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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 -
Bone Oct 2019Current interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical...
Current interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such as Zoledronate (ZOL), are used to treat a variety of bone disorders by increasing bone mass to decrease fracture risk, but long-term use has been shown in some settings to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties in a cell-independent manner by binding to collagen and increasing tissue hydration. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or both from 8 weeks to 16 weeks of age. Using the OIM model allows for investigation of therapeutic effects on a quality-based bone disease. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, which are direct measures of the tissue's ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, trabecular bone volume fraction was significantly higher with combination treatment in both genotypes. Combination treatment resulted in higher ultimate stress in both genotypes. RAL and combination treatment in OIM+/- also increased resilience compared to the control. In conclusion, this study demonstrates the beneficial effects of using combination drug treatments to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a potential method to improve bone health and combat skeletal fragility on both the microscopic and macroscopic levels.
Topics: Animals; Biomechanical Phenomena; Bone Diseases; Calcification, Physiologic; Cancellous Bone; Diaphyses; Drug Therapy, Combination; Femur; Fractures, Bone; Male; Mice, Inbred C57BL; Raloxifene Hydrochloride; Zoledronic Acid
PubMed: 31233931
DOI: 10.1016/j.bone.2019.06.018 -
The American Journal of Pathology Apr 2018The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available....
The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype. The mice were treated with the drugs for 1 year through daily gavage. We demonstrate that tamoxifen and raloxifene significantly ameliorated the disease progression. The improvement includes increase in grip force production, extended running time and distance in treadmill test, and enhancement in cardiac and respiratory functions. Significant reduction in muscle pathology includes diminished fibrosis and fiber degeneration. Tamoxifen and raloxifene also significantly mitigated bone loss. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs. The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies. Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.
Topics: Animals; Body Weight; Bone Density; Dystroglycans; Female; Glycosylation; Heart; Male; Mice, Inbred C57BL; Muscles; Muscular Dystrophy, Animal; Organ Specificity; Pentosyltransferases; Phenotype; Proteins; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Time Factors; Transferases
PubMed: 29571322
DOI: 10.1016/j.ajpath.2017.12.011 -
Medicina (Kaunas, Lithuania) Aug 2023The study aimed to assess the efficacy of using Raloxifene with ultrasonic processing to enhance Bio-Oss, a bone graft substitute, for maxillary sinus bone height...
The study aimed to assess the efficacy of using Raloxifene with ultrasonic processing to enhance Bio-Oss, a bone graft substitute, for maxillary sinus bone height reconstruction. A total of 24 rabbit maxillary sinuses were distributed into three groups, each receiving different treatments: Bio-Oss only, sonicated Bio-Oss, and sonicated Bio-Oss with Raloxifene. Surgical procedures and subsequent histomorphometric and immunohistochemistry analyses were conducted to evaluate the bone formation, connective tissue, and remaining biomaterial, as well as the osteoblastic differentiation and maturation of collagen fibers. Results indicated that the sonicated Bio-Oss and Bio-Oss groups showed similar histological behavior and bone formation, but the Raloxifene group displayed inflammatory infiltrate, low bone formation, and disorganized connective tissue. The statistical analysis confirmed significant differences between the groups in terms of bone formation, connective tissue, and remaining biomaterial. In conclusion, the study found that while sonicated Bio-Oss performed comparably to Bio-Oss alone, the addition of Raloxifene led to an unexpected delay in bone repair. The findings stress the importance of histological evaluation for accurate bone repair assessment and the necessity for further investigation into the local application of Raloxifene. Future research may focus on optimizing bone substitutes with growth factors to improve bone repair.
Topics: Animals; Rabbits; Maxillary Sinus; Raloxifene Hydrochloride; Bone Regeneration; Bone Substitutes; Minerals; Biocompatible Materials
PubMed: 37763640
DOI: 10.3390/medicina59091521 -
Annals of Internal Medicine Apr 2013Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low. (Review)
Review
BACKGROUND
Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low.
PURPOSE
To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer.
DATA SOURCES
MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists.
STUDY SELECTION
English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment.
DATA EXTRACTION
Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria.
DATA SYNTHESIS
Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer.
LIMITATION
Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking.
CONCLUSION
Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cataract; Endometrial Neoplasms; Female; Fractures, Bone; Humans; Medication Adherence; Patient Participation; Raloxifene Hydrochloride; Risk Assessment; Tamoxifen; Thromboembolism; Treatment Outcome
PubMed: 23588749
DOI: 10.7326/0003-4819-158-8-201304160-00005 -
Endocrinology Feb 2021Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor...
Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases.
Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Male; Mice; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Sex Characteristics; Spinal Cord; Ubiquitination
PubMed: 33269387
DOI: 10.1210/endocr/bqaa221 -
Microbiology Spectrum Jun 2022Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of...
Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of drug-resistant parasite strains. Given a long and risky development path of new drugs, repurposing existing drugs for the treatment of malaria is an attractive and shorter path. Tamoxifen, a selective estrogen receptor modulator (SERM) for the treatment and prevention of estrogen receptor-positive breast cancer, possesses antibacterial, antifungal, and antiparasitic activities. Hence, we assessed tamoxifen, raloxifene, and bazedoxifene, which represent the first-, second-, and third-generation SERMs, respectively, for antimalarial activity. Raloxifene and bazedoxifene inhibited the erythrocytic development of Plasmodium falciparum with submicromolar 50% inhibitory concentration (IC) values. Among the three, bazedoxifene was the most potent and also decreased P. berghei infection in female mice but not in male mice. However, bazedoxifene similarly inhibited P. falciparum growth in erythrocytes of male and female origin, which highlights the importance of sex-specific host physiology in drug efficacy. Bazedoxifene was most potent on early ring-stage parasites, and about 35% of the treated parasites did not contain hemozoin in the food vacuole. Bazedoxifene-treated parasites had almost 34% less hemozoin content than the control parasites. However, both control and bazedoxifene-treated parasites had similar hemoglobin levels, suggesting that bazedoxifene inhibits hemozoin formation and that toxicity due to accumulation of free heme could be a mechanism of its antimalarial activity. Because bazedoxifene is in clinical use and bazedoxifene-chloroquine combination shows an additive antiparasitic effect, bazedoxifene could be an adjunctive partner of currently used antimalarial regimens. The emergence and spread of drug-resistant strains of the human malaria parasite Plasmodium falciparum has necessitated new drugs. Selective estrogen receptor modulators are in clinical use for the prevention and treatment of breast cancer and postmenopausal osteoporosis. We demonstrate that bazedoxifene, a third-generation selective estrogen receptor modulator, has potent inhibitory activity against both susceptible and drug-resistant strains of Plasmodium falciparum. It also blocked the development of Plasmodium berghei in mice. The inhibitory effect was strongest on the ring stage and resulted in the inhibition of hemozoin formation, which could be the major mechanism of bazedoxifene action. Hemozoin is a nontoxic polymer of heme, which is a by-product of hemoglobin degradation by the malaria parasite during its development within the erythrocyte. Because bazedoxifene is already in clinical use for the treatment of postmenopausal osteoporosis, our findings support repurposing of bazedoxifene as an antimalarial.
Topics: Animals; Antimalarials; Female; Heme; Hemeproteins; Hemoglobins; Humans; Indoles; Malaria; Malaria, Falciparum; Male; Mice; Neoplasms; Osteoporosis, Postmenopausal; Plasmodium falciparum; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen
PubMed: 35616371
DOI: 10.1128/spectrum.02781-21 -
Calcified Tissue International Mar 2023Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to...
Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to 32 °C range improves bone quality by reducing the consequences of cold stress, such as shivering and metabolic energy consumption (Chevalier et al. in Cell Metab 32(4):575-590.e7, 2020; Martin et al. in Endocr Connect 8(11):1455-1467, 2019; Hankenson et al. in Comp Med 68(6):425-438, 2018). Previous work suggests that Raloxifene can enhance bone strength and geometry (Ettinger et al. in Jama 282(7):637-645, 1999; Powell et al. in Bone Rep 12:100246, 2020). An earlier study in our lab utilized long bones to examine the effect of thermoneutral housing and Raloxifene treatment in mice, but no significant interactive effects were found. The lack of an impact is hypothesized to be connected to the short 6-week duration of the study and the type of bone analyzed. This study will examine the same question within the axial skeleton, which has a higher proportion of trabecular bone. After 6 weeks of treatment with RAL, vertebrae from female C57BL/6 J mice underwent microcomputed tomography (μCT), architectural analysis, and compression testing. Most of the tested geometric properties (bone volume/tissue volume percent, trabecular thickness, trabecular number, trabecular spacing) improved with both the housing and RAL treatment. The effect sizes suggested an additive effect when treating mice housed under thermoneutral conditions. While ultimate force was enhanced with the treatment and housing, force normalized by bone volume fraction was not significantly different between groups. For longer pre-clinical trials, it may be important to consider the impacts of temperature on mice to improve the accuracy of these models.
Topics: Mice; Female; Animals; Raloxifene Hydrochloride; Cancellous Bone; X-Ray Microtomography; Housing; Mice, Inbred C57BL; Bone Density
PubMed: 36371724
DOI: 10.1007/s00223-022-01038-z -
Clinical Therapeutics Apr 2021In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019... (Review)
Review
PURPOSE
In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely.
METHODS
This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19.
FINDINGS
Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired.
IMPLICATIONS
Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely.
Topics: Bone Density; COVID-19; Calcium; Cinacalcet; Diphosphonates; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Middle Aged; Parathyroidectomy; Raloxifene Hydrochloride; Vitamin D
PubMed: 33752899
DOI: 10.1016/j.clinthera.2021.02.003