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- Raloxifene inhibits cloned Kv4.3 channels in an estrogen receptor-independent manner. [JOURNAL ARTICLE]
- Pflugers Arch 2014 Sep 18.
Raloxifene is widely used for the treatment and prevention of postmenopausal osteoporosis. We examined the effects of raloxifene on the Kv4.3 currents expressed in Chinese hamster ovary (CHO) cells using the whole-cell patch-clamp technique and on the long-term modulation of Kv4.3 messenger RNA (mRNA) by real-time PCR analysis. Raloxifene decreased the Kv4.3 currents with an IC50 of 2.0 μM and accelerated the inactivation and activation kinetics in a concentration-dependent manner. The inhibitory effects of raloxifene on Kv4.3 were time-dependent: the association and dissociation rate constants for raloxifene were 9.5 μM(-1) s(-1) and 23.0 s(-1), respectively. The inhibition by raloxifene was voltage-dependent (δ = 0.13). Raloxifene shifted the steady-state inactivation curves in a hyperpolarizing direction and accelerated the closed-state inactivation of Kv4.3. Raloxifene slowed the time course of recovery from inactivation, thus producing a use-dependent inhibition of Kv4.3. β-Estradiol and tamoxifen had little effect on Kv4.3. A preincubation of ICI 182,780, an estrogen receptor antagonist, for 1 h had no effect on the inhibitory effect of raloxifene on Kv4.3. The metabolites of raloxifene, raloxifene-4'-glucuronide and raloxifene-6'-glucuronide, had little or no effect on Kv4.3. Coexpression of KChIP2 subunits did not alter the drug potency and steady-state inactivation of Kv4.3 channels. Long-term exposure to raloxifene (24 h) significantly decreased the expression level of Kv4.3 mRNA. This effect was not abolished by the coincubation with ICI 182,780. Raloxifene inhibited Kv4.3 channels by interacting with their open state during depolarization and with the closed state at subthreshold potentials. This effect was not mediated via an estrogen receptor.
- Osteoporosis in menopause. [Journal Article]
- J Obstet Gynaecol Can 2014 Sep; 36(9):839-40.
To provide guidelines for the health care provider on the prevention, diagnosis, and clinical management of postmenopausal osteoporosis.Strategies for identifying and evaluating high-risk individuals, the use of bone mineral density (BMD) and bone turnover markers in assessing diagnosis and response to management, and recommendations regarding nutrition, physical activity, and the selection of pharmacologic therapy to prevent and manage osteoporosis.Published literature was retrieved through searches of PubMed and The Cochrane Library on August 30 and September 18, 2012, respectively. The strategy included the use of appropriate controlled vocabulary (e.g., oteoporosis, bone density, menopause) and key words (e.g., bone health, bone loss, BMD). Results were restricted to systematic reviews, practice guidelines, randomized and controlled clinical trials, and observational studies published in English or French. The search was limited to the publication years 2009 and following, and updates were incorporated into the guideline to March 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.The quality of the evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table).The Society of Obstetricians and Gynaecologists of Canada. Recommendations For Postmenopausal Women 1. Health care providers should be aware that the goals of osteoporosis management include assess-ment of fracture risk and prevention of fracture. (I-A) 2. Health care providers should understand that a stable or increasing bone mineral density reflects a response to therapy in the absence of low-trauma fracture or height loss due to vertebral-compression fracture. A pro-gressive decrease in bone mineral density, with the magnitude of bone loss being greater than the precision error of the density assessment, indicates a lack of response to current ther-apy. Management should be reviewed and modified appropriately. (I-A) 3. Health care providers should identify the absolute fracture risk by integrating the key risk factors for fracture; namely, age, bone mineral density, prior fracture, and glucocorticoid use. These risk factors allow estimation of fracture risk using the tool of the Canadian Association of Radiologists and Osteoporosis Canada. (I-A) 4. The Fracture Risk Assessment tool of the World Health Organization (FRAX) has now been validated in a Canadian population and may also be used and incorporates additional risk factors; namely, low body mass index, parental history of fracture, smoking status, alcohol intake, and the presence of secondary causes of osteoporosis. (I-A) 5. Health care providers should be aware that a fragility fracture markedly increases the risk of a future fracture and confirms the diagnosis of osteo-porosis irrespective of the results of the bone density assessment, (I-A) and that the presence of a low-trauma fracture of a vertebra or hip or more than 1 fragility fracture confirms a high fracture risk regardless of the bone mineral density. (I-A) 6. Treatment should be initiated according to the results of the 10-year absolute fracture risk assessment. (I-A) Calcium and Vitamin D 7. Adequate calcium and vitamin D supplementation is key to ensuring prevention of progressive bone loss. For postmenopausal women a total daily intake of 1200 mg of elemental calcium from dietary and supplemental sources and daily supplementation with 800 to 2000 IU of vitamin D are recommended. Calcium and vitamin D supplementation alone is insufficient to prevent fracture in those with osteoporosis; however, it is an important adjunct to pharmacologic intervention with antiresorptive and anabolic therapy. (I-B) Hormone Therapy 8. Hormone therapy should be prescribed for symptomatic postmenopausal women as the most effective option for menopausal symptom relief. (I-A) It represents a reasonable choice for the prevention of bone loss and fracture in this patient population. (I-A) 9. Physicians may recommend low- and ultralow-dosage estrogen therapy to symptomatic women for relief of menopausal symptoms (I-A) but should inform their patients that, despite the fact that such therapy has demonstrated a beneficial effect in osteoporosis preven-tion, (I-A) no data are yet available on reduction of fracture risk. Bisphosphonates 10. Alendronate, risedronate, and zoledronic acid are valuable first-line agents of choice in the treatment of postmenopausal osteoporosis and should be considered to decrease the risk of vertebral, non-vertebral, and hip fractures. (I-A) 11. Etidronate is a weak antiresorptive agent and is not recommended as a first-line agent of choice for the treatment of osteoporosis. (I-D) RANKL Inhibitor 12. Denosumab is an effective antiresorptive agent, shown to reduce the risk of vertebral, non-vertebral, and hip fractures, (I-A) and should be considered as a first-line agent of choice in the treatment of postmenopausal osteoporosis in women at a high fracture risk. (I-A) Selective Estrogen-Receptor Modulators 13. Treatment with raloxifene may be considered to decrease the risk of vertebral fractures, bearing in mind that this agent has not been shown to be effective in reducing the risk of non-vertebral or hip fractures. (I-A) Parathyroid Hormone 14. Treatment with teriparatide should be considered to decrease the risk of vertebral and non-vertebral fractures in postmenopausal women with severe osteoporosis (I-A) and should also be considered in postmenopausal women experiencing bone loss or a new fracture despite antiresorptive therapy. (I-A).
- Raloxifene protects against seizures & neurodegeneration in a mouse model mimicking epilepsy in postmenopausal woman. [JOURNAL ARTICLE]
- Eur J Pharm Sci 2014 Sep 10.
Epilepsy in menopausal women presents several challenges in the treatment including an increased risk of seizures due to hormone replacement therapy. We investigated the hypothesis if raloxifene, a selective oestrogen receptor modulator, could be employed to prevent behavioural seizures and morphological alterations in a mouse model mimicking epilepsy in postmenopausal women. Female mice were made ovotoxic by treatment with 4-vinylcyclohexenediepoxide (VCD) to mimic a postmenopausal state. They were then subjected to kainic acid (KA)-induced seizures and neurotoxicity, as assessed by microscopic examination of hippocampus, relevant to human temporal lobe epilepsy. VCD administration (for 15 days followed by a drug-free period of 30 days) induced ovotoxicity in mice as evidenced by reduced number of primary ovarian follicles. This was accompanied by a 62.4% reduction in serum oestradiol levels. The bone mineral density of ovotoxic mice, however, remained unaffected. Raloxifene (8mg/kg) reduced the seizure severity score in both normal and ovotoxic mice and protected against degeneration induced by KA in the CA3, CA1 sub-fields and hilus of the DG. Hippocampal TGF-β3 levels were not affected by any of the treatments. We show the potential protective role of raloxifene in preventing seizures and neuronal damage in a mouse model mimicking epilepsy in postmenopausal women which was found unrelated to hippocampal TGF-β3. Raloxifene might represent a novel therapeutic option for postmenopausal temporal lobe epileptic woman.
- Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures: An Updated Systematic Review. [JOURNAL ARTICLE]
- Ann Intern Med 2014 Sep 9.
Osteoporosis is a major contributor to the propensity to fracture among older adults, and various pharmaceuticals are available to treat it.To update a review about the benefits and harms of pharmacologic treatments used to prevent fractures in adults at risk.Multiple computerized databases were searched between 2 January 2005 and 4 March 2014 for English-language studies.Trials, observational studies, and systematic reviews.Duplicate extraction and assessment of data about study characteristics, outcomes, and quality.From more than 52 000 titles screened, 294 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use, atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs.Few studies have directly compared drugs used to treat osteoporosis. Data in men are very sparse. Costs were not assessed.Good-quality evidence supports that several medications for bone density in osteoporotic range and/or preexisting hip or vertebral fracture reduce fracture risk. Side effects vary among drugs, and the comparative effectiveness of the drugs is unclear.Agency for Healthcare Research and Quality and RAND Corporation.
- Treatment of post-menopausal osteoporosis: beyond bisphosphonates. [JOURNAL ARTICLE]
- J Endocrinol Invest 2014 Sep 7.
Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m(2). Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.
- Incorporation of raloxifene-impregnated allograft around orthopedic titanium implants impairs early fixation but improves new bone formation. [JOURNAL ARTICLE]
- Acta Orthop 2014 Sep 1.:1-7.
Background - The anti-osteoporotic drug raloxifene reduces the risk of vertebral fractures by increasing bone mass density. We investigated whether raloxifene offers any benefits in augmenting early fixation of orthopedic implants in the setting of impaction bone grafting. Methods - 24 non-weight-bearing grafted gap implants were inserted bilaterally into the tibia of 12 dogs. The 2.5-mm peri-implant gap was filled with either raloxifene-impregnated or untreated bone allograft. Implants were harvested after 28 days. Implant fixation was assessed by mechanical testing and histomorphometric evaluation. Results - Raloxifene-treated allograft reduced early implant fixation compared to untreated allograft, as measured by inferior maximum shear strength (p < 0.001) and apparent shear stiffness (p = 0.001). We found that the raloxifene group had more newly formed bone in the gap around the implant (p = 0.02), but also less allograft (p = 0.03). Interpretation - The accelerated allograft resorption in the raloxifene group explained the impaired early fixation, despite its stimulation of new bone formation. Our results with local and possible high-dose treatment are not consistent with current theory regarding the mechanism of how systemic raloxifene administration counteracts the decrease in BMD in postmenopausal women. Instead of being solely anti-resorptive as generally held, our results indicate a possible anabolic side of raloxifene.
- Estrogen receptor-alpha is a key mediator and therapeutic target for bladder complications of benign prostatic hyperplasia. [JOURNAL ARTICLE]
- J Urol 2014 Aug 25.
While estrogens are important in prostate growth and play a role in benign prostatic hyperplasia (BPH), no current therapies directly target estrogen action. Estrogens act primarily via estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Using a mouse model, we evaluated the relative contribution of these receptors to bladder complications of BPH. We also evaluated prevention of these bladder complications by selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen (ERα selective antagonists) and (R,R)-5,11-Diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (R,R-THC, ERβ selective antagonist).Adult male C57bl/6 mice received implants of 25 mg testosterone (T) and 2.5 mg 17β-estradiol (E2) slow release pellets and untreated controls underwent sham surgery. We used ERα and ERβ knockout (KO) mice compared to their respective wild type (WT) littermates to probe contributions of ER subtypes. WT mice treated with T+E2 were compared to mice treated with T+E2 and 25 mg SERM to evaluate prevention of BPH complications with SERMs.While ERαWT and ERβWT littermates treated with T+E2 developed large bladders with urinary retention, ERαKO mice treated with T+E2 did not. ERβKO mice treated with T+E2 developed large bladders with urinary retention and increased bladder mass. Co-treatment with the ERα antagonist raloxifene resulted in decreased bladder mass compared to WT mice treated with T+E2, while bladders from mice treated with the ERβ antagonist R,R-THC were similar to T+E2-treated mice.ERα, but not ERβ, is a key mediator of bladder complications of BPH, and is a potential target for future therapies.
- Quantitative Assessment of Intestinal First-pass Metabolism of Oral Drugs Using Portal-vein Cannulated Rats. [JOURNAL ARTICLE]
- Pharm Res 2014 Aug 28.
To evaluate the impact of intestinal first-pass metabolism (Fg) by cytochrome P4503A (CYP3A) and uridine 5'-diphosphate-glucuronosyltransferases (UGT) on in vivo oral absorption of their substrate drugs.CYP3A and UGT substrates were orally administered to portal-vein cannulated (PV) rats to evaluate their intestinal availability (Fa · Fg). In the case of CYP3A substrates, vehicle or 1-aminobenzotriazole (ABT), a potent inhibitor of CYP enzymes, was pretreated to assess Fg separately from Fa (Enzyme-inhibition method). On the other hand, since potent inhibitors of UGT have not been identified, Fg of UGT substrate was calculated from total amount of metabolites generated in enterocytes (Metabolite-distribution method).After oral administration of CYP3A substrates in ABT-pretreated rats, the portal and systemic plasma concentrations of the metabolite were nearly the same, indicating almost complete inhibition of intestinal CYP3A-mediated metabolism. Using Enzyme-inhibition method, Fg of midazolam (1 mg/kg) was calculated as 0.71. Additionally, total amount of raloxifene-6-glucuronide generated in enterocytes after oral administration of raloxifene was estimated using Metabolite-distribution method and Fg of raloxifene (0.98 μmol/kg) was calculated as 0.21.PV rats enabled in vivo quantitative assessment of intestinal first-pass metabolism by CYP3A and UGT. This method is useful for clarifying the cause of low bioavailability.
- Use of FRAX(®)-based fracture risk assessments to identify patients who will benefit from osteoporosis therapy. [REVIEW]
- Maturitas 2014 Jul 16.
Several pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, and strontium ranelate have demonstrated efficacy in reducing the incidence of osteoporotic fractures, the most severe consequence of postmenopausal osteoporosis. Until recently, bone mineral density (BMD) was the primary factor used to determine which postmenopausal women may require osteoporosis treatment. However, clinical guidelines now recommend the use of the Fracture Risk Assessment Tool (FRAX(®)), a computer-based algorithm introduced by the World Health Organization, to help primary care physicians identify postmenopausal women who may be candidates for pharmacological osteoporosis therapy based on the level of fracture risk. Beyond its utility as a resource for determining whether or not to initiate osteoporosis treatment, clinical studies have begun to evaluate the correlation between FRAX(®)-based 10-year fracture probability and efficacy of different osteoporosis treatments. Bazedoxifene, clodronate, and denosumab have shown greater fracture risk reduction at higher FRAX(®)-based 10-year fracture probabilities, but the efficacy of raloxifene, alendronate, and strontium ranelate were relatively stable regardless of fracture probability. In summary, these data suggest that the relationship between FRAX(®)-based fracture probability and efficacy of different osteoporosis treatments varies depending upon the agent in question.
- Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells. [JOURNAL ARTICLE]
- Toxicol Appl Pharmacol 2014 Aug 11.
The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3'diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ~5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0μM (P<0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.