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At least 19 recordsLinked to original sources
PubMed2006

Improved control of niacin-induced flushing using an optimized once-daily, extended-release niacin formulation.

INTRODUCTION: Niacin is a recognized treatment for dyslipidemia due to its favorable effects on all lipid parameters. However, the clinical use of niacin has been limited by its adverse effects, particularly cutaneous flushing. A newly reformulated 1,000 mg niacin ER tablet has been designed to reduce flushing relative to the original commercial niacin ER formulation. The aim of this study is to compare the incidence, intensity and duration of flushing between the 1,000 mg reformulated niacin ER and the 1,000 mg commercially available formulation, when administered as a single 2,000 mg dose to healthy male volunteers. METHODS: This was a double-blind, double-dummy, placebo-controlled, 3-way crossover, flush provocation study conducted at a single center. To increase the probability of flushing, subjects were administered niacin ER at the upper limit of the approved dosage range (2,000 mg), and were precluded from using aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) during the study. Subjects received reformulated niacin ER, commercial niacin ER or placebo in a 3-way crossover fashion. The primary flushing variable was the occurrence of a flushing event. Secondary flushing variables included the number of flushing episodes, intensity and duration of flushing for both overall flushing events and for individual symptoms of flushing (redness, warmth, tingling and itching). RESULTS: A total of 156 subjects were enrolled in the study. Of 133 subjects who received at least 1 dose of study medication in at least 2 study periods, 89% of subjects experienced flushing during treatment with reformulated niacin ER, and 98% of subjects experienced flushing during treatment with commercial niacin ER. This difference was statistically significant (p - 0.0027). Reformulated niacin ER resulted in a 42% reduction in median flush intensity (p < 0.0001) and a 43% reduction in median flush duration (p < 0.0001) relative to commercial niacin ER. The duration of first flushing event was more than 1 hour shorter with reformulated niacin ER. During the study, 29% of subjects (45/156) experienced treatment-emergent adverse events, which were mostly mild in intensity and considered to be remotely related or unrelated to the study drug. CONCLUSION: The 1,000 mg reformulated niacin ER tablet substantially decreases the incidence, intensity and duration of flushing relative to the commercially available 1,000 mg niacin ER tablet, and represents an improved niacin therapy option.

Administration, Oral↗
PubMed2006

Dissolution profiles of nonprescription extended-release niacin and inositol niacinate products.

PURPOSE: The dissolution profiles of nonprescription extended-release niacin and inositol niacinate products were studied using the prescription extended-release niacin, Niaspan, as a reference. METHODS: Seven nonprescription extended-release and 12 nonprescription inositol niacinate products were collected from community and online pharmacies in the United States. Extended-release Niaspan was used as a reference. Dissolution profiles were examined by the United States Pharmacopoeia dissolution test, using a paddle method. Release samples were removed every 30 minutes for up to 240 minutes. Niacin was quantified by high-performance liquid chromatography. RESULTS: Ten out of the 12 inositol niacinate products were capsules and 6 of the 7 extended-release formulations were tablets. During the initial 30-minute dissolution study of inositol niacinate products, free niacin was released to various degrees. One product achieved fast dissolution, with >30% cumulative release of niacin. The cumulative percentage of niacin released at 240 minutes of all inositol niacinate products was statistically different (p < 0.0001). The majority of these products reached a plateau of releasing niacin in one to two hours, which was maintained until the end of the study. Six out of the seven extended-release niacin products had extended-release profiles. Five products showed a statistically higher dissolution rate (p < 0.05) than that of Niaspan. CONCLUSION: Significant variations in dissolution profiles were noted among the 7 nonprescription extended-release and 12 nonprescription inositol niacinate products in vitro, and their dissolution rates were not comparable to that of the prescription extended-release niacin. Further studies are warranted to correlate such dissolution data with their in vivo efficacy.

Delayed-Action Preparations↗
PubMed1985

Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin.

To minimize the cutaneous flushing symptoms associated with niacin use, a time-release capsule form of niacin has been formulated. Thus study compares the effects of time-release niacin with those of unmodified niacin on lipoprotein lipids, including HDL2 and HDL3, apoproteins A-I and A-II, clinical chemistries, symptomatic side effects, and adherence to the medication regimen. Seventy-one primarily hypercholesterolemic subjects were randomized to either unmodified niacin or time-release niacin ad took medication for a six-month period. The two groups were closely matched on anthropomorphic and lipid variables. Adherence to the therapeutic regimen at a dose of 1.5 g/d in the first month of treatment was similar in the two groups. Thereafter, at a dose of 3.0 g/d, adherence was in excess of 90% among subjects taking unmodified niacin but only 64% among those taking time-release niacin, chiefly because of aggravated gastrointestinal symptoms; cutaneous flushing side effects, however, were slightly less common with time-release niacin. At these levels of adherence, LDL cholesterol (C) was reduced 21% by unmodified niacin and 13% by the time release form. Plasma total triglyceride was reduced more with unmodified niacin (27%) than with time-release niacin (8% maximum), and HDL-C and HDL2-C were increased significantly with unmodified niacin (26% and 36%) and were not significantly changed by time-release niacin. Increased to a similar degree on both regimens were HDL3-C (approximately 35%) and apoA-I (approximately 12%). ApoA-II was not affected by either drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of niacin supplementation on the concentration of niacin in rumen and duodenal digesta and in whole blood of sheep.

1. Niacin concentrations in rumen liquor, duodenal digesta and blood, and daily duodenal flow of niacin were measured in four wethers which were fed an oatstraw grain concentrate diet (with normal niacin content) or an oatstraw maize diet (with low niacin content). The effect of an intraruminal supplementation of 2 mmoles nicotinic acid (NIA) or nicotinamide (NAM) on concentrations of NIA and NAM in gastrointestinal contents and blood and on daily duodenal flow of NIA and NAM was studied. The animals were equipped with rumen fistula and duodenal re-entrant cannulae. 2. NIA concentration in strained rumen liquor was 384 and 264 nmol/ml and daily duodenal flow of niacin was 616 and 528 mumoles/d in animals fed normal or low niacin diet, respectively. Intraruminal administrations of 2 mmoles of NIA or NAM raised NIA concentration in strained rumen liquor for approximately 6 h. About 20% of the administered dose of NIA or NAM passed out of the rumen and resulted in a 41% increase in daily duodenal flow of niacin. The remaining 80% of the administered dose of NIA or NAM disappeared from rumen liquor without being washed out. 3. Supplemented NAM was rapidly hydrolyzed to NIA and ammonia when administered into the rumen. 4. NAM concentration in blood appeared to be unaffected by the dietary content of NIA or by niacin supplementation. 5. The NIA concentration in strained rumen liquor was positively related with niacin content of the diet. Increases in duodenal flow of niacin had no marked effect on concentration of NAM in blood. It appeared that feeding diets with different NIA content affected apparent niacin synthesis in the rumen.

Animal Feed↗
PubMed1998

Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.

This study compared the efficacy and safety of a once-a-night, time-release niacin formulation, Niaspan (Kos Pharmaceuticals, Miami Lakes, FL), with plain niacin and placebo for the treatment of primary hypercholesterolemia. The study was conducted in nine academic lipid research clinics in a randomized, double-blind design. Niaspan 1.5 g at bedtime was compared with plain niacin 1.5 g/d after 8 weeks and 3.0 g/d after 16 weeks in divided doses and with placebo. A total of 223 hypercholesterolemic adult men and women participated. Compared with placebo at 8 weeks, Niaspan versus plain niacin at 1.5 g/d showed comparable efficacy, comparably lowering total cholesterol (C) (8%/8%), triglycerides (16%/18%), low-density lipoprotein (LDL)-C (12%/12%), apolipoprotein (apo B) (12%/12%), apo E (9%/7%), and lipoprotein(a) [Lp(a)] (15%/11%), and raising high-density lipoprotein (HDL)-C (20%/17%), HDL2-C (37%/33%), HDL3-C (17%/16%), and apo A-I (8%/6%) (P < or = .05 in all instances). After 16 weeks, the Niaspan effect on LDL-C and triglyceride was unchanged while the plain niacin effect approximately doubled. At equal doses of 1.5 g/d of Niapan versus plain niacin, respectively, AST increased 5.0% versus 4.8% (difference not significant [NS]), fasting plasma glucose increased 4.8% versus 4.5% (NS), and uric acid concentrations increased less, 6% versus 16% (P=.0001). Flushing events were more frequent with plain niacin versus Niaspan (1,905 v 576, P < .001). Flushing severity was slightly greater with Niaspan, but still well tolerated. In conclusion, Niaspan 1.5 g hour of sleep (hs) has comparable efficacy, a lower incidence of flushing, a lesser uric acid rise, and an equivalent hepatic enzyme effect than 500 mg thrice-daily plain niacin in hyperlipidemic subjects. Niaspan may be an equivalent or better alternative to plain niacin at moderate doses in the management of hyperlipidemia.

Double-Blind Method↗
PubMed1986

Effect of niacin and niacin-tryptophan deficiency on pancreatic acinar cell function in rats in vitro.

To determine the effect of niacin deficiency on pancreas, rats were fed a standard rat chow ad libitum or an equal amount of a niacin-deficient or niacin-sufficient diet in the first experiment, or of a niacin-tryptophan-deficient or niacin-tryptophan-sufficient diet in the second experiment. Niacin deficiency decreased tissue chymotrypsinogen and trypsinogen content; amylase, chymotrypsinogen, and trypsinogen concentration; and basal secretion of total protein. Niacin-tryptophan deficiency decreased body weight, pancrease weight, and content of DNA, protein, amylase, lipase, chymotrypsinogen, and trypsinogen. Secretion of amylase and trypsinogen was increased. These studies indicate that niacin and niacin-tryptophan deficiency alter digestive-enzyme content and secretion, probably due to metabolic aberrations that result in an altered redox state of the acinar cell.

Amylases↗
PubMed1989

Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites.

Biochemical markers of niacin status were studied in healthy young men fed 6.1 to 32 niacin equivalents (NE) per day over an 11-wk period while residing in a metabolic unit. Methylated metabolites of niacin, N1-methylnicotinamide (NMN) and N1-methyl-2-pyridone-5-carboxamide (2-pyr), in urine and plasma were determined during periods of low (6.1 or 10.1 NE per day), adequate (19 NE per day = 1 RDA) and high (25 or 32 NE per day) niacin intakes and after small test doses of nicotinamide. Urine excretion of less than 1.2 mg/d of either NMN or 2-pyr was a reliable indicator of subjects receiving the lowest intake of 6.1 NE/d, but the NMN metabolite was a better marker of subjects ingesting 10.1 NE/d. The ratio of 2-pyr/NMN in urine was not as good a measure of the 6.1 NE/d intake as the individual metabolite excretions and was not responsive to the 10.1 NE/d intake. Plasma niacin metabolites were generally not as reliable as urinary metabolites for identifying subjects receiving low niacin intakes, however, values for plasma 2-pyr dropped quickly and were eventually nondetectable. After a 1 RDA oral dose of nicotinamide, increases in urine and plasma 2-pyr levels above pre-dose baseline values were significantly decreased in subjects receiving low, as compared to adequate, niacin intake. A leucine supplement had no effect on the rate of repletion of niacin-deficient subjects nor on the level of methylated niacin metabolites in urine or plasma.

Adult↗
PubMed1997

Vitamin B-6 normalizes the altered sulfur amino acid status of rats fed diets containing pharmacological levels of niacin without reducing niacin's hypolipidemic effects.

Niacin (nicotinic acid) in large doses (> 2 g) has been increasingly the choice of lipid-lowering agent by clinicians. However, the potential risks of the use of high doses of the vitamin have not been critically considered in the same way as has the use of other lipid-lowering drugs. The present study provides evidence that pharmacological levels of niacin interfere with the metabolism of methionine, leading to hyperhomocysteinemia and hypocysteinemia. Male Sprague-Dawley rats were fed a semisynthetic diet supplemented with either 400 or 4000 mg niacin/kg (compared with 47 mg/kg diet in the control diet). In Experiment 1, feeding these diets for 3 wk resulted in a dose-related increase in the plasma and urine methionine concentrations while cysteine levels were decreased. This altered methionine metabolism was accompanied by a lower plasma vitamin B-6 concentration in niacin-supplemented rats compared with controls. In Experiment 2, the methionine and cysteine levels in plasma and urine were normalized when vitamin B-6 (10 mg/kg diet) was added to the diet containing 4000 mg niacin/kg and fed for 6 wk. This experiment also showed that plasma and urine homocysteine concentrations were increased by niacin and normalized by vitamin B-6. The hypolipidemic action of niacin was unaffected by the presence of vitamin B-6. These results indicate that niacin at large dosages interferes with methionine metabolism by affecting vitamin B-6 status. The treatment of dyslipidemia with simultaneous administration of niacin and vitamin B-6 could be a better therapy than the use of niacin alone.

Animals↗
PubMed1998

The effect of the mode of administration on the hypolipidaemic activity of niacin: continuous gastrointestinal administration of low-dose niacin improves lipid-lowering efficacy in experimentally-induced hyperlipidaemic rats.

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia-Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg(-1)). Continuous administration of niacin into the duodenum at 1.66 mg h(-1) (total dose 40 mg kg(-1) day(-1)) for up to 7 days (Model A) or at 2.22 mg h(-1) over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15-25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg(-1)) has a greater lipid-lowering effect than a higher dose (200 mg kg(-1)) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.

Animals↗
PubMed1990

Rechallenge with crystalline niacin after drug-induced hepatitis from sustained-release niacin.

Niacin (nicotinic acid) is available in several forms, including crystalline preparations and various types of sustained-release preparations. Evidence exists that sustained-release niacin, with respect to both dosage and severity, is more hepatotoxic than crystalline niacin. Three patients who developed hepatitis during treatment with sustained-release niacin were rechallenged with equivalent or higher doses of crystalline niacin, with no evidence of recurring hepatocellular damage. Although the mechanism for niacin-induced hepatitis is unknown, these cases support previous observations that crystalline niacin may be less hepatotoxic than sustained-release preparations in certain patients.

Chemical and Drug Induced Liver Injury↗
PubMed1989

Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan.

Seven male subjects housed in a controlled metabolic unit for 80 d were fed diets containing amounts of niacin and tryptophan ranging from 6.1 to 32 niacin equivalents (NE) per day. Erythrocyte nicotinamide adenine dinucleotide (NAD) and nicotinamide nucleotide phosphate (NADP), activity of nicotinic acid mononucleotide phosphoribosyltransferase (NMNPRT), plasma tryptophan levels and the urinary excretion of organic acids were measured during dietary periods of low (6.1 or 10.1), adequate (19) and high (25 or 32) NE intake. With both low NE diets, NAD levels in erythrocytes decreased by approximately 70% and increased during repletion with an adequate NE diet. NADP levels remained relatively unchanged. Plasma tryptophan levels decreased by 40% and 10% in subjects ingesting diets of 6.1 and 10.1 NE/d, respectively. A daily 7.8-g leucine supplement during repletion was not associated with changes in plasma tryptophan levels or erythrocyte NAD and NADP levels at the end of the period. No changes in NMNPRT activity or organic acid excretion were found during the study. The results indicate that the erythrocyte NAD level may serve as a sensitive indicator for the assessment of niacin status. Also, a niacin index, the ratio of erythrocyte NAD to NADP, below 1.0 may identify subjects at risk of developing a niacin deficiency.

Adult↗
PubMedDate not supplied

Niacin. II: Identification of isonicotinic acid in niacin by liquid chromatography with diode array detection.

Isonicotinic acid impurity in bulk niacin was detected and identified by comparison with a reference material by liquid chromatography with a diode array detector. The niacin was dissolved in dilute hydrochloric acid and chromatographed on an amine column with a mobile phase of methanol and water acidified with formic acid. Isonicotinic acid has a relative retention time of 1.5 compared with niacin (nicotinic acid), and the wavelengths of maximum ultraviolet (UV) absorbance for isonicotinic acid and niacin are 270 and 260 nm, respectively. The amount of impurity found in the niacin sample was 0.3%. Twelve formulations, including sustained-release products, one bulk material, and the United States Pharmacopoeia (USP) reference standard were tested. The impurity was detected in only the bulk and USP reference material samples.

Chromatography, Liquid↗
PubMed1991

Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia.

Two hundred one male and female subjects, aged 20 to 70 years, with elevated low-density lipoprotein cholesterol values (in the 75th to 95th percentiles), participated in a randomized, controlled, double-blind study using a new form of niacin (Enduracin), which employs a wax-matrix vehicle for sustained release. Four niacin treatment groups (daily doses of 2000, 1500, 1250, and 1000 mg) were compared with placebo- and diet-treated controls to determine side-effect profile and optimal range of efficacy. The groups given 2000 and 1500 mg demonstrated significant reductions in values of low-density lipoprotein cholesterol (-26% and -19.3%, respectively), total cholesterol (-18.4% and -13.3%), and total cholesterol-high-density lipoprotein cholesterol ratio (-20.4% and -19.4%) when compared with diet- and placebo-treated controls. Smaller improvements were seen in high-density lipoprotein cholesterol and triglyceride levels. Blood chemistry monitoring indicated that reduction in low-density lipoprotein cholesterol level strongly correlated with an increase in baseline levels of some enzymes for niacin-treated subjects. The improved side-effect profile of the wax-matrix form of niacin was particularly notable. The dropout rate due to side effects was only 3.4% and was coupled with good medication compliance.

Adult↗
PubMed1991

Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin.

Hepatitis developed in five patients who were taking low dosages (3 g/day or less) of time-release niacin. In four of the five patients, clinical symptoms of hepatitis developed after the medication had been taken for a relatively short time (2 days to 7 weeks). This manifestation of hepatotoxicity seems to differ from that previously reported in association with use of crystalline niacin, which occurred with high dosage and prolonged usage of the medication. In view of the recent increased frequency of prescribing niacin for the treatment of hyperlipidemia, physicians should be aware of the potential for hepatotoxicity with even low-dose and short-term use of time-release niacin.

Adult↗
PubMed2002

Effects of fatty liver induced by niacin-free diet with orotic acid on the metabolism of tryptophan to niacin in rats.

The effects of dietary orotic acid on the metabolism of tryptophan to niacin in weaning rats was investigated. The rats were fed with a niacin-free, 20% casein diet containing 0% (control diet) or 1% orotic acid diet (test diet) for 29 d. Retardation of growth, development of fatty liver, and enlargement of liver were observed in the test group in comparison with the control group. The concentrations of NAD and NADP in liver significantly decreased, while these in blood did not decrease compared to the control group. The formation of the upper metabolites of tryptophan to niacin such as anthranilic acid, kynurenic acid, and 3-hydroxyanthranilic acid were not affected, but the quinolinic acid and beyond, such as nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, were significantly reduced by the administration of orotic acid. Therefore, the conversion ratio of tryptophan to niacin significantly decreased in the test group in comparison with the control group.

Animals↗