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Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.

Lawrence SE, Faught KA, Vethamuthu J, Lawson ML.

Department of Pediatrics, University of Ottawa, Ontario, Canada. slawrence cheo.on.ca

OBJECTIVES: To assess the efficacy of the anti-estrogens tamoxifen and raloxifen in the medical management of persistent pubertal gynecomastia. STUDY DESIGN: Retrospective chart review of 38 consecutive patients with persistent pubertal gynecomastia who presented to a pediatric endocrinology clinic. Patients received reassurance alone or a 3- to 9-month course of an estrogen receptor modifier (tamoxifen or raloxifene). RESULTS: Mean (SD) age of treated subjects was 14.6 (1.5) years with gynecomastia duration of 28.3 (16.4) months. Mean reduction in breast nodule diameter was 2.1 cm (95% CI 1.7, 2.7, P <.0001) after treatment with tamoxifen and 2.5 cm (95% CI 1.7, 3.3, P <.0001) with raloxifene. Some improvement was seen in 86% of patients receiving tamoxifen and in 91% receiving raloxifene, but a greater proportion had a significant decrease (>50%) with raloxifene (86%) than tamoxifen (41%). No side effects were seen in any patients. CONCLUSION: Inhibition of estrogen receptor action in the breast appears to be safe and effective in reducing persistent pubertal gynecomastia, with a better response to raloxifene than to tamoxifen. Further study is required to determine that this is truly a treatment effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15238910&dopt=Abstract raloxifene Evista



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Raloxifene lowers ischaemia susceptibility by increasing nitric oxide generation in the heart of ovariectomized rats in vivo.

Nemcsik J, Morschl E, Egresits J, Kordas K, Laszlo F, Laszlo FA, Pavo I.

Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.

We studied the effects of a 2-week period of oral raloxifene therapy on the cardiac level of nitric oxide (NO) and on the susceptibility to angina in ovariectomized rats. Ovariectomy decreased the activity of Ca2+-dependent nitric oxide synthase (NOS) in the left ventricle, an effect restored by raloxifene (0.2-5 mg kg(-1) day(-1)) or 17beta-oestradiol (0.3 mg kg(-1) day(-1)). Ovariectomy led to a significant ST segment depression after the injection of (1) ornithine-vasopressin (0.5 IU kg(-1), i.v.) or (2) epinephrine (10 microg kg(-1), i.v.), followed 30 s later by phentolamine (15 mg kg(-1), i.v.); both effects were reversed by raloxifene or 17beta-oestradiol treatment. Inhibition of nitric oxide synthase (with NG-nitro-L-arginine methyl ester [L-NAME]; 5 mg kg(-1), s.c.) augmented the ST segment depression in the ovariectomized rat and abolished the anti-ischaemic effect of 17beta-oestradiol or raloxifene. Thus, an oestrogen deficiency down-regulates the cardiac constitutive nitric oxide synthase, which increases the susceptibility of the heart to ishaemia because both actions can be blocked by exogenous administration of the natural oestrogen 17beta-oestradiol or the selective oestrogen-receptor modulator (SERM) raloxifene. In the present in vivo system, raloxifene exerts oestrogen-agonist properties.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15249168&dopt=Abstract raloxifene Evista



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Oxidation of raloxifene to quinoids: potential toxic pathways via a diquinone methide and o-quinones.

Yu L, Liu H, Li W, Zhang F, Luckie C, van Breemen RB, Thatcher GR, Bolton JL.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, M/C 781, Chicago, Illinois 60612-7231, USA.

Raloxifene was approved in 1997 by the FDA for the treatment of osteoporosis in postmenopausal women, and it is currently in clinical trials for the chemoprevention of breast cancer. Before widespread use as a chemopreventive agent in healthy women, the potential cytotoxic mechanisms of raloxifene should be investigated. In the current study, raloxifene was incubated with GSH and either rat or human liver microsomes, and the metabolites and GSH conjugates were characterized using liquid chromatography-tandem mass spectrometry. Raloxifene was converted to raloxifene diquinone methide GSH conjugates, raloxifene o-quinone GSH conjugates, and raloxifene catechols. For comparison, three raloxifene catechols were synthesized and characterized. In particular, 7-hydroxyraloxifene was found to oxidize to the 6,7-o-quinone. As compared with raloxifene diquinone methide, which has a half-life of less than 1 s in phosphate buffer, the half-life of raloxifene 6,7-o-quinone was much longer at t(1/2) = 69 +/- 2.5 min. The stability offered by raloxifene 6,7-o-quinone implies that it may be more toxic than raloxifene diquinone methide. Cytotoxicity studies in the human breast cancer cell lines S30 and MDA-MB-231 showed that 7-hydroxyraloxifene was more toxic than raloxifene in both cell lines. These results suggest that raloxifene could be metabolized to electrophilic and redox active quinoids, which have the potential to cause toxicity in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15257612&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.

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 pound 18,000, pound 23,000, pound 18,000 and pound 21,000 at 50, 60, 70 and 80 years of age. Corresponding estimates for women with prior vertebral fractures were pound 10,000, pound 24,000, pound 18,000 and pound 20,000. 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=15278244&dopt=Abstract raloxifene Evista



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Effect of raloxifene and its interaction with human PTH on bone formation.

Lin Y, Liu LJ, Murray T, Sodek J, Rao L.

Calcium Research Lab, St. Michael Hospital, Toronto, Ontario, Canada.

We studied the of effects raloxifene alone or in combination with human PTH (hPTH) 1-34 in mineralizing cultures of SaOS-2 cells. Raloxifene (10(-8)-10(-6) M) increased bone nodule formation in cultures of SaOS-2 cells when added intermittently from day 8 to day 17. A single 24-h treatment with 10(-8) M hPTH (1-34) at day 8 reduced the nodule area by 75.6% at day 17, and raloxifene added concomitantly with hPTH (1-34) reduced this inhibitory effect in a dose-dependent manner. Raloxifene also reduced the hPTH (1-34)-induced inhibition of alkaline phosphatase (ALP) activity. The 10-fold stimulation of c-fos mRNA expression by hPTH (1-34) was not influenced by raloxifene co-treatment. The protein kinase A (PKA) inhibitor 6-22 amide (1.7 nM) and the protein kinase C (PKC) inhibitor-bisindolylmaleimide 1 (10 nM) did not influence the separate effects of PTH and raloxifene on mineralized bone nodule formation. This is the first report on the interaction of PTH and raloxifene in an osteoblast culture system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15279072&dopt=Abstract raloxifene Evista



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Differential effects of raloxifene and tamoxifen on the expression of estrogen receptors and antigen Ki-67 in human endometrial adenocarcinoma cell line.

Koda M, Jarzabek K, Haczynski J, Knapp P, Sulkowski S, Wolczynski S.

Department of Pathology, Medical University of Bialystok, Waszyngtona 13, 15-269 Bialystok, Poland.

Tamoxifen and raloxifene are widely used in clinical practice. It has been found that tamoxifen treatment increases the risk of development of endometrial cancer. The effects of tamoxifen and raloxifene on endometrium might be caused by different estrogen receptor expression. The aim of the present study was immunohistochemical evaluation of the effects of tamoxifen and raloxifene on estrogen receptors, and Ki-67 antigen expression in the human endometrial adenocarcinoma Ishikawa cell line. Tamoxifen in concentrations of 10 microM and 20 microM increased ERalpha expression without any effect on ERbeta. All used concentrations of tamoxifen and raloxifene (0.1 nM, 1 nM, 10 nM, 1 micro M, 10 microM and 20 microM) had no effect on expression of ERbeta. Tamoxifen, but not raloxifene, increased Ki-67 antigen expression in the Ishikawa cell line. Tamoxifen, in contrast to raloxifene, increased proliferation of endometrial adenocarcinoma cells as well as exerted the shift of ERalpha/ERbeta ratio. Thus, it could be responsible for increased carcinogenic effect during tamoxifen treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15289830&dopt=Abstract raloxifene Evista