Co-administration Of Dexamethasone Research Articles

Efficacy of sarilumab and dexamethasone co-administration for lowering multiple blood biomarkers in the treatment of cytokine release syndrome in hospitalized COVID-19 patients.

The current study was planned to explore the potential synergistic role of the co-administration of sarilumab and dexamethasone in reducing blood biomarkers associated with cytokine release syndrome in hospitalised patients of coronavirus disease-2019. The sample comprised 22 patients hospitalised with severe and critical severity levels and who were treated with sarilumab and dexamethasone. Positive responses were seen in blood biomarkers, including decreased interleukin-6 alpha levels and improved oxygen saturation. Tumour necrosis factor, Ddimer, C-reactive protein, ferritin and lymphocyte count also showed positive responses in patients who survived than those who died. Lactate dehydrogenase levels fluctuated with improvement among the survivors, but had limited effectiveness in those who died. The findings suggested promising avenues for future treatment strategies in patients with severe coronavirus disease-2019 and cytokine release syndrome.

Evaluation of the effects of pregabalin and dexamethasone coadministration on preemptive multimodal analgesia and anxiety in third molar surgeries: a triple-blind randomized clinical trial.

To evaluate the efficacy of pregabalin and dexamethasone coadministration in preemptive analgesia and anxiety control in lower third molar surgery. A triple-blind, split-mouth clinical trial conducted with patients divided into two groups: control group, receiving placebo and dexamethasone, and test group, receiving pregabalin and dexamethasone preoperatively. The evaluated variables were pain, measured by the Visual Analog Scale (VAS), anxiety assessed through the State-Trait Anxiety Inventory (STAI) questionnaires, hemodynamic parameters [Blood Pressure (BP), Heart Rate (HR), Oxygen Saturation (SpO2)], and sedation assessed by the Ramsay scale. A total of 31 patients were included. The test group exhibited a significant reduction in pain at 2,4,6,8,12,16,24, and 48h after surgery and in the consumption of rescue analgesics. Anxiety, evaluated by STAI and VAS, showed a significant decrease in the test group (p < 0.001). Additionally, there was a significant decrease in BP at most of the assessed time points (p < 0.05) and a significant reduction in HR at two different time intervals (p = 0.003 and p = 0.009), indicating a positive effect in the test group. There was no significant difference in SpO2 between the groups. Sedation assessment revealed a significant difference at all time points favoring the test group (p < 0.05). There were no significant postoperative adverse effects. Pregabalin coadministered with dexamethasone demonstrated significant efficacy in controlling postoperative pain and anxiety, as well as a sedative effect. The coadministration of pregabalin with dexamethasone may presents potential advantages in both pain modulation and psychological well-being of individuals undergoing third molar surgeries. Brazilian Clinical Trials Registry (REBEC), No. RBR-378h6t6.

Effectiveness of dexamethasone or adrenaline with lignocaine 2% for prolonging inferior alveolar nerve block: a randomized controlled trial.

ObjectivesInferior alveolar nerve block (IANB) is commonly used for mandibular dentoalveolar surgery. The objective of this study was to evaluate and compare the effectiveness of coadministration of dexamethasone (4 mg/mL) or adrenaline (0.01 mg/mL) as an adjuvant with lignocaine 2% in IANB during third molar surgery (TMS).Patients and Methods This double-blind, randomized controlled trial was conducted between March and August 2020. The investigators screened patients needing elective TMS under local anesthesia. Based on strict inclusion and exclusion criteria, patients were enrolled in this study. These patients were assigned randomly into two study groups dexamethasone group (DXN) or adrenaline group (ADN). Outcome variables were postoperative edema, trismus, visual analogue scale (VAS), perioperative analgesia, onset time, and duration of IANB.ResultsEighty-three patients were enrolled in this study, of whom 23 (27.7%) were eliminated or excluded during follow-up. This study thus included data from 60 samples. Mean age was 32.28±11.74 years, including 28 females (46.7%) in the ADN (16 patients, 57.1%) and DXN (12 patients, 42.9%) groups. The duration of action for DXN (mean±standard deviation [SD], 40207±03401 hours; standard error [SE], 00600 hours; log-rank P=0.001) and for ADN (mean±SD, 15834±02452 hours; SE, 00442 hours; log-rank P=0.001) were found. Similarly, time at which 1st analgesic consume and total number of nonsteroidal antiinflammatory drugs need to rescue postoperative analgesia was found statistically significant between study groups (t (58)=–11.95; confidence interval, –22541 to –14353; P=0.001). Early-hours VAS was also significantly different between the study groups.ConclusionA single injection of dexamethasone prolongs the duration of action of lignocaine 2% IANB. Additionally, it can be used in cases where adrenaline is contraindicated.

Progesterone partially recovers placental glucose transporters in dexamethasone-induced intrauterine growth restriction

Research questionHow does progesterone improve fetal outcome and change the expression of placental glucose transporters (GLUT) in dexamethasone-induced intrauterine growth restriction (IUGR)? DesignA total of 64 rats were divided randomly into four different treatment groups based on daily i.p. injections of either saline or dexamethasone in the presence or absence of progesterone. Injections started on the 15th day of gestation (15dg) and lasted until the day of sacrifice at 19dg or 21dg. Maternal plasma progesterone concentrations were measured by enzyme-linked immunosorbent assay. The gene and protein expression of placental GLUT1 and GLUT3 were evaluated in the placental labyrinth and basal zones by real-time polymerase chain reaction and Western blotting, respectively. The localization of GLUT1 and GLUT3 was evaluated by immunohistochemistry. ResultsDexamethasone induced significant decreases in maternal serum progesterone concentrations (P = 0.029) and placental (P < 0.001) and fetal body (P = 0.009) weights. Dexamethasone also reduced the expression of GLUT1 in the labyrinth zone (P = 0.028) and GLUT3 in both the labyrinth (P = 0.002) and basal zones (P = 0.026). Coadministration of dexamethasone and progesterone prevented the reduction in fetal body weight, placental weight and placental GLUT expression compared with that seen in dexamethasone-treated groups. ConclusionThese results suggest that progesterone prevents the significant reduction in fetal and placental weights in dexamethasone-induced IUGR, possibly through improving the expression of placental GLUT.

Coadministration of a Clinically Relevant Dexamethasone Dosage With Ablative Radiation Therapy Reduces Peripheral Lymphocytes But Does Not Alter In Vivo Intratumoral Lymphocyte Phenotype or Inhibit Efficacy of Radiation Therapy in a Murine Colorectal Tumor Model.

Dexamethasone is commonly given during radiation therapy (RT) to manage toxicities. Our study examines if dexamethasone coadministration with RT inhibits the RT-induced antitumor T cell response in mouse. Intramuscularly implanted MC38 tumors were irradiated with 15 Gy after establishing for 7 days. Tumor bearing mice were administered dexamethasone using multiple schedules and doses. Peripheral lymphocyte reduction was monitored by complete blood count and intratumoral and tumor draining lymph node (tdLN) populations by flow cytometry. Effector phenotype and function of ex vivo stimulated tumor-infiltrating lymphocytes (TILs) and naïve splenocytes as well as in vivo TILs with or without dexamethasone were monitored by flow cytometry and ELISA. Long course high dose, short course high dose, and short course human equivalent dose dexamethasone reduced peripheral lymphocytes yet did not inhibit survival after irradiation. Short course high dose administration decreased TIL and tdLN lymphocyte activation as well as tdLN mass but did not affect TIL frequencies or change tdLN cell population composition. Dexamethasone inhibited effector function of ex vivo stimulated naïve splenocytes and TILs, but magnitude of IFN-γ secretion was consistently higher in TILs regardless of dexamethasone dose. In vivo analysis of TILs after irradiation and HE dexamethasone treatment showed that TILs had a similar effector phenotype compared with vehicle controls. Dexamethasone reduces blood and tdLN lymphocytes. Dexamethasone also suppresses TIL activation/effector function yet does not affect survival in irradiated MC38 tumor bearing mice, which depend on RT-induced immune responses for therapy efficacy. Additional study in human subjects is warranted.

Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.

BackgroundAnakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19.MethodsFor this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491).Findings209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20–0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2/FiO2. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17–0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12–0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37–1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59–3·10]).InterpretationAnakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L.FundingSobi.

Histopathological aspects of co-administration of dexamethasone and diclofenac sodium on male albino rats

Background and objective: Treatment of an animal with dexamethasone will result in sinuses extension, fat accumulation in the liver, and enlargement of hepatocytes. Whereas, non-steroidal anti-inflammatory drugs (diclofenac sodium) administration may lead to degeneration and formation of wide areas in the form of sinusoidal. Hydropic degeneration possibly is seen in the tubular epithelial cells of the kidney tissue. This study aimed to assess the toxic and side effects of dexamethasone and diclofenac sodium on the liver and kidney in rats, whether used separately or together. Methods: A total of 40 male albino rats were divided into four groups of ten in each, including the control group. One set was treated with dexamethasone (1.6 mg/kg/day), the other was treated with diclofenac sodium (30 mg /kg/day), and the last was treated with both drugs together at the same dose without mixture. Both drugs were administered intramuscularly for 30 days. Sections from the liver and kidney were stained by Hematoxeline and Eosin, then examined under a microscope. Results: Histopathological variation in the liver and kidney tissue of the treated animals have revealed that each drug (dexamethasone, diclofenac sodium) showed a significant alteration. Strong changes (+ + +) were observed in kidney tissue include degeneration, inflammatory aggregation, fibrosis, and edema, whereas in liver showed central vein dilatation, necrosis, and kupffer cells hyperplasia. Treating with the two drugs together, less alteration (+) in the tissues was noticed. Conclusion: The effect of both used drugs (dexamethasone and diclofenac sodium) was observed on the liver and kidney tissues of the experimental animals (rats) regardless of being applied separately or the two together. A probable inhibition role of the two drugs on each other have been noticed that lead to call for more detail investigation on this matter in years to come.

Effects of Chronic Glucocorticoid Receptor Stimulation on Circadian Locomotor Activity and Serotonergic Neurotransmission in the Basolateral Amygdala of Rats.

Clinical studies, especially those in animal models, have provided evidence that chronic stress may play a role in the etiology of psychiatric diseases, such as depression. Because chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the excessive secretion of glucocorticoids, the chronic stimulation of glucocorticoid receptors (GRs) may be involved in the pathogenesis of depression. To further investigate the relationship between GR activation and depression, we used the synthetic glucocorticoid dexamethasone (DEX) and the GR antagonist mifepristone to examine the effects of chronic GR stimulation on the circadian rhythms of locomotor activity and serotonergic neurotransmission in the basolateral amygdala (BLA) of rats. Chronic treatment with DEX reduced locomotor activity during the dark phase, without changing overall activity patterns. Measuring the basal release of serotonin in the BLA, using in vivo microdialysis, confirmed that chronic treatment with DEX induced serotonergic hypofunction in the BLA. The co-administration of DEX with mifepristone effectively suppressed the depressive-like symptoms caused by chronic treatment with DEX. Our results provided further evidence for a relationship between GR and depression and suggest that the pharmacological blockade of GR may increase the effectiveness of conventional pharmacotherapies used to treat depression.

The Deep Sedation Conundrum and Paediatric Endoscopy.

See “Dexamethasone Reduces Postoperative Nausea in Pediatric Upper Endoscopy With Deep Sedation: A Randomized Controlled Trial” by Moheimani and Yaseri on page 281. There is a definition of “deep sedation” that must be understood—propofol administration, for instance, is essentially general anaesthesia (GA), as is ketamine use and “total intravenous anaesthesia” (TIVA). “Deep sedation” in children is invariably a synonym for GA. Postprocedure nausea with these techniques is common. Its prevention is important. Moheimani and Yaseri (1) describe the reduction in postendoscopy nausea with dexamethasone after endoscopy in children under deep sedation. Single-dose dexamethasone is 1 element of nausea prevention and management following GA (2). Prevention and treatment strategies for postoperative nausea and vomiting include both pharmacological and nonpharmacological therapies. Pharmacological agents include 5-HT3 receptor antagonists, neurokinin-1 receptor blockers, anti-histamine H1 antagonists, haloperidol and droperidol, prokinetic agents such as metoclopramide, dexamethasone, and a variety of other agents. Nausea after procedures under so-called “deep sedation” is infrequently studied when compared with nausea after GA—one could identify these techniques as similar, however, as noted above. Nausea affects at least 30% of patients after GA with volatile agents but after intravenous anaesthesia with propofol the incidence of early nausea (0–6 hours) is reduced (3). It is likely that comparable patient and procedure factors influence postoperative nausea after procedures performed under sedation or GA. The observation that nausea after procedural sedation for endoscopy was reduced with the coadministration of dexamethasone is comparable with studies observing dexamethasone prophylaxis administered in GA (4). Indeed, an antiemetic policy should form part of the procedure as a standard in children. Moheimani and Yaseri (1) describe provided “deep sedation” for upper gastrointestinal endoscopy. Sedation and anaesthesia are not binary options but represent a continuum from awake to unconsciousness. The American Society of Anesthesiology has defined 4 levels of pharmacologically induced sedation: mild; moderate; deep; and anaesthesia. Differentiation between “deep sedation” and anaesthesia depends upon the presence or absence of a response to painful stimuli. Processed EEG techniques may also differentiate between levels of sedation. A Spanish group observed the processed EEG signal provided with the bispectral index (BIS) during paediatric upper gastrointestinal endoscopy (5). Endoscopy success was likely with a BIS index < 59—a BIS value that represents anaesthesia (6,7). Differentiation between “deep sedation” and anaesthesia is more than semantics, it is about risk. Moheimani and Yaseri (1) reported 4.1% of subjects developed either laryngospasm or bronchospasm—and airway complications can be challenging and costly (8). Invasive diagnostic and therapeutic procedures provided by endoscopy have evolved and may be delivered in a theatre or nontheatre environment. Anaesthetic techniques and agents have also evolved alongside these techniques, with intravenous techniques being deliverable in nontheatre environments with minimal equipment. Traditional airway interventions such as supraglottic devices and formal intubation are being supplanted by the delivery of oxygen through a face mask, nasal cannulae, or high-flow oxygen devices—heated high-flow therapy. Procedural respiratory and cardiac risks can be mitigated through presedation assessment and adherence to published professional standards and guidelines for sedation and anaesthesia (9). Notwithstanding the delivery of “deep sedation” or GA, the objective of the process is to provide an environment acceptable to both operator and patient. This requires care from the practitioner that balances the depth of sedation whilst avoiding respiratory and cardiovascular deterioration. The delivery of “deep sedation” probably carries no less risk than GA (10). The use of volatile agents requires the exhaustion of the waste gases, which is challenging with mask anaesthesia and may compromise the safety of personnel in the immediate environment (11). The avoidance of airway manipulation, such as intubation or supraglottic airways, does not mitigate airway risks. The delivery of the procedure in a formal theatre environment does not reduce the cost of delivery of the procedure. The application of volatile anaesthesia increases the risks of early nausea when compared with propofol-based sedation techniques. Therefore the delivery of a deep sedation technique for upper gastrointestinal endoscopy needs to have careful consideration of the aims and objectives of the service. Deaths are rare, and unlikely to be observed in the small sample reported by Moheimani and Yaseri (1). The benefits of the delivery of a sevoflurane-based anaesthetic technique in a theatre environment are not clear, although the adoption of an antiemetic policy may lead to an improvement in outcomes (12).

Pomalidomide Alone or in Combination with Low Dose Dexamethasone As Maintenance Following Induction with Pomalidomide and Low Dose Dexamethasone in Relapsed and Refractory Myeloma (ALLG MM14)

Whilst the addition of dexamethasone to upfront therapy with immunomodulatory (IMiD®) agents in myeloma (MM) is important to mediate rapid reduction in disease burden, preliminary findings suggest that the NK stimulatory effects of IMiD® compounds are best harnessed without the co-administration of dexamethasone. This may be especially effective in the setting of minimal disease burden (i.e. maintenance) when some inherent immune recovery has occurred, however this has yet to be confirmed in a prospective clinical trial.Aims:To evaluate the effect of maintenance with pomalidomide (POM) alone versus POM-low dose dexamethasone (LoDEX) following treatment with POM-LoDEX induction on progression free survival (PFS), overall survival (OS) and kinetics of response (overall response rate (ORR), clinical benefit rate (CBR)) in relapsed/refractory MM patients who were refractory to lenalidomide (R-LEN).Methods:MM14 was a multicentre, open-label, randomised phase 2 study of relapsed R-LEN MM patients who had received at least 2 prior lines of therapy. Patients commenced POM 4mg d1-21 (28d cycle) and LoDEX (40mg weekly). After 4 cycles (induction), patients with stable disease (SD) or better were randomised to receive POM alone (P) or combined with LoDEX (Pd) as maintenance. Therapy continued until toxicity/progression. All statistical analyses were performed using SAS software v9.4. The log-rank test was used to compare the survival distributions in the maintenance arms and pre-specified pointwise comparisons, with adjustment for multiplicity, were used to explore the possibility of non-proportional hazards.Results:154 patients from 11 Australian sites were enrolled (M:F 80:74), median age: 67yrs (range 35-88). Median number of prior treatment lines: 4.5 (2-14). All were R-LEN, 127 (82.5%) were bortezomib refractory (double refractory).Median follow-up for all registered patients was 27.8m. Median PFS for all patients was 4.5m (IQR 2.3-8.3m) and median OS was 14.5m (IQR 6.7-30.7m). ORR was 40.9% (63/154); median time to achieve ORR was 4.6 months. CBR was 53.3% (82/154); median time to achieve CBR was 2.6m.Eighty-one patients were randomised; however 3 were randomised in error. Therefore, a modified intention-to-treat (mITT) analysis included 78 (51%) patients who achieved ≥SD with induction and commenced maintenance: P = 40, Pd = 38. Median PFS (from time of randomisation) for P was 2.58m versus 5.73m for Pd (p=0.051) [Figure A]. Comparison of PFS at six 3-monthly intervals favoured Pd (from 3m to 12m) (p<0.00001), however at 18m, P was favoured (p=0.018). Median OS (from time of randomisation) was 25.6m for P versus 17.4m for Pd (p=0.356) [Figure B]. Comparisons of survival at six 3-monthly time points demonstrated no difference between the arms at months 3-12, however at 15m and 18m, survival favoured P (p=0.006 and p=0.02 respectively).There was no difference in response (ORR, CBR) between P and Pd in the mITT population: ORR P (8/21) versus Pd (8/18), CBR P (12/21) versus Pd (11/18). In a landmark analysis for response achieved (ORR/CBR) at 4 months post registration, there was no difference in PFS or OS for patients within either arm according to whether they achieved ORR/CBR.Of the mITT population (n=78), 39 had post-progression therapy data available (P = 21, Pd = 18). Of the remainder, 18 were palliated and 21 did not have available data. There was no difference in response (ORR, CBR) to salvage therapy between the two arms. However, responses were more durable for P compared to Pd: median second PFS (from start of post-progression therapy) was 12.7m versus 4.6m respectively (p=0.034) [Figure C]. P tended towards superior OS (from start of post-progression therapy): median 19.4m versus 12.5m (p=0.0922) [Figure D]. There was no difference in PFS/OS between individual treatment groups (bortezomib, carfilzomib, chemotherapy, thalidomide, LEN, other).Conclusion:After initial disease control with POM-LoDEX, MM patients continuing with POM-LoDEX had superior PFS compared to maintenance with POM alone. However, this early PFS benefit is lost and in fact reversed by 18m; and in those randomised patients who went on to receive post-progression therapy, more durable responses and superior survival were seen in those previously treated with POM alone. Correlative studies are underway to investigate the immunological mechanisms behind these observations. [Display omitted] DisclosuresKalff:Janssen: Honoraria; Amgen: Other: travel to preceptorship; Celgene: Honoraria; Takeda: Honoraria. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Quach:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding. Ho:Amgen: Honoraria; Celgene: Other: Travel to meeting; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: travel to meeting. Mollee:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Estell:Janssen: Membership on an entity's Board of Directors or advisory committees.

Dexamethasone exacerbates cisplatin-induced muscle atrophy.

Dexamethasone for antiemetic therapy is typically administered with anticancer drugs such as cisplatin. We previously reported that cisplatin upregulates the muscle-specific E3 ubiquitin ligase genes, namely muscle ring-finger protein 1 (MuRF1) and atrophy gene-1 (atrogin-1), and promotes muscle atrophy in mice. It is well known that dexamethasone causes upregulation of MuRF1 and Atrogin-1 expression in skeletal muscles. Although it is speculated that a combination of dexamethasone and cisplatin worsens muscle atrophy, there are no reports based on research. We thereby investigated the effects of cisplatin and dexamethasone, alone or in combination, on the expression of MuRF1 and Atrogin-1 in murine skeletal muscles and C2C12 myotubes. Mice were intraperitoneally injected with cisplatin or the vehicle control once daily for 4days. Dexamethasone or the vehicle control was subcutaneously administered 30minutes prior to the administration of cisplatin. Dexamethasone enhanced MuRF1 and Atrogin-1 gene expression upregulated by cisplatin in murine quadriceps muscles and C2C12 myotubes. Cisplatin-caused upregulation of myostatin and downregulation of IGF-1 gene expression were also enhanced by co-administration of dexamethasone in murine quadriceps muscles and C2C12 myotubes. This study shows that the combination treatment of cisplatin and dexamethasone exacerbated muscle atrophy in mice. Therefore, this treatment regimen might exacerbate muscle atrophy in cancer patients.

Improvement of glucocorticoid-impaired thymus function by dihydromyricetin via up-regulation of PPARγ-associated fatty acid metabolism.

T lymphocytes produced by the thymus are essential mediators of immunity. Accelerated thymic atrophy appears in the patients with administration of glucocorticoids (GCs) which are commonly-used drugs to treat autoimmune and infectious diseases, leading to dysregulation of immunity with manifestation of progressive diminution of new T cell production. However, there is no ideal method to overcome such side effects of GCs. In the current study, we proposed a composition of dexamethasone (DEX) and dihydromyricetin (DMY) derived from a medicinal plant, which could protect from DEX-induced thymus damage and simultaneously enhance the anti-inflammatory effect of DEX. In the current study, we found that DEX-damaged thymic cellularity and architecture, reduced thymocyte numbers, induced thymocyte apoptosis and dropped CD4+ and CD8+ double positive T cell numbers in thymus which was effectively improved by co-treatment with DMY. Quantification of signal joint TCR delta excision circles (TRECs) and Vβ TCR spectratyping analysis were employed to determine the thymus function with indicated treatments. The results showed that DEX-impaired thymus output and decreased TCR cell diversity which was ameliorated by co-treatment with DMY. iTRAQ 2D LC-MS/MS was applied to analyze the proteomic profiling of thymus of mice treated with or without indicated agents, followed by informatics analysis to identify the correlated signaling pathway. After validated by Western blotting and Real-time PCR, we found that PPARγ-associated fatty acid metabolism was increased in the thymic tissues of the animals treated with DMY plus DEX than the animals treated with DEX alone. The agonist and antagonist of PPARγ were further employed to verify the role of PPARγ in the present study. Furthermore, DMY demonstrated a synergistic effect with co-administration of DEX on suppressing inflammation in vivo. Collectively, DMY relieved thymus function damaged by DEX via regulation of PPARγ-associated fatty acid metabolism. Our findings may provide a new strategy on protection of thymus from damage caused by GCs by using appropriate adjuvant natural agents through up-regulation of PPARγ-associated fatty acid metabolism.

Dexamethasone pretreatment impairs the thymidylate synthase inhibition mediated flare in thymidine salvage pathway activity in non-small cell lung cancer.

IntroductionSuccessful inhibition of thymidylate synthase (TS) by pemetrexed, a TS inhibitor, results in a reproducible transient burst or “flare” in thymidine salvage pathway activity at 2 hrs. of therapy which can be measurable with FLT-PET ([18F]fluorothymidine-positron emission tomography) in non-small cell lung cancer (NSCLC). Routine administration of dexamethasone with pemetrexed-based therapy could potentially confound this imaging approach since dexamethasone is known to inhibit expression of thymidine kinase 1, a key enzyme in the thymidine salvage pathway. Here we examine the potential impact of dexamethasone on the TS inhibition-mediated thymidine salvage pathway “flare” in NSCLC.Materials and methodsIn order to determine NSCLC cell line sensitivity to dexamethasone and pemetrexed, IC50 studies were performed on NSCLC cell lines H23, H1975, H460, H1299. TS inhibition-mediated “flare” in thymidine salvage pathway activity was then measured at 2hrs. of exposure to pemetrexed and cisplatin in NSCLC cells lines following using 3H-thymidine incorporation assays under the following conditions: control (no chemotherapy or dexamethasone), or treated with pemetrexed and cisplatin without dexamethasone, with 24 hrs. pre-treatment of dexamethasone or with dexamethasone administered together with chemotherapy. These conditions were chosen to model the delivery of pemetrexed-based therapy in the clinic.ResultsThe IC50 of H23, H1975, H460, H1299 for dexamethasone and pemetrexed were 40, 5.9, 718, 362 μM and 0.22, 0.73, 0.14 and 0.66 μM respectively. Significant blunting of the thymidine salvage pathway “flare” is observed at 2hrs. of pemetrexed-based therapy when dexamethasone sensitive cell lines H23 and H1975 were pretreated with dexamethasone but not when dexamethasone was given together with pemetrexed therapy or in the setting of dexamethasone resistance (H460 and H1299).Conclusion24 hr. pretreatment with dexamethasone, but not same day co-administration of dexamethasone with therapy, impairs the TS inhibition-mediated “flare” in thymidine salvage pathway activity in NSCLC.

Protection from Glucocorticoid-Induced Thymus Atrophy by Dihydromyricetin Via Up-Regulation of PPARγ and Anti-Oxidation

T lymphocytes produced by the thymus are essential mediators of immunity. Accelerated thymic atrophy appears in the patients with administration of glucocorticoids (GCs) which are commonly-used drugs to treat autoimmune and infectious diseases, leading to dysregulation of immunity with manifestation of progressive diminution of new T cell production. However, there is no ideal method to overcome such side effects of GCs. In the current study, we proposed a composition of dexamethasone (DEX) and dihydromyricetin (DMY) derived from a medicinal plant, which could protect from DEX-induced thymus damage and simultaneously enhance the anti-inflammatory effect of DEX. Dexamethasone (DEX)-induced thymus atrophy was effectively prevented by co-treatment with dihydromyricetin (DMY) via activating PPARγ in thymic tissues of mice with delayed type hypersensitivity (DTH) induced by 2,4- dinitrofluorobenzene (DNFB). Simultaneously, DMY demonstrated a synergistic effect on suppressing DTH with co-administration of DEX in the mouse model of DTH and the paw edema induced by carrageenan in rats. Increase of PPARγ expression was found in the thymic tissues of animals treated with DMY plus DEX than the animals treated with DEX alone, which was validated by agonist and antagonist of PPARγ. DMY protected thymus from atrophy induced by DEX via regulation of PPARγ-associated fatty acid metabolism and anti-oxidation in thymic tissues. Our findings may provide a new strategy on protection of thymus from damage caused by GCs by using appropriate co-remedies of GCs together with suitable adjuvant natural agents through up-regulation of PPARγ expression and anti-oxidation. Funding Statement: This work was supported by FDCT grants from the Science and Technology Development Fund of Macao (Project code 081/2013/A3). Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: Animal care and experiments were conducted in accordance with the Laboratory Animal Research Committee Guidelines of Guangdong Provincial Hospital of Chinese Medicine.

Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer

Pemetrexed (PEM) is a novel and multi-targeted antifolate used as an antineoplastic agent for non-small cell lung cancer (NSCLC) and pleural mesothelioma. Although glucocorticoid was often used with PEM to reduce toxicity during the chemotherapy, it is not clear yet whether glucocorticoid co-administration could affect PEM efficacy in NSCLC. Here we established NSCLC cell lines and examined the effects of dexamethasone (DEX) on PEM sensitivity in vitro and in xenograft models. DEX co-administration reduced chemotherapy sensitivity to PEM in xenograft models. DEX co-administration promoted cell growth and weakened senescence growth arrest, such as altered secretions of proinflammatory and mitogenic cytokines, reminiscent of a senescence associate secretory phenotype (SASP). CSCs in DEX co-administration group were subsequently found to be less sensitive towards PEM treatment as measured by cell proliferation and generation of tumor spheres in the presence of PEM. Survival molecule B-cell lymphoma-2 (Bcl-2) may involve in this process and blockage of Bcl-2 could reverse altered senescence and CSCs abilities, thus alleviated PEM insensitivity. As such, DEX might suppress the antitumor activity of PEM through altered SASP level that had induced traits similar to CSCs.

PPARγ activation mitigates glucocorticoid receptor-induced excessive lipolysis in adipocytes via homeostatic crosstalk.

Proper balance between lipolysis and lipogenesis in adipocytes determines the release of free fatty acids (FFA) and glycerol, which is crucial for whole body lipid homeostasis. Although, dysregulation of lipid homeostasis contributes to various metabolic complications such as insulin resistance, the regulatory mechanism remains elusive. This study clarified the individual and combined roles for glucocorticoid receptor (GCR) and peroxisome proliferator-activated receptor (PPAR)γ pathways in lipid metabolism of adipocytes. In mature 3T3-L1 adipocytes, GCR activation using dexamethasone upregulated adipose triglyceride lipase (ATGL) and downregulated phosphoenolpyruvate carboxykinase (PEPCK), resulting in enhanced glycerol release into the medium. In contrast, PPARγ ligand pioglitazone modestly upregulated ATGL and hormone sensitive lipase (HSL), but markedly enhanced PEPCK and glycerol kinase (GK), thereby suppressed glycerol release. Dexamethasone showed permissive like effect on PPARγ target genes including perilipin A and aP2, therefore co-administration of dexamethasone and pioglitazone demonstrated synergistic upregulation of these enzymes excepting PEPCK, of which downregulation by dexamethasone was abolished by pioglitazone to the level above control. Thus, the excessive glycerol release was prevented as the net outcome of the co-administration. Consistently, the bodipy stain demonstrated that dexamethasone reduced the amount of cytosolic lipid, which was preserved in co-treated adipocytes. Moreover, silencing of PPARγ suppressed the synergistic effects of co-treatment on the lipolytic and lipogenic genes, and therefore the GCR pathway indeed involves PPARγ. In conclusion, crosstalk between GCR and PPARγ is largely synergistic but counter-regulatory in lipogenic genes, of which enhancement prevents excessive glycerol and possibly FFA release by glucocorticoids into the circulation.

Effects of co-administered dexamethasone and diclofenac sodium on pain, swelling and trismus following third molar surgery

Background:The synergism between the action of non-steroidal anti-inflammatory drugs (NSAIDS) and steroids suggest that co-therapy may provide beneficial inflammatory and pain relief in the absence of side effects. The aim of the study was to compare the effect of co-administered dexamethasone and diclofenac sodium (diclofenac Na) with diclofenac Na alone on the postoperative pain, swelling and trismus after surgical removal of third molars.Methods:A prospective randomized study was conducted at the clinic of Oral and Maxillofacial Surgery, Dentistry College/ Mustansirya University. A total of 30 patients were randomly divided into two treatment groups, the first were given dexamethasone (30 minutes preoperative 8 mg and postoperative 4 mg IV 6 hours postoperatively in two doses) and oral dose of diclofenac Na 50 mg 30 minutes before and after surgery, while the second group were given 50 mg diclofenac Na orally alone 30 minutes before and after surgery (as with first group). The overall analgesic effect of the drug was assessed postoperatively by determination of pain severity using a category rating scale. Facial swelling was measured using a tape measure placed from tragus to gonion to tragus, while interincisal mouth-opening of patients was measured using a calibrated vernier pre-operatively and post-operatively.Results:Co-administration of dexamethasone and diclofenac Na was significantly superior to diclofenac alone for the relief of pain (P &lt; 0.05), and facial swelling up to 48 hour postoperativly (P &lt; 0.05). However, there was no significant difference for trismus relief between the two medication protocols (P &gt; 0.05).Conclusion:This study shows enhanced effects of co-administered dexamethasone and diclofenac Na on short-term post-operative pain and swelling, compared to diclofenac sodium alone in third molar surgery

Abstract 11: Progression from newly diagnosed multiple myeloma to relapsed refractory multiple myeloma is associated with significant alterations in the CD4+ Treg population phenotype

Abstract Introduction: Immune compromise is a recognized complication of multiple myeloma (MM), aging, and anti-MM therapies used throughout the course of the disease. Our group have previously reported that patients with relapsed/refractory MM (RRMM) have marked CD4+ T lymphopenia that is not present in newly diagnosed MM (NDMM) and does not recover with successive cycles of lenalidomide and dexamethasone (len/dex) treatment1,2. However, the proportion of Tregs within the CD4+ T-cell population (defined as CD127dimCD25hiFoxp3+) increased with successive cycles of treatment and approached normal range by cycle 9. We hypothesized that this represented homeostatic proliferation of peripherally-derived Tregs (pTreg) as opposed to thymic production of naturally-derived Tregs (nTreg), which can be differentiated by methylation status of the T-cell specific demethylation region (TSDR) found in intron 1 of the Foxp3 gene3. This bears relevance, as (a) pTregs are likely to be derived from senescent cells that are functionally different to recent thymic emigrants, (b) pTregs may exhibit plasticity, as opposed to nTregs, and (c) the population of effector memory T (TEM) cells may be compromised. Methods: We sought to investigate at what point this change occurred throughout the course of disease in MM by analyzing 5 paired samples from patients with NDMM (ANZCTR trial ID ACTRN12613000344796) and RRMM (ANZCTR trial ID NCT00482261), and comparing with 5 age-matched normal donors. In the NDMM cohort, we examined Tregs from samples at baseline, after 4 cycles of len/dex, and after autologous stem cell transplant (ASCT), and in the RRMM cohort samples from baseline and after 9 cycles of len/dex. Tregs (defined as CD4+CD127-CD25+) were FACS sorted from each sample and DNA was extracted and bisulfite converted. The TSDR was PCR amplified using primers previously described3, and transformed into chemically competent E.coli. Individual colonies were picked and their DNA plasmids were sequenced. Cytosine matches/mismatches at CpG sites in the TSDR were identified and % methylation was calculated. Results: The TSDR methylation status of Tregs from baseline NDMM patient samples is largely unmethylated and similar to age-matched controls, i.e., predominantly nTregs. (1) The TSDR methylation status of Tregs from baseline RRMM patient samples is largely methylated, i.e., predominantly pTregs. (2) Len/dex treatment in both NDMM and RRMM patient did not alter the respective phenotypes. (3) After ASCT, 2 of the 5 NDMM patient samples analyzed had changed to a “pTreg phenotype.” Both these patients subsequently relapsed from complete remission, compared to 2 of 3 of the patients with an “nTreg phenotype” maintaining CR 8-9 years later. Conclusions: This study adds evidence that the character of the CD4+ T cell population is radically altered in RRMM, compared with NDMM and age-matched controls. It is likely that thymic involution is a contributor to this, which is not only a normal occurrence with immunosenescence, but may be accelerated with ASCT in some patients. In this way, methylation status of the TSDR could potentially represent a biomarker for poorer prognosis.

Short-Term and Long-Term Effects of Dexamethasone on Cognitive Dysfunction Induced by Sevoflurane in Adult Rats.

Postoperative cognitive dysfunction (POCD) is common after anaesthesia in elderly patients. However, it may appear in patients of all ages. The main pathogenesis of cognitive dysfunction remains unclear, although there is some evidence that brain inflammation may alter cognitive abilities. In the present study, we aim to evaluate short-term and long-term effects of dexamethasone on cognitive dysfunction induced by sevoflurane anaesthesia in adult rats. Seven-month-old 30 male Wistar albino rats were randomised into three groups: sevoflurane group (exposure to sevoflurane), sevoflurane + dexamethasone group (exposure to sevoflurane and dexamethasone injection), and control group (exposure to 100% oxygen). Spatial learning and short-term (7 days after exposure) and long-term (30 days after exposure) memory were evaluated using Morris water maze test. Sevoflurane induced significant deficit in spatial learning and short-term and long-term memory in adult rats. Dexamethasone-treated animals exposed to sevoflurane had equivalent performance as control animals in training and probe trials. Sevoflurane may impair spatial learning and short-term and long-term memories in adult rats. The co-administration of dexamethasone and sevoflurane may ameliorate short-term and long-term cognitive dysfunctions induced by sevoflurane in adult rats.

Palmar-plantar erythrodysesthesia syndrome following treatment with high-dose methotrexate or high-dose cytarabine.

Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown. A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate. Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10-7 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10-5 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10-6 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10-4 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10-5 ). These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society.