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- Effects of ospemifene on the female reproductive and urinary tracts: translation from preclinical models into clinical evidence. [JOURNAL ARTICLE]
- Menopause 2014 Nov 24.
Treatment of menopausal symptoms by compounds with tissue-selective estrogen agonist/antagonist effects, often called selective estrogen receptor modulators, has been researched as an alternative to the use of estrogen therapy. These structurally diverse molecules elicit tissue-dependent responses in hormone-responsive tissues and organs, exhibiting variations in estrogenic activity in preclinical models of postmenopausal reproductive tissues that may improve postmenopausal women's health (eg, prevention and treatment of breast cancer, osteoporosis, and vulvar and vaginal atrophy).This literature review investigates whether preclinical data predicted the clinical effects of ospemifene on female reproductive and urinary tract tissues and compares these findings with the specific vaginal effects of other estrogen receptor agonists/antagonists (tamoxifen, raloxifene, and bazedoxifene) in preclinical and clinical studies. Lasofoxifene, although not currently available, is included because of its unique effects on vaginal tissue.The response of endometrial and vaginal tissues to estrogen receptor agonists/antagonists can be differentiated using transvaginal ultrasound, endometrial histopathology, cytologic examination of vaginal smears, assessment of physical changes in the vagina, and relief of symptoms associated with vulvar and vaginal atrophy (such as dyspareunia).Available evidence indicates that ospemifene has unique effects on tissue, leading to a favorable long-term profile for the relief of vulvar and vaginal atrophy compared with other estrogen receptor agonists/antagonists (eg, tamoxifen, raloxifene, and bazedoxifene) with no short-term concerns about endometrial safety (based on endometrial hyperplasia, carcinoma, endometrial spotting, and endometrial bleeding).This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
- In vitro evaluation of a tetrahydroisoquinoline derivative as a steroid sulfatase inhibitor and a selective estrogen receptor modulator. [JOURNAL ARTICLE]
- Invest New Drugs 2014 Nov 21.
Selective estrogen receptor modulators (SERMs) are currently in use in the hormonal therapy of breast cancer. In that respect, a new hormone-related approach is the therapeutical inhibition of steroid sulfatase (STS), which converts inactive, sulfated steroids into active hormones. We investigated the potential of 6-EO-14, a non-steroidal STS inhibitor with SERM potential. The latter compound, which exhibits a sulfamate moiety, releases the phenol derivative 8-EO-14 after the irreversible inhibition of STS. STS was inhibited by 6-EO-14 (IC50 = 0.3 μM), but not 8-EO-14, in HEK-293 cells transfected with an STS expression vector. The SERM potential of 8-EO-14 was assessed in osteoblast-like Saos-2 cells by investigating its effect on cell proliferation and on the activity of alkaline phosphatase (ALP), a specific differentiation marker. Saos-2 cell proliferation was increased by 21 % following 8-EO-14 addition (1 μM), and 8-EO-14 induced ALP activity (31 % increase at 0.1 nM) via estrogen receptor alpha (ERα) similarly to the SERM raloxifene. As compared to estradiol (E2) (100 %), the relative binding affinity of 6-EO-14 and 8-EO-14) for ERα was found to be weak (0.09 and 0.01 %, respectively). When assessed in two estrogen-dependent human breast cancer cell lines (MCF-7 and T-47D), 8-EO-14 did not support MCF-7 cell proliferation, whereas both 8-EO-14 and 6-EO-14 exhibited estrogen-like growth stimulation in T-47D cells. These two compounds were also unable to block E2-induced cell proliferation, suggesting their lack of antiestrogenic activity. Despite the known potency of 6-EO-14 as an STS inhibitor, the observed trophic activity of this new scaffold towards ERα-positive cells needs to be carefully considered prior to its potential utilization as a therapeutic agent.
- Psychometric properties of the osteoporosis patient assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study. [JOURNAL ARTICLE]
- BMC Musculoskelet Disord 2014 Nov 17; 15(1):374.
We explored psychometric properties of the Osteoporosis Patient Assessment Questionnaire 2.0 in terms of reliability, validity, and responsiveness with generic, clinical, demographic, and preference-based data collected from a population of postmenopausal women with osteoporosis.The Multiple Outcomes of Raloxifene Evaluation study was a randomized, placebo-controlled, multinational clinical trial evaluating efficacy and safety of raloxifene. The Osteoporosis Patient Assessment Questionnaire 2.0, a generic quality of life measure (Nottingham Health Profile), and a preference-based measure (Health Utilities Index) were administered at baseline and annually. Psychometric properties of the 14 Osteoporosis Patient Assessment Questionnaire 2.0 domains were evaluated by standard statistical techniques.This study included a subset of 1477 women from the Multiple Outcomes of Raloxifene Evaluation study population completing the questionnaires. Mean (standard deviation) age was 68.4 (6.8) years. Prevalent vertebral fractures were found in 70% (n =1038) of women. Internal consistency was >0.7 in 9 Osteoporosis Patient Assessment Questionnaire 2.0 domains. Correlations were moderate and significant for similar Osteoporosis Patient Assessment Questionnaire 2.0 domain scores, Nottingham Health Profile domains, and Health Utilities Index scores. All but 2 Osteoporosis Patient Assessment Questionnaire 2.0 domains distinguished between patients with or without prevalent vertebral fractures and detected worsening with increased number of vertebral fractures. Women with >=1 incident vertebral fracture generally had a greater worsening in Osteoporosis Patient Assessment Questionnaire 2.0 scores (excluding social activity and support of family and friends) from baseline to study endpoint compared with women without incident vertebral fractures.Most domains in the Osteoporosis Patient Assessment Questionnaire 2.0 demonstrated robust psychometric properties; however, several domains not showing these criteria may need to be reassessed and removed for a potentially shorter and validated version of the Osteoporosis Patient Assessment Questionnaire.
- Systematic review of raloxifene in postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia). [REVIEW]
- Clin Interv Aging 2014.:1879-1893.
To systematically review the literature describing the efficacy, effectiveness, and safety of raloxifene for postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia).Medline via PubMed and Embase was systematically searched using prespecified terms. Retrieved publications were screened and included if they described randomized controlled trials or observational studies of postmenopausal Japanese women with osteoporosis or osteopenia treated with raloxifene and reported one or more outcome measures (change in bone mineral density [BMD]; fracture incidence; change in bone-turnover markers, hip structural geometry, or blood-lipid profile; occurrence of adverse events; and change in quality of life or pain). Excluded publications were case studies, editorials, letters to the editor, narrative reviews, or publications from non-peer-reviewed journals; multidrug, multicountry, or multidisease studies with no drug-, country-, or disease-level analysis; or studies of participants on dialysis.Of the 292 publications retrieved, 15 publications (seven randomized controlled trials, eight observational studies) were included for review. Overall findings were statistically significant increases in BMD of the lumbar spine (nine publications), but not the hip region (eight publications), a low incidence of vertebral fracture (three publications), decreases in markers of bone turnover (eleven publications), improved hip structural geometry (two publications), improved blood-lipid profiles (five publications), a low incidence of hot flushes, leg cramps, venous thromboembolism, and stroke (12 publications), and improved quality of life and pain relief (one publication).Findings support raloxifene for reducing vertebral fracture risk by improving BMD and reducing bone turnover in postmenopausal Japanese women with osteoporosis or osteopenia. Careful consideration of fracture risk and the risk-benefit profile of antiosteoporosis medications is required when managing patients with osteoporosis.
- Clinically used selective estrogen receptor modulators increase LDL receptor activity in primary human lymphocytes. [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Nov 13.
Treatment with selective estrogen receptor modulators (SERMs) reduces low-density lipoprotein (LDL)-cholesterol levels. We assessed the effect of tamoxifen, raloxifene and toremifene and their combinations with lovastatin on LDL receptor activity in lymphocytes from normolipidemic and familial hypercholesterolemic (FH) subjects, and human HepG2 hepatocytes and MOLT-4 lymphoblasts.Lymphocytes were isolated from peripheral blood, treated with the different compounds and 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (DiI)-labeled LDL uptake was analyzed by flow cytometry.Tamoxifen, toremifene and raloxifene, in this order, stimulated DiI-LDL uptake by lymphocytes through inhibiting LDL-derived cholesterol trafficking and subsequent downregulation of LDL receptor expression. Differently to what occurred in HepG2 and MOLT-4 cells, only tamoxifen consistently displayed an enhancement effect with lovastatin in primary lymphocytes. The SERM-mediated increase of LDL receptor activity was not altered by the antiestrogen ICI 182,780, nor was reproduced by 17β-estradiol. However, the tamoxifen active metabolite endoxifen was equally effective as tamoxifen. The SERMs produced similar effects on LDL receptor activity in heterozygous FH lymphocytes than in normal lymphocytes, although none of them had an enhancement effect with lovastatin in the former cells. No effects of SERMs were observed in homozygous FH lymphocytes.Clinically used SERMs upregulate LDL receptor in primary human lymphocytes. SERMs have a mild enhancement effect with lovastatin in these cells, the potentiation being greater in HepG2 and MOLT-4 cells. The effect of SERMs is estrogen receptor-independent, but is preserved in the tamoxifen active metabolite endoxifen. This mechanism may contribute to the cholesterol-lowering action of SERMs.
- Preventative therapies for healthy women at high risk of breast cancer. [Journal Article, Review]
- Cancer Manag Res 2014.:423-30.
Tamoxifen has been shown to reduce the risk of developing estrogen receptor (ER)-positive breast cancer by at least 50%, in both pre- and postmenopausal women. The current challenge is to find new agents with fewer side effects and to find agents that are specifically suitable for premenopausal women with ER-negative breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, arzoxifene, and lasofoxifene, have been shown to reduce the incidence of breast cancer by 50%-80%. SERMs are interesting agents for the prevention of breast cancer, but longer follow-up is needed for some of them for a complete risk-benefit profile of these drugs. Aromatase inhibitors have emerged as new drugs in the prevention setting for postmenopausal women. In the Mammary Prevention 3 (MAP3) trial, a 65% reduction in invasive breast cancer with exemestane was observed, and the Breast Cancer Intervention Study-II trial, which compared anastrozole with placebo, reported a 60% reduction in those cancers. Although SERMs and aromatase inhibitors have been proven to be excellent agents in the preventive setting specifically for postmenopausal women and ER-positive breast cancer, newer agents have to be found specifically for ER-negative breast cancers, which mostly occur in premenopausal women.
- Effect of raloxifene on parathyroid hormone in osteopenic and osteoporotic postmenopausal women with chronic kidney disease stage 5. [Journal Article]
- Iran J Kidney Dis 2014 Nov; 8(6):461-6.
Introduction.This study was aimed to investigate the effects of raloxifene on intact parathyroid hormone (PTH) level and bone mineral density (BMD) for 8 months in women on hemodialysis and women with chronic kidney disease stage 5 not dependent on dialysis to determine its effect on secondary hyperparathyroidism and osteoporosis. Materials and Methods. Fifty-one women on hemodialysis and 9 with chronic kidney disease stage 5 were randomly assigned to receive oral raloxifene, 60 mg/d, or placebo for 8 months. Baseline blood determinations and BMD were done and repeated after 8 months. Serum levels of total calcium, phosphorus, alkaline phosphatase, and intact PTH were measured.
Results.Serum levels of intact PTH significantly decreased in both groups, and there was no difference between the two groups after 8 months (P = .37). Serum phosphorus levels also decreased by 1.8% in the two groups. After 8 months of treatment, the BMD of the lumbar spine and femural neck decreased by 1.9% in the control group, while an increase in BMD was observed in the raloxifene group,with an average increase in both BMDs of the lumbar spine and the femural neck by 2% (significant in the lumbar spine; P = .01).
Conclusions.Raloxifene has proven to be an effective medication in terms of improving BMD, with no adverse effects. However, it had no effect on controlling hyperparathyroidism in our patients. Long-term studies should be done to investigate the effects of raloxifene in chronic kidney disease and dialysis patients.
- Raloxifene modulates regulators of osteoclastogenesis and angiogenesis in an oestrogen deficiency periapical lesion model. [JOURNAL ARTICLE]
- Int Endod J 2014 Oct 29.
To analyse the local regulatory mechanisms of osteoclastogenesis and angiogenesis during the progression of periapical lesions in female rats with oestrogen deficiency and treatment with raloxifene (RLX).Female Wistar rats were distributed into groups: SHAM-veh, subjected to sham surgery and treated with a vehicle; OVX-veh, subjected to ovary removal and treated with a vehicle; and OVX-RLX, subjected to ovary removal and treated with RLX. Vehicle or RLX was administered orally for 90 days. During treatment, the dental pulp of mandibular first molars was exposed to the oral environment for induction of periapical lesions, which were analysed after 7 and 30 days. After the experimental periods, blood samples were collected for measurement of oestradiol, calcium, phosphorus and alkaline phosphatase. The rats were euthanized and the mandibles removed and processed for immunohistochemical detection of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), hypoxia-inducible factor-1 alpha (HIF-1α) and bone-specific alkaline phosphatase (BALP). Data were compared using Kruskal-Wallis followed by Dunn test (nonparametric values) and anova followed by the Tukey's test (parametric values).The plasma concentration of oestradiol showed hypo-oestrogenism in the rats subjected to ovary removal. On day 7, alkaline phosphatase activity, calcium and phosphorus were higher in the OVX-RLX group than in the OVX-veh group (P < 0.001), but immunolabelling for RANKL and HIF-1α was lower in OVX-RLX group (P < 0.001). On day 30, the OVX-veh group had higher immunolabelling for RANKL than the OVX-RLX group (P < 0.05). There were no significant differences in the immunoreactivity of OPG and BALP between any groups at either time-point (P > 0.05).RLX therapy reversed the increased levels of the local regulators of both osteoclastogenesis and angiogenesis induced by oestrogen deficiency.
- Raloxifene hydrochloride treatment leads to better outcomes than medroxyprogesterone acetate when paired with estrogen in ovariectomized cholesterol-fed rabbits. [Journal Article]
- Acta Biochim Biophys Sin (Shanghai) 2014 Dec; 46(12):1080-3.
- Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection? [JOURNAL ARTICLE]
- Curr Org Chem 2014 Jan 1; 18(1):61-69.
The formation of quinone methides (QMs) from either direct 2-electron oxidation of 2- or 4-alkylphenols, isomerization of o-quinones, or elimination of a good leaving group could explain the cytotoxic/cytoprotective effects of several drugs, natural products, as well as endogenous compounds. For example, the antiretroviral drug nevirapine and the antidiabetic agent troglitazone both induce idiosyncratic hepatotoxicity through mechanisms involving quinone methide formation. The anesthetic phencyclidine induces psychological side effects potentially through quinone methide mediated covalent modification of crucial macromolecules in the brain. Selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene, and raloxifene are metabolized to quinone methides which could potentially contribute to endometrial carcinogenic properties and/or induce detoxification enzymes and enhance the chemopreventive effects of these SERMs. Endogenous estrogens and/or estrogens present in estrogen replacement formulations are also metabolized to catechols and further oxidized to o-quinones which can isomerize to quinone methides. Both estrogen quinoids could cause DNA damage which could enhance hormone dependent cancer risk. Natural products such as the food and flavor agent eugenol can be directly oxidized to a quinone methide which may explain the toxic effects of this natural compound. Oral toxicities associated with chewing areca quid could be the result of exposure to hydroxychavicol through initial oxidation to an o-quinone which isomerizes to a p-quinone methide. Similar o-quinone to p-quinone methide isomerization reactions have been reported for the ubiquitous flavonoid quercetin which needs to be taken into consideration when evaluating risk-benefit assessments of these natural products. The resulting reaction of these quinone methides with proteins, DNA, and/or resulting modulation of gene expression may explain the toxic and/or beneficial effects of the parent compounds.