Evista
Assessment of maintenance therapy with reduced doses of PTH(1-34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariectomized rat.

Hodsman AB, Watson PH, Drost D, Holdsworth D, Thornton M, Hock J, Bryant H, Fraher LJ.

Department of Medicine, Lawson Research Institute, University of Western Ontario, London, Canada. anthonyh stj.stjosephs.london.on.ca

This experiment was designed to evaluate the ability of a raloxifene analogue (RA), LY117018, with or without reduced dosing of human parathyroid hormone (hPTH)(1-34) to maintain gains in bone mass after a fully anabolic treatment regimen given to aging osteopenic rats. Six-month-old rats were ovariectomized (ovx) or sham-operated (sham). After 1 month, ovx rats were treated with an anabolic regimen consisting of subcutaneous hPTH(1-34) 80 microg/kg/day and oral raloxifene 3 mg/kg/day, each given 5 days/week for 3 months. Thereafter, the treated ovx rats went on to an 8 week maintenance phase of treatment with either RA alone at the same dose, hPTH(1-34) at a reduced dosing interval (twice a week), or a combination of the two. Bone mineral density (BMD) was measured ex vivo at four skeletal sites, lumbar spine (L2-4), proximal hemipelvis, whole femur, and tibia, by dual-energy X-ray densitometry. All four sites showed a similar pattern of response. After the 3 month anabolic phase, the sham group had significantly higher BMD values than ovx rats at all skeletal sites (p < or = 0.002). The ovx rats treated with PTH + RA during the anabolic phase of the protocol had significantly higher BMD than the sham group in the femur, tibia, and spine (p < or = 0.02) and higher but not significantly different values in the pelvis. Following the 2 month maintenance phase, comparisons were made with the PTH-RA group at the end of the anabolic phase. Decrements in BMD were seen in all three maintenance therapy groups, but they were not statistically significant in the RA plus reduced PTH dose group. However, reduced hPTH(1-34) dosing and RA alone resulted in significant reductions of bone mass measurements at several skeletal sites during the maintenance phase. We conclude that the raloxifene analogue LY117018 may be useful in maintaining bone mass in aging ovx rats following anabolic therapy with hPTH(1-34) and raloxifene analogue, but that this strategy only allows for dose reduction of hPTH(1-34) rather than its discontinuation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10321904&dopt=Abstract raloxifene Evista



Evista
Uterotrophic effects of tamoxifen, toremifene, and raloxifene do not predict endometrial cell proliferation in the ovariectomized CD1 mouse.

Carthew P, Edwards RE, Nolan BM.

MRC Toxicology Unit, University of Leicester, Leicester, LE1 9HN, United Kingdom.

The uterotrophic responses of ovariectomized CD1 mice to tamoxifen, toremifene, and raloxifene have been compared to 17beta-estradiol after a treatment period of 72 h. Uterine and vaginal weight, luminal epithelial thickening, and 5-bromodeoxyuridine (BrdU) labeling index in the endometrial stroma were examined. All three pharmaceuticals, as well as 17beta-estradiol, produced increases in the classic estrogen-dependent variables of uterine and vaginal weights after the 3-day treatment period. Tamoxifen, toremifene, raloxifene, and estradiol all increased luminal epithelial thickness, and increased the BrdU labeling index in the endometrial stroma of the uterus. Although the dose response for the uterotrophic effect and the vaginal weight increases for toremifene differed from tamoxifen and raloxifene, in that there was no dose at which these effects were maximal, the stimulation of BrdU labeling index in the endometrial stroma was dose dependent and very similar for all three, at the clinically relevant doses. Treatment-related hypertrophic effects were estimated by examination of the nuclear profile density in the endometrial stroma. Estradiol and tamoxifen caused a greater hypertrophic effect than toremifene and raloxifene, indicating that factors other than an increase in cell number contribute to the overall uterotrophic effect. This demonstrates that the use of uterine weight to estimate the relative estrogenicity of drugs could give a misleading impression of the response of the uterus to estrogen agonists. Variables, such as increased DNA replication, which may be more important to a subsequent potential carcinogenic process in the uterus, for a particular drug, requires separate evaluation. Copyright 1999 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10387929&dopt=Abstract raloxifene Evista



Evista
Questions about Tamoxifen and the Future Use of Antiestrogens.

Yao K, Jordan VC.

Department of Surgery and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, 60611, USA.

Tamoxifen is the most widely prescribed anticancer drug in the world. It not only improves overall survival and decreases recurrence from breast cancer, but has beneficial effects on bone density and lipid profiles. Unfortunately, tamoxifen carries disadvantages such as unpleasant side effects and a questionable connection to endometrial carcinoma. However, after intense debate, the general consensus among the medical community is that the benefits of tamoxifen far outweigh the risks. Nonetheless, resistance to tamoxifen has been seen both in the clinic and in the laboratory prompting investigators to look for new antiestrogens in the treatment and prevention of breast cancer. We report on three agents: toremifene (Fareston&reg;), ICI 182, 780 (Faslodex&reg;), and raloxifene (Evista&reg;). Unfortunately, clinical studies comparing tamoxifen and toremifene in the treatment of breast cancer have not shown a clear advantage of toremifene over tamoxifen. ICI 182, 780 is a "pure antiestrogen" that carries a low incidence of side effects and may hold promise as an effective agent for patients who have failed tamoxifen therapy or even as primary adjuvant therapy. Raloxifene displays beneficial bone and cardiovascular effects without uterine stimulation. It is being used as an agent to prevent osteoporosis and holds promise as an agent for advanced breast cancer. We hope that these new antiestrogens will revolutionize the way we treat breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10388091&dopt=Abstract raloxifene Evista



Evista
Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women.

Col NF, Pauker SG, Goldberg RJ, Eckman MH, Orr RK, Ross EM, Wong JB.

Department of Medicine, Tupper Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Mass 02111, USA.

BACKGROUND: Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions. OBJECTIVE: To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile. METHODS: We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects. RESULTS: Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer. CONCLUSION: Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10399897&dopt=Abstract raloxifene Evista



Evista
Effect of raloxifene, 17beta-estradiol, and progesterone on mRNA for vascular endothelial growth factor isoforms 121 and 165 and thrombospondin-1 in Ishikawa cells.

Navarro FJ, Mirkin S, Archer DF.

The Clinical Research Center, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA.

OBJECTIVE: To compare the mRNA expression of vascular endothelial growth factor (VEGF) 121 and 165 isoforms and thrombospondin-1 (TSP-1) after raloxifene, 17beta-E(2), and P administration in cultured Ishikawa cells. DESIGN: Prospective basic research study. SETTING: Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia. PATIENT(S): None. INTERVENTION(S): Ishikawa cells were cultured in vitro. Raloxifene, 17beta-E(2), and P at concentrations of 0.01, 0.1, and 1.0 microM were added to confluent cells. MAIN OUTCOME MEASURES: The VEGF 121 and 165 isoforms and TSP-1 mRNA expression from treated Ishikawa cells were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULT(S): 17beta-Estradiol increased both VEGF 121 and 165 mRNA compared to control. Raloxifene did not increase either VEGF 121 or 165 mRNA above control values. Progesterone at all concentrations did not increase VEGF 121 isoform mRNA, whereas VEGF 165 isoform was minimally increased by P at the lowest concentration. Progesterone and raloxifene increased TSP-1 mRNA expression. 17beta-Estradiol did not stimulate TSP-1 mRNA expression at any concentration. CONCLUSION(S): Raloxifene did not stimulate VEGF 121 and 165, whereas it increased TSP-1 mRNA synthesis in Ishikawa cells. Our hypothesis is that raloxifene's lack of endometrial stimulation may be partly mediated by an antiangiogenic effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12798890&dopt=Abstract raloxifene Evista



Evista
Raloxifene acutely relaxes rabbit coronary arteries in vitro by an estrogen receptor-dependent and nitric oxide-dependent mechanism.

Figtree GA, Lu Y, Webb CM, Collins P.

Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, UK.

BACKGROUND: Selective estrogen receptor modulators (SERMs) have been defined as compounds that display tissue specificity with regard to estrogenic effects. They appear to share the beneficial effects of estrogen on bone and lipids but are not associated with an increased risk of breast or uterine carcinoma. Estrogen relaxes coronary arteries and has long-term protective effects on the vascular system. The effect of SERMs on the coronary vasculature is unknown. We therefore investigated the effects of the SERM raloxifene on isolated rabbit coronary arteries. METHODS AND RESULTS: Rings of coronary artery from adult male and nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension was then measured. Raloxifene induced coronary arterial relaxation in male and female coronary arteries by an endothelium-dependent and estrogen receptor-dependent mechanism involving nitric oxide. Raloxifene also had a direct calcium antagonistic effect on the coronary myocyte. Estrogen, however, induced only endothelium-independent coronary arterial relaxation. The endothelium-dependent component of relaxation induced by raloxifene 10(-6) mol/L resulted in almost 100% (79+/-7% versus 43+/-3%, P<0.001) more relaxation than that induced by estrogen 10(-6) mol/L. CONCLUSIONS: These data demonstrate that raloxifene has vascular relaxing properties. The surprising finding is that the receptor-dependent effects via the endothelium are observed in coronary arteries from both male and female animals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10477535&dopt=Abstract raloxifene Evista