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Calcified Tissue International Jun 2023To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen... (Meta-Analysis)
Meta-Analysis Review
The Clinical Effectiveness of Denosumab (Prolia®) for the Treatment of Osteoporosis in Postmenopausal Women, Compared to Bisphosphonates, Selective Estrogen Receptor Modulators (SERM), and Placebo: A Systematic Review and Network Meta-Analysis.
To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs; bazedoxifene, raloxifene) or placebo, for the treatment of osteoporosis in postmenopausal women (PMW). Systematic searches were run in PubMed, Embase & Cochrane Library on 27-April-2022. Randomized controlled trials (RCTs) that included osteoporotic PMW allocated to denosumab, SERMs, bisphosphonates, or placebo were eligible for inclusion. RCTs were appraised using Cochrane Risk of Bias 2.0. Bayesian network and/or pairwise meta-analyses were conducted on predetermined outcomes (i.e. vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, adverse events [AEs], serious AEs (SAEs), withdrawals due to AEs, AEs caused by denosumab discontinuation). A total of 12 RCTs (k = 22 publications; n = 25,879 participants) were included in the analyses. Denosumab, reported a statistically significant increase in lumbar spine (LS) and total hip (TH) BMD, compared to placebo. Similarly, denosumab also resulted in a statistically significant increase in TH BMD compared to the raloxifene and bazedoxifene. However, relative to denosumab, alendronate, ibandronate and risedronate resulted in significant improvements in both femoral neck (FN) and LS BMD. With regards to vertebral fractures and all safety outcomes, there were no statistically significant differences between denosumab and any of the comparator. Relative to placebo, denosumab was associated with significant benefits in both LS and TH BMD. Additionally, denosumab (compared to placebo) was not associated with reductions in vertebral and nonvertebral fractures. Finally, denosumab was not associated with improvement in safety outcomes, compared to placebo. These findings should be interpreted with caution as some analyses suffered from statistical imprecision.
Topics: Female; Humans; Diphosphonates; Selective Estrogen Receptor Modulators; Denosumab; Alendronate; Bone Density Conservation Agents; Risedronic Acid; Raloxifene Hydrochloride; Ibandronic Acid; Network Meta-Analysis; Postmenopause; Osteoporosis, Postmenopausal; Osteoporosis; Bone Density; Spinal Fractures; Treatment Outcome
PubMed: 37016189
DOI: 10.1007/s00223-023-01078-z -
Chemical Biology & Drug Design Sep 2023Multidrug resistance in breast cancer and the associated side-effects of anticancer therapies are significant hurdles in chemotherapy-based treatment. Biodegradable...
Multidrug resistance in breast cancer and the associated side-effects of anticancer therapies are significant hurdles in chemotherapy-based treatment. Biodegradable polymeric nano-based targeted drug delivery technologies showed tremendous advantages in targeted local delivery with limited off-targeted side effects. Therefore, there is a persistent need to develop targeted nanomedicine systems for treatment of breast cancer. The current research attempted to develop poly (lactic-co-glycolic acid) nanoparticles loaded with raloxifene by modified emulsification solvent diffusion evaporation method to improve oral bioavailability by using Taguchi design. It was observed that the optimized formulation (1:4 drug to polymer ratio) poly (lactic-co-glycolic acid) showed a mean particle size and Polydispersity index of 218 ± 23.7 nm and 0.231 ± 0.04, respectively. The entrapment efficiency was found to be 82.30% ± 1.02%. In vitro drug delivery was found to be 92.5% ± 1.48% in 40 h. The nanoparticles were to remain stable at 2°C-8°C even after 30 days. Differential scanning calorimetry and Fourier transform infrared spectroscopy characterization techniques showed that there was no interaction between the drug and excipient. Stability studies indicate that polymeric nanoparticles were stable at 2°C-8°C after 6 months. Raloxifene nanoparticles may be the most potent targeting moieties to treat highly invasive and metastatic MCF-7 breast cancer cells.
Topics: Humans; Female; Polylactic Acid-Polyglycolic Acid Copolymer; Raloxifene Hydrochloride; Breast Neoplasms; Drug Carriers; Polyglycolic Acid; Lactic Acid; Particle Size; Nanoparticles
PubMed: 36856306
DOI: 10.1111/cbdd.14222 -
Journal of Microencapsulation Mar 2023Scaffolds are implanted to spur the regeneration of damaged tissues. The inappropriate construction of scaffolds laden with cells is not efficient. The optimisation of...
Scaffolds are implanted to spur the regeneration of damaged tissues. The inappropriate construction of scaffolds laden with cells is not efficient. The optimisation of the scaffolds' constituents is essential for tissue repair. In this study, a scaffold embedded with Raloxifene drug was optimised via Response Surface Methodology (RSM), targeting controlled cell proliferation. The independent variables for RSM (fibronectin, collagen I, glutaraldehyde, and Raloxifene) were screened in Swiss target prediction software (probability ≥99%) to optimise dependent variables (porosity, cell viability, degradation, and swelling) by ANOVA and characterised with FTIR, SEM and contact angle measurement. The scaffold was tested for antimicrobial property, and proliferation and attachment of mouse mesenchymal stem cells. The ANOVA analysis with value ≤ 0.0001 suggested the optimal concentration of biomaterials and drugs. The optimised scaffold displayed 80% porosity with pore size 33 ± 3 µm. We also observed significant cell attachment and proliferation ( value ≤ 0.05) in optimised scaffold. The scaffold may be further evaluated for its potential for tissue repair.
Topics: Mice; Animals; Tissue Scaffolds; Collagen; Raloxifene Hydrochloride; Biocompatible Materials; Porosity; Cell Proliferation; Tissue Engineering
PubMed: 36719352
DOI: 10.1080/02652048.2023.2175922 -
Calcified Tissue International Apr 2023The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP)... (Randomized Controlled Trial)
Randomized Controlled Trial
The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.
Topics: Humans; Aged; Female; Raloxifene Hydrochloride; Bone Density Conservation Agents; Selective Estrogen Receptor Modulators; Spinal Fractures; Prospective Studies; Bone Density; Osteoporosis; Fractures, Bone; Cholesterol; Osteoporosis, Postmenopausal
PubMed: 36707436
DOI: 10.1007/s00223-023-01060-9 -
Genes Jan 2023The present study analyzed the effect of vitamin D receptor () gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical...
The present study analyzed the effect of vitamin D receptor () gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, raloxifene, and ibandronate) in 356 postmenopausal women from Slovakia. Association analysis revealed a significant effect of BsmI polymorphism on lumbar spine BMD, serum osteocalcin (OC), and β-CrossLaps levels. While ApaI and Cdx2 polymorphisms were associated with OC and alkaline phosphatase, TaqI polymorphism affected all turnover markers. ApaI, TaqI, and BsmI genotypes increased the risk of spinal, radial, or total fractures with odds ratios ranging from 2.03 to 3.17. Each of therapy types evaluated had a beneficial effect on all osteoporosis-related traits; however, the gene affected only ibandronate and raloxifene treatment. ApaI/aa, TaqI/TT, and BsmI/bb genotypes showed a weaker or no response to ibandronate therapy in femoral and spinal BMD. The impact of aforementioned polymorphisms on turnover markers was also genotype dependent. On the contrary, only TaqI and BsmI polymorphisms influenced raloxifene therapy, even only in lumbar spine BMD. These results point to the potential of using the gene in personalized pharmacotherapy of osteoporosis.
Topics: Female; Humans; Receptors, Calcitriol; Raloxifene Hydrochloride; Ibandronic Acid; Polymorphism, Genetic; Osteoporosis; Fractures, Bone
PubMed: 36672934
DOI: 10.3390/genes14010193 -
Regulatory Toxicology and Pharmacology... Feb 2023In Canada, the Canadian Environmental Protection Act (1999) requires human health and environmental risk assessments be conducted for new substances prior to their...
In Canada, the Canadian Environmental Protection Act (1999) requires human health and environmental risk assessments be conducted for new substances prior to their manufacture or import. While this toxicity data is historically obtained using rodents, in response to the international effort to eliminate animal testing, Health Canada is collaborating with the National Research Council (NRC) of Canada to develop a New Approach Method by refining existing NRC zebrafish models. The embryo/larval zebrafish model evaluates systemic (whole body) general toxicity which is currently unachievable with cell-based testing. The model is strengthened using behavioral, toxicokinetic and transcriptomic responses to assess non-visible indicators of toxicity following chemical exposure at sub-phenotypic concentrations. In this paper, the predictive power of zebrafish transcriptomics is demonstrated using two chemicals; Raloxifene and Resorcinol. Raloxifene exposure produced darkening of the liver and malformation of the nose/mandible, while Resorcinol exposure produced increased locomotor activity. Transcriptomic analysis correlated differentially expressed genes with the phenotypic effects and benchmark dose calculations determined that the transcriptomic Point of Departure (POD) occurred at subphenotypic concentrations. Correlating gene expression with apical (phenotypic) effects strengthens confidence in evaluation of chemical toxicity, thereby demonstrating the significant advancement that the larval zebrafish transcriptomics model represents in chemical risk assessment.
Topics: Animals; Humans; Zebrafish; Transcriptome; Larva; Raloxifene Hydrochloride; Canada; Risk Assessment; Water Pollutants, Chemical
PubMed: 36642323
DOI: 10.1016/j.yrtph.2023.105336 -
Acta Psychiatrica Scandinavica Apr 2023We conducted a comprehensive meta-analysis of all available trials to evaluate the efficacy and safety of estrogen and selective estrogen receptor modulators as... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
We conducted a comprehensive meta-analysis of all available trials to evaluate the efficacy and safety of estrogen and selective estrogen receptor modulators as adjunctive treatment for women with schizophrenia.
METHODS
Multiple databases were searched from the inception until March 2022. Only randomized, double-blind, placebo-controlled studies (randomized controlled trials) were included. Mean differences (MDs) and their 95% confidence intervals (CIs) were calculated using random effects models.
RESULTS
The meta-analysis included six estradiol versus placebo studies (n = 724) and seven raloxifene versus placebo studies (n = 419), covering a total of 1143 patients. Adjunctive estradiol outperformed the placebo in terms of the Positive and Negative Syndrome Scale (PANSS) total score (MD = -7.29; 95% CI = -10.67 to -3.91; I = 59.1%; p < 0.001; k = 9; N = 858), positive symptom score (MD = -1.54; 95% CI = -3.04 to -0.72; I = 45.8%; p < 0.001; k = 7; N = 624), negative symptom score (MD = -1.9; 95% CI = -1.77 to -0.34; I = 37.6%; p < 0.05; k = 14; N = 1042), and general psychopathology score (MD = -4.27; 95% CI = -7.14 to -1.41; I = 76.3%; p < 0.005; k = 7; N = 624). Adjunctive raloxifene outperformed the placebo in terms of the PANSS total score (MD = -6.83; 95% CI = -11.69 to -1.97; I = 67.8%; p = 0.006; k = 8; N = 432) and general psychopathology score (MD = -3.82; 95% CI = -6.36 to -1.28; I = 65.3%; p < 0.005; k = 8; N = 432).
CONCLUSIONS
Our meta-analysis showed that estradiol and raloxifene are effective and safe adjunctive treatments that improve schizophrenia symptoms in women. Moreover, the effects of estradiol and raloxifene differed in terms of timing and dosage. Both are promising adjunctive treatments that merit further study.
Topics: Humans; Female; Raloxifene Hydrochloride; Schizophrenia; Estradiol; Antipsychotic Agents; Drug Therapy, Combination; Postmenopause; Double-Blind Method; Randomized Controlled Trials as Topic
PubMed: 36585771
DOI: 10.1111/acps.13530 -
Scientific Reports Dec 2022Benign paroxysmal positional vertigo (BPPV) is associated with menopause and/or osteopenia. Morphological changes in the otoconial layer have been reported after...
Benign paroxysmal positional vertigo (BPPV) is associated with menopause and/or osteopenia. Morphological changes in the otoconial layer have been reported after ovariectomy (OVX). Moreover, hormone replacement therapy decreases BPPV risk. However, knowledge concerning the effect of hormonal therapy on the otoconial changes caused by estrogen deficiency is limited. We aimed to examine the effect of hormonal therapy on otoconial changes caused by estrogen deficiency. We hypothesized that hormonal therapy could reduce otoconial changes caused by OVX. Eight-week-old C57BL/6 mice were divided into four groups: sham operation with implantation of vehicle (sham + v), OVX with implantation of vehicle (OVX + v), OVX with implantation of estradiol (E2) (OVX + E2), and OVX with implantation of raloxifene (RAL) (OVX + RAL) groups. Otoconial layer volume was measured by micro-CT at 4 weeks after OVX or the sham operation. The otic bullae were removed; immunohistochemistry was performed for estrogen receptor alpha and 4-hydroxynonenal. Otoconial layer volume was significantly higher in the OVX + v than in the sham + v group. E2 and RAL significantly reduced these changes in the endometrial layer. The staining of estrogen receptor alpha and 4-hydroxynonenal were stronger in the OVX + v than in the sham + v group but equal in the sham + v, OVX + E2, and OVX + RAL groups. These results indicate that E2 and RAL are effective against morphological changes of the otoconial layer caused by estrogen deficiency via oxidative stress reduction.
Topics: Animals; Female; Humans; Mice; Estradiol; Estrogen Receptor alpha; Estrogens; Mice, Inbred C57BL; Ovariectomy; Raloxifene Hydrochloride
PubMed: 36585504
DOI: 10.1038/s41598-022-27240-5 -
Behavioural Brain Research Mar 2023The existence of sex differences in schizophrenia is a well documented phenomenon which led to the hypothesis that female sex hormones are neuroprotective and hence...
The existence of sex differences in schizophrenia is a well documented phenomenon which led to the hypothesis that female sex hormones are neuroprotective and hence responsible for the more favorable disease characteristics seen in women. The current study sought to investigate the effects of estrogen-like agents administered during early adolescence on behavioral outcomes in adulthood using the neurodevelopmental maternal immune activation (MIA) rodent model of schizophrenia. Female MIA offspring were administered during the asymptomatic period of adolescence with either 17β-estradiol, raloxifene or saline and were tested in late adolescence and adulthood for schizophrenia-related behavioral performance. We report here that whereas adult female MIA offspring exhibited cognitive deficits in the form of retarded spatial learning, the administration of raloxifene during adolescence was sufficient in preventing these deficits and resulted in intact performance in the MIA group.
Topics: Animals; Humans; Female; Male; Raloxifene Hydrochloride; Schizophrenia; Rodentia; Poly I-C; Behavior, Animal; Disease Models, Animal; Prenatal Exposure Delayed Effects; Cognition
PubMed: 36574844
DOI: 10.1016/j.bbr.2022.114276 -
Journal of Neurology, Neurosurgery, and... Apr 2023The decline of humoral response to COVID-19 vaccine led to authorise a booster dose. Here, we characterised the kinetics of B-cell and T-cell immune responses in...
Longitudinal characterisation of B and T-cell immune responses after the booster dose of COVID-19 mRNA-vaccine in people with multiple sclerosis using different disease-modifying therapies.
BACKGROUND
The decline of humoral response to COVID-19 vaccine led to authorise a booster dose. Here, we characterised the kinetics of B-cell and T-cell immune responses in patients with multiple sclerosis (PwMS) after the booster dose.
METHODS
We enrolled 22 PwMS and 40 healthcare workers (HCWs) after 4-6 weeks from the booster dose (T3). Thirty HCWs and 19 PwMS were also recruited 6 months (T2) after the first dose. Antibody response was measured by anti-receptor-binding domain (RBD)-IgG detection, cell-mediated response by an interferon (IFN)-γ release assay (IGRA), Th1 cytokines and T-cell memory profile by flow cytometry.
RESULTS
Booster dose increased anti-RBD-IgG titers in fingolimod-treated, cladribine-treated and IFN-β-treated patients, but not in ocrelizumab-treated patients, although antibody titres were lower than HCWs. A higher number of fingolimod-treated patients seroconverted at T3. Differently, T-cell response evaluated by IGRA remained stable in PwMS independently of therapy. Spike-specific Th1-cytokine response was mainly CD4 T-cell-mediated, and in PwMS was significantly reduced (p<0.0001) with impaired IL-2 production compared with HCWs at T3. In PwMS, total Th1 and IFN-γ CD4 T-cell responders to spike protein were increased from T2 to T3.Compared with HCWs, PwMS presented a higher frequency of CD4 and CD8 terminally differentiated effector memory cells and of CD4 effector memory (T) cells, independently of the stimulus suggesting the association of this phenotype with MS status. CD4 and CD8 T cell frequency was further increased at T3 compared with T2.
CONCLUSIONS
COVID-19 vaccine booster strengthens humoral and Th1-cell responses and increases T cells in PwMS.
Topics: Humans; COVID-19 Vaccines; Multiple Sclerosis; T-Lymphocytes; Fingolimod Hydrochloride; COVID-19; Cytokines; RNA, Messenger; Immunoglobulin G; Antibodies, Viral
PubMed: 36522154
DOI: 10.1136/jnnp-2022-330175