The mechanism and mitigation of niacin-induced flushing

Aims: To summarise the metabolic responses to niacin that can lead to flushing and to critically evaluate flushing mitigation research.

[1]  A. Hamsten,et al.  Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid , 1989, Journal of internal medicine.

[2]  J. Mckenney,et al.  Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). , 2007, Atherosclerosis.

[3]  D. Hunninghake,et al.  A dose‐ranging study of a new, once‐daily, dual‐component drug product containing niacin extended‐release and lovastatin , 2003, Clinical cardiology.

[4]  J. Stamler.  Clofibrate and niacin in coronary heart disease. , 1975, JAMA.

[5]  J. Warren,et al.  Prolonged microvascular vasodilation induced by leukotriene B4 in human skin is cyclooxygenase independent. , 1995, The Journal of pharmacology and experimental therapeutics.

[6]  H. Hirai,et al.  The second PGD(2) receptor CRTH2: structure, properties, and functions in leukocytes. , 2003, Prostaglandins, leukotrienes, and essential fatty acids.

[7]  C. O'connor,et al.  Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. , 1998, American Journal of Cardiology.

[8]  G. Walldius,et al.  Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2, and HDL3, in hyperlipoproteinaemia , 1990, Journal of internal medicine.

[9]  P. Kadowitz,et al.  Bronchoactive metabolites of arachidonic acid and their role in airway function. , 1981, Prostaglandins.

[10]  James R. Campbell,et al.  Effect of two aspirin pretreatment regimens on niacin-induced cutaneous reactions , 1997, Journal of General Internal Medicine.

[11]  L. Gibbons,et al.  The prevalence of side effects with regular and sustained-release nicotinic acid. , 1995, The American journal of medicine.

[12]  Xavier Collet,et al.  Ectopic β-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis , 2003, Nature.

[13]  V. Kamanna,et al.  Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents? , 2007, The American journal of cardiology.

[14]  S. Dowell,et al.  Molecular Identification of High and Low Affinity Receptors for Nicotinic Acid* , 2003, The Journal of Biological Chemistry.

[15]  R. Piepho.  The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. , 2000, The American journal of cardiology.

[16]  S. Narumiya,et al.  The DP receptor, allergic inflammation and asthma. , 2003, Prostaglandins, leukotrienes, and essential fatty acids.

[17]  Lin-hua Zhang,et al.  Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells. , 2009, Atherosclerosis.

[18]  Z. Benyó,et al.  GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. , 2005, The Journal of clinical investigation.

[19]  G. O'neill,et al.  Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D. Capuzzi,et al.  A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. , 1998, The American journal of cardiology.

[21]  C. Blum,et al.  High density lipoprotein metabolism in man. , 1977, The Journal of clinical investigation.

[22]  Jeannie K. Lee,et al.  Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A Double-Blind, Placebo-Controlled Study of Extended-Release Niacin on Atherosclerosis Progression in Secondary Prevention Patients Treated With Statins , 2004, Circulation.

[23]  J. Mckenney.  Niacin for dyslipidemia: considerations in product selection. , 2003, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[24]  A. Heggelund,et al.  Influence of indomethacin on flush induced by nicotinic acid in man. , 2009, Acta pharmacologica et toxicologica.

[25]  A. Lewin,et al.  Acetylsalicylic acid reduces niacin extended-release-induced flushing in patients with dyslipidemia. , 2009, American journal of cardiovascular drugs : drugs, devices, and other interventions.

[26]  L. Kaijser,et al.  Prostaglandins contribute to the vasodilation induced by nicotinic acid. , 1979, Prostaglandins.

[27]  J. Morrow,et al.  Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. , 1992, The Journal of investigative dermatology.

[28]  S. Kihara,et al.  Increased compliance of niceritrol treatment by addition of aspirin: relationship between changes in prostaglandins and skin flushing. , 1987, International journal of clinical pharmacology, therapy, and toxicology.

[29]  R. Stern,et al.  Tolerance to nicotinic acid flushing , 1991, Clinical pharmacology and therapeutics.

[30]  J. Pieper.  Understanding niacin formulations. , 2002, American Journal of Managed Care.

[31]  P. Leff,et al.  The biology and pharmacology of PGD2. , 1988, Prostaglandins.

[32]  J. Mckenney,et al.  Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. , 2000, Archives of internal medicine.

[33]  J. Mckenney,et al.  Comparison of the safety and efficacy of a combination tablet of niacin extended release and simvastatin vs simvastatin monotherapy in patients with increased non-HDL cholesterol (from the SEACOAST I study). , 2008, The American journal of cardiology.

[34]  R. Ramakrishnan,et al.  Lipoprotein(a): an elusive cardiovascular risk factor. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[35]  M. Greaves,et al.  Prostaglandin activity in sustained inflammation of human skin before and after aspirin. , 1977, Clinical science and molecular medicine.

[36]  A. Goldberg,et al.  Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia. , 1998, Metabolism: clinical and experimental.

[37]  K. Martin,et al.  Prostacyclin, atherothrombosis, and cardiovascular disease. , 2007, Current medicinal chemistry.

[38]  J. D. Proctor,et al.  A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. , 1994, JAMA.

[39]  M. Ford,et al.  Low-Dose Aspirin and Ibuprofen Reduce the Cutaneous Reactions Following Niacin Administration. , 1995, American journal of therapeutics.

[40]  M. Davidson.  Niacin use and cutaneous flushing: mechanisms and strategies for prevention. , 2008, The American journal of cardiology.

[41]  R. B. Norris.  "Flush-free niacin": dietary supplement may be "benefit-free". , 2006, Preventive cardiology.

[42]  R. Andersson,et al.  Studies on the mechanism of flush induced by nicotinic acid. , 2009, Acta pharmacologica et toxicologica.

[43]  H. Superko,et al.  Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B, or I. , 2004, The American journal of cardiology.

[44]  Clare L. Bennett,et al.  Nicotinic Acid-Induced Flushing Is Mediated by Activation of Epidermal Langerhans Cells , 2006, Molecular Pharmacology.

[45]  G. O'neill,et al.  Suppression of Niacin‐induced Vasodilation with an Antagonist to Prostaglandin D2 Receptor Subtype 1 , 2007, Clinical pharmacology and therapeutics.

[46]  R. Breyer,et al.  Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. , 2004, Pharmacology & therapeutics.

[47]  S. Narumiya,et al.  Prostaglandin E Receptors* , 2007, Journal of Biological Chemistry.

[48]  D J Greenblatt,et al.  Pharmacokinetics and pharmacodynamics. , 1990, Hospital practice.

[49]  C. Stannek,et al.  Characterization of a G protein-coupled receptor for nicotinic acid. , 2001, Molecular pharmacology.

[50]  F. Hirata,et al.  A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[51]  S. Levitsky,et al.  Endogenous vasoconstrictor prostanoids: role in serotonin and vasopressin-induced coronary vasoconstriction. , 1991, The Journal of pharmacology and experimental therapeutics.

[52]  E J Stanek,et al.  Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation. , 2007, International journal of clinical pharmacology and therapeutics.

[53]  A. Riutta,et al.  Nicotinic acid and pyridoxine modulate arachidonic acid metabolism in vitro and ex vivo in man. , 1999, Pharmacology & toxicology.

[54]  L. Kaijser,et al.  Dissociation of the effects of nicotinic acid on vasodilatation and lipolysis by a prostaglandin synthesis inhibitor, indomethacin, in man. , 1979, Medical biology.

[55]  J. Morrow,et al.  Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid. , 1989, Prostaglandins.

[56]  H. L. Mason,et al.  Nicotinic acid treatment of hypercholesteremia. Comparison of plain and sustained-action preparations and report of two cases of jaundice. , 1961, JAMA.

[57]  C J Hull,et al.  Pharmacokinetics and pharmacodynamics. , 1979, British journal of anaesthesia.

[58]  J. Albers,et al.  Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin. , 1985, Metabolism: clinical and experimental.

[59]  T. Sakai,et al.  Niacin, but Not Gemfibrozil, Selectively Increases LP-AI, a Cardioprotective Subfraction of HDL, in Patients With Low HDL Cholesterol , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[60]  C. Stannek,et al.  G protein-coupled receptor for nicotinic acid in mouse macrophages. , 2002, Biochemical pharmacology.

[61]  M. Herslöf,et al.  The potential link between atherosclerosis and the 5-lipoxygenase pathway: investigational agents with new implications for the cardiovascular field , 2007, Expert opinion on investigational drugs.

[62]  M. McGovern,et al.  Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. , 2002, The American journal of cardiology.

[63]  A. Goldberg,et al.  Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. , 2000, The American journal of cardiology.

[64]  I. Adcock,et al.  Cytokine induction of cytosolic phospholipase A2 and cyclooxygenase-2 mRNA is suppressed by glucocorticoids in human epithelial cells. , 1996, Life sciences.

[65]  S. Tunaru,et al.  PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect , 2003, Nature Medicine.

[66]  N. Svedmyr,et al.  The relationship between the plasma concentration of free nicotinic acid and some of its pharmacologic effects in man , 1969, Clinical pharmacology and therapeutics.

[67]  H. Karlsson.  The prevalence of what? , 2009, Nordic journal of psychiatry.

[68]  R. Karas,et al.  Long-Term Safety and Efficacy of a Combination of Niacin Extended Release and Simvastatin in Patients with Dyslipidemia , 2008, American journal of cardiovascular drugs : drugs, devices, and other interventions.

[69]  Lin-hua Zhang,et al.  Niacin inhibits surface expression of ATP synthase β chain in HepG2 cells: implications for raising HDL This study was supported by grants from the Southern California Institute for Research and Education. Published, JLR Papers in Press, March 3, 2008. , 2008, Journal of Lipid Research.

[70]  S. Narumiya,et al.  International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. , 1994, Pharmacological reviews.

[71]  L. L. Lin,et al.  Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[72]  J. Mckenney,et al.  Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study. , 2008, Journal of Clinical Lipidology.

[73]  J. Brunzell,et al.  Varying Cost and Free Nicotinic Acid Content in Over-the-Counter Niacin Preparations for Dyslipidemia , 2003, Annals of Internal Medicine.

[74]  Charles Chree,et al.  The Relationship between the , 1925 .

[75]  A. Goldberg,et al.  Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. , 1998, The American journal of cardiology.