Tolerance to nicotinic acid flushing

Stern, Robert L.; Spence, J. David; Freeman, David J.; Parbtani, Anwar

doi:10.1038/clpt.1991.104

Cited by 70 publications

(41 citation statements)

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“…Carlson and Oro ( 17 ) found that niacin lowered the arterial plasma concentration of FFAs in fasting humans within minutes. This effect is dose dependent ( 20 ) and is not desensitized after 6 months of regular treatment ( 21 ), in contrast with niacin's fl ushing effect which undergoes tachyphylaxis within a week ( 22 ). This suppression of plasma FFAs reduced the supply of substrate for the hepatic synthesis of TGs, VLDL and LDL particles ( 23 ).…”

Section: Effect On Ldl and Vldlmentioning

confidence: 99%

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Niacin, an old drug with a new twist

Song

FitzGerald

2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org the only approved drug with such an effect ( 1 ). It has proven to be an attractive option for those intolerant of statin treatment. It has been demonstrated to reduce risk of atherosclerotic cardiovascular disease ( 4 ). The clinical use of niacin has been markedly limited by cutaneous fl ushing. The molecular target of niacin responsible for lipid metabolic changes and fl ushing was unknown until 2003 ( 5-7 ), when the niacin receptor, namely HM74A in humans and PUMA-G in mice, was discovered. The niacin receptor, also known as GPR109A, was shown to be activated by niacin and to mediate its antilipolytic effect as well as the fl ushing effect ( 8-10 ). Interest in niacin has risen because there is still signifi cant residual risk in patients with intensive statin therapy ( 11 ). However, recent outcome trials ( 11, 12 ) failed to show niacin's benefi t on top of statin therapy in lipid-targeted approaches to reduce major cardiovascular events in high-risk patients. In this review we will summarize the pharmacology of niacin, with a particular emphasis on recent outcome trials, including discussion of their limitations . NIACIN'S LIPID EFFECTSNiacin has long been shown to have effects on lipids ( 13 ). Niacin increases high density lipoprotein cholesterol (HDLc), but reduces low density lipoprotein cholesterol (LDLc), VLDL cholesterol, and triglycerides (TGs) ( 14 ) Niacin is also known as vitamin B3. Chronic dietary defi ciency of niacin can cause pellagra ( 1 ). It is a precursor to NAD+/NADH and NADP+/NADPH, both of which play essential metabolic roles in living cells ( 2 ). Niacin has been used for more than half a century in the treatment of dyslipidemia. When Altschul, Hoffer, and Stephen ( 3 ) discovered that niacin could lower plasma levels of cholesterol, it was

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Section: Effect On Ldl and Vldlmentioning

confidence: 99%

“…During chronic drug administration, niacin-induced fl ushing and prostaglandin release are subject to tachyphylaxis within a week ( 22,75 ).…”

Section: Effects On Hdlmentioning

confidence: 99%

Niacin, an old drug with a new twist

Song

FitzGerald

2013

Journal of Lipid Research

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“…Intriguingly, these acute effects decrease upon prolonged niacin treatment. Adipocyte lipolysis normalizes ( 15,16 ) and fl ushing diminishes ( 17 ).…”

Section: Quantitative Pcrmentioning

confidence: 99%

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Heemskerk

Dharuri

Berg

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words drug therapy/hypolipidemic drugs • adipocytes • fatty acid/biosynthesis • omega-3 fatty acids • cytochrome P450 • polyunsaturated fatty acid Niacin (vitamin B3) treatment reduces CVD and atherosclerosis development ( 1 ). These benefi cial effects are mediated, in part, by lowering circulating levels of LDLcholesterol, VLDL-TG, and lipoprotein(a) ( 2 ), as well as by increasing HDL-cholesterol ( 3 ). In addition, prolonged niacin treatment also decreases plasma, adipose tissue, and vascular infl ammation ( 4, 5 ), which might contribute to reducing CVD. The induction of these benefi cial effects after prolonged niacin treatment is in striking contrast to the unwanted acute niacin effects.Acutely, niacin binds to the inhibitory hydroxycarboxylic acid receptor 2 (HCA 2 ) (previously known as GPR109A). In adipocytes, this leads to an inhibition of adipocyte lipolysis followed by an acute reduction of plasma nonesterifi ed fatty acid (NEFA) levels. Lowering NEFA levels causes metabolic stress ( 6, 7 ), which increases stress hormone levels ( 8-12 ) after niacin treatment. In the skin Langerhans cells and keratinocytes, acute niacin binding to the

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“…However, it has now been well established that both methyl nicotinate and nicotinic acid-induced flushing response is the result of increased prostaglandin synthesis in skin cells, suggested to be macrophages or adipocytes, which then act upon capillary epithelial cells to cause vasodilation (Wilkin et al, 1982(Wilkin et al, , 1985Morrow et al, 1989;Turenne et al, 2001). Interestingly, healthy subjects develop tolerance to the nicotinic acid-induced flushing response (Stern et al, 1991). This appears to be due to diminished prostaglandin D 2 synthesis, which has been implicated as the main prostaglandin subtype responsible for nicotinic acid-induced vasodilation (Morrow et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Methyl Nicotinate-Induced Vasodilation in Generalized Social Phobia

Katzman

Cornacchi

Coonerty-Femiano

et al. 2003

Neuropsychopharmacol

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Elevated vasodilatory response (blushing) to social situations is characteristic of social phobia (SP). A relatively unexplored basis for this phenomenon is alteration in underlying vasodilatory mechanisms. To investigate this possibility, we evaluated the vasodilatory response induced by methyl nicotinate (niacin ester derivative) in 31 generalized SP patients and 41 matched healthy volunteers (HV). A patch impregnated with 0, 0.1, 0.5, 1, and 10 mM methyl nicotinate was applied to the forearm or face of subjects for 1 min, followed by 20-min laser Doppler spectroscopy blood flow monitoring. Blood flow stimulation with 1 and 10 mM methyl nicotinate was significantly reduced in SP patients by 35 and 17%, respectively. Induced blood flow was negatively correlated with patients' Leibowitz Social Phobia Scale (LSAS) at 1 and 10 mM doses. Furthermore, the maximal rate of change of vasodilatory reaction was correlated with symptom scores at 1 and 10 mM doses. Induced increases in the arm and face blood flow measurements correlated, supporting the external validity of the former location. Generalized SP patients vasodilate less to topical methyl nicotinate challenges, with effect amplification in severely ill patients. Although the mechanism for this is unclear, we propose desensitization of the prostaglandin-mediated vasodilating system as an explanation.

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Tolerance to nicotinic acid flushing

Cited by 70 publications

References 0 publications

Niacin, an old drug with a new twist

Niacin, an old drug with a new twist

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Methyl Nicotinate-Induced Vasodilation in Generalized Social Phobia

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