Effects Of Raloxifene Research Articles

A Combination Treatment of Raloxifene and Vitamin D Enhances Bone-to-Tendon Healing of the Rotator Cuff in a Rat Model

Background: Tearing and degeneration of the rotator cuff at the tendon-to-bone junction are common in adults aged ≥50 years. Few studies have reported on the relationship between estrogen and the rotator cuff enthesis. In addition to preventing bone loss, selective estrogen receptor modulators have been shown to improve tendon and muscle quality. Purpose: To evaluate the effects of raloxifene (RLX) and vitamin D on rotator cuff tendon-to-bone healing in a rat model. Study Design: Controlled laboratory study. Methods: A total of 29 female rats (58 shoulders) were assigned to 4 groups: (1) control group, (2) ovariectomy (OVX)–only group, (3) no RLX group (OVX and rotator cuff repair [RCR]), and (4) RLX group (OVX, RCR, and RLX). Rats that did not undergo rotator cuff tear (RCT) surgery were divided into the control and OVX-only groups according to OVX surgery. Rats that underwent RCT surgery and RCR were divided into the no RLX and RLX groups according to RLX and vitamin D administration. An estrogen-deficient state was induced by OVX at 12 weeks of age. Bone mineral density (BMD) and trabecular bone characteristics were measured by micro–computed tomography, and healing of the tendon-to-bone junction was evaluated by biomechanical testing, histomorphometry, and micro–magnetic resonance imaging (MRI). Results: The mean final body weight (BW; 461.6 ± 47.3 g) of the OVX-only group was significantly higher and BMD (0.25 ± 0.07 g/cm3) was significantly lower (P < .001) than the mean final BW (338.5 ± 35.1 g) and BMD (0.48 ± 0.05 g/cm3) of the control group. In contrast, the RLX group showed that the BW (369.6 ± 35.8 g) and BMD (0.41 ± 0.08 g/cm3) were not significantly different from the control group. The RLX group had a significantly higher histomorphometric total score (8.50 ± 1.05) than the no RLX group (4.83 ± 2.48). On biomechanical testing, the RLX group (29.7 ± 9.1 N) showed a significantly higher load to failure than the no RLX group (19.4 ± 8.8 N). On micro-MRI, the RLX group had a more homogeneous low signal and tendon continuity than the no RLX group. Conclusion: The combination treatment of RLX and vitamin D prevented a decrease in local BMD (greater tuberosity of the proximal humerus) and enhanced tendon-to-bone healing of the rotator cuff in a rat model. Clinical Relevance: This study induced an estrogen-deficient state similar to the human postmenopausal state and used drugs that are actually being prescribed in a clinical situation.

Raloxifene improves TNF-α-induced osteogenic differentiation inhibition of bone marrow mesenchymal stem cells and alleviates osteoporosis.

Effect of raloxifene (RLF) on the improvement of inhibited osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) resulted from tumor necrosis factor-α (TNF-α) induction, thus alleviating the progression of osteoporosis (OP), was investigated. An in vivo OP rat model was constructed by performing the procedures of ovariectomy (OVX). Rats were randomly divided into sham group, OVX group and RLF+OVX group. BMSCs were extracted from healthy rats, and randomly divided into control group, TNF-α group, RLF group and TNF-α+RLF group. Viability and cellular calcification ability in each group were detected. The relative levels of osteocalcin (OCN), Runx2 and NF-κB in cells with different treatments were determined. The body weight of rats in the OVX group and RLF+OVX group gradually increased compared with that in the sham group on the 8th week. No significant difference in body weight was observed between the rats of the OVX group and RLF+OVX group. Bone metabolism index (BMD) in the rats of the RLF+OVX group was higher than that of the OVX group, and lower compared with that of the sham group. Compared with the sham group, the elastic/max radial degree and elastic/max load of femora were reduced in the OVX group and RLF+OVX group, especially in the OVX group. The relative levels of OCN and Runx2, as well as the ALP activity and calcification ability, were decreased in the OVX group compared with the sham group, and the effect was partially reversed by the RLF treatment. After osteogenic differentiation of BMSCs, the viability and calcification ability were markedly reduced in TNF-α group, which was reversed by RLF treatment. Moreover, TNF-α induction downregulated the relative levels of OCN and Runx2, and RLF treatment could enhance their levels. The upregulated NF-κB protein level, induced by TNF-α, was reduced after RLF treatment. TNF-α induction inhibits osteogenic differentiation of BMSCs, which could be remarkably alleviated by RLF. It is suggested that RLF contributes to the alleviation of OP progression.

Effect of Raloxifene on Bone Formation Around Implants in the Osteoporotic Rat Maxilla: Histomorphometric and Microcomputed Tomographic Analysis.

Raloxifene, an antiresorptive drug, prevents bone loss and promotes bone formation by secondary anabolic action. The purpose of this study was to investigate the effectiveness of raloxifene on the osseointegration of implants in the rat model of the osteoporotic maxilla. Thirty Sprague-Dawley female rats aged 10 weeks were randomly assigned to the following groups: (1) raloxifene (RAL) group (n = 10), (2) ovariectomized (OVX) group (n = 10), and (3) control group (sham-operated, n = 10). Both ovaries were removed to induce osteoporosis, and the maxillary right molar was extracted. After 4 weeks, an implant was placed on the same edentulous area. Raloxifene 1 mg/kg/day was administered to the experimental animals in the RAL group, while those in the ovariectomized group and sham-operated group were given the same amount. All experimental animals were sacrificed at 4 weeks after implants were placed. Histomorphometric measurements of the bone area ratio (BA, %) and bone-to-implant contact ratio (BIC, %) around the implant were performed. Three-dimensional (3D) microcomputed tomographic (micro-CT) analysis of peri-implant bone microarchitecture was also performed and statistically analyzed. In the histomorphometric analysis, the BA ratio of the implant in the RAL group was higher than that in the OVX group (53.3% ± 7.2% vs 38.2% ± 11.7%, P = .024). BIC around the implant in the RAL group did not show a statistical difference compared with that in the OVX group (42.7% ± 15.0% vs 34.5% ± 16.2%, P > .05). In microstructural analysis, the RAL group showed a significant increase of trabecular thickness compared with the OVX group (0.09 ± 0.02 mm vs 0.06 ± 0.01 mm, P = .013). However, raloxifene did not show convincing differences between the groups in other micro-CT parameters (P > .05). The results show that raloxifene administration demonstrated enhanced new peri-implant bone formation in the osteoporotic rat maxilla. Further research is needed to reveal the effect of raloxifene on the clinical outcome of patients with poor bone quality who undergo dental implant treatment.

Raloxifene administration enhances retention in an orthodontic relapse model.

Orthodontic relapse is a physiologic process that involves remodelling of the alveolar bone and principle periodontal ligament fibres. Raloxifene is an Food and Drug Administration (FDA)-approved selective oestrogen receptor modulator that inhibits systemic bone loss. In our study, we examined the effects of Raloxifene on alveolar bone modelling and orthodontic relapse in a rodent model. The efficacy of raloxifene was evaluated in 15-week-old male Wistar rats, 8 in each group (Control, Raloxifene, Raloxifene + 7-day relapse, Raloxifene + 14-day relapse) for a total of 42 days. All animals had 14 days of orthodontic tooth movement with a closed nickel-titanium coil spring tied from incisors to right first molar applying 5-8 gm of force. On the day of appliance removal, impression was taken with silicon material and the distance between first molar and second molar was filled with light-cured adhesive resin cement for retention phase. Raloxifene Retention, Raloxifene Retention + 7D, Raloxifene Retention + 14D groups received 14 daily doses of raloxifene (2.0 mg/kg/day) subcutaneously after orthodontic tooth movement during retention. After 14 days of retention, the retainer was removed and right first molar was allowed to relapse for a period of 14 days. Raloxifene injection continued for the Raloxifene + 14-day relapse group during relapse phase too. Control group received saline injections during retention. Animals were euthanized by CO2 inhalation. The outcome measure included percentage of relapse, bone volume fraction, tissue density, and histology analysis using tartrate-resistant acid phosphatase staining and determining receptor activator of nuclear factor-кB-ligand (RANKL) and osteoprotegerin expression. Raloxifene Retention + 14D group had significantly less (P < 0.05) orthodontic relapse when compared with other groups. There was a significant increase (P < 0.05) in bone volume fraction and tissue density in the Raloxifene Retention + 14D group when compared with other groups. Similarly, there was significant decrease in number of osteoclasts and RANKL expression in Raloxifene Retention + 14D group when compared with Raloxifene Retention + 7D group (P < 0.05). Raloxifene could decrease post-orthodontic treatment relapse by decreasing bone resorption and indirectly enhancing bone formation.

Medical Management of Patients After Atypical Femur Fractures: a Systematic Review and Recommendations From the European Calcified Tissue Society.

ContextAtypical femur fractures (AFFs) are serious adverse events associated with bisphosphonates and often show poor healing.Evidence acquisitionWe performed a systematic review to evaluate effects of teriparatide, raloxifene, and denosumab on healing and occurrence of AFF.Evidence synthesisWe retrieved 910 references and reviewed 67 papers, including 31 case reports, 9 retrospective and 3 prospective studies on teriparatide. There were no RCTs. We pooled data on fracture union (n = 98 AFFs on teriparatide) and found that radiological healing occurred within 6 months of teriparatide in 13 of 30 (43%) conservatively managed incomplete AFFs, 9 of 10 (90%) incomplete AFFs with surgical intervention, and 44 of 58 (75%) complete AFFs. In 9 of 30 (30%) nonoperated incomplete AFFs, no union was achieved after 12 months and 4 (13%) fractures became complete on teriparatide. Eight patients had new AFFs during or after teriparatide. AFF on denosumab was reported in 22 patients, including 11 patients treated for bone metastases and 8 without bisphosphonate exposure. Denosumab after AFF was associated with recurrent incomplete AFFs in 1 patient and 2 patients of contralateral complete AFF. Eight patients had used raloxifene before AFF occurred, including 1 bisphosphonate-naïve patient.ConclusionsThere is no evidence-based indication in patients with AFF for teriparatide apart from reducing the risk of typical fragility fractures, although observational data suggest that teriparatide might result in faster healing of surgically treated AFFs. Awaiting further evidence, we formulate recommendations for treatment after an AFF based on expert opinion.

Comparison of the skeletal effects of annatto tocotrienol and raloxifene in an animal model of advanced bone loss due to oestrogen deficiency

Comparison of the skeletal effects of annatto tocotrienol and raloxifene in an animal model of advanced bone loss due to oestrogen deficiency

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.

We assessed the utility of raloxifene (60mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight beganthe clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann-Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect.ClinicalTrials.gov Identifier: NCT01573637.

Clinical effectiveness of denosumab, raloxifene, romosozumab, and teriparatide for the prevention of osteoporotic fragility fractures: A systematic review and network meta-analysis.

To determine the clinical effectiveness of denosumab (DEN), raloxifene (RLX), romosozumab (ROMO) and teriparatide (TPTD), within their licensed (or anticipated licensed) indications, for the treatment of osteoporosis. A systematic review was conducted. Nine electronic databases and trial registries were searched up to the end of July 2018. Studies were eligible for inclusion if they were randomised controlled trials (RCT) in a population at risk of osteoporotic fracture, comparing these four non-bisphosphonates DEN, RLX, ROMO, or TPTD with each other, a non-active treatment, or the bisphosphonates alendronate (ALN), risedronate (RIS), ibandronate (IBN) and zoledronic acid (ZOL). Quality of included studies was assessed using the Cochrane Risk of Bias tool. Network meta-analyses (NMA) were used to determine the relative effectiveness of treatments. The systematic review identified 7898 citations. Forty-six RCTs of non-bisphosphonates met the inclusion criteria for the review and provided data for analyses. Additionally 49 RCTs of bisphosphonates were used in the NMAs. Forty-six RCTs were included in the NMA of vertebral fracture data, 23 RCTs for hip fractures and 73 RCTs in the NMA of femoral neck bone mineral density (FN BMD). For vertebral fractures, all four non-bisphosphonates showed statistically significant benefit relative to placebo: TPTD HR 0.23 (95% credible internal (CrI) 0.16, 0.32); ROMO followed by ALN 0.25 (95% CrI 0.15, 0.43); DEN HR 0.30 (95% CrI 0.21, 0.43); RLX HR 0.61 (95% CrI 0.44, 0.80). The four non-bisphosphonates interventions studied also showed statistically significant benefit relative to placebo for FN BMD, and for hip fractures TPTD, ROMO followed by ALN, and DEN showed statistically significant benefit relative to placebo. The four non-bisphosphonate interventions studied were all statistically significantly clinically effective for reducing vertebral fractures when compared to placebo, and were beneficial for change in FN BMD compared to placebo. All reduced hip fractures, and this was statistically significant for TPTD, ROMO followed by ALN, and DEN.

Raloxifene alleviates amyloid-β-induced cytotoxicity in HT22 neuronal cells via inhibiting oligomeric and fibrillar species formation.

Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-β (Aβ) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aβ42 aggregation and destabilizes preformed Aβ42 fibrils through directly interacting with the N-terminus and middle domains of Aβ42 peptides. Consequently, raloxifene not only reduces direct toxicity of Aβ42 in HT22 neuronal cells, but also suppresses expressions of tumor necrosis factor-α and transforming growth factor-β induced by Aβ42 peptides, and then alleviates microglia-mediated indirect toxicity of Aβ42 to HT22 neuronal cells. Our results suggested an alternative possible explanation for the neuroprotective activity of raloxifene in AD prevention.

Raloxifene recovers effects of prenatal immune activation on cognitive task-induced gamma power

There is currently no treatment available for the cognitive symptoms of schizophrenia, but evidence suggests that selective estrogen receptor modulators (SERMs) may provide relief. Our recent animal model data showed that a lack of female sex hormones in mice impairs the ability of hippocampal neurons to synchronise and generate oscillations within the frequency range of 30–80 Hz (gamma power) leading to cognitive impairment, while both estradiol and the SERM, raloxifene, recovered this. Given that cognitive impairment is accompanied by abnormal gamma power in schizophrenia, this study aimed to determine the effects of raloxifene on gamma power during spatial memory tasks in the prenatal immune challenged (poly-I:C) mouse model with relevance to schizophrenia.Pregnant dams received the viral mimetic poly-I:C (20 mg/kg, i.p.) at gestational day 17. Male and female offspring were treated with placebo or raloxifene implants at adulthood. Local field potentials from the CA1 hippocampus were simultaneously recorded during the Y-maze test of short term spatial memory and the cheeseboard maze test of long-term spatial learning and memory and cognitive flexibility.In female but not male mice, poly I:C exposure reduced gamma power during decision making and prolonged the time spent in the centre (decision making phase) during the Y-maze task. Female poly-I:C exposed mice also showed increased gamma power during acquisition of the cheeseboard long term memory task and perseverative behaviour. Treatment with raloxifene recovered gamma power and decision making deficits in the Y-maze and restored gamma power changes during the cheeseboard maze task as well as perseverative behaviour. Male mice showed no electrophysiological or behavioural effects of poly-I:C or raloxifene treatment.In summary, poly-I:C exposure induced female specific cognitive impairments accompanied by altered neural oscillations in the gamma frequency and raloxifene recovered these abnormalities.

EFFECT OF RALOXIFENE IN THE PREVENTION OF OSTEOPOROSIS OF ALVEOLAR BONE INDUCED BY HIGH FAT DIET IN RATS

INTRODUCTION: Obesity is positively associated with many chronic disorders such as osteoporosis, as it decreases the osteoblastic cell formation, increases the osteoclastic activity and decreases the vascularity of the bone marrow as well. Raloxifene belongs to a class of drugs called selective estrogen receptor modulators (SERMs). It reduces the expression of bone turnover markers and increases bone mineral density. OBJECTIVES: To investigate the effect of Raloxifene in the prevention of osteoporosis of alveolar bone induced by high fat diet in the rats. MATERIALS AND METHODS Thirty female albino rats were divided randomly into 3 equal groups, (10 rats each) as follows: Group I: control group, Group II: High fat diet group (59.28% of fats in their chow), Group III: High fat diet group (59.28%) with intake of Raloxifene 1mg/ kg once daily for 12 weeks. After 12 weeks all rats were sacrificed, molar segments of the mandibles were dissected and prepared for histological and histomorphometric analysis. RESULTS: In high fat diet group, there was a significant deterioration in alveolar bone architecture and decrease in its surface area. Bone surface became irregular with multiple osteoclasts. It consisted of thin trabeculae enclosing wide fatty infiltrated bone marrow. In the high fat diet group treated with Raloxifene the alveolar bone surface and architecture relatively returned back to the normal. The histomorphometric results, revealed a significant decrease in the total bone surface area in high fat diet group and a significant restoration of the bone surface area in high fat diet group treated with Raloxifene in relation to control group. CONCLUSIONS: High fat diet can induce alveolar bone osteoporosis and Raloxifene is an effective drug in restoring alveolar bone density and architecture

Is there any potential anticancer effect of raloxifene and fluoxetine on DMBA-induced rat breast cancer?

Breast cancer is the most common cancer among women in the world and the incidence is increasing alarmingly. It was aimed to determine the effect of raloxifene (RAL) and fluoxetine (FLX) on selected parameters in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma. Thirty-two female Wistar albino rats were assorted into four groups: DMBA (group I), DMBA+RAL (group II), DMBA+FLX (group III), and DMBA+RAL+FLX (group IV). Mammary tissue vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-9 (MMP-9), and tissue inhibitors of matrix metalloproteinase-1 (TIMP-1) levels were determined by the enzyme-linked immunosorbent assay method. The tissue VEGF levels were lower in group IV compared with DMBA group. Decreased M-CSF levels were observed in all therapeutic groups rather than the DMBA group, but the most effective decrease was found in group IV. Compared with the DMBA group, MMP-9 levels were statistically significantly decreased in group II and group IV. However, TIMP-1 levels were higher in the whole therapeutic groups rather than the DMBA group and the most effective increase was observed in group IV. Results of the present study suggest that combined therapy of RAL with FLX might lead to a better outcome targeting breast tumor.

The Effect of Raloxifene on Serum Prolactin Level in Patients with Prolactinoma

Objective: To evaluate the effect of raloxifene on prolactin (PRL) levels in addition to dopamine agonist (DA) therapy in patients with prolactinoma. Methods: We conducted a retrospective chart review of 14 patients with prolactinoma on stable dose of DA for 6 months who received raloxifene 60 mg daily, as PRL could not be normalized despite being on fairly high doses of DA. Patients were informed that raloxifene is not approved by the Food and Drug Administration for prolactinoma treatment. PRL level was measured at 1 to 6 months after starting raloxifene and at 1 to 3 months following its discontinuation. Raloxifene was stopped in 8 out of 14 patients after 2 (1 to 6) months of treatment as the absolute change in PRL level was felt to be small. Results: The median age and female/male sex ratios were 50 years (range 18 to 63 years), 6/8 respectively. The baseline DA dose was 3 mg/week (0.5 to 7 mg/week) for cabergoline and 15 mg/day for bromocriptine. Ten patients had an absolute and percentage decrease in PRL of 8.3 ng/mL (1.5 to 54.2 ng/mL) and 25.9% (8 to 55%) from baseline, respectively, after 1 to 6 months on raloxifene treatment. Among 10 patients with a decrease in PRL level, 2 (20%) achieved PRL normalization. Two patients had no change in PRL and two patients had an increase in PRL level by 22.8 ng/mL and 8.8 ng/mL (47% and 23.6%), respectively. Conclusion: Raloxifene was associated with a 25.9% (8 to 55%) decrease in PRL level in 10/14 (71%) patients with prolactinoma who were on stable doses of DA including 2 patients (14%) who achieved normoprolactinemia. Abbreviations: CV = coefficient of variation; DA = dopamine agonist; FSH = follicule-stimulating hormone; LH = luteinizing hormone; PRL = prolactin; PTTG = pituitary tumor transforming gene.

Raloxifene decreases cell viability and migratory potential in prostate cancer cells (LNCaP) with GPR30/GPER1 involvement.

This study evaluated raloxifene (ral) effects on LNCaP prostate tumour cells modulating the activity of GPER1/GPR30 receptors. LNCaP cells were submitted for 40/120min and 12h to the following treatments: C: RPMI+DMSO; R: RPMI+Ral; G: RPMI+Ral+G15 (GPER1 antagonist). Trypan blue staining measured cell viability. Migratory potential (12h) was measured by transwell migration test in translucent inserts, which were then stained with DAPI and analysed under a fluorescence microscope for quantification. Cells from 40- and 120-min treatments were subjected to protein extraction to the study of AKT, pAKT, ERK, pERK, ERβ and SIRT1. There is a reduction in cellular viability in R compared to C at all evaluated times, and an increased cell viability in G when compared to R; cell viability was similar in C and G in all times studied. The migration assay demonstrated a significant decrease in migration potential of tumour cells in R compared to C and G. Ral treatment reduced pERK expression and increased pAKT in the treated groups after 40min, pointing out to an antiproliferative and apoptotic effect in the GPER1-controlled rapid-effect pathways. Raloxifene was able to modulate GPER1 in LNCaP prostate tumour cells, decreasing cell viability and their migratory potential.

Effect of Raloxifene Administration on Bone Response Around Implant in the Maxilla of Osteoporotic Rats.

To determine the effect of raloxifene (RAL) on bone response around implants in the maxilla of osteoporotic rats. Forty-five female rats at 8 weeks-old were divided into 3 groups: (1) control group, sham-operated rats, (2) ovariectomized group (OVX), and (3) ovariectomized and raloxifene-administered group (RAL). Eight weeks after the ovariectomy, upper right molar was extracted and an implant was placed at 4 weeks post-extraction. The RAL group was administered with 1 mg/kg/d of raloxifene via gavage while the OVX group and the control group received saline only. Three rats in each group were sacrificed at 1, 4, 7, 14, and 28 days and histologic sections were evaluated by hematoxylin and eosin staining and micro-computerized tomography was taken. The RAL group showed faster bone formation around the implant than the OVX group. At 4 weeks after implantation, newly formed bone close to implant threads was mature with considerable quantity of bone marrow in the RAL group. Raloxifene showed increased bone formation around implant. This might have clinical implications in prosthetic restoration by dental implants for patients with poor bone quality.

Inhibition of Human Sulfotransferase 2A1-Catalyzed Sulfonation of Lithocholic Acid, Glycolithocholic Acid, and Taurolithocholic Acid by Selective Estrogen Receptor Modulators and Various Analogs and Metabolites.

Lithocholic acid (LCA) is a bile acid associated with adverse effects, including cholestasis, and it exists in vivo mainly as conjugates known as glyco-LCA (GLCA) and tauro-LCA (TLCA). Tamoxifen has been linked to the development of cholestasis, and it inhibits sulfotransferase 2A1 (SULT2A1)-catalyzed dehydroepiandrosterone (DHEA) sulfonation. The present study was done to characterize the sulfonation of LCA, GLCA, and TLCA and to investigate whether triphenylethylene (clomifene, tamoxifen, toremifene, ospemifene, droloxifene), benzothiophene (raloxifene, arzoxifene), tetrahydronaphthalene (lasofoxifene, nafoxidine), indole (bazedoxifene), and benzopyran (acolbifene) classes of selective estrogen receptor modulator (SERM) inhibit LCA, GLCA, and TLCA sulfonation. Human recombinant SULT2A1, but not SULT2B1b or SULT1E1, catalyzed LCA, GLCA, and TLCA sulfonation, whereas each of these enzymes catalyzed DHEA sulfonation. LCA, GLCA, and TLCA sulfonation is catalyzed by human liver cytosol, and SULT2A1 followed the substrate inhibition model with comparable apparent K m values (≤1 µM). Each of the SERMs inhibited LCA, GLCA, and TLCA sulfonation with varying potency and mode of enzyme inhibition. The potency and extent of inhibition of LCA sulfonation were attenuated or increased by structural modifications to toremifene, bazedoxifene, and lasofoxifene. The inhibitory effect of raloxifene, bazedoxifene, and acolbifene on LCA sulfonation was also observed in HepG2 human hepatocellular carcinoma cells. Overall, among the SERMs investigated, bazedoxifene and raloxifene were the most effective inhibitors of LCA, GLCA, and TLCA sulfonation. These findings provide insight into the structural features of specific SERMs that contribute to their inhibition of SULT2A1-catalyzed LCA sulfonation. Inhibition of LCA, GLCA, and TLCA detoxification by a SERM may provide a biochemical basis for adverse effects associated with a SERM.

Effects of Raloxifene on the Aortic Valve Function of Mice Fed with High-sugar and High-fat Diets

The current study aimed to explore the effects of raloxifene on the aortic valve function of mice fed with high-sugar and high-fat diets. C57 mice were randomly divided into five groups, 10 mice per group, normal diet group or control group, high-sugar, high-fat group, raloxifene 4.5 mg/kg+high-sugar, high-fat group, raloxifene 9 mg/kg+high-sugar, high-fat group, and raloxifene 18 mg/kg+high-sugar, high-fat group. Raloxifene was intragastrically administered every day for a total of three months. Steatosis and calcification of aortic valve was detected through hematoxylin and eosin staining and alizarin red staining and relative expression levels of caspase-3 and caspase-8 using immunohistochemical staining and real-time quantitative polymerase chain reaction. Compared with the high-sugar, high-fat group, both the hematoxylin and eosin staining and alizarin red staining showed that aortic valve steatosis and calcification in mice significantly improved after treatment with raloxifene, especially in the group administered with 18 mg/kg. In addition, quantitative immunohistochemical staining and real-time quantitative polymerase chain reaction showed that raloxifene treatment sharply decreased mRNA expression levels of caspase-3 and caspase-8 compared to the high-sugar, high-fat group. Raloxifene at certain concentrations induced inhibitory effects on calcification and apoptosis in the aortic valves of mice after high-sugar, high-fat diet, thereby laying a foundation for therapeutic benefits raloxifene.

The importance of inhibition of a catabolic pathway of methotrexate metabolism in its efficacy for rheumatoid arthritis

Methotrexate (MTX), an antifolate, is the anchor drug for the treatment of rheumatoid arthritis (RA). It is inexpensive, effective, and generally safe. When clinical response is inadequate, biological therapies are commonly used in combination with MTX. However, biological agents have safety concerns (i.e. infections, malignancy) and the addition of a biologic agent is expensive, making strategies to improve MTX efficacy important.Inhibition of pathways of folate metabolism involving purine metabolism by MTX, have been traditionally emphasized as important in MTX efficacy. However, inhibition MTX catabolism may also be important. MTX is irreversibly hydroxylated to form 7-hydroxy methotrexate (7-OH-MTX) by aldehyde oxidase (EC 1.2.3.1) (AOX). Catabolism of MTX to 7-OH-MTX is the first metabolic process imposed on an oral dose of MTX and will alter subsequent interactions of MTX with other enzymes. 7-OH-MTX is less potent than MTX in the treatment of rat adjuvant arthritis. RA patients with a low capacity to catabolize MTX to 7-OH-MTX do better clinically than individuals who are rapid formers of 7-OH-MTX. Therefore, altering the catabolism of MTX may be an innovative way to improve MTX efficacy.Raloxifene is a FDA-approved therapy for postmenopausal osteoporosis and for the reduction of invasive breast cancers but has no known activity in RA. Raloxifene is a potent inhibitor of human liver AOX. Postmenopausal women with RA frequently have low bone mineral density and would be candidates for raloxifene and MTX combination therapy. The effect of raloxifene on MTX metabolism has never been studied.Our hypothesis is that in postmenopausal women with RA and osteoporosis treated with MTX and raloxifene, the inhibition of AOX with resultant decreased formation of 7-OH MTX; will increase MTX levels and improve MTX efficacy. This hypothesis could be studied in an open-label, proof of concept clinical study in individuals before and after the addition of raloxifene. Red blood cell MTX and 7-OH-MTX levels and RA disease activity (DAS28) would be measured. In possible future studies, there are dietary substances, as supplements, (e.g. epigallocatechin gallate in green tea and resveratrol) which inhibit human liver AOX which could be evaluated.

Raloxifene in Reducing the Risk of Postmenopausal Fracture amongst Osteoporotic Subjects

Background: Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent decrease in bone mineral density (BMD) and increase in bone fragility and susceptibility to fracture. Hence; we planned the present study to assess the effect of raloxifene in reducing the risk of postmenopausal fracture amongst osteoporotic subjects. Methods: The present study included assessment of effect of raloxifene in reducing the risk of postmenopausal fracture amongst osteoporotic subjects. A total of 120 postmenopausal women were included in the present study. All the subjects were broadly divided into two broad groups with 60 subjects in each group; Group A: Subjects who were given placebo for two years Group B: Subjects who were given raloxifene 60 mg/d for 2 years. Assessment of Risk of Postmenopausal Fracture in all the subjects was done by evaluating the bone mineral density (BMD) at two years follow-up time. All the results were compiled and assessed by SPSS software. Results: Non- significant results were obtained while comparing the adverse effects among subjects of both the study groups. Overall incidence of new vertebral fractures among subjects of group A and group B included 6 and 4 percent respectively. Significant results were obtained while comparing the incidence of new vertebral fractures among subjects of group A and group B respectively. Conclusion: Significant reduction in the risk of fractures occur under the influence of raloxifene in postmenopausal women with osteoporosis.

The Synergistic Effect of Raloxifene, Fluoxetine, and Bromocriptine Protects Against Pilocarpine-Induced Status Epilepticus and Temporal Lobe Epilepsy.

The present antiepileptic drugs pose several problems in the management of seizures owing to their meager neuroprotective potential, adverse effects on bone, detrimental effects on cognitive function, chronic toxicity, drug interactions, side effects including aggression, agitation, and irritability and sometimes exacerbation of seizures. We followed up progressive preclinical investigation in mice against pilocarpine (PILO)-induced status epilepticus (SE) and temporal lobe epilepsy (TLE). To determine the response of raloxifene (RF) (4 and 8mg/kg), fluoxetine (FT) (14 and 22mg/kg), bromocriptine (BC) (6 and 10mg/kg), and their low-dose combinations, oral treatment was scheduled for 28days followed by PILO (300mg/kg, i.p). The response was stalked for intensive behavioral monitoring of convulsions, hippocampal neuropeptide Y (NPY), and oxidative stress discernment along with histomorphological studies. The resultant data confirmed the therapeutic potential of triple drug combination of raloxifene (4mg/kg) with fluoxetine (14mg/kg) and bromocriptine (6mg/kg) compared to monotherapy with raloxifene (4mg/kg), and bromocriptine (6mg/kg) as otherwise monotherapy with fluoxetine (14mg/kg) was ineffective to suppress convulsions; an effect better than sodium valproate (300mg/kg), a standard AED, was validated. Most profoundly, PILO-induced compensatory increases in hippocampal NPY levels (20.01%), which was escalated (100%) with the triple drug combination. The same pattern of results was superseded for oxidative stress indices and neuronal damage. The results for the first time demonstrate the propitious role of triple drug combination in the management of SE and TLE. Therapeutically, this enhancing profile of drugs fosters a safer and more effective drug-combination regimen. Graphical abstract.