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Medical research on raloxifene
Drug Dev Ind Pharm. 2008 Dec 1; 1-16
Garg A, Singh S, Rao VU, Bindu K, Balasubramaniam J
This study investigated the effects of different classes of hydrophilic carriers (poly vinyl pyrrolidones [PVPs] [Plasdone K-25 and Plasdone S-630], cellulosic polymers [hydroxypropyl methyl cellulose and hydroxy propyl cellulose], and Sodium Alginate) on the solid state and dissolution rate of Raloxifene hydrochloride (R-HCl). Solid state characterizations of co-ground mixtures and physical mixtures in 1:1 and 1:2 ratios of drug to polymer were performed by employing laser diffractometer for particle size and differential scanning calorimetry (DSC) for solid state interactions. The results of particle size studies showed that only co-grinding with PVPs was more effective in the reduction of particle size than the milling of drug alone. DSC study indicated that the crystalline nature of the drug was reduced after co-grinding with PVPs when compared with their corresponding physical mixtures. The hydrophilic carriers other than PVPs did not reduce the crystalline nature of the drug significantly. X-ray diffraction and scanning electron microscopy were carried out for selected batches to confirm DSC results. Significant enhancement in dissolution rate and extent was observed with co-ground mixtures of drug and PVPs. Plasdone S-630 was found to be a better carrier for R-HCl in terms of achieving improvement in dissolution. In vitro dissolution data can be described by Hixson-Crowell model, indicating the drug release mechanism predominated by erosion.
Langenbecks Arch Surg. 2008 Dec 2;
Stuermer EK, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, Wuttke W, Frosch KH, Stuermer KM
BACKGROUND: Fracture healing in osteoporosis is delayed. Quality and speed of fracture healing in osteoporotic fractures are crucial with regard to the outcome of patients. The question arises whether established antiosteoporotic drugs can further improve fracture healing. MATERIALS AND METHODS: Osteoporosis manifests predominantly in the metaphyseal bone. Nevertheless, an established metaphyseal fracture model is lacking. A standardized metaphyseal fracture-healing model with stable plate fixation was developed for rat tibiae. The healing process was analyzed by biomechanical, gene expression, and histomorphometric methods in ovariectomized (OVX) and sham-operated rats (SHAM), compared to standardized estrogen (E)- and raloxifene (R)-supplemented diets. RESULTS: Estrogen and raloxifene improved the biomechanical properties of bone healing compared to OVX (Yield load: [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). Estrogen vs OVX was significant based on a denser trabecular network. Raloxifene greatly induced total callus formation ([Formula: see text], [Formula: see text], [Formula: see text],[Formula: see text]), whereas estrogen mainly enhanced new endosteal bone formation. There was no correlation between the gene expression (osteocalcin, collagen1alpha1, IGF-1, tartrate-resistant phosphatase) in the callus and the morphology and quality of callus formation. CONCLUSION: Raloxifene and estrogen improve fracture healing in osteoporotic bone significantly with regard to callus formation, resistance, and elasticity. The biomechanically stable metaphyseal osteotomy model with T-plate fixation presented here has proven to be appropriate to investigate fracture healing in osteoporosis.
Maturitas. 2008 Nov 28;
Sumino H, Ichikawa S, Kasama S, Takahashi T, Kumakura H, Takayama Y, Kanda T, Murakami M, Kurabayashi M
OBJECTIVES: Hormone replacement therapy (HRT) increases skin elasticity in postmenopausal women. However, the effects of raloxifene, a selective estrogen receptor modulator (SERM), on skin degenerative changes in postmenopausal women remain unknown. We investigated whether raloxifene increases skin elasticity, similar to HRT, in postmenopausal women. METHODS: In a 12-month trial, 17 postmenopausal women (mean age, 66.4+/-7.8 years) received continuous raloxifene treatment (60mg/day), 19 women (56.2+/-6.4 years) received continuous 17-beta estradiol treatment using a patch (0.72mg/2 days) plus cyclic medroxyprogesterone acetate (2.5mg/day, for 12 days/month), and 11 women (58.1+/-7.3 years) did not receive either therapy. In each subject, the skin elasticity of the forearm was measured using a suction device at baseline and at 12 months after the start of the study. RESULTS: Raloxifene and HRT significantly increased skin elasticity from 52.4+/-3.8% and 64.1+/-7.2% at baseline to 55.1+/-4.7% and 67.4+/-7.4% after 12 months, respectively (P
Mol Endocrinol. 2008 Nov 26;
Berrodin TJ, Chang KC, Komm BS, Freedman LP, Nagpal S
The use of estrogen based therapies, and the selective estrogen receptor modulator (SERM), raloxifene, which are approved for post-menopausal osteoporosis, is associated with uterine/breast hyperproliferation, thromboembolism, and hot flashes side effects. A combination of a new SERM, bazedoxifene (BZA), and Premarin (conjugated estrogens; CE) is under investigation to mitigate the estrogen/SERM side effects with promising results in Phase III clinical trials. To explore the mechanism of BZA/CE action, we investigated the recruitment of cofactor peptides to ERalpha by components of CE and a mixture containing the 10 major components of CE with or without three different SERMs. Here, we demonstrate differential recruitment of cofactor peptides to ERalpha by the individual CE components using a multiplex nuclear receptor-cofactor peptide interaction assay. We show that estrone and equilin are partial agonists in comparison to 17beta-estradiol in recruiting cofactor peptides to ERalpha. Further, CE was more potent than 17beta-estradiol in mediating ERalpha interaction with cofactor peptides. Interestingly, BZA was less potent than other SERMs in antagonizing the CE-mediated cofactor peptide recruitment to ERalpha. Finally, in accordance with these biochemical findings, 17beta-estradiol and CE as well as SERM/CE combinations showed differential gene regulation patterns in MCF-7 cells. In addition, BZA showed antagonism of a unique set of CE-regulated genes, and did not downregulate the expression of a number of CE-regulated genes whose expression was effectively antagonized by the other two SERMs. These results indicate that SERMs in combination with CE exhibit differential pharmacology, and therefore, combinations of other SERMs and estrogen preparations may not yield the same beneficial effects that are observed in clinic by pairing BZA with CE.
Glia. 2008 Nov 20;
Bebo BF, Dehghani B, Foster S, Kurniawan A, Lopez FJ, Sherman LS
Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system. (c) 2008 Wiley-Liss, Inc.
Neuroscience. 2008 Oct 31;
Kajta M, Wójtowicz AK, Maćkowiak M, Lasoń W
Activation of aryl hydrocarbon receptors (AhRs) induces neuronal damage, but the mechanism by which this occurs is largely unknown. This study evaluated the effects of an AhR agonist, beta-naphthoflavone, on apoptotic pathways in mouse primary neuronal cell cultures. beta-Naphthoflavone (0.1-100 muM) enhanced caspase-3 activity and lactate dehydrogenase (LDH) release in neocortical and hippocampal cells. These data were supported at the cellular level with Hoechst 33342 and calcein AM staining. alpha-Naphthoflavone inhibited the action of beta-naphthoflavone, thus confirming specific activation of AhRs. A high-affinity estrogen receptor (ER) antagonist, ICI 182,780, and a selective estrogen receptor modulator (SERM), tamoxifen, enhanced beta-naphthoflavone-mediated apoptosis. Another SERM, raloxifene, and an ERalpha antagonist, methyl-piperidino-pyrazole, did not affect beta-naphthoflavone-induced caspase-3 activity. However, they inhibited beta-naphthoflavone-induced LDH release at a late hour of treatment, thus suggesting delayed control of AhR-mediated neuronal cell death. The apoptotic effects of beta-naphthoflavone were accompanied by increased levels of AhRs, and these receptors colocalized with ERbeta as demonstrated by confocal microscopy. These data strongly support apoptotic effects of AhR activation in neocortical and hippocampal tissues. Moreover, this study provides evidence for direct interaction of the AhR-mediated apoptotic pathway with estrogen receptor signaling, which provides insight into new strategies to treat or prevent AhR-mediated neurotoxicity.
Effects of various SERMs with or without conjugated estrogens on mouse mammary gland.
Endocrinology. 2008 Nov 20;
Peano BJ, Crabtree JS, Komm BS, Winneker RC, Harris HA
Selective estrogen receptor modulators (SERMs) are small molecules that, depending on the endpoint measured, may either function as estrogen receptor (ER) agonists or antagonize estrogens' agonist activity. A key feature of SERMs is the inhibition of ER agonist action on the uterus and mammary gland, but the degree of antagonism varies among compounds and endpoints. Bazedoxifene is a SERM that is being clinically evaluated both as a monotherapy for the prevention and treatment of osteoporosis and in combination with conjugated estrogens (CE) for the treatment of menopausal symptoms and prevention of osteoporosis. The studies reported here compare the relative ER agonist and antagonist effects of three pharmacologically-distinct SERMs (bazedoxifene, raloxifene and lasofoxifene) on the ovariectomized mouse when administered alone or as a tissue selective estrogen complex (TSEC), a term used to describe the partnering of a SERM and one or more estrogens. At the minimum dose required to maximally reduce CE-stimulated uterine wet weight increase for each SERM, the degree of inhibition varied among the SERMs, with a rank order of bazedoxifene approximately raloxifene > lasofoxifene, where only bazedoxifene was statistically similar to vehicle. In the mammary gland, where amphiregulin mRNA and morphological effects were measured, bazedoxifene generally exhibited less agonist activity and was a more effective antagonist of CE than raloxifene or lasofoxifene. In summary, in an animal model evaluating estrogen-modulated uterine effects and mammary gland development, bazedoxifene exhibited less ER agonist activity than raloxifene or lasofoxifene, and, as a TSEC, bazedoxifene/CE demonstrated less mammary gland stimulation than raloxifene/CE and lasofoxifene/CE.
Endocrine. 2008 Nov 20;
Henderson JA, Bethea CL
To further understand the role of ovarian hormones in the function of the serotonin neural system, we investigated the effects of estradiol (E), progesterone (P), and raloxifene on 5HT 1A and 2C receptor protein expression in the dorsal raphe region using Western blot analysis. Adult rhesus macaques (Macaca mulatta) were ovariectomized (Ovx) and implanted with Silastic capsules containing E or P. In the first paradigm, animals that had been Ovx for 6-16 months were treated for 1 month with E (E1) or E + P (EP1) and compared to animals that were untreated and Ovx for 5 months (n = 4 per group). In the second paradigm, comparisons were made between animals that were Ovx and untreated for 5 months, or Ovx and immediately implanted with Silastic capsules containing E or E + P for 5 months (E5, EP5), or administered raloxifene in the diet for 5 months (Ral5) (n = 4 per group). The dorsal raphe region was harvested, homogenized and a crude membrane fraction was obtained for examination of receptor proteins. In the first paradigm, 5HT1A receptor protein expression was significantly lower in E1 and EP1 treatment groups compared to the Ovx-control group (ANOVA P = 0.01; posthoc P < 0.03), but 5HT2C receptor expression was unaffected by 1 month of E or EP treatment. In the second paradigm, there was no difference in 5HT1A receptor expression between the Ovx-control group and the E5 group, but 5HT1A receptor expression was significantly suppressed in the EP5 group (ANOVA P = 0.04; posthoc P < 0.05). In addition, 5HT2C expression increased in the E5 treatment group relative to the Ovx-control group. Addition of P to the E5 regimen prevented the E5-induced increase in 5HT2C receptor expression and significantly reduced 5HT2C receptor expression to a level below that observed in the Ovx-control group (ANOVA P = 0.001; posthoc P < 0.05). Thus, 5HT1A receptor may lose sensitivity to the suppressive effect of E after 5 months, whereas the 5HT2C receptor increases. However, addition of P in the EP5 regimen maintains the regulatory effects observed with 1 month of treatment. 5HT1A receptor protein levels were higher with raloxifene treatment than in Ovx-control animals (P < 0.01), suggesting that raloxifene may antagonize residual E in Ovx animals.
Chemoprevention of breast cancer.
Am J Health Syst Pharm. 2008 Dec 1; 65(23): 2221-8
Thomsen A, Kolesar JM
PURPOSE: The risk factors for and risk assessment of breast cancer, recommendations for risk reduction, and roles of tamoxifen and raloxifene in the prevention of breast cancer are discussed. SUMMARY: Breast cancer either may be a familial syndrome or develop sporadically. In familial syndromes, cancer occurs in multiple family members and the risk factors are primarily genetic. The majority of breast cancers are sporadic, and risk factors are primarily related to estrogen exposure. Recommendation strategies for reducing breast cancer risk include engaging in a healthy lifestyle by decreasing alcohol consumption, following a low-fat diet enriched with fruits and vegetables, exercising, and reducing weight if obese. Breast self-examinations, clinical breast examinations, and screening mammographies are strategies for the early detection of breast cancer. Recommendations for the use of tamoxifen for risk reduction are intended only for women who are at an increased risk for the development of breast cancer as assessed by the Gail model. One study found a significantly increased risk of cardiovascular events and hypertriglyceridemia in the tamoxifen group compared to placebo. Raloxifene is also intended for women at high risk for breast cancer. During clinical trials, hot flashes, influenzalike syndromes, peripheral edema, and leg cramps were reported more frequently in patients receiving raloxifene when compared with patients receiving placebo, and the risk of thromboembolic disease was 3.1 times higher in the raloxifene group compared with the placebo. CONCLUSION: Tamoxifen and raloxifene are both indicated for and equally effective in the prevention of breast cancer in women at high risk for development of the disease. Raloxifene may have a more favorable adverse-effect profile, with fewer thromboembolic events and less uterine hyperplasia when compared with tamoxifen. Despite being at high risk, many women decide against breast cancer chemoprevention with either tamoxifen or raloxifene.
J Clin Psychopharmacol. 2008 Dec; 28(6): 721-2
Yokoyama S, Sugiyama N, Sugiyama E, Amano N