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- The role of encapsulation by β-cyclodextrin in the interaction of raloxifene with macromolecular targets: a study by spectroscopy and molecular modeling. [JOURNAL ARTICLE]
- J Biol Phys 2014 Jul 30.
We report the binding of the drug raloxifene with Calf thymus DNA (ctDNA) and bovine serum albumin (BSA) in the presence and absence of β-cyclodextrin (β-CD) and explain the influence of β-cyclodextrin on the binding of the drug to macromolecules. UV-Vis absorption, fluorescence, proton nuclear magnetic resonance and two-dimensional rotating-frame nuclear overhauser effect spectroscopic techniques are used to study the stoichiometry and the binding strength of the complexes. Molecular modeling is used in combination with other techniques to propose the structure of the inclusion complex and the interaction with ctDNA. The Stern-Volmer quenching constants of the interaction of raloxifene with ctDNA in aqueous and in β-CD solution are compared. The competition for binding of ctDNA with raloxifene and Methylene Blue is studied. The apparent binding constant and the number of binding sites for the binding of raloxifene with BSA in aqueous solution are significantly different from those in the presence of β-CD. The influence of β-CD on the binding of the small molecules with biological macromolecules is discussed. We infer that the binding strengths between raloxifene and macromolecules, viz., ctDNA and BSA are influenced by the β-CD encapsulation. These results may suggest new ways to tune the drug binding to biomacromolecules by encapsulating specific moieties of drugs.
- Fractures and mortality in relation to different osteoporosis treatments. [JOURNAL ARTICLE]
- Clin Exp Rheumatol 2014 Jul 28.
Few studies have assessed the effectiveness of different drugs for osteoporosis (OP). We aimed to determine if fracture and mortality rates vary among patients initiating different OP medications.We used the Medicare 5% sample to identify new users of intravenous (IV) zoledronic acid (n=1.674), oral bisphosphonates (n=32.626), IV ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or parathyroid hormone (n=549). We included beneficiaries who were ≥65 years of age, were continuously enrolled in fee-for-service Medicare and initiated therapy during 2007-2009. Outcomes were hip fracture, clinical vertebral fracture, and all-cause mortality, identified using inpatient and physician diagnosis codes for fracture, procedure codes for fracture repair, and vital status information. Cox regression models compared users of each medication to users of IV zoledronic acid, adjusting for multiple confounders.During follow-up (median, 0.8-1.5 years depending on the drug), 787 subjects had hip fractures, 986 had clinical vertebral fractures, and 2.999 died. Positive associations included IV ibandronate with hip fracture (adjusted hazard ratio (HR), 2.37; 95% confidence interval (CI) 1.25-4.51), calcitonin with vertebral fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality (HR=1.31; 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome comparisons were not statistically significant.IV ibandronate and calcitonin were associated with higher rates of some types of fracture when compared to IV zolendronic acid. The relatively high mortality associated with use of calcitonin may reflect the poorer health of users of this agent.
- The prevention of fragility fractures in diabetic patients. [JOURNAL ARTICLE]
- Aging Clin Exp Res 2014 Jul 25.
Patients with diabetes mellitus (DM) are at greater risk of fractures mostly due to not only extraskeletal factors, such as propensity to falls, but also to bone quality alteration, which reduces bone strength. In people with DM, insulin deficit and hyperglycemia seem to play a role in determining bone formation alteration by AGE accumulation which directly influences osteoblast activity. Although there are conflicting data in the literature, adequate glycemic control with hypoglycemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 DM. Diabetes status is a predictive of future hip and major osteoporosis fractures independently of BMD and FRAX probability. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycemic control. Systematic screening for complications and fall prevention efforts, along with calcium and vitamin D repletion and adequate physical activity, represents the mainstay of fracture prevention in DM patients. All anticatabolic drugs (raloxifene, bisphosphonates, denosumab) seem to be effective in DM patients. On the basis of pathophysiological evidence that suggests low bone formation in DM patients, osteoanabolic therapies such as teriparatide might represent an important therapeutic option for DM patients with severe osteoporosis and/or multiple fractures. The search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with DM might be considered a clinical priority which could improve the prevention of fracture in DM patients.
- Investigation of Estrogen Receptor (ESR1) for Breast Cancer from Traditional Chinese Medicine. [Journal Article]
- Biomed Res Int 2014.:321486.
Recently, an important topic of breast cancer had been published in 2013. In this report, estrogen receptor (ESR1) had defined the relation of hormone-cause breast cancer. The screening of traditional Chinese medicine (TCM) database has found the molecular compounds by simulating molecular docking and molecular dynamics to regulate ESR1. S-Allylmercaptocysteine and 5-hydroxy-L-tryptophan are selected according to the highest docking score than that of other TCM compounds and Raloxifene (control). The simulation from molecular dynamics is helpful in analyzing and detecting the protein-ligand interactions. After a comparing the control and the Apo form, then based on the docking poses, hydrophobic interactions, hydrogen bond and structure variations, this research postulates that S-allylmercaptocysteine may be more appropriate than other compounds for protein-ligand interaction.
- Differentiation of PC12 cells expressing estrogen receptor alpha: A new bioassay for endocrine-disrupting chemicals evaluation. [Journal Article]
- Chemosphere 2014 Oct.:240-7.
Xeno-estrogens, a class of endocrine disrupting chemicals (EDCs), can disturb estrogen receptor-dependent pathways involved in differentiation, proliferation or protection. Multiple methods have been developed to characterize the disturbances induced by EDCs in different cells or organs. In this study we have developed a new tool for the assessment of estrogenic compounds on differentiation. For this purpose we used the global model of NGF-induced neurite outgrowth of a pseudoneuronal PC12 cell line stably transfected with estrogen receptor alpha (PC12 ER). This new test evidences a new selectivity in which estradiol, genistein and 4-hydroxytamoxifen increased the NGF-induced neurite outgrowth of PC12 ER cells in a dose-dependent manner. In contrast, the strong estrogen agonist 17α-ethynylestradiol, the strong antagonist raloxifene and the agonist bisphenol A were unable to modify the neuritogenesis of PC12 ER cells. Therefore, the analysis of neuritogenesis in PC12 ER cells constitutes a complementary tool for the characterization of xeno-estrogen activity and also serves as a basis for further studies focusing on the mechanisms of EDCs in a neuronal context. Moreover, this test constitutes an alternative to animal testing.
- Effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis. [Journal Article]
- Arch Osteoporos 2014 Dec; 9(1):189.
Osteoporosis is a major cause of mortality and morbidity worldwide. Decreased bone turnover markers and increased lumbar spine and total hip bone mineral density (BMD) in raloxifene-treated women add further support to the idea that raloxifene is an effective well-tolerated option for treating Kuwaiti postmenopausal osteoporosis, suitable for long-term use.Osteoporosis is currently a major cause of mortality, morbidity, and medical expense worldwide, and it is important to investigate therapies for the prevention and treatment of osteoporosis in postmenopausal women. This study was designed to detect the effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis.Postmenopausal women who were free of severe or chronically disabling conditions, had their last menstrual period at least 2 years before the beginning of the study, had a T score for femoral neck or lumbar spine BMD measurements ≤2.5, and were without fractures were included in this study. One hundred and seventy-six (176) women were included in this study and were divided into two groups; the first group (study) received raloxifene with calcium and vitamin D daily for 12 months, and the second group (control) received only calcium and vitamin D. BMD and bone metabolism markers were measured before and after treatment.One year after treatment, BMD of lumbar spine and total hip was significantly increased in study group (3.21 ± 5.4 and 1.62 ± 7.4, respectively) compared to controls (0.9 ± 3.8 and -0.8 ± 5.6, respectively); also, Ward's triangle and trochanter BMD was significantly increased in study group (4.84 ± 9.3 and 1.78 ± 8.5, respectively) compared to controls (1.53 ± 6.6 and -1. 4 ± 6.4, respectively). C-telopeptide was significantly decreased in study group (121 ± 7.8) compared to control group (1,480 ± 6.3); also, serum osteocalcin was significantly decreased in study group (14.5 ± 8.3) compared to control group (43.8 ± 1.3) 1 year after treatment. Occurrence of fractures during this study was significantly low in raloxifene group compared to controls (0 (0 %) versus 3 (3.6 %), respectively).Raloxifene appears to be an effective, well-tolerated option for treating osteoporosis in Kuwaiti postmenopausal women, suitable for long-term use.
- Effect of Red Clover on CYP Expression: An Investigation of Herb-Drug Interaction at Molecular Level. [Journal Article]
- Indian J Pharm Sci 2014 May; 76(3):261-6.
Hormone replacement therapy and selective estrogen receptor modulator are the most common therapy for women going through menopause. These therapies though popular fail to relieve withdrawal symptoms such as hot flashes, fatigue, leg cramps and nausea. This scenario necessitates to herbal preparations as alternative which may lead to simultaneous intake of herbal preparations, containing flavonoids, as well as Selective estrogen receptor modulator hence creating a phenomenon of herb drug interaction. Here we investigate the effect of red clover on steady state mRNA levels of rat cytochrome P 450 enzymes. Further, red clover's effect on cytochrome P 450's expression has been investigated when co-administered with tamoxifen and raloxifene. Exposure to red clover resulted in significant down regulation of all the cytochrome P 450 isoform mRNA except cytochrome P 450 2C13 and cytochrome P 450 3A2. When red clover is given in combination with tamoxifen or raloxifene altered level of cytochrome P 450 enzyme mRNA is observed. Present results suggest that herbal medical preparations such red clover has potential for herb drug interaction.
- Cynomolgus Monkey as a Surrogate for Human Aldehyde Oxidase Metabolism of the EGFR Inhibitor BIBX1382. [JOURNAL ARTICLE]
- Drug Metab Dispos 2014 Jul 17.
BIBX1382 was an epidermal growth factor receptor (EGFR) inhibitor under clinical investigation for treatment of cancers. This candidate possessed an attractive pre-clinical ADME profile, yet failed in clinical studies due in part to poor oral exposure, resulting from extensive metabolism by aldehyde oxidase (AO). In vitro metabolism studies were performed in liver cytosol and cryopreserved hepatocytes from multiple species. In addition, a pharmacokinetic study was performed in cynomolgus monkey for comparison to the reported human pharmacokinetics of BIBX1382. Estimated hepatic clearance of BIBX1382 in rhesus (42 ml/min/kg) and cynomolgus monkey (43 ml/min/kg) liver cytosol was comparable to human (≥93% of liver blood flow). Metabolite identification following incubation of BIBX1382 in liver cytosol fortified with the AO inhibitor raloxifene confirmed that AO is involved in the formation of the predominant metabolite (BIBU1476, M1) in cynomolgus monkey. Following intravenous and oral administration of BIBX1382 to cynomolgus monkeys, high plasma clearance (118 ml/min/kg), and low oral exposure (Cmax=12.7 nM and 6% oral bioavailability) was observed, with the exposure of M1 exceeding BIBX1382 following oral dosing. This pharmacokinetic profile compared favorably with the human clinical data of BIBX1382 (plasma clearance 25-55 ml/min/kg and 5% oral bioavailability). Thus, it appears that cynomolgus monkey represents a suitable surrogate for the observed human AO metabolism of BIBX1382. To circumvent clinical failures due to uncharacterized metabolism by AO, in vitro studies in the appropriate subcellular fraction, followed by pharmacokinetic and toxicokinetic studies in the appropriately characterized surrogate species should be conducted for substrates of AO.
- Effect of Sequential Treatments with Alendronate, Parathyroid Hormone (1-34) and Raloxifene on Cortical Bone Mass and Strength in Ovariectomized Rats. [JOURNAL ARTICLE]
- Bone 2014 Jul 10.
Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear.Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples.Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties.Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent.
- Raloxifene adjunctive therapy for postmenopausal women suffering from chronic schizophrenia: a randomized double-blind and placebo controlled trial. [JOURNAL ARTICLE]
- Daru 2014 Jul 10; 22(1):55.
Cumulative evidence from epidemiological, preclinical and clinical studies suggests estrogens may have psychoprotective effects in schizophrenic patients. Selective Estrogen Receptor Modulators could have therapeutic benefits in schizophrenia for both sexes without being hazardous to gynecological tissues or having feminizing effects. Few studies have been conducted regarding the effects of raloxifene on postmenopausal women suffering from schizophrenia. We conducted this placebo-controlled trial to compare the add-on effect of raloxifene to risperidone versus risperidone with placebo.This was an 8-week, parallel-group, placebo-controlled trial undertaken at two universities affiliated psychiatric Hospitals in Iran. Forty-six postmenopausal women with the definite diagnosis of schizophrenia were enrolled in the study. Patients received risperidone (6 mg/day in 3 divided doses) combined with either placebo (N = 23) or 120 mg/day of raloxifene (N = 23) for 8 weeks. Patients were assessed by a psychiatrist at baseline and at 2 and 8 weeks after the start of medical therapy. Efficacy was defined as the change from baseline to endpoint in score on Positive and Negative Syndrome Scale (PANSS).For PANSS scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.77, p = 0.18]. For positive subscale scores, there was marginal significant interaction between intervention type and time [F (2, 47) = 2.93, p = 0.06] and there was substantial main effect for time [F (2, 47) = 24.39, p = 0.001] within both groups showing reduction in positive subscale scores across the three time periods. In addition, the main effect comparing two types of intervention was significant [F (1, 48) = 3.78, p = 0.02]. On the other hand, for negative subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 1.43, p = 0.23]. For general subscale scores, the main effect comparing two types of intervention was not significant [F (1, 48) = 0.03, p = 0.86].According to our findings, raloxifene as an adjunctive treatment to risperidone was only superior in improvement of positive symptoms and it was not effective in treating negative and general psychopathology symptoms.Trial registration: The trial was registered at the Iranian registry of clinical trials: IRCT201205131556N42.