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Audiology & Neuro-otology 2018Dexamethasone phosphate is widely used for intratympanic therapy in humans. We assessed the pharmacokinetics of dexamethasone entry into perilymph when administered as a...
Dexamethasone phosphate is widely used for intratympanic therapy in humans. We assessed the pharmacokinetics of dexamethasone entry into perilymph when administered as a dexamethasone phosphate solution or as a micronized dexamethasone suspension, with and without inclusion of poloxamer gel in the medium. After a 1-h application to guinea pigs, 10 independent samples of perilymph were collected from the lateral semicircular canal of each animal, allowing entry at the round window and stapes to be independently assessed. Both forms of dexamethasone entered the perilymph predominantly at the round window (73%), with a lower proportion entering at the stapes (22%). When normalized by applied concentration, dexamethasone phosphate was found to enter perilymph far more slowly than dexamethasone, in accordance with its calculated lipid solubility and polar surface area properties. Dexamethasone phosphate therefore has a problematic combination of kinetic properties when used for local therapy of the ear. It is relatively impermeable and enters perilymph only slowly from the middle ear. It is then metabolized in the ear to dexamethasone, which is more permeable through tissue boundaries and is rapidly lost from perilymph. Understanding the influence of molecular properties on the distribution of drugs in perilymph provides a new level of understanding which may help optimize drug therapies of the ear.
Topics: Animals; Dexamethasone; Ear, Middle; Glucocorticoids; Guinea Pigs; Injection, Intratympanic; Perilymph; Permeability; Round Window, Ear; Semicircular Canals; Stapes
PubMed: 30497073
DOI: 10.1159/000493846 -
Frontiers in Immunology 2023Severe COVID-19 is characterized by cytokine storm, an excessive production of proinflammatory cytokines that contributes to acute lung damage and death. Dexamethasone...
INTRODUCTION
Severe COVID-19 is characterized by cytokine storm, an excessive production of proinflammatory cytokines that contributes to acute lung damage and death. Dexamethasone is routinely used to treat severe COVID-19 and has been shown to reduce patient mortality. However, the mechanisms underlying the beneficial effects of dexamethasone are poorly understood.
METHODS
We conducted transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild disease, and patients with severe COVID-19 with and without dexamethasone treatment. We then treated healthy donor PBMCs in vitro with dexamethasone and investigated the effects of dexamethasone treatment ion channel abundance (by RT-qPCR and flow cytometry) and function (by electrophysiology, Ca2+ influx measurements and cytokine release) in T cells.
RESULTS
We observed that dexamethasone treatment in severe COVID-19 inhibited pro-inflammatory and immune exhaustion pathways, circulating cytotoxic and Th1 cells, interferon (IFN) signaling, genes involved in cytokine storm, and Ca signaling. Ca influx is regulated by Kv1.3 potassium channels, but their role in COVID-19 pathogenesis remains elusive. Kv1.3 mRNA was increased in PBMCs of severe COVID-19 patients, and was significantly reduced in the dexamethasone-treated group. In agreement with these findings, in vitro treatment of healthy donor PBMCs with dexamethasone reduced Kv1.3 abundance in T cells and CD56dimNK cells. Furthermore, functional studies showed that dexamethasone treatment significantly reduced Kv1.3 activity, Ca2+ influx and IFN-g production in T cells.
CONCLUSION
Our findings suggest that dexamethasone attenuates inflammatory cytokine release via Kv1.3 suppression, and this mechanism contributes to dexamethasone-mediated immunosuppression in severe COVID-19.
Topics: Humans; COVID-19; Leukocytes, Mononuclear; Calcium; Cytokine Release Syndrome; COVID-19 Drug Treatment; Cytokines; Dexamethasone
PubMed: 37033961
DOI: 10.3389/fimmu.2023.1143350 -
PLoS Computational Biology Jan 2022Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the...
Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of dexamethasone. Using time as a bifurcation parameter, we show that (1) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.
Topics: Adult; Cell Line, Tumor; Dexamethasone; Glioblastoma; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Receptors, Chimeric Antigen
PubMed: 35081104
DOI: 10.1371/journal.pcbi.1009504 -
Journal of the Association For Research... Dec 2022The synthetic glucocorticoid dexamethasone is commonly used to treat inner ear disorders. Previous work in larval zebrafish has shown that dexamethasone treatment...
The synthetic glucocorticoid dexamethasone is commonly used to treat inner ear disorders. Previous work in larval zebrafish has shown that dexamethasone treatment enhances hair cell regeneration, yet dexamethasone has also been shown to inhibit regeneration of peripheral nerves after lesion. We therefore used the zebrafish model to determine the impact of dexamethasone treatment on lateral-line hair cells and primary afferents. To explore dexamethasone in the context of regeneration, we used copper sulfate (CuSO) to induce hair cell loss and retraction of nerve terminals, and then allowed animals to recover in dexamethasone for 48 h. Consistent with previous work, we observed significantly more regenerated hair cells in dexamethasone-treated larvae. Importantly, we found that the afferent processes beneath neuromasts also regenerated in the presence of dexamethasone and formed an appropriate number of synapses, indicating that innervation of hair cells was not inhibited by dexamethasone. In addition to regeneration, we also explored the effects of prolonged dexamethasone exposure on lateral-line homeostasis and function. Following dexamethasone treatment, we observed hyperpolarized mitochondrial membrane potentials (ΔΨm) in neuromast hair cells and supporting cells. Hair cells exposed to dexamethasone were also more vulnerable to neomycin-induced cell death. In response to a fluid-jet delivered saturating stimulus, calcium influx through hair cell mechanotransduction channels was significantly reduced, yet presynaptic calcium influx was unchanged. Cumulatively, these observations indicate that dexamethasone enhances hair cell regeneration in lateral-line neuromasts, yet also disrupts mitochondrial homeostasis, making hair cells more vulnerable to ototoxic insults and possibly impacting hair cell function.
Topics: Animals; Zebrafish; Mechanotransduction, Cellular; Calcium; Hair; Dexamethasone; Lateral Line System
PubMed: 36261670
DOI: 10.1007/s10162-022-00875-x -
Medicine Sep 2022This meta-analysis aimed to evaluate the efficacy and safety of dexamethasone in the treatment of acute respiratory distress syndrome (ARDS). (Meta-Analysis)
Meta-Analysis
BACKGROUND
This meta-analysis aimed to evaluate the efficacy and safety of dexamethasone in the treatment of acute respiratory distress syndrome (ARDS).
METHODS
A systematic search of electronic databases was carried out from inception to May 1, 2022, including PUBMED, EMBASE, Cochrane Library, Wangfang, VIP, and CNKI. Other searches were also checked for dissertations/theses and the reference lists of the included studies. Two team members examined all citations and selected eligible articles. Randomized controlled trials (RCTs) reporting the efficacy and safety of dexamethasone for the treatment of ARDS were included, and the quality of eligible RCTs was assessed using the Cochrane Risk of Bias Tool. If necessary, we conducted data synthesis and meta-analysis. The primary outcome was all-cause mortality. Secondary outcomes were mechanical ventilation duration (day), ventilator-free status at 28 days; intensive care unit (ICU) free (day), ICU mortality, hospital mortality, sequential organ failure assessment (SOFA) as mean and range, SOFA as No. of patients, peak airway pressure (cmH2O), arterial oxygen pressure (mm Hg), days with PaO2 > 10kPa, PaO2, and the occurrence rate of adverse events.
RESULTS
Four studies involving 702 patients were included in this analysis. This study showed that dexamethasone could significantly reduce all-cause mortality (odds ratio (OR) = 0.62, 95% confidence interval (CI) [0.44, 0.88], I2 = 30%, P < .001), and decrease ventilator-free status at 28 days (MD = 3.65, 95% CI [1.49, 5.80], I2 = 51%, P < .001). No significant differences in occurrence rates of adverse events were found between dexamethasone and routine or standard care.
CONCLUSIONS
Evidence from the meta-analysis suggests that dexamethasone is an effective and relatively safe treatment for all-cause mortality and ventilator-free status at 28 days in patients with ARDS. Owning to the small number of eligible RCTs, the conclusions of present study are warranted in the future study.
Topics: Dexamethasone; Humans; Intensive Care Units; Oxygen; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 36181003
DOI: 10.1097/MD.0000000000030195 -
Scientific Reports Nov 2023Extensive mechanical stress frequently causes micro-traumas in skeletal muscle, followed by a regeneration period. The effective removal of dead myofibers is a...
Extensive mechanical stress frequently causes micro-traumas in skeletal muscle, followed by a regeneration period. The effective removal of dead myofibers is a prerequisite for proper regeneration, and several cell types, including professional phagocytes, were reported to be active in this process. Myoblasts express several molecules of the phagocytic machinery, such as BAI1, stabilin-2, and TAM (Tyro3, Axl, Mertk) tyrosine kinase receptors, but these molecules were reported to serve primarily cell fusion and survival, and their role in the phagocytosis was not investigated. Therefore, we aimed to investigate the in vitro phagocytic capacity of the C2C12 mouse myoblast cell line. RNA sequencing data were analyzed to determine the level and changes of phagocytosis-related gene expression during the differentiation process of C2C12 cells. To study the phagocytic capacity of myoblasts and the effect of dexamethasone, all-trans retinoic acid, hemin, and TAM kinase inhibitor treatments on phagocytosis, C2C12 cells were fed dead thymocytes, and their phagocytic capacity was determined by flow cytometry. The effect of dexamethasone and all-trans retinoic acid on phagocytosis-related gene expression was determined by quantitative PCR. Both undifferentiated and differentiated cells engulfed dead cells being the undifferentiated cells more effective. In line with this, we observed that the expression of several phagocytosis-related genes was downregulated during the differentiation process. The phagocytosis could be increased by dexamethasone and all-trans retinoic acid and decreased by hemin and TAM kinase inhibitor treatments. Our results indicate that myoblasts not only express phagocytic machinery genes but are capable of efficient dead cell clearance as well, and this is regulated similarly, as reported in professional phagocytes.
Topics: Mice; Animals; Hemin; Phagocytosis; Cell Differentiation; Myoblasts; Tretinoin; Gene Expression; Dexamethasone
PubMed: 38017321
DOI: 10.1038/s41598-023-48492-9 -
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 -
Pharmacology Research & Perspectives Oct 2021Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone...
An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer.
Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels ≤9.1 mmol/L. Trough plasma concentrations of liposomal- and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t ~50 h for liposomal dexamethasone), trough concentrations of liposomal- and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow-up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715.
Topics: Adenocarcinoma; Aged; Bone Neoplasms; Dexamethasone; Drug Delivery Systems; Humans; Liposomes; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant
PubMed: 34414692
DOI: 10.1002/prp2.845 -
BMC Developmental Biology Nov 2021Human Mesenchymal Stem Cells (hMSCs) represent a promising cell source for cell-based therapy in autoimmune diseases and other degenerative disorders due to their...
BACKGROUND
Human Mesenchymal Stem Cells (hMSCs) represent a promising cell source for cell-based therapy in autoimmune diseases and other degenerative disorders due to their immunosuppressive, anti-inflammatory and regenerative potentials. Belonging to a glucocorticoid family, Dexamethasone (Dex) is a powerful anti-inflammatory compound that is widely used as therapy in autoimmune disease conditions or allogeneic transplantation. However, minimal immunomodulatory effect of hMSCs may limit their therapeutic uses. Moreover, the effect of glucocorticoids on the immunomodulatory molecules or other regenerative properties of tissue-specific hMSCs remains unknown.
METHOD
Herein, we evaluated the in vitro effect of Dex at various dose concentrations and time intervals, 1000 ng/ml, 2000 ng/ml, 3000 ng/ml and 24 h, 48 h respectively, on the basic characteristics and immunomodulatory properties of Bone marrow derived MSC (BM-MSCs), Adipose tissue derived MSCs (AD-MSCs), Dental Pulp derived MSC (DP-MSCs) and Umbilical cord derived MSCs (UC-MSCs).
RESULTS
The present study indicated that the concentration of Dex did not ramify the cellular morphology nor showed cytotoxicity as well as conserved the basic characteristics of tissue specific hMSCs including cell proliferation and surface marker profiling. However, quite interestingly it was observed that the stemness markers (Oct-4, Sox-2, Nanog and Klf-4) showed a significant upregulation in DP-MSCs and AD-MSCs followed by UC-MSCs and BM-MSCs. Additionally, immunomodulatory molecules, Prostaglandin E-2 (PGE-2), Indoleamine- 2,3-dioxygenase (IDO) and Human Leukocyte Antigen-G (HLA-G) were seen to be upregulated in a dose-dependent manner. Moreover, there was a differential response of tissue specific hMSCs after pre-conditioning with Dex during mixed lymphocyte reaction, wherein UC-MSCs and DP-MSCs showed enhanced immunosuppression as compared to AD-MSCs and BM-MSCs, thereby proving to be a better candidate for therapeutic applications in immune-related diseases.
CONCLUSION
Dex preconditioning improved the hMSCs immunomodulatory property and may have reduced the challenge associated with minimal potency and strengthen their therapeutic efficacy. Preconditioning of tissue specific hMSCs with dexamethasone biomanufacturers the enhanced potential hMSCs with better stemness and immunomodulatory properties for future therapeutics.
Topics: Adipose Tissue; Cell Proliferation; Cells, Cultured; Dexamethasone; Humans; Immunomodulation; Mesenchymal Stem Cells
PubMed: 34736395
DOI: 10.1186/s12861-021-00246-4 -
Drugs Jul 2020Dextenza, an intracanalicular insert that is placed into the lower punctal opening of the eye, gradually releases dexamethasone for up to 30 days to alleviate pain and... (Review)
Review
Dextenza, an intracanalicular insert that is placed into the lower punctal opening of the eye, gradually releases dexamethasone for up to 30 days to alleviate pain and inflammation associated with ophthalmic surgery. A significantly higher proportion of patients treated with the dexamethasone intracanalicular insert than with the placebo insert had no pain at day 8 (co-primary endpoint, 7 days post-operation) across three pivotal phase III trials, and the inflammation co-primary endpoint (absence of anterior chamber cells) at day 14 (13 days post-operation) was met in two of three trials. Overall, the dexamethasone intracanalicular insert was effective and generally well tolerated for the treatment of post-surgical ocular pain and inflammation following cataract surgery. As low patient adherence is an issue for topical ophthalmic anti-inflammatory medications, the convenience (ease of insertion, single application with no patient input and typically no removal required) of the dexamethasone intracanalicular insert makes it a promising emerging option for the treatment of ocular inflammation and pain following ophthalmic surgery.
Topics: Dexamethasone; Drug Implants; Glucocorticoids; Inflammation; Ophthalmologic Surgical Procedures; Pain, Postoperative; Treatment Outcome
PubMed: 32588339
DOI: 10.1007/s40265-020-01344-6