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Scientific Reports May 2022This study was performed to evaluate quality of life (QOL) and patient satisfaction with raloxifene/cholecalciferol combination therapy in postmenopausal women with low... (Observational Study)
Observational Study
This study was performed to evaluate quality of life (QOL) and patient satisfaction with raloxifene/cholecalciferol combination therapy in postmenopausal women with low bone mass. This multicenter, prospective, noninterventional observational study included 3907 postmenopausal women who received a combination of raloxifene 60 mg and cholecalciferol 800 IU daily to treat or prevent osteoporosis. Changes in QOL and patient satisfaction were evaluated after 3 and 6 months of treatment. In addition, the safety profile was assessed. Mean age was 67.7 ± 9.3 years old. QOL, assessed by European Quality of life instrument 5 Dimensions (EQ-5D) index, improved significantly after 3 months (0.81 ± 0.11, P < 0.001) and 6 months (0.82 ± 0.11, P < 0.001) of treatment compared to the baseline (0.78 ± 0.14). Improvement in QOL was also significant regardless of previous regimens both in women who were switched from other drugs (bisphosphonates or selective estrogen receptor modulators) and in women who received the study drug for the first time (P < 0.001 for all comparisons). Percentage of women satisfied with the effects (from 37.3 to 67.7%, P < 0.001) and convenience (from 42.8 to 74.1%, P < 0.001) of treatment compared to previous medication significantly increased after 6 months of treatment. In addition, serious adverse drug reactions did not occur, and hot flushes were observed only in 12 women (0.3%). Combination therapy with raloxifene and cholecalciferol significantly improves quality of life with no serious adverse events and high patient satisfaction at 6 months. Our real-world data suggest that this regimen is a promising option for postmenopausal women with low bone mass.
Topics: Aged; Cholecalciferol; Female; Humans; Male; Middle Aged; Osteoporosis, Postmenopausal; Patient Satisfaction; Postmenopause; Prospective Studies; Quality of Life; Raloxifene Hydrochloride
PubMed: 35505063
DOI: 10.1038/s41598-022-11298-2 -
Scientific Reports Jul 2020Alendronate and raloxifene are among the most popular anti-osteoporosis medications. However, there is a lack of head-to-head comparative effectiveness studies comparing... (Comparative Study)
Comparative Study Observational Study
Alendronate and raloxifene are among the most popular anti-osteoporosis medications. However, there is a lack of head-to-head comparative effectiveness studies comparing the two treatments. We conducted a retrospective large-scale multicenter study encompassing over 300 million patients across nine databases encoded in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The primary outcome was the incidence of osteoporotic hip fracture, while secondary outcomes were vertebral fracture, atypical femoral fracture (AFF), osteonecrosis of the jaw (ONJ), and esophageal cancer. We used propensity score trimming and stratification based on an expansive propensity score model with all pre-treatment patient characteritistcs. We accounted for unmeasured confounding using negative control outcomes to estimate and adjust for residual systematic bias in each data source. We identified 283,586 alendronate patients and 40,463 raloxifene patients. There were 7.48 hip fracture, 8.18 vertebral fracture, 1.14 AFF, 0.21 esophageal cancer and 0.09 ONJ events per 1,000 person-years in the alendronate cohort and 6.62, 7.36, 0.69, 0.22 and 0.06 events per 1,000 person-years, respectively, in the raloxifene cohort. Alendronate and raloxifene have a similar hip fracture risk (hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.94-1.13), but alendronate users are more likely to have vertebral fractures (HR 1.07, 95% CI 1.01-1.14). Alendronate has higher risk for AFF (HR 1.51, 95% CI 1.23-1.84) but similar risk for esophageal cancer (HR 0.95, 95% CI 0.53-1.70), and ONJ (HR 1.62, 95% CI 0.78-3.34). We demonstrated substantial control of measured confounding by propensity score adjustment, and minimal residual systematic bias through negative control experiments, lending credibility to our effect estimates. Raloxifene is as effective as alendronate and may remain an option in the prevention of osteoporotic fracture.
Topics: Alendronate; Bone Density; Bone Density Conservation Agents; Female; Follow-Up Studies; Humans; Middle Aged; Osteoporosis; Raloxifene Hydrochloride; Retrospective Studies; Treatment Outcome
PubMed: 32632237
DOI: 10.1038/s41598-020-68037-8 -
Cell Death and Differentiation Jan 2022The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to... (Review)
Review
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients.
Topics: Angiotensin-Converting Enzyme 2; Anti-Inflammatory Agents; Antiviral Agents; Drug Repositioning; Estradiol; Estrogen Receptor Modulators; Estrogens; Female; Humans; Male; Raloxifene Hydrochloride; SARS-CoV-2; Sex Factors; COVID-19 Drug Treatment
PubMed: 34404919
DOI: 10.1038/s41418-021-00844-6 -
Experimental Eye Research May 2022Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces...
Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces frequently damage the retina and optic nerves, and work on experimental animals has shown the pro-inflammatory actions of microglia can further exacerbate such injuries. Cannabinoid type-2 receptor (CB2) inverse agonists specifically target activated microglia, biasing them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state. We previously found that treating mice with CB2 inverse agonists after traumatic brain injury, produced by either focal cranial air blast or dorsal cranial impact, greatly attenuated the visual deficits and pathology that otherwise resulted. Here we examined the consequences of single and repeat OBI and the benefit provided by raloxifene, an FDA-approved estrogen receptor drug that possesses noteworthy CB2 inverse agonism. After single OBI, although the amplitudes of the A- and B-waves of the electroretinogram and pupil light response appeared to be normal, the mice showed hints of deficits in contrast sensitivity and visual acuity, a trend toward optic nerve axon loss, and significantly increased light aversion, which were reversed by 2 weeks of daily treatment with raloxifene. Mice subjected to repeat OBI (5 blasts spaced 1 min apart), exhibited more severe visual deficits, including decreases in contrast sensitivity, visual acuity, the amplitudes of the A- and B-waves of the electroretinogram, light aversion, and resting pupil diameter (i.e. hyperconstriction), accompanied by the loss of photoreceptor cells and optic nerve axons, nearly all of which were mitigated by raloxifene. Interestingly, optic nerve axon abundance was strongly correlated with contrast sensitivity and visual acuity across all groups of experimental mice in the repeat OBI study, suggesting optic nerve axon loss with repeat OBI and its attenuation with raloxifene are associated with the extent of these two deficits while photoreceptor abundance was highly correlated with A-wave amplitude and resting pupil size, suggesting a prominent role for photoreceptors in these two deficits. Quantitative PCR (qPCR) showed levels of M1-type microglial markers (e.g. iNOS, IL1β, TNFα, and CD32) in retina, optic nerve, and thalamus were increased 3 days after repeat OBI. With raloxifene treatment, the overall expression of M1 markers was more similar to that in sham mice. Raloxifene treatment was also associated with the elevation of IL10 transcripts in all three tissues compared to repeat OBI alone, but the results for the three other M2 microglial markers we examined were more varied. Taken together, the qPCR results suggest that raloxifene benefit for visual function and pathology was associated with a lessening of the pro-inflammatory actions of microglia. The benefit we find for raloxifene following OBI provides a strong basis for phase-2 efficacy testing in human clinical trials for treating ocular injury.
Topics: Animals; Blast Injuries; Cannabinoid Receptor Agonists; Cannabinoids; Eye Injuries; Mice; Mice, Inbred C57BL; Microglia; Raloxifene Hydrochloride
PubMed: 35143834
DOI: 10.1016/j.exer.2022.108966 -
Molecular and Cellular Endocrinology Feb 2018Selective estrogen receptor modulators (SERMs) such as bazedoxifene and raloxifene are recognized to mainly act via estrogen receptors (ERs), but there is no study...
Selective estrogen receptor modulators (SERMs) such as bazedoxifene and raloxifene are recognized to mainly act via estrogen receptors (ERs), but there is no study examining the involvement of PPAR-γ in their actions, especially in neurons undergoing hypoxia. Little is also known about age-dependent actions of the SERMs on neuronal tissue challenged with hypoxia. In this study, bazedoxifene and raloxifene protected neocortical cells against hypoxia at early and later developmental stages. Both SERMs evoked caspase-3-independent neuroprotection and increased protein levels of ERα (66 and 46 kDa isoforms) and PPAR-γ. In addition, bazedoxifene enhanced expression of ERα-regulated Cyp19a1 mRNA. Using double siRNA silencing, for the first time we demonstrated a key role of ERα and PPAR-γ in the neuroprotective action of the SERMs in neocortical neurons undergoing hypoxia. This study provides prospects for the development of a new therapeutic strategies against hypoxic brain injury that selectively target ERα and/or PPAR-γ.
Topics: Animals; Aromatase; Caspase 3; Cell Hypoxia; Cells, Cultured; Enzyme Activation; Estrogen Receptor alpha; Hippocampus; Indoles; L-Lactate Dehydrogenase; Membrane Potential, Mitochondrial; Mice; Neocortex; Neurons; Neuroprotective Agents; PPAR gamma; RNA, Messenger; RNA, Small Interfering; Raloxifene Hydrochloride
PubMed: 28859903
DOI: 10.1016/j.mce.2017.08.014 -
International Journal of Biological... Jul 2023Cyclophosphamide (CP) is one of the most widely used anticancer drugs for various malignancies. However, its long-term use leads to ALDH1A1-mediated inactivation and...
Cyclophosphamide (CP) is one of the most widely used anticancer drugs for various malignancies. However, its long-term use leads to ALDH1A1-mediated inactivation and subsequent resistance which necessitates the development of potential ALDH1A1 inhibitors. Currently, ALDH1A1 inhibitors from different chemical classes have been reported, but these failed to reach the market due to safety and efficacy problems. Developing a new treatment from the ground requires a huge amount of time, effort, and money, therefore it is worthwhile to improve CP efficacy by proposing better adjuvants as ALDH1A1 inhibitors. Herein, the database constituting the FDA-approved drugs with well-established safety and toxicity profiles was screened through already reported machine learning models by our research group. This model is validated for discriminating the ALDH1A1 inhibitors and non-inhibitors. Virtual screening protocol (VS) from this model identified four FDA-approved drugs, raloxifene, bazedoxifene, avanafil, and betrixaban as selective ALDH1A1 inhibitors. The molecular docking, dynamics, and water swap analysis also suggested these drugs to be promising ALDH1A1 inhibitors which were further validated for their CP resistance reversal potential by in-vitro analysis. The in-vitro enzymatic assay results indicated that raloxifene and bazedoxifene selectively inhibited the ALDH1A1 enzyme with IC values of 2.35 and 4.41 μM respectively, whereas IC values of both the drugs against ALDH2 and ALDH3A1 was >100 μM. Additional in-vitro studies with well-reported ALDH1A1 overexpressing A549 and MIA paCa-2 cell lines suggested that mafosfamide sensitivity was further ameliorated by the combination of both raloxifene and bazedoxifene. Collectively, in-silico and in-vitro studies indicate raloxifene and bazedoxifene act as promising adjuvants with CP that may improve the quality of treatment for cancer patients with minimal toxicities.
Topics: Humans; Raloxifene Hydrochloride; Molecular Docking Simulation; Drug Repositioning; Cyclophosphamide; Neoplasms; Aldehyde Dehydrogenase, Mitochondrial; Aldehyde Dehydrogenase 1 Family; Retinal Dehydrogenase
PubMed: 37160174
DOI: 10.1016/j.ijbiomac.2023.124749 -
Menopause (New York, N.Y.) Jan 2021We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD).
METHODS
Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure.
RESULTS
Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo.
CONCLUSIONS
This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).
Topics: Depression; Double-Blind Method; Estradiol; Estrogens; Female; Humans; Perimenopause; Phytoestrogens; Raloxifene Hydrochloride; Treatment Outcome
PubMed: 33470755
DOI: 10.1097/GME.0000000000001724 -
Journal of Bone and Mineral Metabolism Jul 2021To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention... (Observational Study)
Observational Study Randomized Controlled Trial
INTRODUCTION
To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis.
MATERIALS AND METHODS
This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed.
RESULTS
The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90-0.96) for ucOC, 1.15 (1.08-1.23) for TRACP-5b, 1.02 (1.01-1.03) for pentosidine, 0.91 (0.88-0.94) for the OLST, and 1.27 (1.01-1.60) for the fall risk index, which were all independent predictors.
CONCLUSION
Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.
Topics: Accidental Falls; Aged; Biomarkers; Bone Density Conservation Agents; Diphosphonates; Female; Humans; Imidazoles; Multivariate Analysis; Osteoporosis; Prevalence; Prospective Studies; Raloxifene Hydrochloride; Risk Factors; Spinal Fractures
PubMed: 33738617
DOI: 10.1007/s00774-021-01208-3 -
European Journal of Pharmaceutical... Jun 2021Apigenin (API) and sodium deoxycholate (NaDC) have different pharmacodynamic properties and can affect pharmacokinetics of drugs without causing significant toxicity....
Apigenin (API) and sodium deoxycholate (NaDC) have different pharmacodynamic properties and can affect pharmacokinetics of drugs without causing significant toxicity. The aim of our study was to investigate the effect of API and NaDC on raloxifene pharmacokinetics in rats as well as on hemostasis parameters after applying the raloxifene therapeutic dose. Rats were treated daily with oral single dose of saline solution (1 ml/kg), API (10 mg/kg) and/or NaDC (4 mg/kg) for 7 days. Raloxifene was given orally or intravenously in a single dose (6 mg/kg) and during period of 24 h blood samples, feces and urine samples were collected. Blood samples were collected at the 15th, 30th, 45th, 60th, 90th minute and 2, 3, 4, 6, 8, 10, 12 and 24 h after raloxifene administration. Urine and feces samples were collected in the 3th, 6, 12th and 24th hour of the experiment. Rats were divided into 10 groups each of which contained 6 animals. Differences were considered statistically significant if p<0.05. Pretreatment with NaDC and API affected raloxifene pharmacokinetic profile after intravenous application. NaDC lead to statistically significant decrease in raloxifene serum concentration and increased volume of distribution and clearance as well as halftime of elimination, while API has also decreased also raloxifene serum concentrations and increased volume of distribution but not as profoundly as NaDC alone. Difference was also noticed in clearance where it was significantly increased in group pretreated with NaDC and slightly decreased in group pretreated with API. NaDC and API increased raloxifene amount in feces, both after peroral (p<0.05) and intravenous application. However, peroral application of raloxifene did not produce measurable raloxifene serum concentration in neither of investigated groups. NaDC shortened activated partial thromboplastin time (aPTT) and prothrombin time (PT). API reduced aPTT, PT and d-dimer level. Fibrinogen level was significantly increased in all experimental groups. Both NaDC and apigenin had significant influence on raloxifene pharmacokinetics and can potentiate the raloxifene effects on hemostasis parameters, by increasing its bioavailability. These substances may be the subject of further investigation into the formulation of raloxifene and other medicines as depot preparations, which could prolong the dosing interval and thus improve patient compliance and quality of life.
Topics: Animals; Apigenin; Deoxycholic Acid; Prothrombin Time; Quality of Life; Raloxifene Hydrochloride; Rats
PubMed: 33741473
DOI: 10.1016/j.ejps.2021.105809 -
JAMA Jul 2020
Review
Topics: Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Primary Prevention; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Uterine Neoplasms; Venous Thromboembolism
PubMed: 32692377
DOI: 10.1001/jama.2020.9246