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- Estrogen or raloxifene during postmenopausal weight loss: Adiposity and cardiometabolic outcomes. [JOURNAL ARTICLE]
- Obesity (Silver Spring) 2013 Oct 29.
Estrogen-based hormone therapy (HT) attenuates abdominal fat gain after menopause, but whether HT improves abdominal fat loss during weight loss is unknown. It was hypothesized that HT or a selective estrogen receptor modulator (raloxifene) would augment reductions in abdominal visceral fat during weight loss when compared to placebo, potentially increasing improvements in glucose tolerance and lipid profile.Healthy postmenopausal women (n = 119; age 50-70 yr) underwent a 6-month weight-loss (primarily exercise) intervention with randomization to raloxifene (60 mg/d), HT (conjugated estrogens, 0.625 mg/d), or placebo. Outcomes were change in total and abdominal (visceral and subcutaneous) fat mass, lipid profile, and fasting and post-challenge glucose and insulin.Neither HT nor raloxifene augmented loss of total or abdominal fat mass during exercise-induced weight loss when compared with placebo. Weight loss-induced improvements in risk factors were similar among the three groups, except for a greater reduction in fasted glucose in the HT group (difference in change [95%CI] from placebo; -0.40 [-0.76, -0.05]) and greater reductions in LDL (-0.36 [-0.63, -0.09]) and increases in HDL (0.15 [0.07, 0.24]) in both treatment groups.Postmenopausal HT and raloxifene did not increase abdominal fat loss during weight loss, but did improve some cardiometabolic outcomes.
- Improving osteoporosis management following minimal trauma fracture in a regional setting: The Coffs Fracture Card Project. [Journal Article]
- Aust J Rural Health 2013 Dec; 21(6):343-9.
To improve osteoporosis (OSP) management following minimal trauma fracture (MTF) with few additional resources.Population intervention with serial cross-sectional analysis.Regional setting involving primary care, base hospital and private hospital.Patients with MTF.A 'Fracture Card' prompting OSP management was provided to all patients post-MTF. Patients were encouraged to attend their general practitioner (GP) with this to discuss bone health issues. The 2-year intervention was supported by a public health education campaign.Number of (i) serum 25-OH vitamin D assays, (ii) dual-energy X-ray absorptiometry (DXA) scans, and (iii) new Pharmaceutical Benefits Scheme (PBS)-subsidised prescriptions for bone protective therapy (bisphosphonates, raloxifene, strontium, teriparatide, denosumab).The number of serum 25-OH vitamin D assays ordered in Coffs Harbour increased from 329 ± 15 per month (July 2009-June 2010) to 568 ± 21 (July 2010-June 2012; P < 0.001). The number of DXA scans performed per month increased from 192 ± 14 (July 2009-June 2010) to 296 ± 12 (July 2010-June 2012; P < 0.001). There was no difference in the number of new PBS-subsidised prescriptions for bone protective therapy in the Coffs statistical subdivision over that time (176 ± 3.8 per month, July 2009-June 2010 versus 180 ± 3.5, July 2010-June 2012, P > 0.05).The intervention was associated with an increased number of 25-OH vitamin D assays and DXA scans but not with more prescriptions for bone protective therapy. This suggests that a public health education campaign and provision of a 'prompt' for GPs was only partially successful at improving OSP management post-MTF. This has driven establishment of a Fracture Liaison Service.
- Cognitive factors associated with adherence to oral anti-estrogen therapy: Results from the Cognition in the Study of Tamoxifen and Raloxifene Study. [JOURNAL ARTICLE]
- Cancer Prev Res (Phila) 2013 Nov 19.
Little is known about the cognitive factors associated with adherence to anti-estrogen therapy. Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral anti-estrogen therapies. We performed a secondary analysis of Co-STAR, an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were randomized to tamoxifen or raloxifene. Co-STAR enrolled non-demented participants ≥65 years old to compare treatment effects on cognition. The cognitive battery assessed global cognitive function (Modified Mini-Mental State Exam), and specific cognitive domains of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, spatial ability, and fine motor speed. Adherence was defined by a ratio of actual time taking therapy per protocol ≥80% of expected time. Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy. The mean age of the 1,331 Co-STAR participants was 67.2±4.3 years. Mean 3MS score was 95.1 (4.7) and 14% were non-adherent. In adjusted analyses, the odds of non-adherence were lower for those with better scores on verbal memory [OR (95% CI): 0.75 (0.62, 0.92)]. Larger relative deficits in verbal memory compared to verbal fluency were also associated with non-adherence [1.28(1.08, 1.51)]. Among non-demented older women, subtle differences in memory performance were associated with medication adherence. Differential performance across cognitive domains may help identify persons at greater risk for poor adherence.
- Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. [Journal Article]
- Biomed Res Int 2013.:584549.
Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN) have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.
- A robotic MCF-7:WS8 cell proliferation assay to detect agonist and antagonist estrogenic activity. [JOURNAL ARTICLE]
- Toxicol Sci 2013 Nov 9.
Endocrine disrupting chemicals with estrogenic (EA) or anti-estrogenic (AEA) activity have been extensively reported to possibly have many adverse health effects. We have developed robotized assays using MCF-7:WS8 cell proliferation (or suppression) to detect EA (or AEA) of 78 test substances supplied by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) for validation studies. We also assayed ICI 182,780, a strong estrogen antagonist. Chemicals to be assayed were initially examined for solubility and volatility to determine optimal assay conditions. For both EA and AEA determinations, a Range-Finder Assay was conducted to determine the concentration range for testing, followed by a Comprehensive Assay. Test substances with potentially positive results from an EA Comprehensive Assay were subjected to an EA Confirmation Assay that evaluated the ability of ICI 182,780 to reverse chemically-induced MCF-7 cell proliferation. The AEA Assays examined the ability of chemicals to decrease MCF-7 cell proliferation induced by non-saturating concentrations of 17β-estradiol (E2), relative to ICI or raloxifene (RAL), also a strong estrogen antagonist. To be classified as having AEA, a saturating concentration of E2 had to significantly reverse the decrease in cell proliferation produced by the test substance in non-saturating E2. We conclude that our robotized MCF-7 EA and AEA Assays have accuracy, sensitivity, and specificity values at least equivalent to validated test methods accepted by the US EPA and the Organisation for Economic Co-operation and Development (OECD).
- Understanding and Communicating the Benefits and Risks of Denosumab, Raloxifene, and Teriparatide for the Treatment of Osteoporosis. [JOURNAL ARTICLE]
- J Clin Densitom 2013 Oct 24.
The number needed to treat is a valuable metric to determine the benefit of therapy, but it must be viewed against the respective number needed to harm. Denosumab and teriparatide (TPTD) have proven antifracture efficacy at vertebral and nonvertebral sites, whereas raloxifene has proven antifracture efficacy at the spine only. Denosumab use has been associated with a small, yet statistically significant, increased incidence of eczema and serious cellulitis. Raloxifene use has been associated with statistically significant increases in the risk of venous thromboembolism and possibly deadly stroke, although not an increase in total strokes. No significant, nontransient adverse events have been reported with TPTD use. When used for the treatment of postmenopausal osteoporosis, denosumab, raloxifene, and TPTD all generally have favorable risk-to-benefit profiles, but therapy-specific contraindications necessitate thoughtful consideration of all available clinical information and individualization of treatment decisions.
- Direct, differential effects of tamoxifen, 4-hydroxytamoxifen, and raloxifene on cardiac myocyte contractility and calcium handling. [Journal Article]
- PLoS One 2013; 8(10):e78768.
Tamoxifen (Tam), a selective estrogen receptor modulator, is in wide clinical use for the treatment and prevention of breast cancer. High Tam doses have been used for treatment of gliomas and cancers with multiple drug resistance, but long QT Syndrome is a side effect. Tam is also used experimentally in mice for inducible gene knockout in numerous tissues, including heart; however, the potential direct effects of Tam on cardiac myocyte mechanical function are not known. The goal of this study was to determine the direct, acute effects of Tam, its active metabolite 4-hydroxytamoxifen (4OHT), and related drug raloxifene (Ral) on isolated rat cardiac myocyte mechanical function and calcium handling. Tam decreased contraction amplitude, slowed relaxation, and decreased Ca(2+) transient amplitude. Effects were primarily observed at 5 and 10 μM Tam, which is relevant for high dose Tam treatment in cancer patients as well as Tam-mediated gene excision in mice. Myocytes treated with 4OHT responded similarly to Tam-treated cells with regard to both contractility and calcium handling, suggesting an estrogen-receptor independent mechanism is responsible for the effects. In contrast, Ral increased contraction and Ca(2+) transient amplitudes. At 10 μM, all drugs had a time-dependent effect to abolish cellular contraction. In conclusion, Tam, 4OHT, and Ral adversely and differentially alter cardiac myocyte contractility and Ca(2+) handling. These findings have important implications for understanding the Tam-induced cardiomyopathy in gene excision studies and may be important for understanding effects on cardiac performance in patients undergoing high-dose Tam therapy.
- Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions. [JOURNAL ARTICLE]
- Xenobiotica 2013 Oct 24.
Abstract 1. Aldehyde oxidase (AO) is a liver cytosolic molybdoflavoprotein enzyme whose importance in drug metabolism is gaining in the recent. The objective of this work is to find a potent and selective inhibitor for AO activity using phthalazine oxidation as a marker reaction. 2. Among organic solvents tested, it was identified that methanol was not a suitable choice for AO activity even at concentrations less than 0.2% v/v. Acetonitrile and DMSO did not show any effect till 0.5% v/v but thereafter activites tend to decrease. 3. For selectivity, 23 compounds were selected and evaluated for their effects on AO and nine CYP450 enzymes. Among the tested compounds chlorpromazine, estradiol, hydralazine, quetiapine and raloxifene were selected based on their potency of inhibition towards AO activity. 4. Raloxifene was found to be a non-specific inhibitor of all major tested CYP450 enzymes and was excluded as a selective inhibitor for AO. Quetiapine also showed a degree of inhibition towards the major CYP450 tested. Hydralazine used as a specific inhibitor during the past for AO activity demonstrated a stimulation of AO activity at high and low concentrations respectively and the inhibition noted to be time dependent while inhibiting other enzymes like monoamine oxidase. 5. Estradiol showed no inhibition towards the tested CYP450 enzymes and thus proved to be a selective and specific inhibitor for AO activity with an uncompetitive mode of inhibition.
- Use of health-related quality of life measures to predict health utility in postmenopausal osteoporotic women: results from the Multiple Outcomes of Raloxifene Evaluation study. [JOURNAL ARTICLE]
- Health Qual Life Outcomes 2013 Nov 5; 11(1):189.
The aim of this study is to examine the associations between health utility (HU), health-related quality of life (HRQoL), and patient characteristics in postmenopausal osteoporotic (PMO) women.Baseline data from a subsample of 1,245 participants of the Multiple Outcomes of Raloxifene Evaluation study, a randomized, placebo-controlled, multinational clinical trial to evaluate the safety and efficacy of raloxifene, were analyzed. The study cohort included 694 participants from non-European Union (non-EU) countries and 551 participants from EU countries. All participants with complete baseline HU and HRQoL assessments were included in the following analyses: 1) HU (HUI or EQ-5D) and HRQoL (QualEFFO or OPAQ and NHP) associations; 2) HU variability explained by HRQoL domains; and 3) the percentage of HU variability explained by statistically significant (p < 0.05) HRQoL domains, after adjusting for baseline characteristics.Several domains were significantly associated with HU scores. HU variance was well explained (41% to 61%) by 4 to 6 (p < 0.05) significant HRQoL domains. After controlling for baseline characteristics, 48% to 64% of the HU variance was well explained by 5 to 7 significant (p < 0.05) HRQoL domains. Additional trend analyses detected statistically significant decreases in HRQoL and HU scores with an increased number of vertebral and non-vertebral fractures.Both disease-targeted and generic HRQoL domains were well correlated with HU. A large percentage (48% to 64%) of the HU variance was explained by HRQoL, after adjusting for baseline characteristics. Both disease-targeted and generic HRQoL measures were significant predictors of HU. HRQoL and HU scores decreased with increased vertebral and non-vertebral fractures.