Glucocorticoid Administration Research Articles

Adrenal crisis-induced cardiogenic shock (ACCS): a comprehensive review.

Adrenal insufficiency (AI) is a disorder in which inadequate glucocorticoid and mineralocorticoid hormone production leads to a variety of symptoms, including fatigue, weight loss, and nausea. In some patients with unknown AI, adrenal crisis-induced cardiogenic shock (ACCS) can be the first presentation, resulting in a fatal situation. The ACCS may exhibit unresponsiveness to inotropes and fluid therapy; thus, glucocorticoid administration is the primary vital intervention, making early detection of AI essential. Hence, in this study, we review the case reports demonstrating acute cardiomyopathies in the context of AI. The review addresses the suggested underlying mechanisms, including the diminished protective effects of glucocorticoids against catecholamines in AI. We also highlighted some clues to aid physicians in considering AI as a differential diagnosis in critically ill patients presenting cardiogenic shock.

A glucocorticoid-mediated immunoregulatory circuit integrated at brain levels: our early studies and a present view.

Background It was known since the 1940's that pharmacological administration of glucocorticoids can inhibit inflammatory and immune processes, and these hormones are still today among the most widely used therapeutic tools to treat diseases with immune components. However, it became clear later that endogenous glucocorticoids can either support or restrain immune processes. Summary Early studies showed that: a) endogenous levels of glucocorticoids can modulate immune cell activity; b) the immune response itself can stimulate the hypothalamus-pituitary-adrenal (HPA) axis to release glucocorticoids to levels that can exert immunoregulatory effects; c) immune products, later identified as cytokines, mediate this effect. On these bases, the existence of a glucocorticoid-mediated immunoregulatory circuit was proposed. It was also shown that increased levels of endogenous glucocorticoids exert protective effects during infections and other diseases with immune components. However, it was found in animal models and in humans that these effects can be blunted in several immune-linked diseases by defects at several levels, for example by glucocorticoid resistance or by adrenal insufficiency. Evidence was later provided that the glucocorticoid-mediated immunoregulatory circuit can also be activated by cytokines produced not only as consequence of immune stimulation but also following psycho/sensorial and physical stimuli. Thus, this circuit can be integrated at brain levels and, besides stimulating the HPA axis, cytokines can also affect synaptic plasticity, most likely via a tripartite synapse, with astrocytes as neuro-immune cells acting as the third component. Key Messages It is now well established that the glucocorticoid-mediated immunoregulatory circuit plays a central role in maintaining health. However, several variables can condition the efficacy of the effect of endogenous glucocorticoids. Furthermore, since cytokines and other immune products have many other neuro-endocrine and metabolic effects, other neuro-endocrine-immune circuits could simultaneously operate or become predominant during different pathologies. The consideration of these aspects might help to implement strategies to eventually decrease therapeutic doses of exogenous glucocorticoids.

Suppression of CDK1/Drp1-Mediated Mitochondrial Fission Attenuates Dexamethasone-Induced Extracellular Matrix Deposition in the Trabecular Meshwork.

Aims: Deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), as induced by dexamethasone (Dex), is believed to play an important role in the onset of glucocorticoid-induced glaucoma (GIG). Abnormal ECM deposition is a consequence of mitochondrial dysfunction. We aimed to clarify how mitochondrial dysfunction leads to ECM deposition within the TM and to support the development of novel therapeutic strategies. Results: In primary human TM cells (pHTMCs) and a Dex acetate-induced murine model of GIG, glucocorticoid administration stimulated both mitochondrial fission and ECM deposition. Excessive mitochondrial fission leads to dysfunction and the overexpression of ECM proteins in pHTMCs. Notably, when pHTMCs were treated with the dynamin-related protein 1 (Drp1) inhibitor Mdivi-1 or with Drp1 siRNA, we observed a marked reduction in Dex-induced mitochondrial damage and ECM proteins in vitro. Furthermore, in C57BL/6J mice, treatment with Mdivi-1 mitigated mitochondrial damage and blocked ECM deposition within the TM. We then used Ro3306 to inhibit the cyclin-dependent kinase (CDK)1-mediated phosphorylation of Drp1 at Ser 616, which restored mitochondrial function and diminished Dex-induced ECM protein expression in pHTMCs. Innovation: This study illuminates the pathogenic mechanism linking mitochondrial dysfunction to ECM deposition in GIG. Our innovative approach revealed that Dex stimulates mitochondrial fission via CDK1-mediated p-Drp1s616 overexpression, which drives ECM accumulation. It offered a novel therapeutic strategy for reducing ECM protein expression by inhibiting excessive mitochondrial fission and restoring mitochondrial function. Conclusion: By targeting the CDK1/Drp1-driven mitochondrial fission process, we can counteract Dex-induced ECM deposition in the TM both invivo and in vitro.

Development and validation of a predictive scoring system for hypoglycaemic agents for optimal control of blood glucose during glucocorticoid therapy.

Glucocorticoid (GC) treatments are often used. There is limited information on the prediction of hyperglycaemia after GC administration. This study aimed to identify the risk factors for hyperglycaemia after glucocorticoid (GC) administration and the need for hypoglycaemic agents to correct it and to develop and validate a novel scoring system for predicting GC-induced hyperglycaemia. In a development set, 508 adults receiving prednisolone (PSL) for the first time were divided into two groups based on treatment with or without hypoglycaemic agents. Clinical and laboratory parameters were compared, and risk factors were identified using logistic regression analysis after performing univariate analyses between the two groups. A point-addition scoring system with several categories and coefficients for each risk factor was constructed to predict the need for hypoglycaemic agents. The scoring system was then applied and validated on two validation sets: A and B. Older age, higher glycated haemoglobin percentage, body mass index and initial PSL dosage were identified as risk factors. The sensitivity, specificity and accuracy of the scoring system were 70.6%, 81.9% and 77.1% in the development set; 75.8%, 78.4% and 77.4% in validation set A; and 79.4%, 73.9% and 75.3% in validation set B respectively. By fitting the total score in the development set and the probability of hyperglycaemia to a logistic curve, a figure was created to show the probability of GC-induced hyperglycaemia in patients scheduled to receive GC. This scoring system is a novel, valid and reliable tool for predicting GC-induced hyperglycaemia and the need for hypoglycaemic agents to correct it.

Glucocorticoid chrono-pharmacology promotes glucose metabolism in heart through a cardiomyocyte-autonomous transactivation program.

Circadian time-of-intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its co-factor, Krüppel-like factor (Klf15), play critical roles in maintaining normal heart function in the long-term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of GR-Klf15 axis remain undefined. Here, we demonstrate the critical roles of the cardiomyocyte-specific GR and Klf15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or Klf15, we identified their synergistic role in the activation of adiponectin receptor expression (Adipor1) and the mitochondrial pyruvate complex (Mpc1/2), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic (db/db) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, effectively restored cardiomyocyte glucose oxidation and improved diastolic function towards control-like levels in a sex-independent manner. Collectively, our findings uncover novel cardiomyocyte-autonomous metabolic targets of the GR-Klf15 axis. This study highlights the circadian-dependent cardioprotective effects of glucocorticoids on cardiomyocyte glucose metabolism, providing critical insights into chrono-pharmacological strategies for glucocorticoid therapy in cardiovascular disease.

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be < 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

Glucocorticoid treatment and adrenal suppression in children: current view and open issues.

Glucocorticoids (GCs) are commonly used for several acute and chronic pediatric diseases. However, chronic treatment may result in hypothalamic-pituitary-adrenal axis (HPA) dysfunction. Glucocorticoid-induced adrenal insufficiency (GI-AI) is indeed the most frequent cause of adrenal insufficiency (AI) in children, possibly resulting in a life-threatening event such as adrenal crisis (AC). It is generally underestimated, especially when using non-systemic glucocorticoid formulations. This review aims at summarizing current evidence on the effects of long-term GC treatment on the HPA axis, management of GC tapering and assessment of the HPA recovery. We conducted a narrative review of the relevant literature focusing on pathogenic mechanisms, predictive factors, diagnosis and treatment of GI-AI. All types of GCs, whatever the route of administration, may have suppressive effects on the HPA axis, especially when compounds with higher potency and long half-life are used. Moreover, chronic GC administration is the most common cause of Cushing syndrome in children. In order to overcome the risk of GI-AI, slow withdrawal of GCs is necessary. When approaching the replacement dose, it is recommended to switch to shorter half-life formulations such as hydrocortisone. Assessment of HPA axis recovery with basal and stimulated cortisol levels may help detecting children at risk of AC that may require hydrocortisone supplementation. The management of GI-AI in children is challenging and many areas of uncertainty remain. Improving the knowledge on long-term GC effects on HPA in children, the management of steroid discontinuation and emergency dosing may help preventing GI-AI symptoms and acute hospital admission for AC.

Effect of the combination of Lithospermum erythrorhizon and Lonicera japonica on dexamethasone-induced muscle atrophy in mice

AbstractSkeletal muscle atrophy occurs in several pathological conditions. Among other reasons, high-dose or long-term administration of glucocorticoids increases circulating glucocorticoid levels and causes muscle atrophy. The purpose of this study was to investigate whether Lithospermum erythrorhizon and Lonicera japonica complex extract (LELJ) has a beneficial effect on dexamethasone (Dexa)-induced muscle atrophy. In Dexa-induced myotube atrophy, treatment with LELJ increased myotube diameter, decreased the expression of muscle atrophy markers, and increased the expression of myosin heavy chain (MHC) isoforms. Supplementation with LELJ improved muscle function and performance in mice with Dexa-induced muscle atrophy as demonstrated by grip strength and running tests. Additionally, it increased skeletal muscle mass, size, and expression of MHC isoforms and protein synthesis-related markers. Furthermore, it reduced the upregulated protein levels of skeletal muscle atrophy markers in Dexa-treated mice. Supplementation with LELJ reversed Dexa-induced translocation of the glucocorticoid receptor and forkhead box O3 from the cytosol to the nucleus in skeletal muscles. LELJ also ameliorated age-related muscle loss by extending lifespan and increasing locomotor capacity in Caenorhabditis elegans. We identified loganin and lithospermic acid as bioactive compounds of LELJ and found that treatment with these agents increased myotube diameter, MHC isoform, and puromycin protein levels, and decreased atrophy markers in Dexa-treated myotubes. The current findings underscore how LELJ can prevent Dexa-induced skeletal muscle atrophy, attributing the effects to loganin and lithospermic acid.

Out-of-phase treatment with the synthetic glucocorticoid betamethasone disturbs glucose metabolism in mice

ObjectiveEndogenous glucocorticoid levels display a strong circadian rhythm, which is often not considered when synthetic glucocorticoids are prescribed as anti-inflammatory drugs. In this study we evaluated the effect timing of glucocorticoid administration, i.e. in-phase (administered when endogenous glucocorticoid levels are high) versus out-of-phase (administered when endogenous glucocorticoid levels are low). We investigated the synthetic glucocorticoid betamethasone – which is extensively used in the clinic - and monitored the development of common metabolic side effects in mice upon prolonged treatment, with a particular focus on glucose metabolism. MethodsMale and female C57BL/6J mice were treated with the synthetic glucocorticoid betamethasone in-phase and out-of-phase, and the development of metabolic side effects was monitored. ResultsWe observed that, compared with in-phase treatment, out-of-phase treatment with betamethasone results in hyperinsulinemia in both male and female C57BL/6J mice. We additionally found that out-of-phase betamethasone treatment strongly reduced insulin sensitivity as compared to in-phase administration during morning measurements. Our study shows that the adverse effects of betamethasone are dependent on the time of treatment with generally less side effects on glucose metabolism with in-phase treatment. ConclusionsThis study highlights differences in glucocorticoid outcome based on the time of measurement, advocating that potential circadian variation should be taken into account when studying glucocorticoid biology.

Ciclesonide exhibits lung-protective effects in neonatal rats exposed to intra-amniotic enterotoxin.

Despite the advances in perinatal care, bronchopulmonary dysplasia (BPD) continues to be a highly prevalent chronic lung disease that affects newborns, especially affecting premature newborns. There is no specific cure for BPD, and treatments aimed at reducing the risk of developing BPD focus mainly on lung-protective ventilation strategies, surfactant therapy, and/or corticosteroid administration. Our objective was to evaluate whether systemic postnatal administration of a new glucocorticoid, ciclesonide, can attenuate the alteration of lung structure and pulmonary hypertension in a rat model of chorioamnionitis-induced BPD, with minimal adverse effects on the developing brain. Endotoxin (ETX) or saline was administered to pregnant rats by intra-amniotic (i.a.) injection on day 20 of pregnancy, and pups were delivered by cesarean section on day 22. Ciclesonide (0.5 mg/kg) was administered postnatally for five consecutive days to pups previously exposed to i.a. ETX. On postnatal day 14, we assessed lung function (compliance), lung structure (radial alveolar count, mean linear intercept, pulmonary vessel density), pulmonary hypertension, and brain histology (edema, inflammation, apoptosis, hemorrhage, and infarction). On postnatal day 14, the effects of i.a. ETX administration were evident in neonatal rats not receiving treatment; these animals showed impaired lung compliance, disrupted lung structure, and developing pulmonary hypertension compared to those receiving i.a. saline. Postnatal administration of ciclesonide for 5 days was associated with significantly better outcomes in terms of lung compliance, alveolarization, lung vascular growth, and pulmonary hypertension, without affecting the brain histological parameters evaluated. Postnatal ciclesonide administration preserved lung function and structure and prevented pulmonary hypertension in a BPD model induced by antenatal i.a. ETX administration, without causing any adverse effects on brain development. These findings suggest that the new glucocorticoid, ciclesonide, may provide a novel strategy for the prevention of BPD; however, more long-term studies are required.

Sphingosine kinase 1 is induced by glucocorticoids in adipose derived stem cells and enhances glucocorticoid mediated signaling in adipose expansion.

Sphingosine kinase 1 (SphK1) plays a crucial role in regulating metabolic pathways within adipocytes and is elevated in the adipose tissue of obese mice. While previous studies have reported both pro- and inhibitory effects of SphK1 and its product, sphingosine-1-phosphate (S1P), on adipogenesis, the precise mechanisms remain unclear. This study explores the timing and downstream effects of SphK1/S1P expression and activation during in vitro adipogenesis. We demonstrate that the synthetic glucocorticoid dexamethasone robustly induces SphK1 expression, suggesting its involvement in glucocorticoid-dependent signaling during adipogenesis. Notably, the activation of C/EBPδ, a key gene in early adipogenesis and a target of glucocorticoids, is diminished in SphK1-/- adipose-derived stem cells (ADSCs). Furthermore, glucocorticoid administration promotes adipose tissue expansion via SphK1 in a depot-specific manner. Although adipose expansion still occurs in SphK1-/- mice, it is significantly reduced. These findings indicate that while SphK1 is not essential for adipogenesis, it enhances early gene activation, thereby facilitating adipose tissue expansion.

Postoperative management following endoscopic skull base surgery.

The purpose of this opinion is to review current evidence regarding postoperative management following endoscopic skull base surgery. Postoperative management encompasses consideration of level of care, laboratory tests, analgetic and antiemetic therapy, antibiotic, antithrombotic and antiepileptic prophylaxis, pharmacological and nonpharmacological cerebrospinal fluid (CSF) pressure reduction measures, including CSF diversion, activity restrictions, nasal packing removal, nasal debridement and toilet, nasal glucocorticoid administration, positive pressure ventilation, imaging, CSF leak diagnosis, and future perspectives. Although significant effort has been put into research of postoperative measures after endoscopic skull-base surgery, there is a heterogeneity of practices and deficit of high-level studies, which would enable highly powered systematic reviews and meta-analyses.

Modified tectonic corneoscleral graft technique for treating devastating corneoscleral infections

BackgroundThis study aims to evaluate the clinical outcomes and efficacy of a modified tectonic corneoscleral graft (TCG) in patients suffering from devastating corneoscleral infections.MethodsThirty-eight eyes from 38 patients who underwent the modified TCG were included in this study. The outcomes measured were recurrence rates, best-corrected visual acuity (BCVA), ocular surface stability, postoperative complications, and graft survival.ResultsAmong the 38 patients, 23 had fungal infections, 9 had bacterial infections and 6 had Pythium insidiosum infections. At the final follow-up, with an average duration of 25.1 ± 8.6 months, the rate of monocular blindness decreased from 100 to 58%. Significant improvements in LogMAR BCVA were observed from preoperative to postoperative measurements (P < 0.001). Thirty-two eyes (84.2%) maintained a stable ocular surface. The survival rate of ocular surface stability was 84.2%±5.9% at one year and 57.7%±9.7% at three years post-surgery. Twenty eyes (52.6%) retained a clear graft, with a survival rate for graft clarity was 81.6%±6.3% at one year and 36.0%±10.8% at three years post-surgery. The incidence of immune rejection was 36.8%. Corneal epithelial defects were observed in ten patients, and choroidal detachment occurred in four patients. No cases of elevated intraocular pressure were detected.ConclusionsThe modified TCG is effective in eradicating infections, preserving the eyeball, and maintaining useful vision in cases of devastating corneoscleral infections. Regular use of tacrolimus, timely administration of glucocorticoids, and good patient compliance can help mitigate postoperative challenges.

Re-evaluating intra-cardiac arrest adjunctive medications and routes of drug administration.

This narrative review summarizes the evidence for the most commonly used intra-cardiac arrest adjunctive medications and routes of administration and discusses promising new therapies from preclinical animal models. Large trials on the administration of calcium as well as the combination of vasopressin and glucocorticoids during cardiac arrest have been published. Calcium administration during cardiopulmonary resuscitation does not improve outcomes and might cause harm. Vasopressin and glucocorticoid administration during cardiopulmonary resuscitation improve the chance of return of spontaneous circulation but has uncertain effects on survival. We identified a total of seven ongoing clinical trials investigating the potential role of bicarbonate, of vasopressin and glucocorticoids, and of intravenous versus intraosseous vascular access. Several medications such as levosimendan and inhaled nitric oxide show promise in preclinical studies, and clinical trials are either planned or actively recruiting. Large trials on intra-cardiac arrest administration of calcium and vasopressin with glucocorticoids have been performed. Several trials are ongoing that will provide valuable insights into the potential benefit of other intra-cardiac arrest medications such as bicarbonate as well as the potential benefit of intravenous or intraosseous vascular access.

Oral viscous budesonide solution for enhanced localized treatment of eosinophilic esophagitis through improved mucoadhesion and permeation

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and in vitro elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. >80 % of the budesonide was released after 24 h, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7 % HEC could be stored for >6 months at a temperature of 5 °C ± 3 °C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.

Highly effective inhalable voriconazole-loaded nanomicelles for fungal infections in cystic fibrosis patients: A promising therapeutic strategy for allergic bronchopulmonary aspergillosis

In patients with cystic fibrosis (CF), growth of A. fumigatus and other fungal hyphae within the bronchial lumen can trigger an immunoglobulin E-mediated hypersensitivity response known as allergic bronchopulmonary aspergillosis (ABPA) which can potentially advance to fibrosis.The management of ABPA involves the administration of systemic glucocorticoids alongside azole antifungals, such as voriconazole (VRC). This study evaluated the potential of Soluplus® polymeric micelles as an effective nanocarrier for pulmonary delivery of VRC to improve antifungal therapy in CF patients. The micellar nanoformulation prepared in this study could increase up to 51-fold the aqueous solubility of VRC. Their micellar size, evaluated by dynamic light scattering, was 102.2 ± 1.3 nm for loaded freeze-dried nanoformulations with a unimodal size distribution. Nanomicelles showed excellent colloidal stability during the in vitro nebulization process and under dilution in similar interstitial fluids for pulmonary VRC delivery. Nanoformulations demonstrated high in vitro cytocompatibility in A549 and Vero cells. Interestingly, in vitro antifungal activity of VRC-loaded micelles was at least 2-fold higher than the drug aqueous suspension against different fungal species isolated from CF sputum, regardless of the presence of artificial CF mucus layer. Following single intratracheal dose, significantly (p < 0.05) higher VRC concentrations were observed within 2 h in the lung tissue for the micellar formulations compared with the VRC suspension. We concluded that these findings will help to develop a potent and innovative inhalable VRC micellar nanoformulation that may be effective against different lung disorders caused by fungi, such as ABPA.

Modern Experience of Pharmacotherapeutic Use and Effectiveness of Endolumbal Administration of Glucocorticoids in Progressive Types of Course for Multiple Sclerosis

Effective pharmacotherapy of low-bondly progredient forms of the multiple sclerosis is a difficult task that requires the search for new and improving existing methods of treatment. The author set the task to the optimize the treatment of progredient forms of multiple sclerosis using the method of endolumbal introduction of glucocorticoids and to evaluate its efficiency. The results of treatment of 76 patients with poor curable progresses of multiple sclerosis by intratracal introduction of glucocorticoids (dexamethasone) are presented in the study. The advantages of method, methodic of introduction, the patient`s selection parameters were given. The efficiency criterions of intration of glucocorticoids were defined, including the neurological deficiency regress, stabilization and the delay of multiple sclerosis progressing. Integral assessment of efficiency was made as 4 gradations: “good rate”, “low” and “absence of effect”. The positive dynamics of neurological state was registered predominantly on spastic-paretic syndrome with presence of several active foci with contrast enhancement. The sphincter infringements and brain stem symptomatic were observed as rarely reversible, extremely rarely - cerebellar symptom complex. As the results of the treatment (the term of the observation – 6 months and more) 80.2% of multiple sclerosis patrols marked the efficiency as "good" and "moderate". The obtained data indicated the reasonability of the proposed method of treatment for patrols with saversive counses of multiple sclerosis, occurring inly with spinal symptomatic.

Prehospital Pulse-Dose Glucocorticoid in ST-Segment Elevation Myocardial Infarction

In patients with ST-segment elevation myocardial infarction (STEMI), acute inflammation is related to the extent of myocardial damage and may increase infarct size. Thus, administration of pulse-dose glucocorticoid in the very early phase of infarction may reduce infarct size. To determine the cardioprotective effect of prehospital pulse-dose glucocorticoid in patients with STEMI. This was a 1:1 investigator-initiated, blinded, placebo-controlled, randomized clinical trial conducted between November 14, 2022, and October 17, 2023, with last follow-up on January 17, 2024. Patients 18 years and older with less than 12 hours of acute chest pain and STEMI were included in the prehospital setting throughout the Region Zealand and Capital Region of Denmark and transferred to Rigshospitalet, Denmark. Patients were randomly allocated to intravenous glucocorticoid (methylprednisolone, 250 mg) or placebo in the prehospital setting. The primary outcome was final infarct size on cardiac magnetic resonance (CMR) at 3 months. The power calculation was based on an anticipated final infarct size of 13%. Secondary outcomes included CMR outcomes on acute scan and at 3 months, peak of cardiac biomarkers, clinical end points at 3 months, and adverse events. Of 530 included patients (median [IQR] age, 65 [56-75] years; 418 male [78.9%]) with STEMI, 401 (76%) were assessed for the primary outcome, with 198 patients treated with glucocorticoid and 203 with placebo. Median final infarct size was similar in the treatment groups (glucocorticoid, 5%; IQR, 2%-11% vs placebo, 6%; IQR, 2%-13%; P = .24). Compared with placebo, the glucocorticoid group had smaller acute infarct size (odds ratio, 0.78; 95% CI, 0.61-1.00), less microvascular obstruction (relative risk ratio, 0.83; 95% CI, 0.71-0.99), and greater acute left ventricular ejection fraction (mean difference, 4.44%; 95% CI, 2.01%-6.87%). Other secondary outcomes were similar in both groups. In patients with STEMI, treatment with prehospital pulse-dose glucocorticoid did not reduce final infarct size after 3 months. However, the trial was likely underpowered as the final infarct size was smaller than anticipated. The glucocorticoid group had improved acute parameters compared with placebo. ClinicalTrials.gov Identifier: NCT05462730.

A small secret of big rheumatology

Current recommendations for RA treatment determine the need to reduce the dose and duration of glucocorticoid(GC) use. This is due to the wide spectrum and high frequency (up to 100%) of serious adverse events (AE) during GC treatment. However, in real practice GCs in RA are used very often (in Russia, Western Europe and the USA they are used in about 50% of patients), and often in long-term courses. This is explained by the fact that the combination of disease-modifying antirheumatic drugs (DMARDs), including biologics (bDMARDs) and Janus kinase inhibitors (JAK), with GCs allows to achieve faster improvement of patients’ condition and therefore is very “convenient” for many patients and physicians.However, it is very difficult to ensure dose reduction and (especially!) complete discontinuation of GC administration afterwards. Clinical and observational studies show that 30–40% of patients manage to discontinue the use of GCs during treatment with bDMARDs and JAK. In addition, discontinuation of GCs may significantly increase the risk of RA flare, even with complex pathogenetic therapy.Nevertheless, prolonged use of GCs, including low doses (less than 7.5 mg/day of prednisolone) should be considered as an indicator of the severity of the disease course and inadequacy of the current therapy. Therefore, we should strive for personalization of RA therapy, selection of DMARDs based on the assessment of the disease phenotype and predictors of response to treatment with different drugs, achieving the main goal of therapy – remission/low disease activity and achievement of acceptable quality of life, without the use of GCs.

Imaging Identifies Superior Inflammation Targeting of M1 Macrophages for Cryo-Shocked Cell Pulmonary Drug Delivery to Treat Acute Lung Injury.

In the realm of combating acute lung injury (ALI) induced by a myriad of triggers including sepsis, pneumonia, aspiration, trauma, and pancreatitis, macrophages emerge as crucial players. However, traditional treatments such as systemic administration of glucocorticoids come with the baggage of severe side effects, curtailing their utility. Enter an innovative solution: a biomimetic drug delivery system fashioned from cryo-shocked macrophages, tailored for pulmonary drug delivery. Positron emission tomography (PET) imaging has shed light on the remarkable targeting abilities of live M1 macrophages, showcasing their unparalleled efficacy in homing in on local inflammatory foci when contrasted with naive, M1, and M2 macrophages. Building upon this foundation, liquid nitrogen-treated (LNT) M1 macrophages are developed, engineered to preserve their inflammation-targeting prowess while sidestepping the release of pro-inflammatory cytokines. This breakthrough allows for the delivery of glucocorticoids directly to inflamed lung tissues, efficiently quelling inflammation and mitigating pulmonary edema while drastically reducing systemic drug exposure. Inspired by the effectiveness of live M1 macrophages, the potential of glucocorticoid-loaded LNT M1 macrophages are harnessed, utilizing them as a stealthy "Trojan horse" in the battle against pneumonia-induced ALI. This innovative approach holds promise as a safe and potent treatment avenue for acute lung injury.