric acid, and nicotinamide-N1-oxide. More of most of these metabolites evidently was excreted after nicotinamide ingestion than after nicotinic acid. At the highest doses (3000 mg/day), the relative proportions of these metabolites in the urine were changed. There were only slight difference between healthy individuals and mental patients in the quantities of metabolites excreted, and no statistically significant trends were noted. | Dastur DK, Santhadevi N, Quadros EV, Avari FC, Wadia NH, Desai MN, Bharucha EP (1976)
The B-vitamins in malnutrition with alcoholism. A model of intervitamin relationships.
The British journal of nutrition 36, 143-159 [PubMed:182198]
[show Abstract]
1. The B-vitamin status of fifty-nine patients, mainly from the lower socio-economic classes in Bombay, with a history of chronic malnutrition, and of alcoholism of 1-5-20 years' duration, was studied before and during treatment, and in relation to their clinical, especially neurological, condition. These patients were divided into two neurological categories: (I) those with peripheral neuropathy (mainly sensory and distal) alone, (2) those with mental changes (mainly confusion and disorientation) also. Both categories frequently showed pellagrous pigmentation and mucocutaneous signs of B-vitamin deficiency. 2. Thiamin and erythrocyte transketolase (EC 2.2.1.1) activity, riboflavin, nicotinic acid, pantothenic acid, total and pyridoxal fraction of vitamin B6, folate and total vitamin B12 were estimated in the blood and the cerebrospinal fluid (CSF) of these patients, and also in the blood of sixty-nine control subjects and in the CSF of some of them. The concentrations of all the vitamins, except vitamin B12, were highly significantly lower in the blood of patients of category I compared to the controls, and erythrocyte transketolase activity and pyridoxal concentration in patients of category 2 were significantly lower than those of category I patients. Blood pantothenic acid and folate concentrations were reduced less consistently. 3. Serum vitamin B12 concentration was significantly increased (though within normal range) in the patients compared to the control group, probably because of the moderate hepatic insufficiency (as assessed by liver function tests) in the former. 4. The concentrations of thiamin, riboflavin, nicotinic acid and total vitamin B6 were also highly significantly lower in the CSF in patients of category I compared with controls. Furthermore, thiamin, nicotinic acid and total vitamin B6 concentrations were significantly lower in patients of category 2 than those of category I patients, indicating that CSF levels reflect better the neurological status of these patients. 5. There was a moderate increase in the blood concentration of all the vitamins tested, after a relatively poor hospital diet alone. There was a concurrent increase in the blood levels of thiamin, riboflavin, nicotinic acid and pantothenic acid after parenteral treatment with either thiamin or nicotinic acid. The administration of pyridoxine resulted in a significant increase in the blood levels of riboflavin and the pyridoxal fraction of vitamin B6. | Albizati LD, Hedrick JL (1972)
Active-site studies on rabbit liver nicotinamide deamidase.
Biochemistry 11, 1508-1517 [PubMed:4259917] |
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