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Raloxifene acutely stimulates nitric oxide release from human endothelial cells via an activation of endothelial nitric oxide synthase.

Simoncini T, Genazzani AR.

Department of Reproductive Medicine and Child Development, University of Pisa, Italy. t.simoncini obgyn.med.unipi.it

Raloxifene is a selective estrogen receptor modulator (SERM) clinically effective for the prevention of postmenopausal osteoporosis. Estrogen's effect on cardiovascular diseases is mainly dependent on direct actions on the vascular wall. Since raloxifene has an endothelium-dependent relaxing effect, we studied the effects of this molecule on nitric oxide (NO) release from cultured human umbilical vein endothelial cells. Clinically effective concentrations of the compound triggered a rapid and dose-dependent release of NO from endothelial cells. Raloxifene-induced NO production was dependent on an estrogen receptor-mediated mechanism, since it was abolished by the pure estrogen receptor antagonist ICI 182,780. Treatment of endothelial monolayers with raloxifene was not associated with changes in endothelial nitric oxide synthase (eNOS) messenger RNA or protein, showing that raloxifene does not increase NO release through a transcriptional increase of eNOS. Indeed, raloxifene-induced NO production is due to an estrogen receptor-dependent acute stimulation of eNOS enzymatic activity. In conclusion, raloxifene activates eNOS in human endothelial cells, exerting a potentially important direct vasculo-protective effect stimulating endothelial NO production.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10946913&dopt=Abstract raloxifene Evista



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The effects of estrogen and raloxifene treatment on antioxidant enzymes in brain and liver of ovarectomized female rats.

Ozgonul M, Oge A, Sezer ED, Bayraktar F, Sozmen EY.

Department of Biochemistry, Ege University Faculty of Medicine, Bornova-Izmir, Turkey.

Recent studies documented that estrogen have antioxidant properties in-vitro, there are conflicting results on the effect of estrogen in vivo. We aimed to investigate the effects of estradiol and Raloxifene on the antioxidant enzyme [superoxide dismutase (SOD) and catalase (CAT)] activities and MDA levels in brain and liver homogenates of ovariectomized female rats. Twelve weeks after ovariectomy, female Sprague-Dawley rats (n = 26) were divided into three groups: (1) Ovariectomized placebo group (n = 6) was given physiologic saline. (2) Estrogen group (n = 10) was given Ethynyl estradiol, 0.1 mg/kg sc. (3) Raloxifene group (n = 10) was given raloxifene, 1 mg/kg sc during 8 weeks. Ten rats were used as naive controls without any treatment (Sham operated group, n = 10). Ovariectomy lead to an increase in the CAT activities in liver tissue samples compared to the sham group (p = 0.056, Mann-Whitney test). While estrogen treatment reversed to normal levels of CAT activities, raloxifene remained as ineffective. Superoxide dismutase activities and MDA levels in liver were remained unchanged in all groups. There was no significant change in the brain tissue SOD and CAT activities between the control ovariectomy, estrogen treated, and raloxifen treated groups. We determined an increase in MDA levels in brain of ovariectmised rat (p = 0.02). While raloxifene treatment reversed to normal levels of MDA (p = estrogen treatment failed. Our data showed that estrogen may play a role in regulation of CAT and SOD activities in liver due to its antioxidative effects. We can suggest estrogen and raloxifene exert their antioxidative effects in brain rather than liver. Since Raloxifene's effect is more clear than estradiol, raloxifene may be suggested primarily for treatment and/or prevention of diseases which can be resulted from oxidative stress in postmenopausal women.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12856805&dopt=Abstract raloxifene Evista



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Raloxifene (LY156758) produces antimetastatic responses and extends survival in the PAIII rat prostatic adenocarcinoma model.

Neubauer BL, Best KL, Counts DF, Goode RL, Hoover DM, Jones CD, Sarosdy MF, Shaar CJ, Tanzer LR, Merriman RL.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis 46285, USA.

The benzothiophene antiestrogen, raloxifene (LY156758), has selective estrogen pharmacological antagonist activity in rats. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this agent on the lymphatic and pulmonary metastasis and survival in tumor-bearing male Lobund-Wistar (LW) rats. Raloxifene was inactive against colony formation of PAIII cells in vitro. Similarly, following subcutaneous (s.c.) implantation of 10(6) PAIII cells in the tail, s.c. administration of raloxifene (2.0, 10.0, or 20.0 mg/kg/day) for 30 days failed to demonstrate cytoreductive activity against primary tumor growth in the tail. However, in these same animals, raloxifene administration produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 89% and 81% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by raloxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by raloxifene administration in a dose-related manner (maximal reduction = 97% from control values). In these animals, maximal regression of 20% for ventral prostate and 21% for seminal vesicle were also seen after raloxifene administration (P < 0.05 for both). Coadministration of E2B and raloxifene had no consistent antagonistic effect upon the antitumor responses produced by raloxifene. Raloxifene (40.0 mg/kg/day for 28 days) produced marked decreases in PAIII metastasis in the lymphatic and pulmonary components. Continued administration of the compound produced significant (P < 0.05) extension of survival of PAIII-bearing rats. Further studies are needed to define the maximal antitumor efficacy and the mechanism of action of raloxifene in urogenital solid tumor animal models. These data support the contention that raloxifene represents a class of active antimetastatic agents with potential efficacy in the treatment of hormone-insensitive human prostatic cancer.

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The bone-specific estrogen centchroman inhibits osteoclastic bone resorption in vitro.

Hall TJ, Nyugen H, Schaueblin M, Fournier B.

Ciba-Geigy Ltd., Research Department, Basel, Switzerland.

There is considerable interest in identifying bone-specific estrogen-like compounds with beneficial activities on bone and the cardiovascular system, but lacking side effects on the reproductive system. Two such compounds are currently under clinical investigation -raloxifene (Lilly) and centchroman (Novo-Nordisk). There is evidence suggesting that 17 beta-estradiol can inhibit osteoclastic bone resorption although this is somewhat controversial. Therefore, we examined the effect of centchroman and raloxifene, as well as 17 beta-estradiol, in the in vitro bone slice assay, where the direct effect of compounds on osteoclast activity can be assessed. Centchroman (0.001 - 1 microM) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 microM (p = 0.007) with an IC50 = 0.1 microM, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17 beta-estradiol (0.0001 - 1 microM) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 microM, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 microM) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17 beta-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED50 approximately 1 mg/kg in animal models) is a potent inhibitor of osteoclastic bone resorption in vitro, suggesting that bone-specific estrogen-like molecules may have different mechanisms of action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7488162&dopt=Abstract raloxifene Evista



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Longitudinal and cross-sectional analysis of raloxifene effects on tibiae from ovariectomized aged rats.

Sato M, Kim J, Short LL, Slemenda CW, Bryant HU.

Department of Endocrine Research, Lilly Research Laboratories, Indianapolis, Indiana.

To extend and confirm previous data, we examined the effects of raloxifene on the proximal tibia of ovariectomized rats, aged 6 months, longitudinally and cross-sectionally by computed tomography (pQCT) and then compared the effects to those of orally dosed estrogen. Comparative analysis of phantoms and rat bones showed that the pQCT is precise and correlates with a Hologic QDR 1000W (DXA) with R = 0.999 but is capable of measuring significant differences between groups when the DXA cannot. This may reflect the ability of the pQCT to determine bone volume, mineral content (mg) and volumetric mineral density (mg/cm3), compared with two-dimensional analyses performed with DXA. Longitudinal analysis of the proximal tibia in vivo showed a significant 17% reduction in mineral density 31 days after ovariectomy. Examination of the images from ovariectomized rats showed a progressive increase in the cross-sectional area of the proximal tibiae, loss of trabecular bone, widening of marrow spaces and thinning of the cortical bone wall opposite the fibula. Regression analysis of the dose-dependent protective effects of raloxifene showed the half-maximal efficacy on tibiae mineral density to be ED50 = 0.4 mg/kg/day per os by pQCT and 0.2 mg/kg/day by DXA. By comparison, 17 alpha ethynyl estradiol showed dose-dependent effects with ED50 = 0.013 mg/kg/day per os by pQCT. Both raloxifene and ethynyl estradiol had beneficial effects on serum lipids, producing 50% reduction of cholesterol at 0.1 mg/kg/day raloxifene and 80% reduction with 0.01 mg/kg/day ethynyl estradiol. However, raloxifene up to 10 mg/kg/day had little effect on uterine weight, whereas 0.01 mg/kg/day ethynyl estradiol increased uterine wet weight by 300%.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7891341&dopt=Abstract raloxifene Evista



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Raloxifene preserves bone strength and bone mass in ovariectomized rats.

Turner CH, Sato M, Bryant HU.

Department of Ortopaedic Surgery, Indiana University Medical Center, Indianapolis 46202.

We investigated the effects of raloxifene, a nonsteroidal benzothiophene, on bone strength in ovariectomized rats and compared them with estrogen treatment. Sixty ovariectomized Sprague-Dawley rats were divided into three groups for treatment with orally dosed raloxifene (3 mg/kg), ethynyl estradiol (EE, 0.1 mg/kg), or vehicle. A fourth group of 20 rats that underwent sham ovariectomies and received vehicle was used for comparison. Treatments began 3 days after ovariectomy and continued for 6 months. Raloxifene treatment resulted in greater bone strength in the lumbar vertebrae (P < 0.05) and femoral neck (P < 0.01) and greater bone mineral density at the proximal tibia (P < 0.001) and lumbar vertebrae (P < 0.001) when compared with vehicle-treated ovariectomized animals. The positive effects on bone biomechanical properties from raloxifene treatment were not different than those associated with EE treatment. Raloxifene did not cause a significant increase in uterine weight, whereas EE treatment resulted in uterine weight increased 4-fold over vehicle-treated ovariectomized controls. Therefore, in rats, raloxifene has beneficial effects on bone biomechanics that are equivalent to those of EE treatment without substantial effects on the uterus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7956922&dopt=Abstract raloxifene Evista