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Journal of Oncology Pharmacy Practice :... Jan 2024Elotuzumab in combination with dexamethasone and immunomodulating agents (IMiDs) lenalidomide or pomalidomide is 2nd to 4th line therapy for multiple myeloma. The...
Elotuzumab in combination with dexamethasone and immunomodulating agents (IMiDs) lenalidomide or pomalidomide is 2nd to 4th line therapy for multiple myeloma. The labelled dosage of dexamethasone for use in conjunction with elotuzumab and IMiDs splits the dexamethasone dose into two administrations, one oral and one intravenous, on the days of each elotuzumab infusion. Administration of split dose dexamethasone on days of elotuzumab administration is based on the registration trials submitted for drug approval and was intended to ensure standard well-timed immunotherapy premedication using pharmacologically equivalent dexamethasone doses for both study arms. Administration of dexamethasone in the manner delineated by the elotuzumab product label adds complexity to the delivery of care. This commentary provides an empirical assessment of established medication safety and effectiveness which supports administration of dexamethasone standard intermittent dose instead of the split dose approach delineated on elotuzumab package insert. Simplification of regimen administration improves medication adherence, reduces the risk of inadvertent omission or duplication of medication therapy, and improves the workflow required for delivery of care.
Topics: Humans; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Multiple Myeloma; Immunomodulating Agents; Antibodies, Monoclonal, Humanized
PubMed: 37876226
DOI: 10.1177/10781552231207855 -
Scientific Reports Oct 2023Cataract surgery can cause dry eye symptoms. One of the many factors compromising the ocular surface is the use of benzalkonium chloride (BAC)-preserved topical eye... (Randomized Controlled Trial)
Randomized Controlled Trial
Cataract surgery can cause dry eye symptoms. One of the many factors compromising the ocular surface is the use of benzalkonium chloride (BAC)-preserved topical eye drops administered during the postoperative period. In this open-label, prospective, randomized, comparative clinical trial, 40 patients not previously affected by dry eye disease were assigned to receive either preservative-free (PFD) or preserved (PD) dexamethasone 0.1% eye drops for two weeks after a standard phacoemulsification procedure. Fluorescein break-up time, ocular surface staining score, Schirmer test, Ocular Surface Disease Index and anterior chamber (AC) cells were evaluated at baseline prior to the surgery and 2 weeks after surgery. No statistically significant differences in baseline assessments were observed between groups. At week 2, a significant increase in corneal staining scores (p = 0.003) and foreign body sensation (p = 0.04) was observed for the PD group only. The conjunctival staining score was significantly higher in both groups. The mean AC cell grading was higher in the PFD group than in the PD group (0.28 ± 0.30 and 0.07 ± 0.18, respectively; p = 0.013). Preservative-free dexamethasone eye drops after cataract surgery caused milder dry eye symptoms as compared with preserved dexamethasone. The AC inflammation control comparison may require a larger study group. Trial registration: ClinicalTrials.gov identifier NCT05753787, 03/03/2023.
Topics: Humans; Prospective Studies; Preservatives, Pharmaceutical; Dry Eye Syndromes; Ophthalmic Solutions; Cataract; Dexamethasone
PubMed: 37903818
DOI: 10.1038/s41598-023-44939-1 -
European Journal of Pharmaceutics and... May 2024Even though subconjunctival injections are used in clinics, their quantitative pharmacokinetics has not been studied systematically. For this purpose, we evaluated the...
Even though subconjunctival injections are used in clinics, their quantitative pharmacokinetics has not been studied systematically. For this purpose, we evaluated the ocular and plasma pharmacokinetics of subconjunctival dexamethasone in rabbits. Intravenous injection was also given to enable a better understanding of the systemic pharmacokinetics. Dexamethasone concentrations in plasma (after subconjunctival and intravenous injections) and four ocular tissues (iris-ciliary body, aqueous humour, neural retina and vitreous) were analysed using LC-MS/MS. Population pharmacokinetic modelling for plasma data from both injection routes were used, and for first time the constant rate of absorption of dexamethasone from the subconjunctival space into plasma was estimated (k = 0.043 min, i.e. absorption half-life of 17.3 min). Non-compartmental analysis was used for the ocular data analysis and resulting in ocular drug exposure of iris-ciliary body (AUC= 41984 min·ng/g) > neural retina (AUC= 25511 min·ng/g) > vitreous (AUC= 7319 min·ng/mL) > aqueous humour (AUC= 6146 min·ng/mL). The absolute bioavailability values after subconjunctival injection, reported for the first time, were 0.74 % in aqueous humour (comparable to topical dexamethasone suspensions), and 0.30 % in vitreous humour (estimated to be higher than in topical administration). These novel and comprehensive pharmacokinetic data provide valuable information on the potential for exploiting this route in ocular drug development for treating both, anterior and posterior segment ocular diseases. Moreover, the new generated dexamethasone-parameters are a step-forward in building predictive pharmacokinetic models to support the design of new subconjunctival dexamethasone formulations, which may sustain drug effect for longer period of time.
Topics: Animals; Rabbits; Injections, Intravenous; Chromatography, Liquid; Tandem Mass Spectrometry; Vitreous Body; Dexamethasone
PubMed: 38484852
DOI: 10.1016/j.ejpb.2024.114260 -
The Journal of Clinical Endocrinology... Dec 2023Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling...
CONTEXT
Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling (IPSS), is expensive and not widely available.
OBJECTIVE
Evaluate the performance of the corticotropin-releasing hormone stimulation test (CRH-ST) and the 8 mg high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease (CD) from ectopic ACTH syndrome (EAS).
METHODS
Retrospective review in a tertiary referral center. A total of 323 patients with CD or EAS (n = 78) confirmed by pathology or biochemical cure (n = 15) in 96% underwent CRH-ST and HDDST performed between 1986 and 2019. We calculated test sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value, and diagnostic accuracy (DA) for the diagnosis of CD, and determined optimal response criteria for each test, alone and in combination.
RESULTS
The CRH-ST performed better than the HDDST (DA 91%, 95% CI 87-94% vs 75%, 95% CI 69-79%). Optimal response criteria were a ≥40% increase of ACTH and/or cortisol during the CRH test and a ≥69% suppression of cortisol during the HDDST. A ≥40% cortisol increase during the CRH test was the most specific measure, PPV 99%. Seventy-four percent of subjects had concordant positive CRH test and HDDST results, yielding Se 93%, Sp 98%, DA 95%, and PPV 99%, with a pretest likelihood of 85%. A proposed algorithm diagnosed 64% of patients with CD with near perfect accuracy (99%), obviating the need for IPSS.
CONCLUSION
CRH is a valuable tool to correctly diagnose the etiology of ACTH-dependent CS. Its current worldwide unavailability impedes optimal management of these patients.
Topics: Humans; Animals; Sheep; Cushing Syndrome; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Hydrocortisone; Diagnosis, Differential; ACTH Syndrome, Ectopic; Pituitary ACTH Hypersecretion; Dexamethasone
PubMed: 37531629
DOI: 10.1210/clinem/dgad454 -
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 -
Journal of Infection in Developing... Jul 2023The aim of this study was to demonstrate the purpose of adding antiviral (remdesivir) to the existing steroidal (dexamethasone) therapy in treating coronavirus disease... (Observational Study)
Observational Study
INTRODUCTION
The aim of this study was to demonstrate the purpose of adding antiviral (remdesivir) to the existing steroidal (dexamethasone) therapy in treating coronavirus disease 2019 (COVID-19).
METHODOLOGY
A retrospective observational case cohort study was carried out to compare the effect of dexamethasone alone and in combination with remdesivir in treating moderate and severe COVID-19 disease. The patients were divided into 2 groups: Group 1 included patients treated with dexamethasone alone, and Group 2 included patients treated with dexamethasone and remdesivir. Levels of inflammatory markers (C-reactive protein, D- dimer and lactate dehydrogenase), World Health Organization (WHO) ordinal scale scoring, symptomatic improvement in terms of fever, cough, shortness of breath, 6-minutes' walk test and SpO2 levels on day of admission (D0), 3 days and 5 days after admission (D3 and D5), and 10 days overall outcome (determined as death, or discharge with or without Long Term Oxygenation Therapy) were collected and analyzed.
RESULTS
Addition of remdesivir to dexamethasone in treating COVID 19 did not have any additional benefits. No additional role of remdesivir is seen in combating the disease except in case of 10 days outcome. However, the better 10-day outcome associated with the use of remdesivir was thought to be due to the patients who were on mechanical ventilation in the dexamethasone treated group at the time of inclusion.
CONCLUSIONS
Since a similar trend was seen in both groups, our study concluded no additional role of remdesivir in combating COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Retrospective Studies; Cohort Studies; COVID-19 Drug Treatment; Antiviral Agents; Dexamethasone
PubMed: 37515802
DOI: 10.3855/jidc.17971 -
Blood Advances Oct 2023Although randomized controlled trial data suggest that the more intensive triplet bortezomib-lenalidomide-dexamethasone (VRd) is superior to the less intensive doublet... (Randomized Controlled Trial)
Randomized Controlled Trial
Although randomized controlled trial data suggest that the more intensive triplet bortezomib-lenalidomide-dexamethasone (VRd) is superior to the less intensive doublet lenalidomide-dexamethasone (Rd) in patients newly diagnosed with multiple myeloma (MM), guidelines have historically recommended Rd over VRd for patients who are frail and may not tolerate a triplet. We identified 2573 patients (median age, 69.7 years) newly diagnosed with MM who were initiated on VRd (990) or Rd (1583) in the national US Veterans Affairs health care System from 2004 to 2020. We measured frailty using the Veterans Affairs Frailty Index. To reduce imbalance in confounding, we matched patients for MM stage and 1:1 based on a propensity score. Patients who were moderate-severely frail had a higher prevalence of stage III MM and myeloma-related frailty deficits than patients who were not frail. VRd vs Rd was associated with lower mortality (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94) in the overall matched population. Patients who were moderate-severely frail demonstrated the strongest association (HR 0.74; 95% CI, 0.56-0.97), whereas the association weakened in those who were mildly frail (HR, 0.80; 95% CI, 0.61-1.05) and nonfrail (HR, 0.86; 95% CI, 0.67-1.10). VRd vs Rd was associated with a modestly higher incidence of hospitalizations in the overall population, but this association weakened in patients who were moderate-severely frail. Our findings confirm the benefit of VRd over Rd in US veterans and further suggest that this benefit is strongest in patients with the highest levels of frailty, arguing that more intensive treatment of myeloma may be more effective treatment of frailty itself.
Topics: Humans; Aged; Multiple Myeloma; Lenalidomide; Frail Elderly; Frailty; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone
PubMed: 37582048
DOI: 10.1182/bloodadvances.2023011019 -
Journal of Cellular and Molecular... Dec 2023Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast...
Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.
Topics: Rats; Animals; Dexamethasone; NF-E2-Related Factor 2; Osteogenesis; Glucocorticoids; Oxidative Stress; Acetophenones; Apoptosis; Osteoblasts; Mitochondrial Diseases
PubMed: 37749949
DOI: 10.1111/jcmm.17974 -
Journal of Biomolecular Structure &... 2024Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone...
Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone is not used in non-severe cases due to its immunosuppressant action. So, considering this, Estrogen and Estetrol were tested for the treatment of COVID-19 as they all possess a common steroid ring and dislike dexamethasone, they are immunoenhancer. Virtual screening of test ligands was performed through molecular docking, MM-GBSA, simulations, in silico ADMET and drug-likeness prediction to identify their potential to inhibit the effects of SARS-CoV-2. Results showed that test ligands possess drug-like properties and they are safe as drug candidates. The protein-ligand interaction study revealed that they bind with the amino acid residues at the active site of the target proteins and the test ligands possess better binding potential than Dexamethasone. With protein M, Estetrol and Estrogen showed docking score of -7.240 and -5.491 kcal/mol, and with protein ACE2, Estetrol and Estrogen showed docking score of -5.269 and -4.732 kcal/mol, respectively. Further, MD Simulation was carried out and most of the interactions of molecular docking are preserved during simulation. The prominent interactions that our test ligands showed during MD Simulation are similar to drugs that possess anticovid activity as shown in recent studies. Hence, our test ligands possessed potential for anticovid activity and they should be further tested through and studies for their activity against COVID-19.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Estetrol; Molecular Docking Simulation; COVID-19; COVID-19 Drug Treatment; SARS-CoV-2; Estrogens; Dexamethasone; Molecular Dynamics Simulation; Protease Inhibitors
PubMed: 37129196
DOI: 10.1080/07391102.2023.2205944 -
Frontiers in Immunology 2024Glioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied....
BACKGROUND
Glioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied. Age and dexamethasone administration in glioblastoma patients have been hypothesized to limit the effectiveness of immunotherapy, but their effects remain unclear. We compared peripheral blood immune composition in patients with different types of brain tumor to determine the influence of age, dexamethasone treatment, and tumor volume.
METHODS
High-dimensional mass cytometry was used to characterise peripheral blood mononuclear cells of 169 patients with glioblastoma, lower grade astrocytoma, metastases and meningioma. We used blood from medically-refractory epilepsy patients and healthy controls as control groups. Immune phenotyping was performed using FlowSOM and t-SNE analysis in R followed by supervised annotation of the resulting clusters. We conducted multiple linear regression analysis between intracranial pathology and cell type abundance, corrected for clinical variables. We tested correlations between cell type abundance and survival with Cox-regression analyses.
RESULTS
Glioblastoma patients had significantly fewer naive CD4+ T cells, but higher percentages of mature NK cells than controls. Decreases of naive CD8+ T cells and alternative monocytes and an increase of memory B cells in glioblastoma patients were influenced by age and dexamethasone treatment, and only memory B cells by tumor volume. Progression free survival was associated with percentages of CD4+ regulatory T cells and double negative T cells.
CONCLUSION
High-dimensional mass cytometry of peripheral blood in patients with different types of intracranial tumor provides insight into the relation between intracranial pathology and peripheral immune status. Wide immunosuppression associated with age and pre-operative dexamethasone treatment provide further evidence for their deleterious effects on treatment with immunotherapy.
Topics: Humans; Glioblastoma; Leukocytes, Mononuclear; CD4-Positive T-Lymphocytes; Immunotherapy; Dexamethasone
PubMed: 38318180
DOI: 10.3389/fimmu.2024.1343484