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Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes.

Ardans JA, Blum A, Mangan PR, Wientroub S, Cannon RO 3rd, Wahl LM.

Immunopathology Section, National Institute of Dental and Craniofacial Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes, may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 micromol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MMP-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E(2)-independent mechanism. Additionally, compared with monocytes acquired during the placebo phase, peripheral blood monocytes from 5 of 6 healthy postmenopausal women treated with raloxifene (60 mg daily for 1 month) in a clinical trial produced significantly higher levels of MMP-1 when the monocytes were activated with LPS. Furthermore, serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 production compared with that from serum obtained during the placebo phase. In summary, raloxifene increases the production of MMP-1 in activated monocytes; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11498451&dopt=Abstract raloxifene Evista



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Raloxifene: new preparation. Not better than oestrogen.

[No authors listed]

(1) Raloxifene is marketed in France for the prevention of non traumatic vertebral fracture in postmenopausal women. In animal pharmacology studies it was found to both agonise and antagonise oestrogen. (2) The assessment file is methodologically sound but fails to answer a good number of practical questions. (3) A placebo-controlled trial showed that raloxifene reduced the risk of vertebral collapse after two years of treatment, in both the primary and secondary prevention settings, but no effect was demonstrated on non vertebral fractures. Furthermore, raloxifene reduced the risk of breast cancer in this trial. (4) Two trials versus combined hormone replacement therapy showed a more favourable effect of the latter on surrogate end points reflecting the risk of fracture and the cardiovascular risk (changes in bone mineral density and lipid profile). (5) Compared with combined hormone replacement therapy, raloxifene reduced the incidence of menorrhagia and mastodynia, but did not relieve symptoms linked to the menopause. (6) The results of animal studies call for close clinical monitoring to detect a possible increase in the incidence of ovarian cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11503811&dopt=Abstract raloxifene Evista



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Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen.

Kayser J, Ettinger B, Pressman A.

Division of Research, Kaiser Permanente Medical Care Program, Oakland, California 94611, USA.

OBJECTIVE: To determine possible differences in continuation among women initiating treatment with the selective estrogen receptor modulator raloxifene, versus those initiating treatment with estrogen-containing regimens. DESIGN: A pharmacy prescription database search for refill patterns. The study subjects were members of Kaiser Foundation Health Plan, a large health maintenance organization; 1,394 women age >or=60 years who filled index prescriptions for either raloxifene (n = 331) or systemic estrogens (n = 1,063) between April 1998 and March 1999. The main outcome measure was discontinuation based on prescription refill patterns through December 2000. RESULTS: At 24 months, the probabilities of discontinuing were 56% for women starting raloxifene compared to 72% for women starting estrogens. The likelihood of discontinuation was significantly less among women starting raloxifene than among those starting estrogen (hazard ratio = 0.75; 95% confidence interval = 0.64-0.88). Adjustments for age and prescriber specialty did not affect the risk. CONCLUSIONS: We conclude that discontinuation of estrogen by women well beyond the age of menopause is high; more than two-thirds discontinue within 2 years of starting. Women starting therapy with raloxifene are 25% percent less likely to discontinue their medication than those starting estrogen, providing some promise that long-term benefits of raloxifene may be more easily achieved than those of estrogen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11528358&dopt=Abstract raloxifene Evista



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Transcriptional activities of estrogen receptor alpha and beta in yeast properties of raloxifene.

Jisa E, Dornstauder E, Ogawa S, Inoue S, Muramatsu M, Jungbauer A.

Institute of Applied Microbiology, University of Agricultural Sciences, Vienna, Austria.

Raloxifene represents a potent compound for the prevention and treatment of osteoporosis and cardiovascular disease in postmenopausal women. Raloxifene exhibits targeted antiestrogenicity in breast and uterus, but acts as an agonist in bone and liver. This synthetic selective estrogen receptor modulator binds both estrogen receptors alpha and beta. The molecular mechanisms by which raloxifene exerts agonistic or antagonistic activity are still not resolved. Therefore, the binding behavior of raloxifene to estrogen receptors and its effects on DNA binding and transactivation were studied. The equilibrium binding affinity of raloxifene by displacing radiolabeled 17beta-estradiol exhibited a similar affinity behavior to that of its natural ligand. Using BIACORE technology with an immobilized estrogen response element, we showed that 17beta-estradiol and raloxifene increased the binding of estrogen receptor alpha to the DNA, suggesting a ligand-dependent dimerization. The influence of the ligands to the binding of estrogen receptor beta was lower. We may conclude that unliganded estrogen receptor alpha binds as a monomer whereas in the presence of 10(-8) M 17beta-estradiol or higher, homodimers are formed that interact with the estrogen response element. Transactivation studies in a yeast reporter system in a ligand-dependent manner resulted in a similar potency of raloxifene to estrogen receptor beta compared to the control testosterone. Subeffective doses of raloxifene combined with 17beta-estradiol did not shift the efficiency, whereas saturating concentrations of 17beta-estradiol combined with increasing concentrations of raloxifene altered the response induced by 17beta-estradiol. In this pure system, the antagonistic activity of raloxifene could not be detected as was expected by the results from ligand competition analysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11543731&dopt=Abstract raloxifene Evista



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Design and methods of the Raloxifene Use for The Heart (RUTH) study.

Mosca L, Barrett-Connor E, Wenger NK, Collins P, Grady D, Kornitzer M, Moscarelli E, Paul S, Wright TJ, Helterbrand JD, Anderson PW.

Preventive Cardiology, New York Presbyterian Hospital, Columbia University, New York, New York 10032, USA. ljm10 columbia.edu

Raloxifene is a selective estrogen receptor modulator that lowers total and low-density lipoprotein (LDL) cholesterol, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. The Raloxifene Use for The Heart (RUTH) trial is designed to determine whether raloxifene 60 mg/day compared with placebo: (1) lowers the risk of the coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI); and (2) reduces the risk of invasive breast cancer in women at risk for a major coronary event. RUTH is a double-blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women aged > or =55 years from 26 countries. Women are eligible for randomization if they are postmenopausal and have documented coronary heart disease (CHD), peripheral arterial disease, or multiple risk factors for CHD. Use of estrogen within the previous 6 months is an exclusion factor. The study will be terminated after a minimum of 1,670 participants experience a primary coronary end point. Secondary end points include cardiovascular death, myocardial revascularization, noncoronary arterial revascularization, stroke, all-cause hospitalization, all-cause mortality, all breast cancers, clinical fractures, and venous thromboembolic events, in addition to the individual components of the composite primary coronary end point. RUTH will provide important information about the risk-benefit ratio of raloxifene in preventing acute coronary events and invasive breast cancer, as well as information about the natural history of CHD in women at risk of major coronary events.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11545760&dopt=Abstract raloxifene Evista



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Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator.

Long GG, Cohen IR, Gries CL, Young JK, Francis PC, Capen CC.

Toxicology and Drug Disposition, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, IN 46140, USA. Long_Gerald_G Lilly.com

This study assessed the effects of raloxifene, a selective estrogen receptor modulator (SERM), on ovarian morphology and circulating hormone levels in rats. Female Fischer-344 rats (65/group) were given dietary raloxifene for 6 months at average daily doses of 0, 15, 75, and 365 mg/kg. Morphologic evaluation of ovaries was conducted on 25 rats/group at the end of the treatment period and from 20 rats per group after 1 and 3 months withdrawal from treatment. Plasma hormone analyses were conducted on 10 rats pergroup at the end of the treatment period and aftereach withdrawal period. Treatment with raloxifene for 6 months resulted in disruption of the hypothalamic-pituitary-ovarian axis, manifested by increased plasma concentrations of luteinizing hormone (LH) and estradiol-17beta (E2), and failure of ovulation, manifested by ovarian follicular prominence (retained anovulatory follicles), lack of corpora lutea (CL), and depressed plasma progesterone (P4). Many (56% to 80%) rats in all raloxifene treated groups had focal, minimal to slight hyperplasia of granulosa cells within individual retained follicles. A few treated rats in the mid- and high-dose groups (2 of 25 and 3 of 25, respectively) had more extensive focal proliferation of granulosa cells. These foci were approximately 3 to 6 mm in overall size and were characterized by moderate papillary proliferation of large granulosa cells associated with cystic spaces, often with hemorrhage. In 4 of the 5 rats with this focal cystic granulosa cell hyperplasia, the remainder of the involved ovary and the contralateral ovary were atrophic. After 1 or 3 months of drug withdrawal, most previously treated rats examined had morphologic evidence of ovarian cyclic changes. including developing follicles, various stages of CL, and normal plasma levels of LH, E2, and P4. Continued lack of cyclic changes was limited to 4 of 20 rats from the low-dose group after 1 month of recovery and to 1 low dose rat after 3 months. Intrafollicular granulosa cell hyperplasia was not seen in rats in the reversibility phase. Areas of prior focal cystic granulosa cell hyperplasia were represented by focal sclerosis that included hemorrhage and/or hemosiderin. The foci of sclerosis were associated with cystic spaces after 1 month and were solid after 3 months. A granulosa cell tumor, approximately 12-13 mm diameter, was present in a high-dose rat in the 3-month reversibility group. This tumor effaced 1 ovary and was characterized by proliferative granulosa cells, usually in papillary formations and cords within cystic spaces. This rat had atrophy of the uninvolved ovary, excessive plasma levels of E2 and prolactin, and high P4 levels considering the absence of CL. The results of this study indicate that ovarian granulosa cells in rats are susceptible to proliferative changes when stimulated chronically with excessive trophic hormones. Most of these proliferative changes were reversible upon cessation of the hormonal stimulation. However, the proliferative lesion in one treated rat progressed to apparent autonomous (neoplastic) growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11560244&dopt=Abstract raloxifene Evista