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- Differentiation of PC12 cells expressing estrogen receptor alpha: A new bioassay for endocrine-disrupting chemicals evaluation. [JOURNAL ARTICLE]
- Chemosphere 2014 Oct.:240-247.
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.
- Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury. [Journal Article]
- Front Aging Neurosci 2014.:132.
Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II(+) microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: (1) young rats, ovariectomized at 2 months of age; and (2) aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which selective estrogen receptors modulators (SERMs) may exert a neuroprotective effect in the setting of a brain trauma.
- Controlled release of raloxifene by nanoencapsulation: effect on in vitro antiproliferative activity of human breast cancer cells. [Journal Article]
- Int J Nanomedicine 2014.:2979-91.
Raloxifene hydrochloride (RH) is considered to be an antiproliferative agent of mammary tissue. The aim of this study was to investigate the effect of the encapsulation of RH in polymeric nanocapsules with anionic or cationic surface on its release profile and antiproliferative activity. They were prepared by interfacial deposition of preformed polymer, followed by wide physicochemical characterization. The in vitro RH release was assessed by the dialysis membrane method and the data analyzed by mathematical modeling. The antiproliferative effect on MCF-7 cell viability was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as well as by counting viable cells. They had high encapsulation efficiency, low polydispersity, and nanometric mean size. Nanocapsules prepared with Eudragit(®) RS100 and Eudragit(®) S100 presented positive and negative zeta potentials, respectively. Drug release studies demonstrated controlled release of RH from anionic nanocapsules, which could be explained due to a stronger interaction of the drug to these nanocapsules and the larger amount of entrapped drug. On the other hand, this control was not observed from cationic nanocapsules due to the larger amount of drug adsorbed onto their surface. MCF-7 cell viability studies and cell counting showed that RH-loaded Eudragit(®) RS100 nanocapsules promote the best antiproliferative activity after 24 hours of treatment, whereas the best activity was observed for RH-loaded Eudragit(®) S100 nanocapsules after 72 hours. Furthermore, the combined treatment of these formulations improved the antiproliferative effect during the entire treatment.
- Pharmacological management of osteogenesis. [JOURNAL ARTICLE]
- Clinics (Sao Paulo) 2014 Jun; 69(6):438-446.
Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases.
- Management of postmenopausal osteoporosis and the prevention of fractures. [Journal Article]
- Panminerva Med 2014 Jun; 56(2):115-31.
Postmenopausal osteoporosis affects millions of women, being estrogen deficiency the key factor in the pathogenesis of involutional osteoporosis. Fracture prevention is one of the public health priorities worldwide. Different treatments for osteoporosis are available. The various options are aimed to maintain bone health and decrease the risk of fractures. The majority of these drugs are antiresorptive agents, i.e., drugs that lower bone turnover, inhibiting osteoclastic bone resorption. Dietary sources of calcium intake and vitamin D are ideal, while pharmachological supplements should be used if diet alone cannot provide the recommended daily intake. Bisphosphonates are first-line therapy for patients with established osteoporosis at high risk of fracture. Some serious, but rare, adverse events have been associated with their long-term administration. The monoclonal antibody to RANKL, named denosumab, administered as a 60-mg subcutaneous injection every 6 months, is a valuable option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, who are unable to take other osteoporosis treatments. Teriparatide (PTH 1-34) is the only available osteoanabolic drugs for osteoporosis treatment at present. Its use is limited to severe osteoporosis because of the high cost of the treatment. In climacteric women, in different stages of menopausal transition, and beyond, hormone replacement therapy at different doses (HRT) rapidly normalizes turnover, preventing and/or treating osteoporosis. HRT is able to preserve and even increase BMD at all skeletal sites, leading to a significant reduction in vertebral and non-vertebral fractures. Selective estrogen modulators (SERMs) as raloxifene and bazedoxifene reduce bone turnover and maintains or increases vertebral and femoral BMDs in comparison to placebo and reduces the risk of vertebral and new vertebral fractures, in high risk women. The combination of a SERM with an estrogen has been defined as tissue selective estrogen complex (TSEC). The bazedoxifene with conjugated estrogen is able to reduce climacteric symptoms, reducing bone turnover and preserving BMD. Studies investigating the actions of phytoestrogens on BMD or bone turnover are largely contradictory, making them inconclusive. At the present time, phytoestrogens cannot be recommended for postmenopausal osteoporosis. In conclusion, the use of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. Osteoporosis prevention can actually be considered as a major additional effect in climacteric women who use HRT for treatment of climacteric symptoms. Bone protection is one of the major benefits of HRT. The possibility that low dose HRT or TSEC causes a decrease in fracture risk is not demonstrated but the scientific evidence is compelling. Conversely, established osteoporosis, often occurring in elderly women, can better be treated with specific treatments, such as bisphosphonates or, in more severe and selected cases, anabolic agents (teriparatide).