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Bone Nov 2015Loss of muscle or bone mass occurs with ageing, immobility and in association with a variety of systemic diseases. The interaction of these two processes is most evident... (Review)
Review
Loss of muscle or bone mass occurs with ageing, immobility and in association with a variety of systemic diseases. The interaction of these two processes is most evident in the major contribution of falls to the risk of fractures in the elderly population. Exercise and nutrition are key common physiological variables that allow for preservation or formation of greater muscle or bone mass. However, although several pharmacological approaches have the potential to benefit both muscle and bone health, for example vitamin D, selective androgen receptor modulators and ghrelin mimetics, clinical trials with appropriate primary outcomes are lacking. Conventional approaches to address muscle loss are being extended to include stem cell biology and conserved molecular mechanisms of atrophy/hypertrophy. Pharmacological interventions to reduce fracture risk are exploring new mechanisms of action, in particular the uncoupling of bone resorption and formation. Emerging key issues for clinical trial design include adequate phenotyping of patients (personalised medicine), optimisation of the physiological background (multimodal approach) and the use of meaningful and robust outcomes relevant to daily clinical practice. At present, effective treatments that combine beneficial effects on both muscle and bone are lacking, although this is an important target for the future. This review therefore considers current and developing strategies to improve muscle function and bone strength in separate sections.
Topics: Anabolic Agents; Animals; Bone Density; Bone Remodeling; Bone Resorption; Denosumab; Diphosphonates; Fractures, Bone; Humans; Muscle, Skeletal; Osteoporosis; Raloxifene Hydrochloride
PubMed: 26453503
DOI: 10.1016/j.bone.2015.04.013 -
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 -
Cardiovascular Drugs and Therapy Apr 2017Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein and an independent risk factor for atherosclerotic cardiovascular disease. We investigated the effects of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein and an independent risk factor for atherosclerotic cardiovascular disease. We investigated the effects of raloxifene, selective estrogen receptor modulator, on circulating Lp(a) levels in postmenopausal women using a systematic review and meta-analysis of randomized controlled trials (RCTs).
METHODS
To identify relevant studies, electronic databases (PUBMED, Scopus, Web of Science, and Google Scholar) were searched by up to May 2015 to find controlled trials exploring the effects of oral raloxifene treatment on plasma Lp(a) levels in postmenopausal women. A random-effects model and generic inverse variance method were used for quantitative data synthesis.
RESULTS
Overall, seven eligible RCTs with ten treatment arms were included in this meta-analysis. Meta-analysis suggested a significant reduction of Lp(a) levels after treatment with raloxifene (standardized mean difference (SMD) -0.42; 95% CI -0.65, -0.19; p < 0.001), which may be considered as a medium effect size. When the studies were categorized according to the administered dose, there was a significant effect in both subsets of studies with administered doses ≤60 mg/day (SMD -0.43; 95% CI -0.73, -0.13; p = 0.004) and >60 mg/day (SMD -0.36; 95% CI -0.68, -0.05; p = 0.025). No significant association between the changes in plasma concentrations of Lp(a) with dose and baseline Lp(a) levels was found in the random-effects meta-regression analysis. However, a significant inverse association was observed between the Lp(a)-lowering effect of raloxifene and duration of treatment (p = 0.001).
CONCLUSIONS
Results of the present meta-analysis showed a reduction in plasma Lp(a) concentrations of postmenopausal women with oral raloxifene treatment.
Topics: Administration, Oral; Aged; Biomarkers; Down-Regulation; Female; Humans; Lipoprotein(a); Middle Aged; Postmenopause; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Time Factors
PubMed: 28265881
DOI: 10.1007/s10557-017-6721-6 -
Bioorganic & Medicinal Chemistry Mar 2024All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and...
All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7-9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7-9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.
Topics: Humans; Female; Raloxifene Hydrochloride; Estrogen Receptor alpha; Cell Line, Tumor; Enzyme Inhibitors; Steryl-Sulfatase; Breast Neoplasms; Estrogen Receptor Modulators; Sulfonic Acids
PubMed: 38401456
DOI: 10.1016/j.bmc.2024.117645 -
Anti-cancer Agents in Medicinal... 2022Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the...
BACKGROUND
Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation.
METHODS
The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells' capability to form colonies.
RESULT
Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC values after 48 hours of treatment with exemestane were 176, 180, and 120 μM in A549, H661, and H1299, respectively. Curcumin IC values after 48 hours were 80, 43, and 68 μM in A549, H661, and H1299, respectively. The combined treatment of exemestane or curcumin with cisplatin, raloxifene, and celecoxib resulted in a synergistic effect in the A549 lung cell line with a combination index of less than 1, suggesting synergism. Exemestane resulted in approximately 96% inhibition of wound closure at 100 μM, while curcumin resulted in approximately 63% inhibition of wound closure at 50 μM. Exemestane and curcumin inhibited the formation of cell colonies by reducing the number and size of formed colonies of A549, H661, and H1299 cell lines in a concentration dependent manner. Exemestane and curcumin had significantly induced apoptosis in A549 cells compared to control of untreated cells.
CONCLUSION
Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells.
Topics: Agar; Annexins; Apoptosis; Aromatase; Aromatase Inhibitors; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Humans; Lung Neoplasms; Propidium; Raloxifene Hydrochloride
PubMed: 35473535
DOI: 10.2174/1871520622666220426112435 -
Clinical Obstetrics and Gynecology Dec 2021Selective estrogen receptor (ER) modulators have variable tissue specific estrogen agonist and antagonist activities. Tamoxifen is approved for treatment and prevention...
Selective estrogen receptor (ER) modulators have variable tissue specific estrogen agonist and antagonist activities. Tamoxifen is approved for treatment and prevention of breast cancer; acts as an endometrial estrogen agonist. Raloxifene is approved for prevention and treatment of osteoporosis and prevention of breast cancer. The selective ER modulators bazedoxifene paired with conjugated estrogens relieves vasomotor symptoms and prevents bone loss with neutral effects on breast and amenorrhea similar to placebo. Ospemifene is approved to treat dyspareunia. Lasofoxifene is in development for resistant ER positive breast cancer. Estetrol (E4), synthesized by human fetal liver, has dual weak-estrogenic/antiestrogenic features, now approved as a contraceptive.
Topics: Breast Neoplasms; Estrogens, Conjugated (USP); Female; Gynecology; Humans; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators
PubMed: 34310353
DOI: 10.1097/GRF.0000000000000647 -
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 -
Molecular and Biochemical Parasitology Dec 2023Acanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of...
Acanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of these amoebae to switch phenotypes, from an active trophozoite to a resistant cyst form is not well understood; the cyst stage is often resistant to chemotherapy, which is of concern given the rise of contact lens use and the ineffective disinfectants available, versus the cyst stage. Herein, for the first time, a range of raloxifene sulfonate/sulfamate derivatives which target nucleotide pyrophosphatase/phosphodiesterase enzymes, were assessed using amoebicidal and excystation tests versus the trophozoite and cyst stage of Acanthamoeba. Moreover, the potential for cytopathogenicity inhibition in amoebae was assessed. Each of the derivatives showed considerable anti-amoebic activity as well as the ability to suppress phenotypic switching (except for compound 1a). Selected raloxifene derivatives reduced Acanthamoeba-mediated host cell damage using lactate dehydrogenase assay. These findings suggest that pyrophosphatase/phosphodiesterase enzymes may be valuable targets against Acanthamoeba infections.
Topics: Animals; Acanthamoeba castellanii; Raloxifene Hydrochloride; Sulfonic Acids; Trophozoites; Alkanesulfonates; Phosphoric Diester Hydrolases
PubMed: 37562558
DOI: 10.1016/j.molbiopara.2023.111582 -
Breast (Edinburgh, Scotland) Jun 2018Increasing numbers of women are being identified at 'high-risk' of breast cancer, defined by The National Institute of Health and Care Excellence (NICE) as a 10-year... (Review)
Review
Increasing numbers of women are being identified at 'high-risk' of breast cancer, defined by The National Institute of Health and Care Excellence (NICE) as a 10-year risk of ≥8%. Classically women have been so identified through family history based risk algorithms or genetic testing of high-risk genes. Recent research has shown that assessment of mammographic density and single nucleotide polymorphisms (SNPs), when combined with established risk factors, trebles the number of women reaching the high risk threshold. The options for risk reduction in such women include endocrine chemoprevention with the selective estrogen receptor modulators tamoxifen and raloxifene or the aromatase inhibitors anastrozole or exemestane. NICE recommends offering anastrozole to postmenopausal women at high-risk of breast cancer as cost effectiveness analysis showed this to be cost saving to the National Health Service. Overall uptake to chemoprevention has been disappointingly low but this may improve with the improved efficacy of aromatase inhibitors, particularly the lack of toxicity to the endometrium and thrombogenic risks. Novel approaches to chemoprevention under investigation include lower dose and topical tamoxifen, denosumab, anti-progestins and metformin. Although oophorectomy is usually only recommended to women at increased risk of ovarian cancer it has been shown in numerous studies to reduce breast cancer risks in the general population and in those with mutations in BRCA1/2. However, recent evidence from studies that have confined analysis to true prospective follow up have cast doubt on the efficacy of oophorectomy to reduce breast cancer risk in BRCA1 mutation carriers, at least in the short-term.
Topics: Adult; Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemoprevention; Early Detection of Cancer; Female; Genes, BRCA1; Genes, BRCA2; Humans; Mammography; Middle Aged; Nitriles; Precision Medicine; Raloxifene Hydrochloride; Risk Assessment; Risk Factors; Tamoxifen; Triazoles
PubMed: 29610032
DOI: 10.1016/j.breast.2018.03.009 -
Molecular Psychiatry Jun 2015There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.
Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Australia; Cross-Over Studies; Double-Blind Method; Estrogen Antagonists; Female; Humans; Longitudinal Studies; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Patient Compliance; Psychiatric Status Rating Scales; Raloxifene Hydrochloride; Schizophrenia; Sex Characteristics; Statistics, Nonparametric; Treatment Outcome; Young Adult
PubMed: 25980345
DOI: 10.1038/mp.2015.11