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Connective Tissue Research Jan 2022Raloxifene (RAL) is a selective estrogen receptor modulator (SERM) that has previously been shown to cause acellular benefits to bone tissue. Due to these improvements,...
Raloxifene (RAL) is a selective estrogen receptor modulator (SERM) that has previously been shown to cause acellular benefits to bone tissue. Due to these improvements, RAL was combined with targeted tibial loading to assess if RAL treatment during periods of active bone formation would allow for further mechanical enhancements. Structural, mechanical, and microstructural effects were assessed in bone from C57BL/6 mice that were treated with RAL (0.5 mg/kg), tibial loading, or both for 6 weeks, beginning at 10 weeks of age. microcomputed tomography (CT) images indicated RAL and loading work together to improve bone mass and architecture, especially within the cancellous region of males. Increases in cancellous bone volume fraction were heavily driven by increases in trabecular thickness, though there were some effects on trabecular spacing and number. In the cortical regions, RAL and loading both increased cross-sectional area, cortical area, and cortical thickness. Whole-bone mechanical testing primarily indicated the effects of loading. Further characterization through Raman spectroscopy and nanoindentation showed load-based changes in mineralization and micromechanics, while both loading and RAL caused changes in the secondary collagen structure. In contrast to males, in females, there were large load-based effects in the cancellous and cortical regions, resulting in increased whole-bone mechanical properties. RAL had less of an effect on cancellous and cortical architecture, though some effects were still present. RAL and loading work together to impact bone architecture and mechanical integrity, leading to greater improvements than either treatment individually.
Topics: Animals; Bone Density; Female; Male; Mice; Mice, Inbred C57BL; Raloxifene Hydrochloride; Tibia; X-Ray Microtomography
PubMed: 33427519
DOI: 10.1080/03008207.2020.1865938 -
International Journal of Nanomedicine 2014Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability...
Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon(®) 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm(2)/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug.
Topics: Administration, Cutaneous; Animals; Drug Carriers; Models, Biological; Nanostructures; Particle Size; Phospholipids; Raloxifene Hydrochloride; Rats; Rats, Wistar; Reproducibility of Results; Research Design; Skin; Skin Absorption; Surface-Active Agents
PubMed: 25246789
DOI: 10.2147/IJN.S65408 -
Current Opinion in Nephrology and... May 2018Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. The purpose of this review is to... (Review)
Review
PURPOSE OF REVIEW
Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. The purpose of this review is to provide an update on recent findings in the diagnosis and treatment of osteoporosis in patients with CKD.
RECENT FINDINGS
Multiple observational studies have shown that bone mineral density measurement using DEXA is equally predictive in CKD stages 1-3, as in the general population. Post hoc analyses from randomized trials of bisphosphonates, SERM, RANKL inhibitors and PTH agonists all suggest equal efficacy in mild-moderate CKD. A recent systematic review also found evidence for efficacy of bisphosphonates in patients with a kidney transplant.
SUMMARY
Bone mineral density measurement using DEXA is accurate in patients with CKD stages 1-3 and should be considered to guide treatment of osteoporosis. Current treatments are unaffected by mild-to-moderate decline in kidney function, and physicians should use bisphosphonates and other osteoporosis treatments in this population, whenever indicated. Studies evaluating the optimal diagnostic and management strategy in patients with CKD stages (G4-5D) are needed.
Topics: Absorptiometry, Photon; Bone Density; Bone Density Conservation Agents; Denosumab; Diphosphonates; Fractures, Bone; Humans; Osteoporosis; Raloxifene Hydrochloride; Renal Insufficiency, Chronic; Risk Factors
PubMed: 29547405
DOI: 10.1097/MNH.0000000000000411 -
Cellular Oncology (Dordrecht) Feb 2021Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with...
PURPOSE
Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling.
METHODS
Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed.
RESULTS
Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene.
CONCLUSIONS
Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype.
Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Cytokine Receptor gp130; Estrogen Receptor beta; Humans; Interleukin-6; Male; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Raloxifene Hydrochloride; STAT3 Transcription Factor; Signal Transduction; Time Factors; Xenograft Model Antitumor Assays; Mice
PubMed: 32940862
DOI: 10.1007/s13402-020-00559-9 -
The Journal of Antimicrobial... May 2022Pathogenic bacteria can invade and survive inside phagocytic and non-phagocytic cells and use them as a sanctuary against antibiotics. Induction of various host...
BACKGROUND
Pathogenic bacteria can invade and survive inside phagocytic and non-phagocytic cells and use them as a sanctuary against antibiotics. Induction of various host protective mechanisms, including autophagy, can be a novel and effective method to combat intracellular bacteria. Recent studies report that raloxifene, a selective oestrogen receptor modulator, can induce cellular autophagy.
OBJECTIVES
To demonstrate the effect of raloxifene on intracellular invasion and proliferation of pathogenic bacteria and investigate raloxifene-induced metabolic changes in host cells.
METHODS
Autophagic induction was determined by the extent of nuclear fragmentation and expression levels of the LC3B protein. Intracellular invasion of MRSA strains into A549 lung epithelial cells and invasion of Mycobacterium abscessus into RAW264.7 macrophages were assessed by invasion and proliferation assays. Changes in host cell metabolism were examined by transcriptomic profiling using RNA sequencing.
RESULTS
Our data demonstrate increased autophagy in cells upon raloxifene treatment, which contributed to prevention of bacterial invasion and proliferation. Transcriptomic profiling of host cells revealed changes in cholesterol-related pathways and consequent increases in oxidative stress-related genes and in autophagic induction through the TRIM and GABA pathways.
CONCLUSIONS
Our results demonstrate raloxifene's potential as a broad-spectrum antibacterial agent through autophagic induction in host cells and prevention of intracellular invasion and proliferation of pathogenic bacteria.
Topics: Autophagy; Macrophages; Metabolic Networks and Pathways; Mycobacterium abscessus; Raloxifene Hydrochloride
PubMed: 35260900
DOI: 10.1093/jac/dkac069 -
Best Practice & Research. Clinical... Dec 2014During the past 2 decades, many interventions were proven effective in the management of postmenopausal osteoporosis. The objective of an anti-osteoporosis treatment is... (Review)
Review
During the past 2 decades, many interventions were proven effective in the management of postmenopausal osteoporosis. The objective of an anti-osteoporosis treatment is to reduce fracture rates, ideally at all skeletal sites (i.e. spine, hip, and other non-spine). The armamentarium against osteoporosis includes anti-resorptive agents (i.e. bisphosphonates, selective estrogen receptor modulators and denosumab), bone-forming agents (i.e. peptides from the parathyroid hormone family) and one agent with a dual mechanism of action (i.e. strontium ranelate). All these medications combine antifracture efficacy with a reasonable benefit/risk profile. However, the choice of a particular chemical entity, in one individual patient is based on the knowledge and expertise of the physician. Prioritization of drugs should be based on the individual profile of the patient, the severity of osteoporosis and the specific contraindications, warnings and precautions of use of the various available medications.
Topics: Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Denosumab; Diphosphonates; Humans; Indoles; Osteoporosis; Parathyroid Hormone; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Thiophenes
PubMed: 25432354
DOI: 10.1016/j.beem.2014.09.003 -
Drug Development and Industrial Pharmacy Dec 2021In the present study, hyaluronic acid (HA)-coated raloxifene-loaded poly(l-lactic-co-glycolic acid) (PLGA) nanoparticles have been developed to improve the anticancer...
CONTEXT
In the present study, hyaluronic acid (HA)-coated raloxifene-loaded poly(l-lactic-co-glycolic acid) (PLGA) nanoparticles have been developed to improve the anticancer potential and reduce side effects associated with the drug.
AIM AND OBJECTIVES
The investigation was aimed to formulate and optimize raloxifene hydrochloride (RALH)-loaded PLGA nanoparticles with surface modification using HA as a targeting moiety. To perform physicochemical characterization, cytotoxicity study (using MCF-7), drug release study and pharmacodynamic study of optimized formulation.
METHODOLOGY
Raloxifene hydrochloride-loaded PLGA nanoparticles were prepared by nanoprecipitation technique, followed by surface modification with HA. Formulation was optimized by using 23 factorial design and characterized by physicochemical, drug release, cytotoxicity studies, and pharmacokinetics.
RESULTS AND DISCUSSION
The particle size, PDI, zeta potential, entrapment efficiency, and loading capacity of spherically shaped RALH-loaded nanoparticles were 207.3 ± 4.2 d.nm, 0.218 ± 0.127, -.127 mV, 43.75 ± 1.2%, and 7.55 ± 1.14%, respectively. The drug release showed sustained release and followed Korsmeyer-Peppas model with non-Fickian release pattern. The cytotoxicity study of drug-loaded NPs by MTT assay on MCF-7 breast carcinoma cell showed anti-cancer activity after 48 h of treatment.
CONCLUSION
The results of the present investigation suggested that RALH-loaded HA-modified PLGA nanoparticles showed sustained drug release with anticancer activity and can be a promising approach for treatment of breast cancer.
Topics: Breast Neoplasms; Drug Carriers; Female; Humans; Hyaluronic Acid; Lactic Acid; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Raloxifene Hydrochloride
PubMed: 35686735
DOI: 10.1080/03639045.2022.2088784 -
Clinical Interventions in Aging 2014To systematically review the literature describing the efficacy, effectiveness, and safety of raloxifene for postmenopausal Japanese women with osteoporosis or low bone... (Review)
Review
PURPOSE
To systematically review the literature describing the efficacy, effectiveness, and safety of raloxifene for postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia).
MATERIALS AND METHODS
Medline via PubMed and Embase was systematically searched using prespecified terms. Retrieved publications were screened and included if they described randomized controlled trials or observational studies of postmenopausal Japanese women with osteoporosis or osteopenia treated with raloxifene and reported one or more outcome measures (change in bone mineral density [BMD]; fracture incidence; change in bone-turnover markers, hip structural geometry, or blood-lipid profile; occurrence of adverse events; and change in quality of life or pain). Excluded publications were case studies, editorials, letters to the editor, narrative reviews, or publications from non-peer-reviewed journals; multidrug, multicountry, or multidisease studies with no drug-, country-, or disease-level analysis; or studies of participants on dialysis.
RESULTS
Of the 292 publications retrieved, 15 publications (seven randomized controlled trials, eight observational studies) were included for review. Overall findings were statistically significant increases in BMD of the lumbar spine (nine publications), but not the hip region (eight publications), a low incidence of vertebral fracture (three publications), decreases in markers of bone turnover (eleven publications), improved hip structural geometry (two publications), improved blood-lipid profiles (five publications), a low incidence of hot flushes, leg cramps, venous thromboembolism, and stroke (12 publications), and improved quality of life and pain relief (one publication).
CONCLUSION
Findings support raloxifene for reducing vertebral fracture risk by improving BMD and reducing bone turnover in postmenopausal Japanese women with osteoporosis or osteopenia. Careful consideration of fracture risk and the risk-benefit profile of antiosteoporosis medications is required when managing patients with osteoporosis.
Topics: Aged; Aged, 80 and over; Biomarkers; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Female; Fractures, Bone; Hip Joint; Humans; Lipids; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Quality of Life; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic
PubMed: 25395843
DOI: 10.2147/CIA.S70307 -
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 -
Therapeutic Delivery Jul 2021The present study focused on the development of a dry emulsion tablet of raloxifene hydrochloride (RXF) using a solid carrier adsorption technique to enhance oral...
The present study focused on the development of a dry emulsion tablet of raloxifene hydrochloride (RXF) using a solid carrier adsorption technique to enhance oral bioavailability. An oil-in-water emulsion was formulated and converted into dry powder using HPMC K4M plus Aerosil 200, then compressed into tablets. The prepared emulsion was evaluated for globule size, drug content and zeta potential. release study revealed significantly higher release from emulsion. The prepared tablets possessed acceptable hardness, friability, weight variation, disintegration time, thickness, etc. pharmacokinetic studies indicated a more than sevenfold increase in oral bioavailability. Stability studies indicated good physical and chemical stability of the developed formulation. The authors successfully formulated dry emulsion tablets with enhanced oral bioavailability.
Topics: Adsorption; Biological Availability; Emulsions; Raloxifene Hydrochloride; Solubility; Tablets
PubMed: 34165001
DOI: 10.4155/tde-2021-0025