Effects on asymmetric dimethylarginine of HMR 3339, a novel selective estrogen receptor modulator: a 12-week, randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.
OBJECTIVE
To investigate the short-term effects of three different doses of the selective estrogen receptor modulator HMR 3339 in comparison with placebo and raloxifene on asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor.


METHODS
This study was a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. Ninety-four healthy postmenopausal women received daily doses of either placebo (n=16), HMR 3339 2.5 mg (n=20), HMR 3339 10 mg (n=19), HMR 3339 50 mg (n=20), or raloxifene 60 mg (n=19) for 12 weeks. Fasting plasma concentrations of ADMA, arginine, and symmetric dimethylarginine (SDMA) were measured at baseline and after 4 and 12 weeks by high-performance liquid chromatography.


RESULTS
HMR 3339 induced a dose-dependent reduction of ADMA and SDMA concentrations, with the largest effects (P<0.01 for both) in the HMR 3339 50 mg group compared with baseline and placebo (at 12 weeks: -7.0% [95% CI, -14.2% to 0.2%] for ADMA and -16.2% [95% CI, -22.4% to -10.0%] for SDMA). Twelve weeks of raloxifene 60 mg significantly reduced SDMA (P=0.03) but not ADMA concentrations. Arginine concentrations were not altered by any treatment.


CONCLUSIONS
The reduction of the nitric oxide synthase inhibitor ADMA by HMR 3339 may potentially have a beneficial effect on the cardiovascular system in postmenopausal women.
Verhoeven
Marieke O
MO
Project Aging Women, Institute for Cardiovascular Research-Vrije Universiteit, Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
Teerlink
Tom
T
Kenemans
Peter
P
Vogelvang
Tatjana E
TE
van der Mooren
Marius J
MJ
D000284:Administration, Oral; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D019584:Hot Flashes / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D009426:Netherlands; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017698:Postmenopause; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000627:therapeutic use*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
C495287:HMR 3339; D020845:Selective Estrogen Receptor Modulators; C487735:dimethylarginine; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D001120:Arginine; D019001:Nitric Oxide Synthase