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Journal of Cellular and Molecular... Dec 2023Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast...
Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.
Topics: Rats; Animals; Dexamethasone; NF-E2-Related Factor 2; Osteogenesis; Glucocorticoids; Oxidative Stress; Acetophenones; Apoptosis; Osteoblasts; Mitochondrial Diseases
PubMed: 37749949
DOI: 10.1111/jcmm.17974 -
Turkish Neurosurgery 2022To evaluate the effects of dexamethasone (Dex) treatment on neural crest cells and primary and secondary neurulation in chick embryos.
AIM
To evaluate the effects of dexamethasone (Dex) treatment on neural crest cells and primary and secondary neurulation in chick embryos.
MATERIAL AND METHODS
Sixty fertilized eggs with an average weight of 65 ± 2 g were incubated in 60%?70% humidity at 37.2°C ± 0.1°C. After 26 hours of incubation, the control group (n=12) received 0.1 mg/kg physiologic saline (S), group 1 (n=12) received 0.1 mg/kg Dex, group 2 (n=12) received 1 mg/kg Dex, and group 3 (n=12) received 5 mg/kg Dex into each embryonic disc. The eggs were incubated until Hamburger?Hamilton stage (HH) 15, HH18, and HH20. Then, the embryos were dissected and evaluated both macroscopically and microscopically.
RESULTS
The mortality rate in the control group, group 1, and groups 2 and 3 was 27%, 48%, and 100%, respectively. The neural tube thicknesses in group 1 significantly increased in HH 15 and HH20 (p < 0.05). The mitosis number in group 1 significantly decreased in each stage (p < 0.05). Wnt-1 expression was significantly lower in group 1 in HH15 (p < 0.05) and HH18 (p < 0.05), but there was no significant difference in HH20 (p > 0.05). Fibroblast growth factor (FGF) expression was significantly lower in group 1 in HH15 (p < 0.05). The expression of N-cadherin was significantly higher in group 1 in HH20 (p < 0.05). Fibronectin expression decreased in group 1 in HH18 (p < 0.01).
CONCLUSION
Although the Dex treatment did not result in neural tube closure defect, the mortality rates and neural tube thicknesses increased, whereas mitotic activation and Wnt-1 and FGF signal pathways reduced in some stages.
Topics: Animals; Chick Embryo; Dexamethasone; Neural Crest; Neural Tube; Neural Tube Defects; Neurulation
PubMed: 35023136
DOI: 10.5137/1019-5149.JTN.34904-21.2 -
PloS One 2022Liver sinusoidal endothelial cells (LSECs) are specialized fenestrated scavenger endothelial cells involved in the elimination of modified plasma proteins and tissue...
INTRODUCTION
Liver sinusoidal endothelial cells (LSECs) are specialized fenestrated scavenger endothelial cells involved in the elimination of modified plasma proteins and tissue turnover waste macromolecules from blood. LSECs also participate in liver immune responses. A challenge when studying LSEC biology is the rapid loss of the in vivo phenotype in culture. In this study, we have examined biological processes and pathways affected during early-stage primary culture of rat LSECs and checked for cell responses to the pro-inflammatory cytokine interleukin (IL)-1β and the anti-inflammatory drug dexamethasone.
METHODS
LSECs from male Sprague Dawley rats were cultured on type I collagen in 5% oxygen atmosphere in DMEM with serum-free supplements for 2 and 24 h. Quantitative proteomics using tandem mass tag technology was used to examine proteins in cells and supernatants. Validation was done with qPCR, ELISA, multiplex immunoassay, and caspase 3/7 assay. Cell ultrastructure was examined by scanning electron microscopy, and scavenger function by quantitative endocytosis assays.
RESULTS
LSECs cultured for 24 h showed a characteristic pro-inflammatory phenotype both in the presence and absence of IL-1β, with upregulation of cellular responses to cytokines and interferon-γ, cell-cell adhesion, and glycolysis, increased expression of fatty acid binding proteins (FABP4, FABP5), and downregulation of several membrane receptors (STAB1, STAB2, LYVE1, CLEC4G) and proteins in pyruvate metabolism, citric acid cycle, fatty acid elongation, amino acid metabolism, and oxidation-reduction processes. Dexamethasone inhibited apoptosis and improved LSEC viability in culture, repressed inflammatory and immune regulatory pathways and secretion of IL-1β and IL-6, and further upregulated FABP4 and FABP5 compared to time-matched controls. The LSEC porosity and endocytic activity were reduced at 24 h both with and without dexamethasone but the dexamethasone-treated cells showed a less stressed phenotype.
CONCLUSION
Rat LSECs become activated towards a pro-inflammatory phenotype during early culture. Dexamethasone represses LSEC activation, inhibits apoptosis, and improves cell viability.
Topics: Animals; Dexamethasone; Endothelial Cells; Liver; Male; Proteome; Rats; Rats, Sprague-Dawley; Secretome
PubMed: 36054185
DOI: 10.1371/journal.pone.0273843 -
Respiratory Research Jun 2022Dexamethasone improves clinical outcomes in COVID-19 patients requiring supplementary oxygen. We investigated possible mechanisms of action by comparing sixteen plasma...
Dexamethasone improves clinical outcomes in COVID-19 patients requiring supplementary oxygen. We investigated possible mechanisms of action by comparing sixteen plasma host response biomarkers in general ward patients before and after implementation of dexamethasone as standard of care. 48 patients without and 126 patients with dexamethasone treatment were sampled within 48 h of admission. Endothelial cell and coagulation activation biomarkers were comparable. Dexamethasone treatment was associated with lower plasma interleukin (IL)-6 and IL-1 receptor antagonist levels, whilst other inflammation parameters were not affected. These data argue against modification of vascular-procoagulant responses as an early mechanism of action of dexamethasone in COVID-19.
Topics: Biomarkers; Dexamethasone; Humans; Patients' Rooms; COVID-19 Drug Treatment
PubMed: 35659223
DOI: 10.1186/s12931-022-02060-3 -
BMC Medical Research Methodology Aug 2022The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is aimed at addressing the urgent need to find effective treatments for patients hospitalised with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is aimed at addressing the urgent need to find effective treatments for patients hospitalised with suspected or confirmed COVID-19. The trial has had many successes, including discovering that dexamethasone is effective at reducing COVID-19 mortality, the first treatment to reach this milestone in a randomised controlled trial. Despite this, it continues to use standard or 'fixed' randomisation to allocate patients to treatments. We assessed the impact of implementing response adaptive randomisation within RECOVERY using an array of performance measures, to learn if it could be beneficial going forward. This design feature has recently been implemented within the REMAP-CAP platform trial.
METHODS
Trial data was simulated to closely match the data for patients allocated to standard care, dexamethasone, hydroxychloroquine, or lopinavir-ritonavir in the RECOVERY trial from March-June 2020, representing four out of five arms tested throughout this period. Trials were simulated in both a two-arm trial setting using standard care and dexamethasone, and a four-arm trial setting utilising all above treatments. Two forms of fixed randomisation and two forms of response-adaptive randomisation were tested. In the two-arm setting, response-adaptive randomisation was implemented across both trial arms, whereas in the four-arm setting it was implemented in the three non-standard care arms only. In the two-arm trial, randomisation strategies were performed at the whole trial level as well as within three pre-specified patient subgroups defined by patients' respiratory support level.
RESULTS
All response-adaptive randomisation strategies led to more patients being given dexamethasone and a lower mortality rate in the trial. Subgroup specific response-adaptive randomisation reduced mortality rates even further. In the two-arm trial, response-adaptive randomisation reduced statistical power compared to FR, with subgroup level adaptive randomisation exhibiting the largest power reduction. In the four-arm trial, response-adaptive randomisation increased statistical power in the dexamethasone arm but reduced statistical power in the lopinavir arm. Response-adaptive randomisation did not induce any meaningful bias in treatment effect estimates nor did it cause any inflation in the type 1 error rate.
CONCLUSIONS
Using response-adaptive randomisation within RECOVERY could have increased the number of patients receiving the optimal COVID-19 treatment during the trial, while reducing the number of patients needed to attain the same study power as the original study. This would likely have reduced patient deaths during the trial and lead to dexamethasone being declared effective sooner. Deciding how to balance the needs of patients within a trial and future patients who have yet to fall ill is an important ethical question for the trials community to address. Response-adaptive randomisation deserves to be considered as a design feature in future trials of COVID-19 and other diseases.
Topics: Dexamethasone; Humans; Lopinavir; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 35933340
DOI: 10.1186/s12874-022-01691-w -
Acta Veterinaria Scandinavica Jun 2019Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little...
BACKGROUND
Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little quantitative data of the disposition and response to dexamethasone. The aim of this study was to investigate and describe the synovial fluid and plasma dexamethasone concentration over time and to explore the relation between synovial fluid concentration and response using clinical endpoints as response biomarkers after IA injection of dexamethasone disodium salt solution in an equine model of synovitis.
RESULTS
Inflammation was induced in the radiocarpal joint of six horses by injection of 2 ng lipopolysaccharide (LPS). Two hours later either saline or dexamethasone was injected in the same joint in a two treatment cross over design. Each horse was treated once with one of the six doses dexamethasone used (0.01, 0.03, 0.1, 0.3, 1 or 3 mg) and once with saline. Dexamethasone was quantified by means of UHPLC-MS/MS. Dexamethasone disposition was characterised by means of a non-linear mixed effects model. Lameness was evaluated both objectively with an inertial sensor based system and subjectively scored using a numerical scale (0-5). Joint circumference, skin temperature over the joint and rectal temperature were also recorded. The LPS-challenge induced lameness in all horses with high inter-individual variability. Dexamethasone significantly decreased lameness compared with saline. Other variables were not statistically significant different between treatments. Objective lameness scoring was the most sensitive method used in this study to evaluate the lameness response. A pharmacokinetic/pharmacodynamic model was successfully fitted to experimental dexamethasone and lameness data. The model allowed characterization of the dexamethasone synovial fluid concentration-time course, the systemic exposure to dexamethasone after intra-articular administration and the concentration-response relation in an experimental model of synovitis.
CONCLUSIONS
The quantitative data improve the understanding of the pharmacology of dexamethasone and might serve as input for future experiments and possibly contribute to maintain integrity of equine sports.
Topics: Animals; Anti-Inflammatory Agents; Dexamethasone; Horse Diseases; Horses; Injections, Intra-Articular; Lipopolysaccharides; Synovitis
PubMed: 31221173
DOI: 10.1186/s13028-019-0464-2 -
BMC Cancer Dec 2021Currently, no available coherent management protocol exists for pediatric cancers associated with pleural effusion, ascites, and pericardial effusion. This study aimed...
BACKGROUND
Currently, no available coherent management protocol exists for pediatric cancers associated with pleural effusion, ascites, and pericardial effusion. This study aimed to retrospectively present our experience in treating pediatric cancer patients with pleural effusion, ascites, and pericardial effusion using interleukin-2 (IL-2) and dexamethasone (DEX) intracavitary injections.
METHODS
Between January 1st, 2008 and December 31st, 2020, medical reports of patients diagnosed with solid tumors or lymphoma were checked to identify patients diagnosed with > 2 cm pleural effusion, and/or more than grade 1 ascites, and/or more than small pericardial effusion. Patients diagnosed with effusions and treated with IL-2 and DEX were identified as being in the effusion group. Meanwhile, patients with the same primary tumors and effusions but did not receive interleukin 2 and DEX injection were reviewed and classified as the control group.
RESULTS
Forty patients with solid tumors and 66 patients with lymphoma were further diagnosed with pleural effusion, ascites, or pericardial effusion. A total of 85 patients received IL-2 and DEX injection while the remaining 21 did not. The Kaplan Meier analysis revealed a significant difference between the two groups, with p < 0.01 for event free survival (EFS) and p < 0.01 for overall survival (OS), both of which had p < 0.01. Hazard ratio was found to be 0.344 for OS and 0.352 for EFS.
CONCLUSIONS
This retrospective study illustrates that thoracic, intraperitoneal, or pericardial intracavitary injection of DEX plus IL-2 can be an effective and safe treatment for pediatric cancers with pleural effusion, ascites, and pericardial effusion.
Topics: Child; Child, Preschool; Cohort Studies; Dexamethasone; Female; Humans; Interleukin-2; Lymphoma; Male; Pleural Effusion, Malignant; Retrospective Studies
PubMed: 34872514
DOI: 10.1186/s12885-021-09041-7 -
Aging Clinical and Experimental Research Apr 2021This statement addresses the need to provide clinically relevant and practical guidance for long-term care staff working in care homes and other stakeholders engaged in... (Review)
Review
Dexamethasone and oxygen therapy in care home residents with diabetes: a management guide and algorithm for treatment: a rapid response action statement from the European Diabetes Working Party for Older People (EDWPOP) and European Geriatric Medicine Society (EuGMS).
This statement addresses the need to provide clinically relevant and practical guidance for long-term care staff working in care homes and other stakeholders engaged in the care of residents who require consideration for dexamethasone and oxygen therapy. It had been provided following a series of consensus discussions between the EDWPOP and the EuGMS in January and February 2021. Its main aim is to minimise morbidity and mortality from serious acute illnesses including COVID-19 requiring these treatments within the long-term care sector.
Topics: Aged; Aged, 80 and over; Algorithms; Dexamethasone; Diabetes Mellitus; Humans; Oxygen; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33856663
DOI: 10.1007/s40520-021-01822-1 -
Journal of Chromatography. B,... May 2021A pharmacokinetic study was set up to investigate the pharmacokinetics of the anti-emetic agents aprepitant and dexamethasone and the drug-drug interaction between these...
Development and validation of a combined liquid chromatography tandem-mass spectrometry assay for the quantification of aprepitant and dexamethasone in human plasma to support pharmacokinetic studies in pediatric patients.
A pharmacokinetic study was set up to investigate the pharmacokinetics of the anti-emetic agents aprepitant and dexamethasone and the drug-drug interaction between these drugs in children. In order to quantify aprepitant and dexamethasone, a liquid chromatography-tandem mass spectrometry assay was developed and validated for the simultaneous analysis of aprepitant and dexamethasone. Protein precipitation with acetonitrile-methanol (1:1, v/v) was used to extract the analytes from plasma. The assay was based on reversed-phase chromatography coupled with tandem mass spectrometry detection operating in the positive ion mode. The assay was validated based on the guidelines on bioanalytical methods by the US Food and Drug Administration and European Medicines Agency. The calibration model was linear and a weighting factor of 1/concentration was used over the range of 0.1-50 ng/mL for aprepitant and 1-500 ng/mL for dexamethasone. Intra-assay and inter-assay bias were within ±20% for all analytes at the lower limit of quantification and within ±15% at remaining concentrations. Dilution integrity tests showed that samples exceeding the upper limit of quantification can be diluted 100 times in control matrix. Stability experiments showed that the compounds are stable in the biomatrix for 25 h at room temperatures and 89 days at -20 °C. This assay is considered suitable for pharmacokinetic studies and will be used to study the drug-drug interaction between aprepitant and dexamethasone in pediatric patients.
Topics: Adolescent; Aprepitant; Child; Chromatography, Liquid; Dexamethasone; Female; Humans; Linear Models; Male; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry
PubMed: 33756449
DOI: 10.1016/j.jchromb.2021.122639 -
International Journal of Molecular... Sep 2022Functional recovery following traumatic brain injury (TBI) is limited due to progressive neuronal damage resulting from secondary injury-associated neuroinflammation....
Functional recovery following traumatic brain injury (TBI) is limited due to progressive neuronal damage resulting from secondary injury-associated neuroinflammation. Steroidal anti-inflammatory drugs, such as dexamethasone (DX), can reduce neuroinflammation by activated microglia and infiltrated macrophages. In our previous work, we developed hydrolytically degradable poly(ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) hydrogels with dexamethasone (DX)-conjugated hyaluronic acid (HA-DXM) and demonstrated that dexamethasone-loaded hydrogels (PEG-bis-AA/HA-DXM) can reduce neuroinflammation, apoptosis, and lesion volume and improve neuronal cell survival and motor function recovery at seven days post-injury (DPI) in a rat mild-TBI model. In this study, we investigate the effects of the local application of PEG-bis-AA/HA-DXM hydrogels on motor function recovery at 7 DPI and cognitive functional recovery as well as secondary injury at 14 DPI in a rat mild-CCI TBI model. We observed that PEG-bis-AA/HA-DXM-treated animals exhibit significantly improved motor functions by the rotarod test and cognitive functions by the Morris water maze test compared to untreated TBI animals. We also observed that PEG-bis-AA/HA-DXM hydrogels reduce the inflammatory response, apoptosis, and lesion volume compared to untreated animals at 14 DPI. Therefore, PEG-bis-AA/HA-DXM hydrogels can be promising a therapeutic intervention for TBI treatment.
Topics: Animals; Anti-Inflammatory Agents; Biocompatible Materials; Brain Concussion; Brain Injuries, Traumatic; Cognition; Dexamethasone; Disease Models, Animal; Ethylenes; Hyaluronic Acid; Hydrogels; Polyethylene Glycols; Rats
PubMed: 36232454
DOI: 10.3390/ijms231911153