Evista
Estrogen-like activity of tamoxifen and raloxifene on NMDA receptor binding and expression of its subunits in rat brain.

Cyr M, Thibault C, Morissette M, Landry M, Di Paolo T.

Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, CHUL, and Faculty of Pharmacy, Laval University, Sainte-Foy, Quebec, Canada , G1V 4G2.

Hormonal specificity of modulation of N-methyl- D-aspartate (NMDA) receptors was investigated by comparing the effects of estradiol with tamoxifen or raloxifene, which display different responses in breast, bone, and uterus. Two weeks ovariectomy in rats decreased uterine weight, which was prevented by a two-week estradiol treatment; tamoxifen and raloxifene had weaker uterine stimulation than estradiol. Ovariectomy in rats decreased L-[3H]glutamate specific binding to NMDA receptors in CA1 and dentate gyrus but not CA2/3 regions of hippocampus and was without effect in cortex, striatum, nucleus accumbens, and olfactory tubercle. [3H]Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly) specific binding and mRNA levels of NMDA receptor subunits 1 and 2B decreased in CA1 after ovariectomy. Estradiol, tamoxifen, and raloxifene decreased L-[3H]glutamate specific binding to NMDA receptors and [3H]Ro 25-6981 specific binding in cortical area of ovariectomized rats and prevented the decrease of [3H]glutamate specific binding to NMDA receptors in CA1 and dentate gyrus, as well as [3H]Ro 25-6981 specific binding in CA1. Estradiol prevented the decrease of NMDA receptor subunits 1 and 2B mRNA levels in CA1 only; tamoxifen and raloxifene prevented the decrease of NMDA receptor subunit 1 mRNA levels in CA1. No effect of ovariectomy or treatments on L-[3H]CGP 39653 (an NMDA antagonist selective for NR1/NR2A assembly) specific binding and NMDA receptor subunit 2A mRNA levels was observed in all brain regions assayed. Our results showed brain regional and subunits specific agonist estrogenic activity of tamoxifen and raloxifene on NMDA receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11425508&dopt=Abstract raloxifene Evista



Evista
Raloxifene effect on frequency of surgery for pelvic floor relaxation.

Goldstein SR, Neven P, Zhou L, Taylor YL, Ciaccia AV, Plouffe L.

Department of Obstetrics and Gynecology, New York University Medical Center, New York, New York, USA. steven.goldstein med.nyu.edu

OBJECTIVE: To assess the effects of raloxifene therapy on the frequency of surgery for pelvic floor relaxation in postmenopausal women. METHODS: This analysis used safety data through 3 years of treatment from three double-masked, placebo-controlled, randomized trials of raloxifene, which included 6926 postmenopausal women with uteri at entry. Studies 1 and 2 enrolled 969 nonosteoporotic, postmenopausal women who were assigned to 30, 60, or 150 mg per day raloxifene or placebo. Study 3 enrolled 5957 osteoporotic, postmenopausal women randomized to raloxifene 60 or 120 mg per day or placebo. Indications for any reported pelvic operations were identified, including procedures performed for pelvic organ prolapse or urinary incontinence. RESULTS: A total of 34 (1.51%) women in the placebo group and 35 (0.75%) raloxifene-treated women underwent surgical procedures for pelvic floor relaxation. The odds ratio (and 95% confidence interval) for pelvic floor repair in women assigned to raloxifene was 0.50 (0.31, 0.81). Thus, raloxifene therapy was associated with a significantly reduced risk for pelvic floor surgery (P <.005). CONCLUSION: Raloxifene does not increase pelvic floor relaxation. An apparent protective effect on pelvic floor function warrants further investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430963&dopt=Abstract raloxifene Evista



Evista
Estrogenic and antiestrogenic effects of raloxifene on collagen metabolism in breast cancer MCF-7 cells.

Wolczynski S, Surazynski A, Swiatecka J, Palka J.

Department of Gynecological Endocrinology, Medical Academy of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland.

We compared the effects of different concentrations of raloxifene (1, 4 and 10 microM) on collagen biosynthesis, gelatinolytic and prolidase activities and matrix metalloproteinase (MMP) expression (MMP-2 and MMP-9) in estradiol-stimulated (2 nM) breast cancer MCF-7 cells. Raloxifene inhibited in a dose-dependent manner the proliferation of MCF-7 cells, independently of the presence or absence of estradiol in the growth medium. Raloxifene at concentrations of 1 microM and 4 microM inhibited collagen biosynthesis by about 10-fold and prolidase activity by about 50%, while at a concentration of 10 microM it inhibited these processes by only about 25%. This phenomenon was accompanied by differences in gelatinolytic activity and MMP (MMP-2 and MMP-9) expression as demonstrated by zymography and Western immunoblot analysis, respectively. In estrogen-stimulated MCF-7 cells, cultured in the presence of 1 microM raloxifene, a dramatic increase in the activity of both collagenases was found. In contrast, addition of raloxifene at a concentration of 10 microM to the medium of the cells resulted in restoration of gelatinolytic activity to that found in control cells. Similarly, but at both doses (1 and 10 microM), raloxifene was able to reduce MMP-2 expression in the cells. However, when used alone (without estradiol) a concentration of 1 microM raloxifene strongly stimulated MMP-2 expression, while at a concentration of 10 microM the effect was not observed. In the case of MMP-9, only trace amounts of this gelatinase were detected, although in contrast to MMP-2, an increase in its expression was noticed at a concentration of 10 microM raloxifene. The data raise the possibility that in estrogen-stimulated MCF-7 cells, raloxifene at low concentrations (1 and 4 microM) evokes antiestrogenic effect on collagen biosynthesis and prolidase activity on the one hand, and an estrogenic effect on gelatinolytic activity on the other, while at higher concentrations (about 10 microM) it evokes an estrogenic effect on collagen biosynthesis and prolidase activity, and an antiestrogenic effect on gelatinolytic activity. Our data suggest that the effects of raloxifene on collagen synthesis, prolidase and metalloproteinase activities in breast cancer may explain its role in the prevention of breast cancer development.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11447735&dopt=Abstract raloxifene Evista



Evista
Estrogen receptor (ER)-alpha, but not ER-beta, mediates regulation of the insulin-like growth factor I gene by antiestrogens.

Fournier B, Gutzwiller S, Dittmar T, Matthias G, Steenbergh P, Matthias P.

Arthritis & Bone Metabolism Therapeutic Area, Novartis Pharma Research, 4002 Basel, Switzerland. brigitte.fournier pharma.novartis.com

The importance of insulin-like growth factor I (IGF-I) on maintenance of skeletal integrity has been widely recognized. Although osteoblasts secrete some IGF-I, the liver is the primary endocrine source for IGF-I. We have studied the regulation of the human IGF-I promoter in the hepatocyte cell line Hep3B, and we have shown that the IGF-I promoter, when co-transfected in Hep3B cells together with an estrogen receptor (ER)-alpha expression vector, was transcriptionally regulated by raloxifene or raloxifene-like molecules but not by 17beta-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonized by 17beta-estradiol and mediated selectively by ER-alpha, but not by ER-beta. Transfer of IGF-I promoter sequences from -733 to -65 or from -375 to -65 to a minimal Fos promoter resulted in a comparable responsiveness to raloxifene. This region contains two CAAT/enhancer-binding protein sites and an activator protein 1 site, both of which have been shown to be involved in estrogen receptor-mediated transactivation. When the CAAT/enhancer-binding protein sites were mutated in a construct bearing the sequence from -375 to -65 in front of the minimal Fos promoter, raloxifene induction was reduced, whereas mutation of the other elements did not affect induction. In addition, using chimeric proteins, we delineated the domains of ER-alpha that confer to ER-alpha transactivation abilities on the IGF-I promoter that are not exhibited by ER-beta. These data shed new light on the mechanism of action of antiestrogens and might help explain, at least in part, the bone-protective effects observed for some antiestrogens in ovariectomized animals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11457856&dopt=Abstract raloxifene Evista



Evista
Effect of chronic estradiol, tamoxifen or raloxifene treatment on serotonin 5-HT1A receptor.

Landry M, Di Paolo T.

Molecular Endocrinology and Oncology Research Center and Faculte de pharmacie, Universite Laval, 2705 Laurier Boulevard, Sainte-Foy, Quebec G1V 4G2, Canada.

Numerous reports demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. The 5-HT(1A) receptor has been suggested to be implicated in depression and anxiety. Selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene, have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have beneficial effects in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The aim of the present study was thus to investigate in ovariectomized rats the effects of 17beta-estradiol, tamoxifen and raloxifene treatments on 5-HT(1A) receptor binding sites (agonist and antagonist) and mRNA levels in the hippocampal formation, prefrontal and cingulate cortex, as well as dorsal raphea nucleus which are known to express estrogen receptors (ER). Two weeks ovariectomy of female rats led to a 60% decrease of uterine weight, which was prevented by a 2-week 17beta-estradiol treatment; tamoxifen and raloxifene increased uterine weights by 35% and 15%, respectively, but significantly less than estradiol treatment. Specific binding to 5-HT(1A) receptors was determined by autoradiography of brain sections using the selective ligands: [3H]8-OH-DPAT and [3H]MPPF. Ovariectomy and hormone replacement therapy did not significantly affect 5-HT(1A) receptor agonist and antagonist specific binding sites as well as mRNA levels in all subregions of the hippocampus, prefrontal and cingulate cortex as well as dorsal raphea nucleus. Although the present treatments had functional effects as assessed with uterine weights, ovariectomy and estrogen-receptor directed drugs had no effect on hippocampal 5-HT(1A) receptors as compared to 5-HT(2A) receptors previously reported.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12670705&dopt=Abstract raloxifene Evista



Evista
Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin.

Miller JW, Skerjanec A, Knadler MP, Ghosh A, Allerheiligen SR.

Eli Lilly & Co, Inc. Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, Indianapolis 46202, USA. jmil lilly.com

PURPOSE: Evista (raloxifene HCl) is a nonsteroidal selective estrogen receptor modulator that displays estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium. The potential for drug-drug interaction between raloxifene and warfarin was assessed in 15 healthy postmenopausal women. METHODS: Single doses of warfarin (20 mg) were administered prior to and during 2 weeks of dosing with raloxifene 120 mg/day. Each warfarin dose was followed by pharmacokinetic sampling and prothrombin time measurements. RESULTS: Raloxifene administration resulted in 7.1% and 14.1% decreases in the clearance (CLp/F) and 7.4% and 9.8% decreases in the volume of distribution (Vss/F) of R- and S-warfarin, respectively (all p < or = 0.05). In contrast to the slightly higher plasma concentrations of R- and S-warfarin, raloxifene reduced the maximum prothrombin time (PTmax) by 10% and the area under the PT versus time curve from 0-120 h (AUCPT) by 8% (p < 0.01). CONCLUSIONS: Raloxifene administration may result in a small increase in systemic warfarin exposure that is associated with a diminution, not augmentation, of the pharmacodynamic effect. Due to the small magnitude of this effect, concomitant administration of raloxifene and warfarin is not likely to result in clinically significant drug-drug interaction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11496940&dopt=Abstract raloxifene Evista