Acne Rosacea: [rosacea] Merck study on Niacin-induced flushing in humans

Wednesday, November 22, 2006

[rosacea] Merck study on Niacin-induced flushing in humans

I posted this on the other forum, but will repeat here, since
(unlike a lot of recent publications), this one offers the full
length paper for free ...

This is a very serious paper, appearing in the very prestigious Proc
NAS.

Abstract is at http://www.pnas.org/cgi/content/abstract/0601574103v1

Full paper is at http://www.pnas.org/cgi/reprint/0601574103v1.pdf

Pages 6684-6685 describe the clinic experiments against 12 human
subjects in a 3-way randomized crossover experiment. Taking the
Merck selective antagonist clearly blocks the resulting NA (niacin)
flush, with the largest impact occurring if it is taken 60 min ahead
of taking the niacin (as opposed to taking it concurrently).

Many questions come to mind, e.g.
1. Is there a common root-cause shared by niacin-induced flushing
and the broader class of Flushing (e.g. quasi-random late-day
flushing) that many of us endure?
2. If so, will the Merck antagonist block these as well?
3. How does one design an experiment to test this hypothesis?

btw, the antagonist is given orally.

I am going to try and get more info from the lead author.

Rick

----------------
Medical Sciences

Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic
acid-induced vasodilation in mice and humans

( aspirin | prostaglandin D2 receptor 1 antagonist | MK-0524 |
niacin | flushing )

Kang Cheng * , Tsuei-Ju Wu *, Kenneth K. Wu *, Claudio Sturino ,
Kathleen Metters , Keith Gottesdiener , Samuel D. Wright *, Zhaoyin
Wang , Gary O'Neill , Eseng Lai , and M. Gerard Waters *

Departments of *Cardiovascular Diseases and Clinical Pharmacology,
Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065; and
Departments of Medicinal Chemistry and Biochemistry and Molecular
Biology, Merck Frosst Canada, 16711 Trans Canada Highway, Kirkland,
QC, Canada H9H 3L1

Communicated by Peter S. Kim, Merck Research Laboratories, West
Point, PA, March 1, 2006 (received for review October 21, 2005)

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it
elicits an adverse effect, termed flushing, which consists of
cutaneous vasodilation with associated discomfort. An animal model
of NA-induced flushing has been established in mice. As in humans,
NA stimulated vasodilation in a dose-dependent manner, was
associated with an increase of the vasodilatory prostaglandin (PG)
D2 in plasma and could be blocked by pretreatment with aspirin. Two
PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also
called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2
does not mediate NA-induced vasodilation; the DP2-specific agonist
DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous
vasodilation, and DP2-/- mice had a normal vasodilatory response to
NA. By contrast, BW245C, a DP1-selective agonist, induced
vasodilation in mice, and MK-0524, a DP1-selective antagonist,
blocked both PGD2- and NA-induced vasodilation. NA-induced
vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice;
although NA-induced vasodilation depended almost completely on DP1
in female mice, it depended only partially on DP1 in male mice. The
residual NA-induced vasodilation in male DP-/- mice was aspirin-
sensitive. Thus, in the mouse, DP1 appears to be an important
component involved in NA-induced vasodilation, but other
cyclooxygenase-dependent mechanisms also may be involved. A clinical
study in healthy men and women demonstrated that treatment with MK-
0524 reduced the symptoms of flushing and the increase in skin
perfusion after the administration of NA. These studies suggest that
DP1 receptor antagonism may be an effective means to suppress NA-
induced flushing in humans.