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Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor.

Zeng Y, Yokohira M, Saoo K, Takeuchi H, Chen Y, Yamakawa K, Matsuda Y, Kakehi Y, Imaida K.

Onco-Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.

The chemopreventive efficacies of raloxifene and nimesulide, an antiestrogen but with anti-androgen action and a COX-2 selective inhibitor, respectively, were evaluated in probasin/ SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 ppm in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 ppm), and raloxifene (10 mg/kg/day) plus nimesulide (400 ppm). Animals were sacrificed at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure testosterone levels. All animals in the placebo group had tumors in each lobe compared with only 43% each in the dorsolateral (DLP) and anterior prostate (AP) of the animals treated with raloxifene (10 mg/kg/day) plus nimesulide. The total prostate weights and adenocarcinoma portions were significantly reduced in the three raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between nimesulide alone and placebo groups or between raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide, suggesting a lack of cancer preventive effects of the COX-2 inhibitor in this animal model. PCNA positive rates in ventral prostate (VP) and DLP, and androgen receptor (AR) levels in VP were significantly reduced in three raloxifene-treated group. Furthermore, circulating testosterone was decreased after raloxifene (10 mg/kg/day) plus nimesulide treatment. These results demonstrate that raloxifene, but not nimesulide, inhibits prostate carcinogenesis in SV40 Tag TG rats associated with a declined circulating testosterone and a loss of AR expression, as well as an inhibition of cell proliferation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15731164&dopt=Abstract raloxifene Evista



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Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.

Goekoop R, Duschek EJ, Knol DL, Barkhof F, Netelenbos C, Scheltens P, Rombouts SA.

Department of Neurology, VU University Medical Center, De Boelelaan 1117 1081 HV, Amsterdam, The Netherlands.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15734344&dopt=Abstract raloxifene Evista



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Effects of raloxifene on serum malondialdehyde, erythrocyte superoxide dismutase, and erythrocyte glutathione peroxidase levels in healthy postmenopausal women.

Kaya H, Ozkaya O, Sezik M, Arslanoglu E, Yilmaztepe A, Ulukaya E.

Department of Obstetrics and Gynecology, School of Medicine, Suleyman Demirel University, Isparta, Turkey.

Objective: To investigate the relationship between raloxifene administration and serum malondialdehyde (MDA), erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPx) levels in healthy postmenopausal women. Methods: In a randomized and placebo-controlled design, 80 women received either 60mg/day raloxifene or placebo for 24 weeks. MDA, SOD, and GPx levels were assessed at 0,4,12, and 24 weeks. Wilcoxon signed-rank test and Mann-Whitney U test were used for comparisons. Results: Six women in the treatment arm and eight women in the placebo group discontinued the study. Mean serum MDA levels were significantly (p = 0.001) decreased from 11.4nmol/ml at baseline to 8.9nmol/ml at week 12 with raloxifene treatment. Mean erythrocyte SOD activity was significantly (p = 0.02) reduced from 1472U/gHb at baseline to 1173U/gHb at week 12 following raloxifene administration. Lowered serum MDA and erythrocyte SOD levels persisted during treatment. On contrary, erythrocyte GPx levels did not change significantly with raloxifene administration. Conclusions: Raloxifene (60mg/day) lowers serum MDA levels and erythrocyte SOD activity in postmenopausal women after 12 weeks of treatment. The clinical implications of these findings need to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15734599&dopt=Abstract raloxifene Evista



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Hormone replacement therapy, selective estrogen receptor modulators, and tissue-specific compounds: cardiovascular effects and clinical implications.

Vogelvang TE, van der Mooren MJ, Mijatovic V.

Department of Obstetrics and Gynecology, Project Aging Women and the Institute for Cardiovascular Research-Vrije Universiteit, VU University Medical Center, Amsterdam, The Netherlands. t.vogelvang vumc.nl

In industrialized countries, coronary heart disease (CHD) is not only the leading cause of death in women but of disability as well. Menopause, regardless of age at onset, is associated with a marked increase in CHD risk. Based on epidemiologic studies demonstrating mainly positive biologic effects of hormone replacement therapy (HRT) on CHD risk factors and outcomes, earlier recommendations decreed that most, if not all, postmenopausal women should be treated with long-term HRT. Recent randomized controlled trials with clinical CHD endpoints have shown that previously held dicta may not be accurate. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene are alternatives to HRT. SERMs represent a growing class of compounds that act as either estrogen receptor agonists or antagonists in a tissue-selective manner. This pharmacologic profile may offer the opportunity to dissociate favorable cardiovascular effects of estrogen from unfavorable stimulatory effects on the breast and endometrium. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. They showed fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a so-called second-generation SERM. It seems clear that raloxifene increases bone mineral density, has no effect on the endometrium, and holds high promise for the prevention of breast cancer. The effect of raloxifene on cardiovascular disease is uncertain. On the basis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene may offer some protection to women with cardiovascular disease or to those who are at high risk. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Clinical trials have demonstrated that the synthetic 19-nortestosterone derivative tibolone reduces climacteric complaints and prevent osteoporosis without causing menstrual bleeding. Tibolone lowers lipoprotein(a), fibrinogen, and plasminogen activator inhibitor-1 levels and improves glucose tolerance, insulin sensitivity, and endothelial function; however, it also lowers high-density lipoprotein cholesterol by >20%. The long-term impact of tibolone on the risk of CHD is not known and needs to be studied.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15743106&dopt=Abstract raloxifene Evista



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Sodium nitroprusside-induced osteoblast apoptosis is mediated by long chain ceramide and is decreased by raloxifene.

Olivier S, Fillet M, Malaise M, Piette J, Bours V, Merville MP, Franchimont N.

Department of Rheumatology, Laboratory of Clinical Chemistry and Human Genetics, CBIG, CHU Sart-Tilman, University of Liege, 4000 Liege, Belgium.

Release of high levels of nitric oxide (NO) is associated with osteoblastic cell death. The mechanisms of NO-induced cytotoxicity are not well documented and it is presently not known if estrogenic compounds prevent this effect. We studied the role of ceramides in cell death induced by the NO donor sodium nitroprusside (SNP) and we tested the possibility that 17beta-estradiol, the anti-estrogen ICI 182.780 and two selective estrogen receptor modulators raloxifene and tamoxifen modify osteoblastic cell apoptosis. SNP dose-dependently decreased MC3T3-E1 osteoblast viability, increased NO production in the culture media and enhanced the release of intracellular ceramides C22 and C24. Cell death induced by SNP was partially inhibited when MC3T3-E1 cells were pretreated with raloxifene and tamoxifen but was not modified when the cells were pretreated with 17beta-estradiol or ICI 182.780. Cell death induced by SNP resulted from apoptosis as demonstrated by Annexin-V and propidium iodide labeling and a reduction of SNP-induced MC3T3-E1 apoptosis was confirmed in the presence of raloxifene and tamoxifen. SNP induction of C22 and C24 production was inhibited by a pretreatment with raloxifene but not with 17beta-estradiol. Moreover, the synthetic ceramide C24 (0.75 and 1muM) decreased MC3T3-E1 cell viability and osteoblast cell death induced by C24 was partially decreased by raloxifene and to a lesser extent by 17beta-estradiol. These data demonstrate that SNP-induced cell death is mediated by the long chain ceramides C22 and C24 and that raloxifene protected osteoblast from apoptosis induced by SNP, an effect that might be relevant to its pharmacological properties on bone remodeling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15748701&dopt=Abstract raloxifene Evista



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17beta-estradiol, but not raloxifene, decreases thrombomodulin in the antithrombotic protein C pathway.

Richardson MA, Berg DT, Calnek DS, Ciaccia AV, Joyce DE, Grinnell BW.

Lilly Research Laboratories, Indianapolis, IN 46285, USA.

Raloxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that mimics the effects of estrogen on some plasma lipids and may have direct effects on the vascular wall. The objective of this study was to determine the effects of 17beta-estradiol, raloxifene, and LY139,478 (a related benzothiophene SERM) on the anticoagulant protein C pathway. In human vascular endothelial cells activated with interleukin-1 (IL-1), we demonstrated decreased thrombomodulin-dependent protein C activation. 17beta-estradiol reduced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells by decreasing thrombomodulin expression. In contrast, raloxifene and LY139,478 enhanced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells through upregulation of thrombomodulin. Regulation of the protein C pathway via thrombomodulin on vascular endothelium may be a novel mechanism by which SERMs could potentially confer cardioprotective effects and reduce the thrombotic risk associated with HRT in compromised patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11014248&dopt=Abstract raloxifene Evista