Dose Of Dexamethasone Research Articles

FRI342 Hypophysitis Mimicking As Pituitary Adenoma

Abstract Disclosure: A. Chao: None. A. Dhaliwal: None. K. Yu, MD: None. S.N. Polis: None. N.J. Vernetti: None. S. Nakhle: None. Background: Hypophysitis is defined as inflammation of the pituitary gland and causes include lymphocytic, granulomatous, xanthomatous, and IgG4 related hypophysitis. Hypophysitis can sometimes mimic a pituitary mass. It is more common in the female and associated with pregnancy. Lymphocytic hypophysitis may present with symptoms related to expansion of the pituitary gland and hormone deficiency. Expansion of the gland often causes headaches. Compression of the optic chiasm results in a decrease in the visual field, color perception, and in rare cases, diplopia due to lateral expansion of the pituitary gland.It also affects hypothalamic-pituitary axis and commonly impairs hormone production from corticotrophs, gonadotrophs and thyrotrophs. Patients treated with glucocorticoids can have hormonal recovery and resolutions of imaging findings. Clinical Case: Patient is a 30-year-old, previously healthy, female who initially presented to the emergency department with a worsening headache over the preceding three months. Brain MRI demonstrated a 1.8 cm enhancing mass and the radiologist interpreted the findings as a pituitary macroadenoma. The patient was seen by neurosurgery and was started on high doses of dexamethasone at 4 mg twice a day for three months duration. After treatment, the patient’s headache improved although she reported an 80-pound weight gain. CT of the head three months later reported a prominent pituitary gland in size compatible with history of pituitary adenoma but decreased in size to 0.9 cm. Repeated brain MRI six months after treatment showed resolution of the mass. The patient also noted a cessation of her menstrual cycle around the onset of headache and laboratory evaluation consistent with hypogonadotropic hypogonadism (FSH 5.5 mIU/mL, LH 2.8 mIU/mL and estradiol 22 pg/mL). Regular menstrual cycles returned seven months after glucocorticoid treatment. Almost two years after the onset of her headaches, the patient was referred to the endocrine clinic for further evaluation of fatigue, low libido, and persistent weight gain. Repeat anterior pituitary function tests were unremarkable and showed FSH 5.6 mIU/mL, LH 3.3 mIU/mL, Estradiol 34 pg/mL, Sodium 139 mmol/L, IGF-1 129 ng/mL (-0.4 standard deviation), Ferritin 20 ng/mL, Prolactin 15.6 ng/mL, TSH 4.38 mIU/L, T4 free 1.1 ng/dL, Cortisol AM 10.9 mcg/dL, and Testosterone 13 ng/dL. Conclusion: We present a case of hypophysitis mistaken for a non-functioning macroadenoma with mild mass effect on the undersurface of the optic chiasm, headache and hypogonadotropic hypogonadism. The patient did not have risk factors such as pregnancy or other autoimmune conditions. After glucocorticoid treatment, recovery of hypogonadotropic hypogonadism and resolution of headache, and radiographic findings. Presentation: Friday, June 16, 2023

Impact of Dosing and Duration of Dexamethasone on Serious Corticosteroid-Related Adverse Events

ContextCorticosteroids are commonly prescribed in oncology, but few studies have examined its adverse events (AEs) compared to placebo control. ObjectivesUsing data from a double-blind, placebo-controlled randomized trial, we evaluated the association between the dose and duration of dexamethasone and serious AEs. MethodsThis is a pre-planned secondary analysis of the Alleviating Breathlessness in Cancer Patients with Dexamethasone (ABCD) trial in which patients were randomized to dexamethasone 8 mg BID x1 week, then 4 mg BID x1 week or placebo, followed by an optional open-label phase with 4 mg BID x1 week, then 2 mg BID x1 week. The primary outcome was Grade 3+ AEs (CTCAE v4.03). We evaluated the association between AEs and dexamethasone exposure using multivariable logistic regression. ResultsAmong 119 cancer patients, 32 received intervention followed by open label (mean exposure 243 mg over 27 days), 47 received intervention with no open label, 20 received placebo followed by open label, and 20 received no dexamethasone. The most common AEs included insomnia (31%), dyspepsia (21%), neuropsychiatric symptoms (18%), and infections (17%). Overall, 38 (32%) had Grade 3+ AEs and 27 (23%) were hospitalized. Patients with the greatest exposure to dexamethasone experienced more Grade 3+ AEs compared to those with no exposure (65% vs. 15%); odds ratio of 15.1 (95% CI 1.4–160.8, P = 0.01). ConclusionGreater dexamethasone exposure, even at moderate doses, was associated with more serious AEs. Prescribers should cautiously weigh the risks and benefits of dexamethasone use, especially when considering for palliation of symptoms.

Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis

The impact of different doses of dexamethasone on outcomes from acute COVID-19 pneumonia is unknown. We performed a systematic review and meta-analysis of randomised control trials comparing different doses of dexamethasone in adult patients with COVID-19. High dose dexamethasone treatment was defined as 12-24mg daily, whereas low-dose treatment was 6-8mg daily. Primary outcome was 28-day mortality. Eight trials including 3469 patients were identified, with 1775 patients receiving high dose dexamethasone. There was no difference in mortality between patients receiving high dose or low-dose dexamethasone (22.0% vs. 20.2%; odds ratio 1.20 [95% confidence interval 0.86-1.67]; p=0.29; I2 =63%; TSA-adjusted CI [0.31-4.66]; very low QoE). Meta-regression did not demonstrate a dose-dependent effect of steroids on mortality. High dose dexamethasone was associated with an increased risk of hyperglycaemia (23.6% vs. 17.2%; 1.51 [1.19-1.92]; p=0.0008; I2 =0%; TSA-adjusted CI [0.90-2.54]; low QoE) but not secondary infections (14.3% vs. 15.0%; 0.87 [0.56-1.37]; p=0.56; I2 =72%; very low QoE). Risk of bias was low for seven of the eight studies. The mortality of patients with acute COVID-19 receiving high-dose dexamethasone is similar to patients receiving low-dose dexamethasone, although high-dose dexamethasone is associated with an increased risk of hyperglycaemia.

Xuanbai Chengqi Decoction alleviates acute lung injury by inhibiting NLRP3 inflammasome

Ethnopharmacological relevanceAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a prevalent critical respiratory disorder caused mostly by infection and other factors. However, effective drug therapies are currently lacking. Xuanbai Chengqi Decoction (XCD), a traditional Chinese medicine (TCM) prescription, is commonly employed to treat lung diseases. It has been recommended by Chinese health authorities as one of the TCM prescriptions for COVID-19. Nonetheless, its underlying mechanism for the treatment of ALI has not been fully understood. Aim of the studyThe study aims to investigate the therapeutic effect of XCD on lipopolysaccharide (LPS) -induced ALI in mice and explore its anti-inflammatory mechanism involving pyroptosis. Materials and methodsUltra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was employed to identify the active compounds of XCD, and quantitative analysis of the main compounds was conducted. Male C57BL/6J mice were given different doses of XCD (4.5 and 9.0 g/kg/day) or dexamethasone (5 mg/kg/day) by oral gavage for 5 consecutive days. Subsequently, ALI was induced by injecting LPS (20 mg/kg) intraperitoneally 2 h after the last administration, and serum and lung tissues were collected 8 h later. J774A.1 cells were pretreated with different doses of XCD (100, 200, 400 μg/ml) for 12 h, then incubated with LPS (1 μg/ml) for 4 h and ATP (1 mM) for 2 h to induce pyroptosis. Supernatant and cells were collected. Moreover, J774A.1 cells were transfected with an NLRP3 overexpression plasmid for 24 h, followed by subsequent experiments with XCD (400 μg/ml). Lung histopathological changes were evaluated using hematoxylin and eosin (HE) staining. To assess the efficacy of XCD on ALI/ARDS, the levels of inflammatory factors, chemokines, and proteins associated with NLRP3 inflammasome signaling pathway were evaluated. ResultsXCD was found to ameliorate lung inflammation injury in ALI mice, and reduce the protein expression of TNF-α, IL-1β, and IL-6 in both mouse serum and J774A.1 cell supernatant. Meanwhile, XCD significantly decreased the mRNA levels of IL-1β, pro-IL-1β, CXCL1, CXCL10, TNF-α, NLRP3, NF-κB P65, and the protein expression of NLRP3, Cleaved-Caspase1, and GSDMD-N in the lung and J774A.1 cells. These effects were consistent with the NLRP3 inhibitor MCC950. Furthermore, overexpression of NLRP3 reversed the anti-inflammatory effect of XCD. ConclusionThe therapeutic mechanism of XCD in ALI treatment may involve alleviating inflammatory responses in lung tissues by inhibiting the activation of the NLRP3 inflammasome-mediated pyroptosis in macrophages.

Post-operative nausea and vomiting prophylaxis: A meta-review on systematic reviews and meta-analyses

Introduction: Postoperative nausea and vomiting (PONV) are common complications in surgical patients undergoing general anesthesia, and multiple strategies have been suggested to prevent them.
 Objective: To describe the available evidence on the effectiveness of pharmacological and non-pharmacological strategies for preventing PONV in adults undergoing surgery under general anesthesia, as reported in previous meta-analyses and systematic reviews.
 Methodology: An overview of systematic reviews and meta-analyses was conducted. Searches were performed in PubMed, EBSCO, EMBASE, Cochrane Database, Science Direct, and Scopus, without restrictions as to gender, clinical condition, or date of publication, including articles in Spanish, French, and English only. Two reviewers independently and in duplicate did the screening, data extraction, quality evaluation, and risk of bias assessment according to AMSTAR-2. The PRISMA and PRIOR statements were followed for reporting. PROSPERO registration number CRD42021251999.
 Results: Out of 80 candidate articles, three were viable for meta-analysis. 1.5 mg to 18 mg doses of Dexamethasone showed a significant reduction in the risk of PONV, with a RR of 0.48 (95 % CI 0.41-0.57; p<0.001), I2=63 % (p=0.07), and a NNTc of 5 and 7. Other effective strategies included the use of acoustic stimulation/acupuncture/acupressure, 5HT3 antagonists, NK1 antagonists, gabapentinoids, haloperidol, droperidol, metoclopramide, midazolam, mirtazapine, among others. The risk of publication bias was low.
 Conclusion: Different strategies are effective for PONV prophylaxis in surgeries under general anesthesia. Dexamethasone shows the best available evidence at the moment. The documented methodological quality suggests the need for better studies to establish the effectiveness of the strategies.

P06.11.B NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, data for patients with CNS involvement are limited. Whether CAR T-cells represent a viable therapeutic avenue for such patients remains therefore unclear. MATERIAL AND METHODS We retrospectively searched our institutional database for patients with primary and secondary CNS lymphoma who were treated with CD19-directed CAR T-cells for active CNS disease. Clinical data, CNS-specific toxicities, imaging findings, and outcome were analyzed. RESULTS We identified 45 consecutive CAR T-cell transfusions for active CNS lymphoma at the Massachusetts General Hospital over a five-year period. This cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild neurotoxicity (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe neurotoxicity (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of neurotoxicity were detected in SCNSL. Early fever and baseline C-reactive protein levels predicted neurotoxicity occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of Ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CD19-directed CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in patients with CNS lymphoma. Further evaluation on the role of bridging regimens and corticosteroids is urgently warranted.

P11.15.A IMPACT OF PERIOPERATIVE DEXAMETHASONE IN THE CONTEXT OF NEUROSURGICAL BRAIN METASTASIS RESECTION

Abstract BACKGROUND Patients with brain metastases that undergo brain metastasis resection regularly receive perioperative dexamethasone. We sought to evaluate whether perioperative dexamethasone in brain metastases is linked to survival. MATERIAL AND METHODS Retrospective data on perioperative dexamethasone dosage in resected brain metastasis patients at three hospital sites of the Charité from 2010-2022 were collected. Cut-off values for cumulative perioperative dexamethasone dose as a continuous predictor variable for survival were determined using maximally selected rank statistics. Patients were dichotomized based on determined cut-offs of cumulative dexamethasone (pre-operative: < 40 mg vs ≥ 40 mg; post-operative: < 180 mg vs ≥ 180 mg) and pre- and postoperative: < 281 mg vs ≥ 281 mg). Medical records included baseline demographic, radiological, histopathological and treatment-related characteristics. Based on cut-off values for dexamethasone downstream statistical analyses included Kaplan-Meier, Cox proportional hazards regression for overall survival with adjustment for potential confounders including age, gender, Karnofsky performance index and presence of extracranial metastasis via propensity score matching. RESULTS 539 patients were included. Median follow-up time was 58,97 months. After adjusting for age, gender, Karnofsky performance index and presence of extracranial metastasis patients with higher cumulative perioperative dexamethasone (≥281 mg) showed shorter survival (HR: 1.47 (1.20-1.80, p<0.001) as compared to patients with lower cumulative doses (<281 mg). This effect remained significant after correction for patients that died within 3 months after resection and for patients with KPS below 50% and, independently from this approach performing propensity score matched-based analysis of the total cohort of patients, respectively. CONCLUSION Cumulative perioperative dexamethasone is associated with decreased survival in the context of brain metastasis resection. Strict dosage, down taper or methods reducing corticosteroid dependency should be regularly evaluated in clinical practice in patients with brain metastases

Systemic corticosteroids for the prevention of bronchopulmonary dysplasia, a network meta-analysis.

Systemic corticosteroids for the prevention of bronchopulmonary dysplasia, a network meta-analysis.

Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial

BackgroundThe respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC).MethodsWe performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects.ResultsOverall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not.ConclusionsIn this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings.Trial registration: NCT04344730, date of registration April 14, 2020 (https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1); EudraCT: 2020-001457-43 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43).

Comparison of Three Different Doses of Dexamethasone Added to Midazolam for Prophylaxis against Nausea and Vomiting after Laparoscopic Cholecystectomy during Early Postoperative Period

Abstract Background General anesthesia using volatile anesthetics is associated with high incidence of postoperative nausea and vomiting ranging between 20% - 30% within 24 hours after surgery. Postoperative nausea and vomiting is thought to be of multifactorial etiology involving anesthetics, surgical and individual factors. Objective To compare between three different doses of Dexamethasone in conjunction with predetermined fixed dose of Midazolam which can provide effective prophylaxis against postoperative nausea and vomiting after laparoscopic cholecystectomy. Patients and Methods 1ry outcome was to decrease nausea and vomiting after laparoscopic cholecystectomy and 2ry outcome was itching and dizziness. The present study was conducted in Ain shams University hospitals on 120 adult female patients aged 21 to 60 years, American Society of Anesthesiologists (ASA) class I or II scheduled to an elective laparoscopic cholecystectomy. After obtaining approval from the research ethical committee of faculty of medicine of Ain Shams University, a written informed consent was obtained from every patient after explaining the procedure. Results Over 24 h, the incidence of nausea, vomiting and rescue antiemtic use reduced significantly in Group ІІ and Group ІІІ when compared to group І. As with incidence, the severity of nausea was even significantly reduced in the group ІІ and group ІІІ group (P 0.043 and 0.009) respectively compared to group І in 24 hours postoperative. Postoperative pain was assessed for initial 6 h. Group ІІ and group ІІІ had significant reduction in severity of pain (P &amp;lt; 0.016 and 0.006) respectively when compared to group І while there was no significant difference between group ІІ and group ІІІ. Moreover, the incidence of use of rescue analgesia significantly reduced from 82.5% in group І to 52.5% and 45% in group ІІ and group ІІІ, respectively. However, dose of rescue analgesia used in 6 h was significantly reduced in Group ІІІ only (P = 0.013). Conclusion The minimum effective dose for prevention of postoperative nausea is 4 mg of Dexamethasone in combination with Midazolam in female patients undergoing Laparoscopic cholecystectomy with additional advantage of analgesia in the early postoperative period. Further reduction in incidence and severity of PONV can be achieved with a dose of 8 mg dexamethasone.

Glucocorticoid-Induced Dose-Dependent Reproductive Impairments in Male Albino Rat

The present study is aimed at elucidating the effect of different doses of Dexamethasone (DEX) on testis and epididymis of male Wistar rats. Thirty-six rats were divided into six groups, each containing six rats: one control (CON), and five groups of rats treated with five (30 μg, 40 μg, 50 μg, 60 μg, 70 μg/100 g body weight) doses of dexamethasone intraperitoneally (i.p.) for twenty-one days. The results revealed a dose-dependent decrease in testes and epididymis weight. DEX-treated rats evidenced significant increase in TBARS levels, this being the highest in 70 μg/100 g body weight (bw) which could be a consequence of the highest level of free radical generation. The activity level of antioxidative enzymes Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH), and protein content significantly declined in dexamethasone-treated rats in a dose-dependent manner. Histological observation revealed different degrees of germ cell degeneration/alterations in testis and epididymis The present finding suggests that exposure to dexamethasone (70 μg/100 g bw) can potentially lead to severe impairments in male reproductive tissues (testis and epididymis) structure and function, which may consequently lead to male infertility.

Biochemical Changes of Dexamethasone on Liver and Kidney Functions in Laboratory Mice Mus musculus L.

Background: The present study sought to verify the effect of dexamethasone on the biochemical changes in different organs, such as liver and kidney organs of both sexes, male and female mice. Materials &amp; Method: Muc muscular males and female mice (n=48) were used. To determine the effects of dexamethasone on the biochemical changes of liver and kidney organs, mice received a low dose (2mg/kg) and a high dose (4 mg/kg) of dexamethasone continuously for one month. Result: The results showed a significant increase (P&lt;0.05) in Liver enzymes (ALP, AST, ALT). The urea and creatinine levels also increased in the treated mice and both sexes with the pesticide compared with the control group. Keywords: mice, histological, liver, kidney, dexamethasone, toxicity

Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway

BackgroundHigh dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy.Methods3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs (1times {10}^{6} cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 muM Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining.ResultsADSC treatment significantly increased body lean mass (10–20%), muscle wet weight (15–30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45–65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo.ConclusionsADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

Abstract P2144: Irisin, An Exercise-induced Myokine, Exhibits Protective Effects In Glucocorticoid-induced Cardiac Muscle Dysfunctions

Myocardial infarction caused by pharmacological substances, such as anti-inflammatory drugs, is a serious adverse drug effect in the cardiovascular system that often causes heart failure. Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used as potent anti-inflammatory and immunosuppressive drugs, but is classified as one of the prime suspects of drug-induced acute myocardial infarction. High dose of DEX increased oxidative stress of the heart, induced myocardial degeneration and cardiomyocyte apoptosis and impaired cardiac contraction. Thus, therapeutic approaches are required to alleviate glucocorticoids-induced cardiotoxicity and prevent DEX-mediated cardiac complications. Exercise-induced secretion of irisin showed the beneficial effects against cardiovascular diseases on energy metabolism, anti-oxidant effects, and decreased inflammation and apoptosis by promoting mitochondria biogenesis, decreasing oxidative stress and inflammatory responses, and regulating intracellular calcium signaling. In this study, we investigate the endocrine effects of muscle-secreted irisin against DEX-induced cardiotoxicity. We engineered anisotropic human induced-pluripotent stem cell-derived cardiomyocyte tissues and designed three experimental groups: control, dex treatment, and dex plus irisin treatment. We then analyze the tissues with qPCR, immunostaining (muscle atrophy markers), contractility assay, and oxygen consumption assay to evaluate the protective effects of irisin on DEX-induced cardiac injury. Injured cardiac tissues showed systolic dysfunction by decreasing oxygen consumption, increasing muscle atrophy marker (MuRF-1), and significantly reducing systolic contractile force, but not diastolic stress. In contrast, these DEX-induced maladaptive responses was alleviated by irisin pretreatment by reducing proteolytic activity and muscle atrophy signaling pathways and promoting mitochondria biogenesis. In conclusion, our micro-physiological system showed the therapeutic effects of irisin against DEX-induced cardiotoxicity.

Phase 3 randomized controlled trial comparing the effectiveness of dexamethasone in reducing cancer-associated fatigue in patients on palliative chemotherapy.

134 Background: Short-term steroids (&lt; 2 weeks) have been used to alleviate fatigue in patients with advanced cancer. However, the efficacy and safety of long-term steroids (12 weeks) in patients with advanced cancer receiving palliative chemotherapy have not been studied. Methods: The study was an open-label, placebo-controlled, phase 3 RCT to evaluate the efficacy and safety of low dose dexamethasone (DEX) in reducing chemotherapy and cancer associated fatigue. Patients aged 18-60 years with performance status ≤2, undergoing palliative chemotherapy for advanced solid malignancies were randomized 1:1 to receive either DEX (4mg/day) or a placebo for 12 weeks. Fatigue was measured using the Symbolic Assessment of Fatigue Extent (SAFE) scale and EORTC FA12 scale, and QOL was assessed using the EORTC QLQ c30 at baseline, 6 weeks, and 12 weeks.The primary endpoint was to compare fatigue between the study arms at 6 weeks. Secondary endpoints were to compare fatigue at 12 weeks, QOL and toxicities. With a power of 80%, α of 5%, 126 patients (including 25% drop-outs) were required to show the superiority of DEX in reducing SAFE fatigue extent score by 50% at 6 weeks. Results: A total of 126 patients were randomized (64 in the placebo arm and 62 in the DEX arm) between Oct 2018-Sep 2022. The median age was 46.5 years and 67% were females. Metastatic breast (28%) and lung (16%) cancer were the common diagnosis. Twelve and 23 patients in the placebo arm and 13 and 22 patients in the DEX arm did not undergo week 6 and 12 assessment respectively due to disease progression. The results showed no significant differences in mean SAFE scores, FA12 scores, or QOL between the study arms at 6 and 12 weeks, except for higher FA12 social sequelae in the DEX arm at 12 weeks (P = 0.048) (Table). There were no significant differences in toxicities between the arms. Conclusions: The results of this study suggest that low-dose DEX is not effective in reducing chemotherapy associated fatigue or improving QOL in patients with advanced cancer. Clinical trial information: CTRI/2018/08/015222 .[Table: see text]

Olfactory mucosa steroid injection in treatment of post-COVID-19 olfactory dysfunction: a randomized control trial

BackgroundOlfactory dysfunction can be a troublesome condition affecting the quality of life of the patient. Post-viral olfactory dysfunction is the most common cause attributing to up to 40% of anosmia. COVID-19 infection commonly causes anosmia in 30–66% of patients. The long-term effect of post-COVID olfactory dysfunction is reported to be increasing in incidence. Steroids are usually used in the treatment of olfactory dysfunction and most commonly used locally in the form of nasal steroid sprays, rinses, or drops. Oral systemic steroids are sometimes used; however, they have several known side effects. Other treatments experimented include giving vitamins, minerals, antioxidants, antivirals, and monoclonal antibodies, in addition to olfactory training, counseling, and acupuncture. In this study, the effect of intranasal steroid injection is studied in post-COVID olfactory dysfunction.ResultsForty patients with olfactory dysfunction post-COVID-19 for more than 3 months were randomly divided into 2 groups. Group A patients received 8 doses of dexamethasone over 2 months (twice weekly) injected near the olfactory mucosa in the nasal septum and middle turbinate, compared to group B who received saline injected in the same way as placebo. Numerically, nasal injection of corticosteroids in group A showed more subjective improvement using the questionnaire of olfactory disorders-negative statement QOD-NS than the control patients in group B but this improvement was statistically insignificant.ConclusionThe use of intranasal corticosteroids injection should be considered in the treatment of post-COVID anosmia.

Investigations of Lipid Droplets Role in Attenuating Chemotherapeutic Responses to 5-FU in Cancer Cells in vitro

Cancer has been considered as a main cause of death worldwide. Despite the effectiveness of traditional anticancer therapies such as 5-Flurouracil (5-FU), poor therapeutic outcomes are reported in many cases, due to tumor recurrence and chemoresistance. Intracellular lipid accumulation as lipid droplets (LDs) is now a well-recognized hallmark of cancer. However, the influence of LDs accumulation in cancer progression and treatment remains to be elucidated. Adjuvant use of non-chemotherapeutic drugs (e.g. NSAIDs and corticosteroids) with anticancer drugs to manage cancer related symptoms, may though serve as factors modulating the therapeutic response to anticancer agents via LDs related mechanisms. The aim of this study is to evaluate possible strategies influencing chemoresistance by attenuating LDs biogenesis and function. LDs levels in eight human cancer cell lines were measured. The existence of correlation between the cellular levels of LDs and cytotoxicity of ten chemotherapeutic agents was evaluated. A moderate correlation between basal LDs levels and the half inhibitory concentration (IC50) values of 5-FU on selected cell lines was established (r2= 0.5235). Nevertheless, LDs levels were significantly elevated following exposure to 5-FU. A549 human lung cancer cells showed the highest increase in LD accumulation (***P &gt;0.001) compared to their basal levels of LDs. LDs levels were also assessed following exposure to 5-FU in the presence of sub-lethal doses of celecoxib (CXB), dexamethasone (DEX), and simvastatin (SMV). Interestingly, CXB and DEX exposure to 5-FUtreated cells resulted in an alleviation in the antiproliferative activities of 5-FU in MDA-MB-468 and HCT116 but not in A549 cells. While, SMV exposure to 5-FU-treated cells resulted in reduced antiproliferative activities of 5-FU in MDA-MB-468 only. These results strongly suggest that increased LDs levels caused by CXB, DEX, and SMV may contribute in the development of a resistance mechanism exist only in some cancer types, which therefore, attenuates responses to 5- FU. The inhibition of phospholipid metabolism by DEX, as well as the inhibition of 3-hydroxy-3- methylglutaryl-CoA reductase (HMGCR) by SMV were expected to result in the up regulation of triacylglycerol (TAG), leading to LDs accumulation. This study highlights the importance of assessing drug-drug interaction before designing integrated therapy regimens for cancer patients receiving 5-FU treatment. Further studies are needed to discover the role of TAG inhibition on the sensitivity of cancer cells against 5-FU.

Effect of Dexamethasone in Management of Postoperative Nausea, Vomiting and Pain After Tonsillectomy in Paediatric Patients

Introduction: The effectiveness of dexamethasone (DEX) in reducing complication rates following paediatric tonsillectomy is still up for debate. The incidence of postoperative nausea and vomiting (PONV) and the severity of pain following paediatric tonsillectomy were examined by comparing concentrations of DEX 0.15 and DEX 0.5 mg/kg, respectively. Aim of the study: The aim of the study is to assess the effect of Dexamethasone in management of postoperative nausea, vomiting and pain after tonsillectomy where the targeted patients are of 3 to 10 years children. Methods: This prospective cross sectional study was conducted in the Department of Paediatric Anaesthesiology and Surgical ICU in Bangladesh Shishu Hospital and Institute, Dhaka, Bangladesh during July 2019 to June 2022. This study included 123 children undergoing elective tonsillectomy. The Institutional Ethics Committee approved this study and informed parental written consent was obtained from the parents before collecting the patients’ information. Results: The prevalence of early PONV was lower in both DEX groups (DEX 0.15: 22%; DEX 0.5: 26%; placebo: 48%; P=0.001). On the second day after surgery, the DEX groups had a lower rate of severe pain (DEX 0.15: 20%; DEX 0.5: 5%; placebo: 47%; P&lt;0.001). The study was not conducted to assess a difference between the two dose groups of Dexamethasone. Conclusions: The frequency of early and late PONV and the level of pain on the second postoperative day were both reduced by an i.v injection of DEX during the induction of anesthesia. To reduce the incidence of PONV, it appeared that a dose of DEX 0.15 mg/kg was just as effective as a dose of DEX 0.5 mg/kg.

Focus on the anti-inflammatory effect of glucocorticosteroids in experimental acute lung injury

AIM: Assessment of the effect of various doses of dexamethasone as an inflammation modulator in experimental lipopolysaccharide-induced acute lung injury in rats.&#x0D; MATERIALS AND METHODS: Acute lung injury in rats was modeled by intratracheal administration of cell wall lipopolysaccharide from the Salmonella enterica. White male rats were divided into groups: a group of intact animals (n = 10); the control group (n = 40), in which the animals were simulated acute lung injury without further treatment and removed from the experiment on day 3; three experimental groups (n = 40), in which, 3 hours after modeling acute lung injury, and then daily once a day for 3 days, dexamethasone solution was administered intraperitoneally in the following doses: in group 1 0.52 mg/kg (equivalent to 6.0 mg/day for a person), in group 2 1.71 mg/kg (20.0 mg/day for a person), in group 3 8.0 mg/kg (94.0 mg/day, pulse therapy for humans). On the 3rd day, blood samples were taken from the caudal vena cava in surviving animals for clinical analysis and evaluation of the function of mitochondria of peripheral blood leukocytes. To determine the severity of local inflammatory reactions and pulmonary edema, bronchoalveolar lavage was performed with the study of an endopulmonary cytogram and an assessment of pathomorphological changes in the lung tissue.&#x0D; RESULTS: indicate that dexamethasone reduces the amount of lung tissue damage and animal mortality, dose-dependently reduces the functions of mitochondria and the number of lymphocytes and monocytes in peripheral blood, as well as neutrophils, lymphocytes and macrophages in bronchoalveolar lavage samples.&#x0D; CONCLUSION: The use of dexamethasone at a dose of 0.52 mg/kg (equivalent to 6.0 mg/day for humans) is accompanied by better survival, minimal effect on the viability and functional activity of inflammatory cells. Pulse therapy leads to a significant decrease in the number of immunocompetent cells in bronchoalveolar lavage, mitochondrial dysfunction in the form of a decrease in the ability of these cells to use the reserve power of mitochondrial respiration in response to the action of a stress factor. Excessive inhibition of immunocompetent cells can contribute to the activation of latent and opportunistic infections, which must be taken into account when choosing a dosing regimen for glucocorticosteroids.

Gracilaria chorda subcritical-water extracts as ameliorant of insulin resistance induced by high-glucose in zebrafish and dexamethasone in L6 myotubes

Background and aimInsulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. Loss of insulin sensitivity disrupts glucose homeostasis and elevates the risk of developing the metabolic syndrome that includes Type 2 diabetes. This study assesses the effect on subcritical-water extract of Gracilaria chorda (GC) at 210 °C (GCSW210) in IR induction models of high glucose (HG)-induced zebrafish larvae and dexamethasone (DEX)-induced L6 myotubes. Experimental procedureThe dose of HG and DEX for IR induction in zebrafish larvae and L6 myotubes was 130 mM or 0.5 μM. The capacity of glucose uptake was quantified by fluorescence staining or intensity. In addition, the activation of protein and mRNA expressions for insulin signaling (insulin-dependent or independent pathways) was measured. Results and conclusionExposure of zebrafish larvae to HG significantly reduced the intracellular glucose uptake with dose-dependnet manner compared to control. However, the group treated with GCSW210 significantly averted HG levels like the insulin-treated group, and significantly up- or down-regulated the mRNA expressions related to insulin production (insα) and insulin signaling pathways. Moreover, the treatment with GCSW210 effectively regulated the protein expression of PI3K/AKT, AMPK, and GLUT4 involved in the action of insulin in IR models of L6 myotubes compared to DEX-treated control. Our data indicate that GCSW210 stimulates activation of PI3K/AKT and AMPK pathways to attenuate the development of IR induced by HG in zebrafish and DEX in L6 myotubes. In conclusion, GCSW210 is a potential agent for alleviating various diseases associated with the insulin resistance.