Effects of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans

Journal of Clinical Lipidology

Volumn 2, Issue 5, 2008, Pages 375-383

  Lai, Eseng ^a   Waters, M Gerard ^a   Tata, James R ^a   Radziszewski, Waldemar ^a   Perevozskaya, Inna ^a   Zheng, Wei ^a   Wenning, Larissa ^a   Connolly, Daniel T ^b   Semple, Graeme ^b   Johnson Levonas, Amy O ^a   Wagner, John A ^a   Mitchel, Yale ^a   Paolini, John F ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b ARENA PHARMACEUTICALS   (United States)

Author keywords

Flushing; Free fatty acid; GPR109A Niacin; Niacin receptor; Nicotinic acid; Partial agonist

Indexed keywords

ANTILIPEMIC AGENT; FATTY ACID; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MK 0354; NICOTINIC ACID; PLACEBO; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AREA UNDER THE CURVE; ARTICLE; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; CONFIDENCE INTERVAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CREATINE KINASE BLOOD LEVEL; DOSAGE SCHEDULE COMPARISON; DOSE RESPONSE; DOSE TIME EFFECT RELATION; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSLIPIDEMIA; EVENING DOSAGE; FATTY ACID BLOOD LEVEL; FEMALE; FLUSHING; FOOD; FOOD DRUG INTERACTION; HUMAN; HYPERGLYCEMIA; HYPERINSULINEMIA; LIPID BLOOD LEVEL; LIVER DISEASE; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MORNING DOSAGE; MULTICENTER STUDY; MULTIPLE DRUG DOSE; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; SINGLE DRUG DOSE; TREATMENT DURATION; TRIACYLGLYCEROL BLOOD LEVEL; UNSPECIFIED SIDE EFFECT;

EID: 53249145678     PISSN: 19332874     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jacl.2008.08.445     Document Type: Article

References (25)

1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285 (2001) 2486-2497
2. The Coronary Drug Project. The coronary drug project. JAMA 221 (1972) 918
3. Brown B.G., Hillger L., Zhao X.Q., Poulin D., and Albers J.J. Types of change in coronary stenosis severity and their relative importance in overall progression and regression of coronary disease. Observations from the FATS Trial. Familial Atherosclerosis Treatment Study. Ann N Y Acad Sci. 748 (1995) 407-417
4. Brown B.G., Zhao X.Q., Chait A., et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 345 (2001) 1583-1592
5. Taylor A.J., Sullenberger L.E., Lee H.J., Lee J.K., and Grace K.A. 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. Circulation 110 (2004) 3512-3517
6. Canner P.L., Berge K.G., Wenger N.K., et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 8 (1986) 1245-1255
7. Morgan J.M., Capuzzi D.M., and Guyton J.R. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 82 (1998) 29U-34U
8. Mills E., Prousky J., Raskin G., et al. The safety of over-the-counter niacin. A randomized placebo-controlled trial [ISRCTN18054903]. BMC Clin Pharmacol. 3 (2003) 4
9. Benyo Z., Gille A., Bennett C.L., Clausen B.E., and Offermanns S. Nicotinic acid-induced flushing is mediated by activation of epidermal Langerhans cells. Mol Pharmacol. 70 (2006) 1844-1849
10. Lorenzen A., Stannek C., Burmeister A., Kalvinsh I., and Schwabe U. G protein-coupled receptor for nicotinic acid in mouse macrophages. Biochem Pharmacol. 64 (2002) 645-648
11. Tunaru S., Kero J., Schaub A., et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 9 (2003) 352-355
12. Lewis G.F. Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol. 8 (1997) 146-153
13. Sniderman A.D., and Cianflone K. Substrate delivery as a determinant of hepatic apoB secretion. Arterioscler Thromb. 13 (1993) 629-636
14. Maciejewski-Lenoir D., Richman J.G., Hakak Y., Gaidarov I., Behan D.P., and Connolly D.T. Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Invest Dermatol. 126 (2006) 2637-2646
15. van Herk T., Brussee J., van den Nieuwendijk A.M., et al. Pyrazole derivatives as partial agonists for the nicotinic acid receptor. J Med Chem. 46 (2003) 3945-3951
16. Kenakin T. Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol Sci. 16 (1995) 232-238
17. Richman J.G., Kanemitsu-Parks M., Gaidarov I., et al. Nicotinic acid receptor agonists differentially activate downstream effectors. J Biol Chem. 282 (2007) 18028-18036
18. Semple G., Skinner P.J., Gharbaoui T., et al. 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. J Med Chem. 51 (2008) 5101-5108
19. Norquist J.M., Watson D.J., Yu Q., Paolini J.F., McQuarrie K., and Santanello N.C. Validation of a questionnaire to assess niacin-induced cutaneous flushing. Curr Med Res Opin. 23 (2007) 1549-1560
20. Carlson L.A., and Oro L. The effect of nicotinic acid on the plasma free fatty acid: demonstration of a metabolic type of sympathicolysis. Acta Med Scand. 172 (1962) 641-645
21. Kaijser L., Eklund B., Olsson A.G., and Carlson L.A. Dissociation of the effects of nicotinic acid on vasodilatation and lipolysis by a prostaglandin synthesis inhibitor, indomethacin, in man. Med Biol. 57 (1979) 114-117
22. Paolini J.F., Mitchel Y.B., Reyes R., et al. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol. 101 (2008) 625-630
23. Carlson L.A. Inhibition of the mobilization of free fatty acids from adipose tissue. Physiological aspects on the mechanisms for the inhibition of mobilization of FFA from adipose tissue. Ann N Y Acad Sci. 131 (1965) 119-142
24. Carlson L.A., and Oroe L. Persistence of the inhibitory effect of nicotinic acid on catecholamine-stimulated lipid mobilization during prolonged treatment with nicotinic acid. J Atheroscler Res. 5 (1965) 436-439
25. Kamanna V.S., and Kashyap M.L. Mechanism of action of niacin. Am J Cardiol. 101 suppl (2008) 20B-26B