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RSC Advances Oct 2023The computational analysis of drug release from metal-organic frameworks (MOFs), specifically UiO-66, is the primary focus of this research. MOFs are recognized as...
The computational analysis of drug release from metal-organic frameworks (MOFs), specifically UiO-66, is the primary focus of this research. MOFs are recognized as nanocarriers due to their crystalline structure, porosity, and potential for added functionalities. The research examines the release patterns of three drugs: temozolomide, alendronate, and 5-fluorouracil, assessing various factors such as the drugs' distance from the UiO-66 centers, the interaction of drug functional groups with Zr metal ions, and the drug density throughout the nanocarrier. Findings reveal that 5-fluorouracil is located furthest from the UiO-66 center and exhibits the highest positive energy compared to the other drugs. Alendronate's density is observed to shift to the carrier surface, while 5-fluorouracil's density significantly decreases within the system. The drug density diminishes as the distance from the UiO-66 center of mass increases, suggesting a stronger positive interaction between the drugs and the nanocarrier. Moreover, Monte Carlo calculations were employed to load drugs onto the UiO-66 surface, leading to a substantial release of 5-fluorouracil from UiO-66. Quantum and Monte Carlo adsorption localization calculations were also conducted to gather data on the compounds' energy and geometry. This research underscores the potential of MOFs as nanocarriers for drug delivery and highlights the crucial role of temperature in regulating drug release from UiO-66. It provides insights into the complex dynamics of drug release and the factors influencing it, thereby emphasizing the promise of UiO-66 as a viable candidate for drug delivery. This work contributes to our understanding of UiO-66's role and sets the stage for improved performance optimization in the cancer treatment.
PubMed: 37920197
DOI: 10.1039/d3ra05587f -
Annals of Hematology Jan 2024Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone...
Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone marrow, and are often caused by aberrant protein tyrosine kinase activity. The protein tyrosine phosphatase CD45 is a trans-membrane molecule expressed on all haemopoietic blood cells except that of platelets and red cells. CD45 regulates various cellular physiological processes including proliferation, apoptosis, and lymphocyte activation. However, its role in chemotherapy response is still unknown; therefore, the aim of this study was to investigate the role of CD45 in myeloid malignancies in terms of cellular growth, apoptosis, and response to chemotherapy. The expression of CD45 on myeloid leukaemia primary cells and cell lines was heterogeneous with HEL and OCI-AML3 cells showing the highest level. Inhibition of CD45 resulted in increased cellular sensitivity to cytarabine and ruxolitinib, the two main therapies for AML and MPN. Bioinformatics analysis identified genes whose expression was correlated with CD45 expression such as JAK2, ACTR2, THAP3 Serglycin, and PBX-1 genes, as well as licensed drugs (alendronate, allopurinol, and balsalazide), which could be repurposed as CD45 inhibitors which effectively increases sensitivity to cytarabine and ruxolitinib at low doses. Therefore, CD45 inhibition could be explored as a potential therapeutic partner for treatment of myeloid malignancies in combination with chemotherapy such as cytarabine especially for elderly patients and those showing chemotherapy resistance.
Topics: Humans; Aged; Leukemia, Myeloid; Pyrazoles; Nitriles; Cytarabine; Myeloproliferative Disorders; Leukemia, Myeloid, Acute
PubMed: 37917373
DOI: 10.1007/s00277-023-05520-y -
International Journal of Rheumatology 2023Osteoporosis is characterized as a metabolic bone disease defined by low bone mineral density (BMD) and bone tissue degeneration, particularly a reduction in the number...
Osteoporosis is characterized as a metabolic bone disease defined by low bone mineral density (BMD) and bone tissue degeneration, particularly a reduction in the number of trabeculae and a drop in cortical bone thickness, and a rise in porosity, which is mainly due to an imbalance between bone resorption and formation. As a result, it increases bone fragility, and the susceptibility to fracture increases, especially among the elderly. The objective is to assess the effectiveness of dual-energy X-ray absorptiometry (DXA) scan in monitoring the response to osteoporosis treatment and compare the scan's response to different osteoporosis treatments. This retrospective cohort study included 51 adults selected from 300 patients diagnosed with osteoporosis based on World Health Organization (WHO) diagnostic criteria of a -score of -2.5. Data were acquired from the electronic medical records between 2016 and 2019 from a private hospital in Dubai, United Arab Emirates (UAE). The study included sociodemographic characteristics, biomedical parameters, comorbidities, history of fracture, medications, laboratory, and DXA scan results. Ninety-four percent of the patients were females; the mean (±SD) age was 58.1 ± 11.5 years. Most patients were expatriates (84.3%), of which Asian ethnicity was 66.7%. The mean (±SD) duration of osteoporosis was 2.82 ± 1.8 years. Eleven (21.6%) patients had a history of fragility fracture. Ninety-six percent of the patients had vitamin D deficiency. One-third (29.4%) of the patients had hyperparathyroidism. Alendronate/cholecalciferol, received by nine patients (17.6%), showed a significant improvement ( = 0.018) in the BMD of the femoral neck among the study group. In conclusion, the DXA scan as a monitoring tool has shown a significant improvement in the BMD of the femoral neck among patients taking alendronate/cholecalciferol treatment compared to other medications.
PubMed: 37908491
DOI: 10.1155/2023/2160346 -
MDM Policy & Practice 2023To conduct cost-utility analyses for Computed Tomography To Strength (CT2S), a novel osteoporosis screening service, compared with dual-energy X-ray absorptiometry...
Cost-Effectiveness Analysis of CT-Based Finite Element Modeling for Osteoporosis Screening in Secondary Fracture Prevention: An Early Health Technology Assessment in the Netherlands.
UNLABELLED
To conduct cost-utility analyses for Computed Tomography To Strength (CT2S), a novel osteoporosis screening service, compared with dual-energy X-ray absorptiometry (DXA), treat all without screening, and no screening methods for Dutch postmenopausal women referred to fracture liaison service (FLS). CT2S uses CT scans to generate femur models and simulate sideways fall scenarios for bone strength assessment. Early health technology assessment (HTA) was adopted to evaluate CT2S as a novel osteoporosis screening tool for secondary fracture prevention. We constructed a 2-dimensional simulation model considering 4 strategies (no screening, treat all without screening, DXA, CT2S) together with screening intervals (5 y, 2 y), treatments (oral alendronate, zoledronic acid), and discount rate scenarios among Dutch women in 3 age groups (60s, 70s, and 80s). Strategy comparisons were based on incremental cost-effectiveness ratios (ICERs), considering an ICER below €20,000 per QALY gained as cost-effective in the Netherlands. Under the base-case scenario, CT2S versus DXA had estimated ICERs of €41,200 and €14,083 per QALY gained for the 60s and 70s age groups, respectively. For the 80s age group, CT2S was more effective and less costly than DXA. Changing treatment from weekly oral alendronate to annual zoledronic acid substantially decreased CT2S versus DXA ICERs across all age groups. Setting the screening interval to 2 y increased CT2S versus DXA ICERs to €100,333, €55,571, and €15,750 per QALY gained for the 60s, 70s, and 80s age groups, respectively. In all simulated populations and scenarios, CT2S was cost-effective (in some cases dominant) compared with the treat all strategy and cost-saving (more effective and less costly) compared with no screening. CT2S was estimated to be potentially cost-effective in the 70s and 80s age groups considering the willingness-to-pay threshold of the Netherlands. This early HTA suggests CT2S as a potential novel osteoporosis screening tool for secondary fracture prevention.
HIGHLIGHTS
For postmenopausal Dutch women who have been referred to the FLS, direct access to CT2S may be cost-effective compared with DXA for age groups 70s and 80s, when considering the ICER threshold of the Netherlands. This study positions CT2S as a potential novel osteoporosis-screening tool for secondary fracture prevention in the clinical setting.A shorter screening interval of 2 y increases the effectiveness of both screening strategies, but the ICER of CT2S compared with DXA also increased substantially, which made CT2S no longer cost-effective for the 70s age group; however, it remains cost-effective for individuals in their 80s.Annual zoledronic acid treatment with better adherence may contribute to a lower cost-effectiveness ratio when comparing CT2S to DXA screening and the treat all strategies for all age groups.
PubMed: 37900721
DOI: 10.1177/23814683231202993 -
Pharmaceuticals (Basel, Switzerland) Oct 2023A novel osteolytic disorder due to mutation was discovered recently as early-onset Paget's disease of bone (PDB). Bone loss and pain in adult PDB patients have been...
A novel osteolytic disorder due to mutation was discovered recently as early-onset Paget's disease of bone (PDB). Bone loss and pain in adult PDB patients have been treated using bisphosphonates. However, therapeutic strategies for this specific disorder have not been established. Here, we evaluated the efficiency of alendronate (ALN) on a mutant mouse line, recapitulating this disorder. Five-week-old conditional osteoclast-specific -deficient mice (-cKO) and control littermates (33 females and 22 males) were injected with ALN (0.1 mg/kg) or vehicle twice weekly until 8 weeks of age. After euthanizing, bone histomorphometric parameters and skeletal deformities were analyzed using 3D μCT images and histological sections. Three weeks of ALN administration significantly improved bone mass at the distal femur, L3 vertebra, and nose in -cKO mice. Histologically increased osteoclasts with expanded distribution in the distal femur were normalized in these mice. Geometric bone shape analysis revealed a partial recovery from the distal femur deformity. A therapeutic dose of ALN from 5 to 8 weeks of age significantly improved systemic bone loss in -cKO mice and femoral bone deformity. Our study suggests that preventive treatment of bony deformity in early-onset PDB is feasible.
PubMed: 37895866
DOI: 10.3390/ph16101395 -
The American Journal of Case Reports Oct 2023BACKGROUND Bisphosphonates inhibit bone resorption in patients with postmenopausal osteoporosis and reduce osteoporotic fracture incidence. Medication-related...
BACKGROUND Bisphosphonates inhibit bone resorption in patients with postmenopausal osteoporosis and reduce osteoporotic fracture incidence. Medication-related osteonecrosis of the jaws (MRONJ) and atypical femoral fractures (AFF) are both rare but serious adverse effects of anti-resorptive drugs (ARD) such as bisphosphonates. The most advanced form of MRONJ is termed stage 3 and can lead to severe local sequelae like pathologic mandibular fractures (PMF). This study reports a case of MRONJ-related PMF and AFF with osteomyelitis secondary to bisphosphonate treatment for osteoporosis. CASE REPORT A 63-year-old white woman was diagnosed with PMF related to MRONJ stage 3 during treatment of an AFF with osteomyelitis. She had been treated for postmenopausal osteoporosis with 70 mg of alendronate weekly for 2 years. The PMF was treated by stable internal fixation combined with debridement and sequestrectomy, but further debridement was required and 2 mandibular implants were then removed. Postoperative recovery was uneventful and the mandibular infection was controlled after the second surgery. Three weeks later, she was discharged from the hospital, instructed to discontinue the use of alendronate, and referred for 30 sessions of hyperbaric oxygen therapy. At the 3-year follow-up, the PMF was completely healed without signs of mandibular infection or bone exposure. CONCLUSIONS This report raises awareness of both MRONJ and AFF as possible adverse effects of short-term bisphosphonate therapy for postmenopausal osteoporosis, and highlights the importance of dental and orthopedic follow-ups. It is crucial to emphasize the need for early diagnosis and treatment to prevent MRONJ progression to PMF.
Topics: Female; Humans; Middle Aged; Diphosphonates; Alendronate; Osteoporosis, Postmenopausal; Bone Density Conservation Agents; Mandibular Fractures; Osteoporosis; Fractures, Spontaneous; Femoral Fractures; Osteomyelitis
PubMed: 37867315
DOI: 10.12659/AJCR.941144 -
Cureus Sep 2023Bisphosphonates have been accepted as the first-line treatment for postmenopausal osteoporosis. Atypical femoral shaft fracture is one of the side effects of long-term...
Bisphosphonates have been accepted as the first-line treatment for postmenopausal osteoporosis. Atypical femoral shaft fracture is one of the side effects of long-term bisphosphonate therapy. The mainstay treatment of this atypical fracture is bisphosphonates cessation and stabilization with internal fixation. We are reporting a rare case of a blocked intramedullary femoral canal found during surgery of an 85-year-old Indian lady with an atypical femoral shaft fracture related to her five-year alendronate therapy. We found difficulty in passing the guidewire through the fracture site during the closed method, which renders open reduction to manage the obliterated intramedullary canal. The importance of changing decisions intraoperatively should be highlighted to avoid further complications. Fracture union is achieved during our follow-up in the clinic.
PubMed: 37859907
DOI: 10.7759/cureus.45441 -
Calcified Tissue International Nov 2023Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional... (Randomized Controlled Trial)
Randomized Controlled Trial
Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional formulations of alendronate (ALN). The clinical effectiveness of ALN-EFF, however, has not been investigated. This study aims to investigate if ALN-EFF is non-inferior to ALN in suppressing bone turnover markers (BTM). We conducted a 16-week prospective, randomized, open-label study comprising 64 postmenopausal women with BMD T-score < -1 naïve to osteoporosis treatment. Participants were randomized 1:1 to ALN or ALN-EFF. We collected blood samples at 0, 4, 8, and 16 weeks. Non-inferiority margin was determined as 12% (80% of efficacy retained), and an SD of 15% on change in CTx. CTx decreased by 58.2% ± 24.1% in the ALN group and by 46.9% ± 23.3% (CI - 38.42:- 55.35) in the ALN-EFF group (p = 0.08). The non-inferiority limit was 46.6%. With ALN-EFF the CI crosses the non-inferiority limit thus the test for non-inferiority was indeterminate. PINP decreased by 45.7 ± 22.6% in the ALN group and by 35.1 ± 20.7% in the ALN-EFF group (p = 0.07). Changes over time in the BTMs were not significantly different between the groups, p > 0.10 for both CTx and PINP. There was no difference in frequency of AEs or compliance between the two groups, but rate of discontinuation was lower with ALN-EFF. In conclusion, suppression of BTMs was not significantly different between the groups but formal non-inferiority could not be established.
Topics: Female; Humans; Alendronate; Osteoporosis, Postmenopausal; Prospective Studies; Bone Density; Bone Remodeling; Bone Density Conservation Agents
PubMed: 37803182
DOI: 10.1007/s00223-023-01140-w -
BMC Musculoskeletal Disorders Sep 2023Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed...
BACKGROUND
Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed for the treatment of osteoporosis based on evidence that, correctly taken, bisphosphonates can improve bone strength and lead to a reduction in the risk of fragility fractures. However, it is currently unclear how decisions to select between bisphosphonate regimens, including intravenous regimen, are made in practice and how clinicians support patients with different treatments.
METHODS
This was an interpretivist qualitative study. 23 semi-structured telephone interviews were conducted with a sample of general practitioners (GPs), secondary care clinicians, specialist experts as well as those providing and leading novel treatments including participants from a community intravenous (IV) zoledronate service. Data analysis was undertaken through a process of iterative categorisation.
RESULTS
The results report clinicians varying experiences of making treatment choices, as well as wider aspects of osteoporosis care. Secondary care and specialist clinicians conveyed some confidence in making treatment choices including on selecting IV treatment. This was aided by access to diagnostic testing and medication expertise. In contrast GPs reported a number of challenges in prescribing bisphosphonate medications for osteoporosis and uncertainty about treatment choice. Results also highlight how administering IV zoledronate was seen as an opportunity to engage in broader care practices.
CONCLUSION
Approaches to making treatment decisions and supporting patients when prescribing bisphosphonates for osteoporosis vary in practice. This study points to the need to co-ordinate osteoporosis treatment and care across different care providers.
Topics: Humans; Female; Zoledronic Acid; Osteoporosis; Diphosphonates; Ibandronic Acid; Alendronate; Bone Density Conservation Agents; Osteoporosis, Postmenopausal
PubMed: 37770860
DOI: 10.1186/s12891-023-06865-1 -
Biomolecules Aug 2023While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions,...
While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions, including T cell priming and activation against tumor antigens. Alendronate is a potent amino-bisphosphonate that modulates the function of macrophages in vitro, with potential as an immunotherapy if its low systemic bioavailability can be addressed. We repurposed alendronate in a non-leaky and long-circulating liposomal carrier similar to that of the clinically approved pegylated liposomal doxorubicin to facilitate rapid clinical translation. Here, we tested liposomal alendronate (PLA) as an immunotherapeutic agent for cancer in comparison with a standard of care immunotherapy, a PD-1 immune checkpoint inhibitor. We showed that the PLA induced bone marrow-derived murine non-activated macrophages and M2-macrophages to polarize towards an M1-functionality, as evidenced by gene expression, cytokine secretion, and lipidomic profiles. Free alendronate had negligible effects, indicating that liposome encapsulation is necessary for the modulation of macrophage activity. In vivo, the PLA showed significant accumulation in tumor and tumor-draining lymph nodes, sites of tumor immunosuppression that are targets of immunotherapy. The PLA remodeled the tumor microenvironment towards a less immunosuppressive milieu, as indicated by a decrease in TAM and helper T cells, and inhibited the growth of established tumors in the B16-OVA melanoma model. The improved bioavailability and the beneficial effects of PLA on macrophages suggest its potential application as immunotherapy that could synergize with T-cell-targeted therapies and chemotherapies to induce immunogenic cell death. PLA warrants further clinical development, and these clinical trials should incorporate tumor and blood biomarkers or immunophenotyping studies to verify the anti-immunosuppressive effect of PLA in humans.
PubMed: 37759709
DOI: 10.3390/biom13091309