Disease relevance of Keoxifene

• The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo [1].
• Tamoxifen, raloxifene findings unlikely to encourage genetic screening for breast cancer [2].
• Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis [3].
• Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7) [4].
• Raloxifene reduces spinal fractures postmenopausally [5].

Psychiatry related information on Keoxifene

• For SERMs, current evidence supports tamoxifen use for breast cancer risk reduction whereas raloxifene requires further study [6].
• Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60) [7].
• Risks of mild cognitive impairment, Alzheimer's disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene [8].
• Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial [8].
• Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day) [9].

High impact information on Keoxifene

• Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known [10].
• CONCLUSIONS: Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium [1].
• METHODS: We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women [1].
• Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene [11].
• CONTEXT: Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known [12].

Chemical compound and disease context of Keoxifene

• A woman's estradiol level may alter the effects of raloxifene on breast cancer and other outcomes [13].
• METHODS: In a 5-year multicenter, double-blind, randomized, placebo-controlled osteoporosis prevention trial, healthy postmenopausal women who had undergone hysterectomy less than 15 years before the study and had no history of breast cancer received placebo, raloxifene (at one of two doses), or conjugated estrogens (ERT) [14].
• DATA SYNTHESIS: Raloxifene hydrochloride was developed in an effort to find a treatment for breast cancer and osteoporosis [15].
• Arzoxifene (ARZ) is a selective estrogen receptor (ER) modulator with greater bioavailability than raloxifene which is being developed as treatment for breast cancer [16].
• Blockade of the stimulatory effect of estrogens, OH-tamoxifen, OH-toremifene, droloxifene, and raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells [17].

Biological context of Keoxifene

• For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons) [1].
• CONTEXT: Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting [4].
• To investigate the possibility that caspase activation is involved in raloxifene-induced apoptosis, cells were treated with the pan-caspase inhibitor ZVAD [18].
• In proliferation assays, EM-652 is as effective as raloxifene in inhibiting cell growth [19].
• After treatment with raloxifene, a dramatic increase in cell death occurred in a dose-dependent manner (10(-9) to 10(-6) M range) [20].

Anatomical context of Keoxifene

• After oral administration of raloxifene for 5 wk (0.1-10 mg/kg per d) to OVX rats, bone mineral density in the distal femur and proximal tibia was significantly greater than that observed in OVX controls (ED50 of 0.03-0.3 mg/kg) [21].
• In the uterus, raloxifene does not stimulate the endometrium [15].
• After the treatment with raloxifene, a dramatic increase in cell death was observed in a dose-dependent manner in the three prostate cancer cell lines (10(-9) to 10(-6) M range) [18].
• In the uterus, raloxifene had minimal effects on the endometrium and smaller effects on uterine eosinophil peroxidase activity than nafoxidine, tamoxifen, or estrogen, respectively [22].
• Induction of endothelial nitric-oxide synthase phosphorylation by the raloxifene analog LY117018 is differentially mediated by Akt and extracellular signal-regulated protein kinase in vascular endothelial cells [23].

Associations of Keoxifene with other chemical compounds

• The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis [24].
• Chemoprevention of mammary carcinogenesis in the rat: combined use of raloxifene and 9-cis-retinoic acid [25].
• This strategy has resulted in the development of a pharmacophore model that attributes the differences in effects on the uterus between raloxifene and tamoxifen to a low-energy conformational preference imparting an orthogonal orientation of the basic side chain with respect to the stilbene plane [26].
• Selective estrogen receptor modulators 4-hydroxytamoxifen and raloxifene impact the stability and function of SRC-1 and SRC-3 coactivator proteins [27].
• Linear regression analysis was used to calculate half-maximal efficacious doses for ethynyl estradiol ED(50) =0.04mg /kg, which was threefold more potent than tamoxifen, which in turn was threefold more potent than raloxifene, which was more efficacious than nafoxidine [22].
• Decreased levels of mRNA for both tumor necrosis factor alpha and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM [28].
• Tamoxifen was more effective than raloxifene at activating the elements with ERalpha, whereas raloxifene was superior with ERbeta [29].

Gene context of Keoxifene

• Raloxifene, a selective estrogen receptor (ER) modulator, is a mixed estrogen agonist/antagonist that has been shown to prevent osteoporosis and breast cancer in women [20].
• Because the prostate contains a high level of ER-beta, the present study investigated the effect of raloxifene in the androgen-sensitive human prostate cancer cell line LNCaP [20].
• The results demonstrated that raloxifene does not significantly alter androgen receptor activity in LNCaP cells [20].
• Moreover, cotreatment with an IkappaBalpha phosphorylation inhibitor, BAY-11-7082, or a specific NFkappaB nuclear translocation inhibitor, SN50, significantly attenuated the raloxifene-induced telomerase activity and the association of NFkappaB with hTERT [30].
• In addition, raloxifene induced both the phosphorylation of hTERT and IkappaB [30].

Analytical, diagnostic and therapeutic context of Keoxifene

• Clearly, the successful crystallization of ER alpha with raloxifene (Brzozowski et al., 1997) must act as a stimulus for the crystallization of ER beta [31].
• OBJECTIVE: To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT) [32].
• Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women [4].
• The results demonstrated that the dramatic change in cellular morphology after treatment with raloxifene was no longer observed when cells were pretreated with ZVAD [18].
• Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants [33].

References