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LIV-3D-QSAR model for estrogen receptor ligands.

Da Cunha EF, Martins RC, Albuquerque MG, De Alencastro RB.

CCMN, Laboratorio de Modelagem Molecular (LabMMol), Departamento de Quimica Organica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Centro de Tecnologia, Bloco A, 6o andar, Sala 609, Ilha do Fundao, Cidade Universitaria, 21949-900, Rio de Janeiro, RJ, Brazil.

We have employed the Local Intersection Volume (LIV), a three-dimensional (3D) local shape descriptor, to study quantitative structure-activity relationships (QSAR) of 2-arylbenzothiophene analogs of raloxifene (1), a selective estrogen-receptor modulator (SERM), using the raloxifene bound conformation (PDB code: 1ERR) to build the structures of all ligands. The best LIV-3D-QSAR model obtained by a combined GA-PLS optimization,MODEL 1, was derived from RMS three-atom alignment using a training set of 44 compounds. The fit of the pIC(50) values, expressed by the squared correlation coefficient, R(2), was 0.78. After LOO-cv, a predictive squared correlation coefficient, Q(2), of 0.63 was obtained.MODEL 1 has three LIVs (1091, 1554, and 1654) with positive coefficients and three LIVs (597, 1463, and 1655) with negative coefficients. Four descriptors (LIVs) show excellent correspondence with pharmacophoric groups of the raloxifene series of compounds in accordance with SAR studies. Most interesting is the result of the prediction for 14 compounds (test set) used for external validation. The results provide the tools for predicting the pIC(50) values of related compounds and for the design and synthesis of new ER ligands.FIGURE LIV-3D-QSARMODEL 1 obtained using a series of raloxifene (1) analogs

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15290320&dopt=Abstract raloxifene Evista



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Safety profile of raloxifene as used in general practice in England: results of a prescription-event monitoring study.

Layton D, Clarke A, Wilton LV, Shakir SA.

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK.

Raloxifene, a selective estrogen receptor modulator (SERM) licensed for the prevention of non-traumatic vertebral fractures in postmenopausal women at increased risk of osteoporosis, was launched in the UK in August 1998. The aim of the study was to monitor the safety of raloxifene prescribed in the primary care setting in England using prescription-event monitoring (PEM). Patients were identified by means of prescription data supplied by the Prescription Pricing Authority between September 1998 and November 2000. Demographic and clinical event data were collected from questionnaires posted to primary care physicians (GPs) at least 6 months after the date of the first prescription for each patient. Information on medical events, suspected adverse drug reactions (ADRs), reasons for stopping treatment, pregnancies, and causes of death was requested. Event rates [Incidence Densities (IDs): no. first reports /1000 patient-months of treatment] were calculated. Differences between IDs for events reported in month one (ID(1)) and months 2-6 (ID(2-6)) of treatment were examined. The cohort comprised 13,987 patients [median age 62 years (IQR 55,69); 99.8% female]. The major indication was osteoporosis (40.9%, n=5725). Flushing was the event with the highest ID in month 1 (22.8), reported most frequently by GPs as an ADR to raloxifene (67/461 reports) and as the reason for stopping (700/4592 reports). Events associated with starting treatment included flushing, malaise/lassitude, headache/migraine, nausea/vomiting, sweating, cramp, pain abdomen, dizziness, diarrhea, mastalgia and vaginal hemorrhage. Less common events reported during treatment included deep vein thrombosis ( n=13), pulmonary embolism ( n=13), thrombophlebitis ( n=31) and visual disturbance ( n=29). In this study, there were 122 (0.9%) confirmed deaths, of which 32 causes of death were unknown. This study shows that raloxifene is generally well tolerated when used in general practice in England. Potential signals of unrecognised ADRs requiring further evaluation included gastrointestinal adverse symptoms and vaginal hemorrhage. There were also a small number of reports of events associated with venous thromboembolism and visual disorders that require further investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15309382&dopt=Abstract raloxifene Evista



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Tamoxifen and the Rafoxifene analog LY117018: their effects on arachidonic acid release from cells in culture and on prostaglandin I2 production by rat liver cells.

Levine L.

Department of Biochemistry, Brandeis University Waltham, MA 02454, USA. llevine brandeis.edu

BACKGROUND: Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention. METHODS: Rat liver, rat glial, human colon carcinoma and human breast carcinoma cells were labelled with [3H] arachidonic acid. The release of the radiolabel from these cells during incubation with tamoxifen and the raloxifene analog LY117018 was measured. The prostaglandin I2 produced during incubation of the rat liver cells with microM concentrations of tamoxifen and the raloxifene analog was quantitatively estimated. RESULTS: Tamoxifen is about 5 times more effective than LY117018 at releasing arachidonic acid from all the cells tested. In rat liver cells only tamoxifen stimulates basal prostaglandin I2 production and that induced by lactacystin and 12-O-tetradecanoyl-phorbol-13-acetate. LY117018, however, blocks the tamoxifen stimulated prostaglandin production. The stimulated prostaglandin I2 production is rapid and not affected either by preincubation of the cells with actinomycin or by incubation with the estrogen antagonist ICI-182,780. CONCLUSIONS: Tamoxifen and the raloxifene analog, LY117018, may prevent estrogen-independent as well as estrogen-dependent breast cancer by stimulating phospholipase activity and initiating arachidonic acid release. The release of arachidonic acid and/or molecular reactions that accompany that release may initiate pathways that prevent tumor growth. Oxygenation of the intracellularly released arachidonic acid and its metabolic products may mediate some of the pharmacological actions of tamoxifen and raloxifene.

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Comparison of raloxifene and atorvastatin effects on serum lipids composition of healthy post-menopausal women.

Piperi C, Kalofoutis C, Lagogianni I, Troupis G, Kalofoutis A.

Department of Biological Chemistry, School of Medicine, University of Athens, Athens, Greece.

The aim of this study was to evaluate the effects of the selective oestrogen receptor modulator, raloxifene, and those of statin, atorvastatin, in reducing the cardiovascular risks associated with the post-menopausal status. A detailed study of serum lipid concentrations was performed in four groups of post-menopausal women receiving either placebo, raloxifene or atorvastatin alone or their combination for the period of three months. Group A (raloxifene) showed significant decrease in total cholesterol levels (P < 0.05) and an increase in phospholipids concentration (P < 0.05), followed by a marked reduction in low-density lipoprotein cholesterol (LDL-C) levels (P < 0.01) and ApoB amounts (P < 0.001). Additionally, ApoA-I concentration was significantly increased (P < 0.01). Group B (atorvastatin) presented decreased cholesterol (P < 0.05) and triglycerides levels (P < 0.01), followed by elevated high-density lipoprotein cholesterol (HDL-C) concentration (P < 0.05) and low LDL-C amounts (P < 0.001). ApoA-I was significantly increased (P < 0.001) whereas ApoB was reduced (P < 0.001). The combined treatment in Group C (raloxifene and atorvastatin) showed significant changes in the majority of serum lipids. In particular, total cholesterol was reduced (P < 0.001), as well as triglycerides (P < 0.001) levels. Phospholipids were raised (P < 0.01) whereas LDL-C was reduced (P < 0.001) as was ApoB (P < 0.001). Furthermore, ApoA-I was elevated (P < 0.001). A further attempt to evaluate each treatment group was performed and the significance of these results is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15362487&dopt=Abstract raloxifene Evista



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In vivo properties of the urinary bladder wall and their modulation by estradiol and raloxifene in a rat model.

Schultens A, Becker T, Balmer D, Seidlova-Wuttke D, Wuttke W.

Department of Clinical and Experimental Endocrinology, University of Goettingen, Germany.

OBJECTIVES: Urinary incontinence is a common symptom of urogenital aging that affects a considerable proportion of postmenopausal women. Morphological and morphometrical modulation of the bladder by estrogen are known. Yet data showing that this translates into changes of in vivo function of the urinary bladder are missing. METHODS: We measured urodynamic parameters in anaesthetized, surviving rats. Following ovariectomy animals were divided into three groups and fed either an estradiol-, raloxifene-, or unsupplemented soy-free formula for ten weeks. Via a transurethral catheter the intravesical pressure was recorded during a stretch period (the urinary bladder was filled), and a one-minute isometric accommodation period immediately after the filling period. Upon termination of the experiment upper and lower halves of the bladder were processed histologically. RESULTS: The estrogen-, and raloxifene-treated animals showed significantly higher pressures in responses to rapid stretch. Bladder compliance during the isometric period on the other hand was not significantly affected by these treatments. Thickness of the epithelial layer, collagen content and muscle bundles were significantly increased by estrogen and raloxifene treatment. CONCLUSIONS: This is a good animal model to investigate modulation of detrusor muscle contractility and stiffness. Both estradiol and raloxifene increase bladder contractility. Urinary bladder morphology indicates that estrogen acts primarily in the upper half of this organ since significant effects on collagen content and muscle fibers are only found in this part.

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Treatment with raloxifene for 2 years increases vertebral bone mineral density as measured by volumetric quantitative computed tomography.

Genant HK, Lang T, Fuerst T, Pinette KV, Zhou C, Thiebaud D, Diez-Perez A.

Department of Radiology, University of California, San Francisco, CA 94143-0628, USA. harry.genant oarg.ucsf.edu

Volumetric quantitative computed tomography (vQCT), using multiple thin-slice acquisition, measures three-dimensional volumetric bone mineral density (BMD, mg/cm3). vQCT is often used to measure BMD of lumbar vertebrae and may detect early changes in trabecular, cortical, or integral BMD that extend beyond the technical limits of areal dual X-ray absorptiometry (DXA) BMD measurements. The objective of this study was to determine the effect of 2 years of raloxifene (RLX) treatment on several volumetric BMD measures in a subset of postmenopausal women (n=58) enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Patients in this study were randomized to one of three treatment groups: placebo (n=21), RLX 60 mg/day (n=17), or RLX 120 mg/day (n=20), and all patients received daily calcium (500 mg) and vitamin D (400-600 IU) supplementation. Data from the raloxifene treatment groups were pooled for each analysis. Following 2 years of raloxifene treatment, there was a significant percent change from baseline in the vQCT regions of interest (ROIs) of midintegral BMD, total trabecular BMD, and total integral BMD (P<0.05) compared to placebo, while there was no significant change in the spinal DXA BMD measurement. These data provide the first longitudinal assessment by vQCT of changes in vertebral bone density after 2 years of treatment with raloxifene. vQCT appears to be a valuable technique for measuring the effects of raloxifene treatment in this population of postmenopausal women with osteoporosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15542042&dopt=Abstract raloxifene Evista