Abstract
Niacin lowers serum cholesterol, low-density lipoprotein, and triglycerides, and it raises high-density lipoprotein. However, most patients experience cutaneous warmth and vasodilation (flush). Acetylsalicylic acid (ASA) can reduce this flush, presumably by decreasing prostaglandin D2 (PGD2) release from macrophages. Here, we show that methylnicotinate induces significant PGD2 release from human mast cells and serotonin from human platelets. Intradermal injection of methylnicotinate induces rat skin vasodilation and vascular permeability. Niacin increases plasma PGD2 and serotonin in a rat model of flush. The phenothiazine prochlorperazine, the H1, serotonin receptor antagonist cyproheptadine, and the specific serotonin receptor-2A antagonist ketanserin inhibit niacin-induced temperature increase by 90% (n = 5, p < 0.05), 90 and 50% (n = 3, p < 0.05), and 85% (n = 6, p = 0.0008), respectively, in this animal model. These results indicate that niacin-induced flush involves both PGD2 and serotonin, suggesting that drugs other than ASA are required to effectively inhibit niacin-induced flush.
Footnotes
-
This study was supported in part by Kos Pharmaceuticals, Inc. (Cranbury, NJ) and by Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA).
-
The following patents awarded to T.C.T cover methods and composition claims for blocking niacin-induced flush: Theoharides TC (2003) inventor; Theta Biomedical Consulting and Development Co., Inc., assignee. Proteoglycan compositions for treatment of cardiovascular inflammatory diseases. US 6,624,148. 2003 Sept 23; Theoharides TC (2004) inventor; Theta Biomedical Consulting and Development Co., Inc., assignee. Method of treating mast cell activation-induced diseases with a proteoglycan. US 6,689,748. 2004 Feb 10; Theoharides TC (2006) inventor; Theta Biomedical Consulting and Development Co., Inc., assignee. Synergistic proteoglycan compositions for treatment of inflammatory diseases. US 6,984,667. 2006 Jan 10; Theoharides TC (2006) inventor; Theta Biomedical Consulting and Development Co., Inc., assignee. Proteoglycan compositions for the treatment of cardiovascular inflammatory diseases. U.S. Patent 7,115,278. 2006 Oct 3; Theoharides TC (2006) inventor; Theta Biomedical Consulting and Development Co., Inc., assignee. Proteoglycan compositions for the treatment of inflammatory diseases. World Patent EPO 1365777. 2006 Apr 19; Theoharides TC (2008) inventor; Theta Biomedical Consulting and Development Co., Inc., assignee. US Patent application 12/151,268. 2008 May 5. (This application is CIP of US 11/999,991, which is CIP of US 11/651,161, which is CIP of 10/811,828 filed Mar 30, 2004).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.141333.
-
ABBREVIATIONS: HDL, high-density lipoprotein; LDL, low-density lipoprotein; PGD2, prostaglandin D2; ASA, acetylsalicylic acid; hCBMC, human cord blood mononuclear cell; EIA, enzyme immunoassay; MK-0524, [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclo pentaindol-3-yl)acetic acid.
- Received May 20, 2008.
- Accepted September 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
Log in using your username and password
Purchase access
In this issue
Niacin-induced “Flush” Involves Release of Prostaglandin D2 from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and an Animal Model
