- Anti-osteoporotic treatments in France: initiation, persistence and switches over 6 years of follow-up. [Journal Article]
- OIOsteoporos Int 2016 Oct 20
- CONCLUSIONS: This study showed that persistence with anti-osteoporotic treatment was relatively low in France, with high proportions of treatment discontinuations and switches, and that patients with osteoporosis were insufficiently monitored by bone specialists.
- The Tissue-Selective Estrogen Complex: A Review of Current Evidence. [Review]
- RTRheumatol Ther 2015; 2(1):47-58
- The tissue-selective estrogen complex (TSEC) has recently entered the market for the treatment of postmenopausal osteoporosis, and is particularly targeted to women with significant vasomotor symptom...
The tissue-selective estrogen complex (TSEC) has recently entered the market for the treatment of postmenopausal osteoporosis, and is particularly targeted to women with significant vasomotor symptoms. This review appraises the evidence behind the only approved TSEC to-date, a combination of bazedoxifene and conjugated estrogens, with regards to its efficacy and relevant safety concerns. The majority of evidence that has led to its approval is derived from the SMART study. This large phase III trial with several substudies was aimed at discerning the effects of the TSEC on various estrogen-responsive tissues in comparison to raloxifene and placebo. Overall, the evidence thus far suggests a superior improvement in lumbar bone mineral density of 1.01% ± 0.28% as well as decrease in the frequency of hot flushes. Regarding safety concerns, endometrial thickness did not change over the treatment course, and investigators also identified a modest reduction in breast density. While there was no difference in rates of venous thromboembolism between treatment and placebo groups in a 2-year follow-up period, the effects of the drug on coagulation profiles are similar to those seen with hormone replacement therapy. Thus, the drug's effects on venous thromboembolism risk over a longer treatment course remain unclear. In conclusion, the actual efficacy of the TSEC for postmenopausal osteoporosis remains as yet undefined, given the lack of fracture prevention data. The evidence thus far does seem to suggest a beneficial effect on vasomotor symptoms and a generally favorable side effect profile. However, it should be noted that only one study has addressed this question thus far, and so the repeatability of the findings is still in question.
- Unwanted effects of some breast cancer medication. [Journal Article]
- NSNurs Stand 2010 Jan 6; 24(18):16-17
- Tamoxifen and raloxifene reduce the risk of primary breast cancer, but increase the risk of thromboembolic events. Tamoxifen also increases the risk of endometrial cancer, while tibolone increases th...
Tamoxifen and raloxifene reduce the risk of primary breast cancer, but increase the risk of thromboembolic events. Tamoxifen also increases the risk of endometrial cancer, while tibolone increases the risk of stroke.
- Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction. [Journal Article]
- CircCirculation 2016 Oct 11; 134(15):1085-1099
- CONCLUSIONS: Inhibition of the RNA binding motif-20-based titin splicing system upregulates compliant titins, which improves diastolic function and exercise tolerance in the TAC/DOCA model. Titin holds promise as a therapeutic target for heart failure with preserved ejection fraction.
- Antiestrogens: structure activity relationships and use in breast cancer treatment. [Journal Article]
- JMJ Mol Endocrinol 2016 Oct 11
- About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens...
About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as Selective Estrogen Receptor Modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second and third generation AEs however suggests induction of diverse ERα structural conformations, resulting in variable degrees of receptor down-regulation and different patterns of systemic properties in animal models and in the clinic.
- A transgenic mouse model expressing an ERα folding biosensor reveals the effects of Bisphenol A on estrogen receptor signaling. [Journal Article]
- SRSci Rep 2016 Oct 10; 6:34788
- Estrogen receptor-α (ERα) plays an important role in normal and abnormal physiology of the human reproductive system by interacting with the endogenous ligand estradiol (E2). However, other ligands, ...
Estrogen receptor-α (ERα) plays an important role in normal and abnormal physiology of the human reproductive system by interacting with the endogenous ligand estradiol (E2). However, other ligands, either analogous or dissimilar to E2, also bind to ERα. This may create unintentional activation of ER signaling in reproductive tissues that can lead to cancer development. We developed a transgenic mouse model that constitutively expresses a firefly luciferase (FLuc) split reporter complementation biosensor (NFLuc-ER-LBDG521T-CFLuc) to simultaneously evaluate the dynamics and potency of ligands that bind to ERα. We first validated this model using various ER ligands, including Raloxifene, Diethylstilbestrol, E2, and 4-hydroxytamoxifen, by employing FLuc-based optical bioluminescence imaging of living mice. We then used the model to investigate the carcinogenic property of Bisphenol A (BPA), an environmental estrogen, by long-term exposure at full and half environmental doses. We showed significant carcinogenic effects on female animals while revealing activated downstream ER signaling as measured by bioluminescence imaging. BPA induced tumor-like outgrowths in female transgenic mice, histopathologically confirmed to be neoplastic and epithelial in origin. This transgenic mouse model expressing an ERα folding-biosensor is useful in evaluation of estrogenic ligands and their downstream effects, and in studying environmental estrogen induced carcinogenesis in vivo.
- Raloxifene for schizophrenia and symptoms of hyperprolactinaemia? [Letter]
- ANAust N Z J Psychiatry 2016 Sep 28
- The role of selective estrogen receptor modulators in the treatment of schizophrenia. [Journal Article]
- PDPsychiatr Danub 2016; 28(Suppl-1):45-48
- CONCLUSIONS: SERMs could be an effective augmentation strategy in the treatment of both men women with schizophrenia, although further research efforts are needed to study potential long-term side effects.
- Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease. [Journal Article]
- NANeurobiol Aging 2016 Aug 16; 48:61-71
- Motor symptoms in Parkinson's disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastr...
Motor symptoms in Parkinson's disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastric emptying. These gastrointestinal impairments are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric plexus of the gut. Recently, we demonstrated the anti-inflammatory properties of estrogens to treat intestinal neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The present study aimed to investigate the neuroprotective and anti-inflammatory roles of raloxifene, a selective estrogen receptor modulator (SERM) already commercialized for osteoporosis treatment. In MPTP-treated mice, we found that raloxifene decreased the loss of DAergic neurons and prevented the increase in proinflammatory macrophage density in the myenteric plexus. Interestingly, raloxifene activity was prevented by the G protein-coupled estrogen receptor 1 (GPER1) antagonist G15, suggesting that raloxifene effects were mainly mediated by GPER1. Moreover, monocytic cell proinflammatory polarization, nuclear factor-kappa B (NF-κB) response, nitric oxide (NO), and proinflammatory cytokines production following 1-methyl-4-phenylpyridinium (MPP(+)) treatment were also prevented by raloxifene in vitro. Overall, the present results suggest that raloxifene may help preventing the loss of DAergic neurons in the myenteric plexus in an MPTP mouse model of PD, at least in part through its anti-inflammatory effects. This suggests that drug repurposing of raloxifene might represent a promising therapeutic avenue to prevent systemic inflammation and peripheral neuronal dysfunction at early PD stages.
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- Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport. [Journal Article]
- SRSci Rep 2016 Sep 07; 6:32105
- Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific ...
Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages.