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Raloxifene does not prevent fibrinogen oxidation in vitro.

Blasbichler M, Arakil-Aghajanian A, Sinzinger H.

Institute for Diagnosis and Treatment of Atherosclerosis and Lipid Disorders (ATHOS), Vienna, Austria.

Background: Modification of proteins may play a central role in a great variety of pathophysiological processes. It has already been ascertained that raloxifene (LY 139481), a selective estrogen receptor modulator (SERM), is an effective inhibitor of LDL oxidation. Therefore, we examined potential anti-oxidant activity related to the oxidation of the glycoprotein fibrinogen. Material/Methods: In this study we investigated whether raloxifene is able to inhibit<i> in vitro</i> iron-mediated oxidation of fibrinogen. We tested three different concentrations of raloxifene (5, 10, and 125 M) corresponding to the usual dosage in postmenopausal women of between 10 and 300 mg/day, choosing two incubation periods (60 and 120 min). Results: Our results in the examined dose-range provide no evidence that raloxifene is able to prevent iron-induced fibrinogen oxidation<i> in vitro</i>. Considering the chemical structure of the glycoprotein fibrinogen, it is likely that raloxifene is unable to attack a particle without lipophilic properties, although the site of its action on LDL is still unknown. Conclusions: Our data suggest that raloxifene, in contrast to its effect on LDL, lacks the capability to inhibit the oxidation of fibrinogen. The biological relevance of this finding still needs to be assessed in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15614199&dopt=Abstract raloxifene Evista



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Estradiol and raloxifene protect cultured SN4741 neurons against oxidative stress.

Biewenga E, Cabell L, Audesirk T.

Biology Department, University of Colorado at Denver, P.O. Box 173364, Denver, CO 80217-3364, USA.

A large body of research has documented neuroprotective effects of estrogen against oxidative stress. Some neurodegenerative diseases such as Parkinson's disease, in which oxidative stress has been implicated as a contributing factor, affect more males than females, suggesting a possible protective effect of estrogen. We used the clonal substantia nigra cell line SN4741 to compare the neuroprotective properties of estrogen and raloxifene against oxidative stress, and to determine whether raloxifene acted as an estrogen agonist or antagonist in this system. We pretreated SN4741 cultures with alpha-estradiol, beta-estradiol, and raloxifene, and exposed them to hydrogen peroxide. Low nanomolar levels of raloxifene, beta-estradiol, and alpha-estradiol all significantly reduced cell death caused by oxidative stress. The estrogen receptor (ER) antagonist ICI 182,780 failed to reverse the neuroprotection by beta-estradiol, suggesting that the effect is not mediated by a classical ER. Western blotting using an antibody to the C-terminus region of ER-alpha revealed two bands, one at approximately 67 kDa (corresponding to ER-alpha) and a more prominent band at approximately 55-56 kDa. These results suggest that, in this cell line, both raloxifene and estrogen may be acting via a non-classical estrogen receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15619539&dopt=Abstract raloxifene Evista



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Cost-effectiveness of raloxifene in the UK: an economic evaluation based on the MORE study.

Kanis JA, Borgstrom F, Johnell O, Oden A, Sykes D, Jonsson B.

WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK. w.j.Pontefract shef.ac.uk

Raloxifene treatment has been shown to reduce the risk of vertebral fractures and breast cancer in postmenopausal women. The long-term economic implications of treatment with raloxifene have not yet been investigated. The aim of this study was to assess the cost-effectiveness of treating postmenopausal women in the UK with raloxifene. A previously developed computer simulation model was used to estimate the cost-effectiveness of osteoporotic treatments with extra skeletal benefits. The model was populated with epidemiological data and cost data relevant for a UK female population. Data on the effect of treatment were taken from the Multiple Outcomes of Raloxifene (MORE) study, which recruited women with low bone mineral density or with a prior vertebral fracture. Cost-effectiveness was estimated using Quality Adjusted Life Years (QALYs) and life years gained as primary outcome measures. The cost per QALY gained of treating postmenopausal women without prior vertebral fractures was 18,000 pounds, 23,000 pounds , 18,000 pounds and 21,000 pounds at 50, 60, 70 and 80 years of age. Corresponding estimates for women with prior vertebral fractures were 10,000 pounds, 24,000 pounds, 18,000 pounds and 20,000 pounds. In relation to threshold values that are recommended in the UK, the analysis suggests that raloxifene is cost-effective in the treatment of postmenopausal women at an increased risk of vertebral fractures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15672210&dopt=Abstract raloxifene Evista



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Raloxifene improves bone mass in osteopenic women with primary biliary cirrhosis: results of a pilot study.

Levy C, Harnois DM, Angulo P, Jorgensen R, Lindor KD.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

BACKGROUND/AIMS: Bone disease is common in patients with primary biliary cirrhosis (PBC). Our aim was to evaluate safety and efficacy of raloxifene in this population. METHODS: Nine postmenopausal women with PBC were enrolled and seven completed the study. Subjects received raloxifene 60 mg daily for 1 year. Each patient on raloxifene was age-matched to three controls. Liver biochemistries were monitored periodically; bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) was measured at baseline and at 1 year. RESULTS: No significant adverse effects were reported. Liver biochemistries remained unchanged. Baseline LS-BMD was similar in the treatment group and controls [median 0.720 g/cm(2) (range 0.620-0.867) vs. 0.740 g/cm(2) (0.570-1.040), P=0.5]. CONCLUSION: Compared with baseline, LS-BMD improved significantly with 1 year of therapy [0.72 g/cm(2) (0.62-0.87) vs. 0.74 g/cm(2) (0.63-0.97), P=0.02]. FN-BMD remained stable [0.53 g/cm(2) (0.50-0.60) vs. 0.54 g/cm(2) (0.49-0.63), P=0.6]. Improvement in LS BMD was seen in patients on raloxifene but not in matched controls [0.02 g/cm(2) (0.01-0.10) vs. 0.00 g/cm(2) (-0.120-0.040), P=0.06)]. In conclusion, raloxifene appears safe and of benefit in preventing bone loss in patients with PBC. Larger studies with longer follow-up are warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15698408&dopt=Abstract raloxifene Evista



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Differential Effects of 17{beta}-Estradiol and Raloxifene on Vascular Smooth Muscle Cell Phenotype and Expression of Osteoblast-Associated Proteins.

Rzewuska-Lech E, Jayachandran M, Fitzpatrick LA, Miller VM.

Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.

Several studies demonstrate an association between osteoporosis and arterial calcific disease both of which being common in elderly women. Estradiol and raloxifene, a selective estrogen receptor modulator, prevent bone loss in post-menopausal women. Little is known regarding how these agents affect arterial calcification. The aim of this study was to determine whether or not 17beta-estradiol and raloxifene reduced vascular smooth muscle cell differentiation and expression of bone-associated proteins during phosphate-induced calcification in vitro. Aortic smooth muscle cells (VSMC) were cultured from adult gonadally intact and ovariectomized (OVX) female pigs. Calcifying media was added and cells were treated with solvent (control), 17beta-estradiol (E2) or raloxifene. Extent of calcification and phenotypic expression of bone-associated proteins [matrix gla protein (MGP), osteoprotegerin (OPG) and bone sialoprotein (BSP)] were examined at three-day intervals over two weeks. Calcium content increased in all groups but was greater in VSMC derived from intact compared to OVX animals. E2 reduced calcification and preserved a contractile phenotype. Expression of OPG significantly decreased with time; this decrease was significantly greater in VSMC derived from OVX compared to gonadally intact pigs. E2 and raloxifene preserved expression of OPG only in VSMC from intact pigs. Expression of MGP increased significantly with time and was not affected by E2 or raloxifene treatments. E2 treatment significantly inhibited synthesis of BSP in cells from both groups. In conclusion, 17beta-estradiol slows differentiation of VSMCs induced by excess phosphate. Effectiveness of raloxifene to preserve expression of bone cell-associated proteins depends upon the hormonal status of the tissue donor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15713688&dopt=Abstract raloxifene Evista



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Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx.

Leung FP, Yao X, Lau CW, Ko WH, Lu L, Huang Y.

Department of Physiology, Chinese University of Hong Kong, Hong Kong, Hong Kong.

Raloxifene may confer vascular benefits without causing estrogen-related side effects. However, its action on renal vascular circulation is unknown. This study aimed to examine the sex difference and roles of endothelium and Ca(2+) channels in the rat renovascular relaxation to raloxifene. On isolated intralobar renal artery rings mounted in a myograph and contracted by U46619, concentration-relaxation curves were constructed for raloxifene and contractions to CaCl2 were studied. Changes in intracellular Ca(2+) levels ([Ca(2+)]i) of vascular smooth muscle (VSM) were measured by Fura-2 fluorescence. Raloxifene or 17beta-estradiol was equally effective in relaxing renal artery from both sexes with raloxifene being more potent than 17beta-estradiol. Endothelial denudation did not affect raloxifene-or 17beta-estradiol-induced relaxation. N(G)-nitro-L-arginine methyl ester, charybdotoxin plus apamin, indomethacin, or ICI 182,780 did not modify the effect of raloxifene. Raloxifene caused similar relaxations in rings contracted by U46619 and high K(+). Nifedipine attenuated the potency of raloxifene. Raloxifene reduced CaCl2-induced contractions. 80 mM K(+) stimulated an increase in VSM [Ca(2+)]i and raloxifene attenuated this effect. Raloxifene-induced reduction in contraction and increase in VSM [Ca(2+)]i was insensitive to ICI 182,780. In summary, raloxifene causes relaxation in rat renal arteries; this effect is independent of a functional endothelium and is not mediated by ICI 182,780-sensitive estrogen receptors. Raloxifene inhibited both contractions and VSM [Ca(2+)]i in response to CaCl2, indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca(2+) influx via Ca(2+) channels. There is little sex difference in raloxifene-induced relaxation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15713909&dopt=Abstract raloxifene Evista