Synthetic Corticosteroid Research Articles

Deflazacort-induced Steven-Johnson syndrome: a case report and literature review

Objective: To summarize the clinical features and outcomes of deflazacort-induced Steven Johnson syndrome (SJS)-toxic epidermal necrolysis (TEN) to raise awareness among patients with Duchenne muscular dystrophy (DMD), neurologists as well as other deflazacort users. Methods: The clinical data of a boy with DMD who had SJS induced by deflazacort treated at the Department of Rheumatology & Clinical Immunology of Tianjin Children's Hospital in July 2024 was analyzed retrospectively. Taking "deflazacort" "Steven-Johnson syndrome" "toxic epidermal necrolysis" in Chinese or English as the keywords, literature was searched at CNKI, Wanfang, China Biomedical Literature Database and PubMed up to July 2024. The clinical characteristics, treatment and outcomes of deflazacort-induced SJS-TEN were summarized. Results: A 12-year-old boy was admitted with a 3-day history of rash. He was diagnosed with DMD at the age of 3 and had been treated with prednisolone since the age of 8. Forty-four days before admission, the patient started deflazacort to replace prednisolone. Three days before admission, progressively worsening erythematous maculopapular rashes, blisters and skin peeling (8% body surface area), oral mucosal erosion, and exudative conjunctivitis occurred, thus deflazacort was discontinued. Complete remission of SJS was achieved after treatment with intravenous immunoglobulin (IVIG, total 1.4 g/kg), 2 doses of etanercept (0.9 mg/kg, once), subcutaneous injection and intravenous methylprednisolone (0.7 mg/(kg·d)). Based on the literature, there were 5 reports in English while none in Chinese, altogether 7 cases were reported. All the patients were male, aged 3-45 years. Duration of deflazacort exposure was 2-8 weeks. Dermatology diagnosis of our case was SJS, and 5 cases were TEN. One patient was diagnosed with exudative erythema multiforme, and subsequent deflazacort oral challenge test was positive. Treatment included methylprednisolone or dexamethasone in 5 cases, IVIG in 6 cases, etanercept in 3 cases and cyclosporine in 1 case. All patients recovered completely. Conclusion: The synthetic corticosteroid deflazacort can cause rare but severe adverse reactions such as SJS-TEN, which needs close monitoring and prompt recognition and management.

Stress Can Induce Bovine Alpha-Herpesvirus 1 (BoHV-1) Reactivation from Latency.

Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are importantsites for latency. Reactivation from latency can lead to reproductive problems in pregnant cows, virus transmission to young calves, suppression of immune responses, and bacterial pneumonia. BoHV-1 is also a significant cofactor in bovine respiratory disease (BRD). Stress, as mimicked by the synthetic corticosteroid dexamethasone, reproducibly initiates reactivation from latency. Stress-mediated activation of the glucocorticoid receptor (GR) stimulates viral replication and transactivation of viral promoters that drive the expression of infected cell protein 0 (bICP0) and bICP4. Notably, GR and Krüppel-like factor 15 (KLF15) form a feed-forward transcription loop that cooperatively transactivates immediate early transcription unit 1 (IEtu1 promoter). Two pioneer transcription factors, GR and KLF4, cooperatively transactivate the bICP0 early promoter. Pioneer transcription factors bind silent viral heterochromatin, remodel chromatin, and activate gene expression. Thus, wepredict that these novel transcription factors mediate early stages of BoHV-1 reactivation from latency.

Efficacy of a single dose of cryopreserved human umbilical cord mesenchymal stromal cells for the treatment of knee osteoarthritis:a randomized, controlled, double-blind pilot study

BackgroundKnee osteoarthritis (OA) is the most prevalent degenerative musculoskeletal disorder, which is particularly common in older population. While conventional treatments have limited effectiveness, the development of more effective therapeutic strategies is necessary to address this primary source of pain and disability. Umbilical cord mesenchymal stromal cells (UC-MSCs) offer a promising therapeutic approach for treating knee OA. AimThis randomized, prospective, double-blind and controlled pilot study was carried out to evaluate and compare the safety and therapeutic efficacy of a single intra-articular injection of a standardized product CellistemOA (5 × 106 ± 5 × 105 UC-MSCs), vs. triamcinolone (a synthetic corticosteroid) (10 mg/mL) in thirty patients with symptomatic knee OA (Kellgren–Lawrence grade II or III). MethodsThe outcomes included changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores based on a Likert scale, numerical rating score (NRS) for pain, Magnetic Resonance Imaging (MRI), and quality of life (SF-36 questionnaire), from baseline and throughout 12-months of follow-up. ResultsPatients treated with CellistemOA showed significant improvement in WOMAC score (including the three subscale scores (pain, stiffness and function), NRS in pain, and SF-36 profile from baseline to 12 months (p < 0.05) compared to the triamcinolone group, and no severe adverse events were reported. There were no significant differences in MRI WORMS scores between the two groups. However, patients who received the cellular treatment experienced a significant improvement in their SF-36 profile (p < 0.05). ConclusionsThis pilot study revealed that a single dose of CellistemOA is safe and superior to the active comparator in knee OA at 1-year of follow-up, making it a compelling therapeutic alternative to treat symptomatic OA patients.

Multicenter observational study on the efficacy of selective Janus Kinase-1 inhibitor upatacitinib in rheumatoid arthritis.

Upadacitinib (UPA) is a selective, reversible Janus kinase inhibitor (JAKi) approved for the treatment of RA. However, there is still no solid evidence on the long-term efficacy of UPA in treated patients. The purpose of this study was to determine the efficacy of UPA to obtain remission or low disease activity (LDA) in a series of UPA patients in patients with RA after 6 and 12 months of treatment in a real-world setting. A series of 111 consecutive patients treated with UPA in 23 rheumatology centers were enrolled. Personal history, treatment history and disease activity at baseline, after 6 and 12 months were recorded. Intention-to-treat (ITT) and per-protocol (PP) analyses assessed achievement of remission or LDA or defined as DAS28 <2.6 and ≤3.2, respectively. Logistic regression analysis examined the role of several independent factors on the reduction of disease activity after 6 months of treatment. Of the initial group of 111 subjects at baseline, 86 and 29 participants completed clinical assessments at 6 and 12 months. According to ITT analysis, the rates of remission and LDA were 18% and 18% at 6 months and 31.5% and 12.5% at 12 months, respectively. PP analysis showed higher rates of remission and LDA at 6 (23.3% and 19.8%) and 12 months (55.2% and 20.7%). Results of multivariate logistic regression analysis indicated that a low DAS28 score (P=0.045) was the only predictor of achieving remission at 6 months. None of the baseline factors predicted remission/LDA at 6 months. RA patients treated with UPA achieved a significant rate of disease remission or LDA in a real-world setting. The 6-month response was found to depend only on the baseline value of DAS28, while it was not influenced by other factors such as disease duration, line of treatment or concomitant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids.

Efficacy and Safety of Mometasone Furoate Nasal Spray in Treating Nasal Polyposis: A Systematic Review and Meta-Analysis.

Topical and systemic corticosteroids are the most effective medical treatment for nasal polyps, this study aims to systematically explore the efficacy and safety of mometasone furoate (MTF) for patients with nasal polyps (NP). The systematic review was conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and was registered in The International Prospective Register of Systematic Reviews (PROSPERO.) Data were extracted from relevant and appropriate randomized controlled trials (RCTs) of synthetic corticosteroids for patients with nasal polyps from PubMed, Google Scholar, Web of Science, and Science Direct, encompassing studies published between January 1995 and July 2024. A total of 834 publications were found based on the search criteria. Around 1,710 patients were reviewed for this systematic review from full full-text articles. Primary outcomes include achange in polyp size(assessed by total polyp size scores), and nasal congestion (assessed by measuring changes from baseline in nasal congestion/obstruction scores). secondary outcomes consist of nasal symptoms, including loss of smell, anterior rhinorrhea, postnasal drip, quality of life outcomes, and adverse events. Mometasone furoate nasal spray (MFNS) significantly improves nasal symptoms and reduces nasal polyp size for patients with nasal polyps (NP).

Potential teratogenic effect of prenatal dexamethasone administration on palate development: Experimental study in rats

BackgroundThe interaction of cell populations and synchronization of cell signaling pathways during craniofacial development can cause malformations such as facial clefts when interrupted by teratogenic agents including synthetic corticosteroids. Therefore, this study aimed to determine the potentially disturbing dexamethasone (Dex) effect on palatal shelf development in rat embryos and the possible reasons for this teratogenic potential in relation to fibroblast growth factor 10 (FGF10) as well as FGF10 receptor2 (FGFR2) signaling. MethodsThirty pregnant rats were used, which were then randomly categorized into three groups of ten animals each: the control group, where pregnant rats received no treatment, Sham group in which pregnant rats were injected subcutaneously with saline (0.4 mg/kg body weight) during the mid-pregnancy period at gestational day 9–14, and Dex-treated group, where pregnant rats received 0.4 mg/kg of Dex at mid-gestational period. Pregnant animals from all groups were sacrificed on day 20 of gestation before birth and the fetuses were removed for examination of the palatal shelves using a light microscope (LM). In addition, a real-time polymerase chain reaction and a reverse transcription-polymerase chain reaction (RT-PCR) were done to evaluate FGF10 and its receptor FGFR2 gene expression. ResultsThe cleft palate incidence rates in the groups of embryos were determined. Only the offspring in the Dex group showed a cleft palate. Moreover, the cleft palate incidence rate in the Dex group was significantly different compared to controls. Moreover, a significant decrease in FGF10 and FGFR2 expression levels was reported in the Dex group than in the controls. ConclusionsDex treatment in mid-gestation may increase the incidence of cleft palate development, which may be due to modulation of FGF signaling. This calls for caution when using this medication in the first half of pregnancy unless absolutely necessary and under close medical supervision.

Corticosteroids alter kidney development and increase glomerular filtration rate in larval zebrafish (Danio rerio).

Pharmaceutical drugs and other chemicals can impact organogenesis, either during pregnancy or by postnatal exposure of very preterm infants. Corticosteroids are administered to pregnant women at risk of preterm delivery in order to reduce neonatal morbidity and mortality. In addition, high-dose corticosteroid exposure of very preterm infants regularly serves to maintain blood pressure and to prevent and treat bronchopulmonary dysplasia, a form of chronic lung disease in prematurely born infants. Despite clinical benefits, there is increasing evidence of corticosteroid-mediated short- and long-term detrimental developmental effects, especially in the kidney. Here, we performed a detailed morphological and functional analysis of corticosteroid-mediated effects on pronephros development in larval zebrafish. About 24-h postfertilization (hpf) transgenic Tg(wt1b: EGFP) zebrafish larvae were exposed to a set of natural and synthetic corticosteroids (hydrocortisone, dexamethasone, 6α-methylprednisolone, betamethasone, prednisolone, fludrocortisone, 11-deoxycorticosterone) with varying glucocorticoid and mineralocorticoid potency for 24 h at different concentrations. A semiautomated, multiparametric in vivo workflow enabled simultaneous assessment of kidney morphology, renal FITC-inulin clearance, and heart rate within the same larva. All corticosteroids exerted significant morphological and functional effects on pronephros development, including a significant hypertrophy of the pronephric glomeruli as well as dose-dependent increases in FITC-inulin clearance as a marker of glomerular filtration rate. In conclusion, the present study demonstrates a significant impact of corticosteroid exposure on kidney development and function in larval zebrafish. Hence, these studies underline that corticosteroid exposure of the fetus and the preterm neonate should be carefully considered due to potential short- and long-term harm to the kidney.

Therapeutic effect of epidural dexamethasone palmitate in a rat model of lumbar spinal stenosis

BackgroundDexamethasone palmitate (DEP), a prodrug of dexamethasone (DEX), is a synthetic corticosteroid medication distinguished by the inclusion of a fatty acid component known as palmitate. This study introduces DEP as...

A cell cycle regulator, E2F2, and glucocorticoid receptor cooperatively transactivate the bovine alphaherpesvirus 1 immediate early transcription unit 1 promoter.

Bovine alpha-herpesvirus 1 (BoHV-1) acute infection in cattle leads to establishment of latency in sensory neurons in the trigeminal ganglia (TG). A synthetic corticosteroid dexamethasone consistently initiates BoHV-1 reactivation in latently infected calves. The BoHV-1 immediate early transcription unit 1 (IEtu1) promoter regulates expression of infected cell protein 0 (bICP0) and bICP4, two viral transcriptional regulators. Hence, the IEtu1 promoter must be activated for the reactivation to occur. The number of TG neurons expressing E2F2, a transcription factor and cell cycle regulator, increased during early stages of reactivation from latency. The glucocorticoid receptor (GR) and E2F2, but not E2F1, E2F3a, or E2F3b, cooperatively transactivated a 436-bp cis-regulatory module (CRM) in the IEtu1 promoter that contains two GR responsive elements. Chromatin immunoprecipitation studies revealed that E2F2 occupies IEtu1 promoter sequences in cultured cells. GR and E2F2 mediate cooperative transactivation of IEtu1 promoter activity, which is predicted to stimulate viral replication following stressful stimuli.

OA20 Serious infections hospital admissions and mortality in patients with early inflammatory arthritis: results from the National Early Inflammatory Arthritis Audit

Abstract Background/Aims To identify the risk of serious infections (SI) according to initial treatment strategy, using conventional synthetic disease modifying anti-rheumatic drugs (csDMARD) and corticosteroids, in patients recruited to the National Early Inflammatory Arthritis Audit (NEIAA). Methods An observational cohort study design was used. The population included adults in England with a new onset rheumatoid arthritis (RA), fulfilling ACR/EULAR 2010 criteria, between April 2018-March 2021. Outcomes studied were SI, defined by infections requiring hospitalisation (primary admission diagnosis/nosocomial acquisition) or death (SI stated on death certificate), identified using NHS Digital linkage. Patients' characteristics were tabulated by treatment strategies. Hazard ratios (HR) were calculated using single failure Cox proportional-hazards models, with confounders-adjusted models (age, gender, smoking status, comorbidities, social deprivation) and fully-adjusted models including disease factors (seropositivity, DAS28). Individuals were considered at risk from the date of RA diagnosis, and censored at SI event, death, or March 2021 (whichever was earliest). Results 20,060 patients with RA were included. Initial DMARD therapy was known for 19,572 patients, of whom 11,966 were on methotrexate/MTX based strategies (mono or combo), 5,059 on csDMARD combination strategies (other than MTX) and 2,547 on no DMARD strategy. 15,319 patients were on corticosteroids at baseline. Mean age 59.5 years (+/-15); 63% female; smoking status (20% current; 30% ex-smokers); comorbidities (21% hypertension; 10% diabetes; and 12% lung disease). Rheumatoid Factor/CCP antibodies were positive in 68%. At presentation, median disease scores were 5.1 (interquartile range [IQR]: 4.0-5.9) for DAS28, 1.1 (IQR: 0.6-1.7) for health assessment questionnaire (HAQ) and 24 (IQR: 16.0-33.0) for musculoskeletal health questionnaire (MSKHQ).There were 519 SI admissions and 17 SI deaths, corresponding to incidence rates per 100 person-years for admissions: 3.19 (95% CI: 2.93-3.48) and deaths: 0.10 (95% CI: 0.06-0.16). In fully-adjusted models, increasing age predicted both SI admissions and deaths. Being a smoker, having a comorbidity, higher disease activity (DAS28), symptom burden (MSKHQ) and disability (HAQ) at presentation associated with more SI admissions. For each 1 unit increase in DAS28, the risk of SI increased by 8% (HR 1.08 [95% CI:1.01-1.16]). Seropositivity did not associate with SI. MTX-based strategies 0.75 (95% CI:0.62-0.91) and csDMARD combination therapy 0.70 (95% CI:0.53-0.94) associated with fewer SI admissions compared to no DMARD. In unadjusted models, corticosteroid associated with more SI admissions 1.29 (95% CI:1.10 -1.62); however, in fully-adjusted models this association was no longer statistically significant. csDMARD strategies did not associated with SI deaths in any of the models. Conclusion Patient and disease factors at diagnosis appear to be important predictors of admissions and mortality for serious infections. Infection risk appears to be greatest in those with higher RA disease activity. An important limitation is that NEIAA does not capture data on treatment changes over time and steroid use beyond baseline. Disclosure M. Adas: None. K. Bechman: None. M. Russell: Honoraria; Lilly and Menarini. Other; upport for attending conferences from Lilly, Pfizer, Janssen, and UCB, and advisory board fees from Biogen.. I. Karafotias: None. D. Nagra: None. S. Patel: None. S. Gallagher: None. E. Price: None. M. Garton: None. A. Rutherford: None. A. Cope: None. S. Norton: None. J. Galloway: Honoraria; from Abbvie, Biovitrum, Bristol Myers Squib (BMS), Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, and UCB.

Effect of suprachoroidal triamcinolone on intraocular pressure: a systematic review and meta-analysis.

Triamcinolone acetonide is a synthetic corticosteroid with multiple ocular uses. Like other corticosteroids, it too is associated with ocular side effects such as increased intraocular pressure (IOP), glaucoma and cataracts. Suprachoroidal administration of triamcinolone is hoped to reduce the ocular side effects of the drug, especially rises in IOP. Our systematic review and meta-analysis aims to study this phenomenon. The purpose of this study was to evaluate the effect of suprachoroidal triamcinolone injections on IOP. Systematic review and meta-analysis. We utilized the Medline, Scopus and Cochrane databases for this review. Studies published till June 2023, which fulfilled the eligibility criteria, were included. Studies in the English language with adult participants who were administered suprachoroidal triamcinolone without any concurrent intervention were included, whereas studies that did not report the mean and standard deviation for IOP were excluded. The outcome of interest was IOP at 1, 3 and 6 months post-suprachoroidal triamcinolone injection. IOP values from included studies were extracted onto Review Manager version 5.4 for analysis. Our search yielded 104 results, from which 22 papers were shortlisted for full-text screening. Finally, 12 studies were included in the analysis. Our analysis suggests a statistically significant increase in IOP in the first month after suprachoroidal triamcinolone injection but no significant differences at 3 and 6 months post-injection as compared to baseline. Elevated IOP at 1 month post-injection must be considered when using suprachoroidal triamcinolone and adequate safety measures must be taken. However, the absence of a significant rise at 3 and 6 months post-injection indicates that this modality is safer than other existing drug delivery methods. Registered with the Research Registry with the unique identifying number 'reviewregistry1656.' https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/648eefe65b6523002995eb21/.

Dexamethasone induces sleep disturbance in a dose-dependent manner in mice.

Synthetic corticosteroids, the most well-known anti-inflammatory drugs globally, are effective against inflammatory diseases despite their adverse effects that decrease a patient's quality of life (QOL). One of these effects is sleep disturbance, which causes other health issues and further diminishes the QOL. However, the acute effects of steroid drugs on sleep-wake issues are not fully understood and must be clarified in detail using experimental animals. Therefore, this study examines the dose-dependent effect of dexamethasone (DXM), one of the strongest steroid drugs, on the sleep-wake architecture of mice. We conducted acute DXM administration at multiple doses and 24-hour EEG/EMG recordings. Our results revealed that DXM increased the time spent in arousal and decreased that of NREM sleep, even at very low doses. These results imply that steroid-induced sleep disturbance must be addressed at any dosage.

Spectroscopic and Photonic Properties of Dexamethasone used in the Treatment of COVID-19 Patients

Dexamethasone is a synthetic adrenal corticosteroid with potent anti-inflammatory properties. Dexamethasone (MK-125) is a position 9 fluorinated corticosteroid used to treat endocrine, rheumatic, collagen, dermatological, allergic, ophthalmic, gastrointestinal, respiratory, hematological, neoplastic, edematous, and other conditions. On June 16, 2020, a press release for the Randomized Evaluation of COVID-19 Treatment (RECOVERY) trial recommended the use of dexamethasone in COVID-19 patients with severe respiratory symptoms. Dexamethasone reduced deaths by approximately one-third in ventilated patients and one-fifth in patients requiring oxygen. Therefore, Dexamethasone is used in the treatment of COVID-19 patients in some countries. In this study, we researched the spectroscopic and photonic properties of Dexamethasone. We have extensively studied the absorption spectra at different concentrations and their response to light. This study shows the absorbance spectra of the Dexamethasone for various concentrations. On the other hand, we continue to work intensively on some herbal suggestions that can be considered equivalent to Dexamethasone.

Effect of dexamethasone on human neutrophil adhesion and concomitant secretion

Neutrophils play a dual role in protecting the body. They are able to penetrate infected tissues and destroy pathogens there, releasing aggressive bactericidal substances. Getting into the surrounding tissues, aggressive secretion products of neutrophils initiate the development of inflammatory processes. Invasion of neutrophils into tissues is observed during the development of pneumonia in patients with lung diseases of various etiologies, including acute respiratory distress syndrome caused by coronavirus disease. The synthetic corticosteroid hormone dexamethasone has a therapeutic effect in the treatment of lung diseases, including reducing mortality in patients with severe Covid-19. The acute (short-term) effect of dexamethasone on neutrophil adhesion to fibrinogen and concomitant secretion was studied. Dexamethasone did not affect either the attachment of neutrophils to the substrate or their morphology. The production of reactive oxygen species (ROS) and nitric oxide (NO) by neutrophils during adhesion also did not change in the presence of dexamethasone. Dexamethasone stimulated the release of metalloproteinases in addition to proteins secreted by neutrophil adhesion under control conditions, and selectively stimulated the release of the free amino acid hydroxylysine, a product of lysyl hydroxylase. Metalloproteinases play a key role and closely interact with lysyl hydroxylase in the processes of rearrangement of the extracellular matrix. The therapeutic effect of dexamethasone may be associated with its ability, by changing the composition of neutrophil secretions, to reorganize the extracellular matrix in tissues, which can lead to improved gas exchange in patients with severe lung diseases.

Specificity protein 1 (Sp1) and glucocorticoid receptor (GR) stimulate bovine alphaherpesvirus 1 (BoHV-1) replication and cooperatively transactivate the immediate early transcription unit 1 promoter.

Bovine alphaherpesvirus 1 (BoHV-1) infections cause respiratory tract disorders and suppress immune responses, which can culminate in bacterial pneumonia. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons present in trigeminal ganglia (TG) and unknown cells in pharyngeal tonsil. Latently infected calves consistently reactivate from latency after an intravenous injection of the synthetic corticosteroid dexamethasone (DEX), which mimics the effects of stress. The immediate early transcription unit 1 (IEtu1) promoter drives expression of infected cell protein 0 (bICP0) and bICP4, two key viral transcriptional regulators. The IEtu1 promoter contains two functional glucocorticoid receptor (GR) response elements (GREs), and this promoter is transactivated by GR, DEX, and certain Krüppel transcription factors that interact with GC-rich motifs, including consensus specificity protein 1 (Sp1) binding sites. Based on these observations, we hypothesized that Sp1 stimulates productive infection and transactivates key BoHV-1 promoters. DEX treatment of latently infected calves increased the number of Sp1+ TG neurons and cells in pharyngeal tonsil indicating that Sp1 expression is induced by stress. Silencing Sp1 protein expression with siRNA or mithramycin A, a drug that preferentially binds GC-rich DNA, significantly reduced BoHV-1 replication. Moreover, BoHV-1 infection of permissive cells increased Sp1 steady-state protein levels. In transient transfection studies, GR and Sp1 cooperatively transactivate IEtu1 promoter activity unless both GREs are mutated. Co-immunoprecipitation studies revealed that GR and Sp1 interact in mouse neuroblastoma cells (Neuro-2A) suggesting this interaction stimulates IEtu1 promoter activity. Collectively, these studies suggested that the cellular transcription factor Sp1 enhances productive infection and stress-induced BoHV-1 reactivation from latency.IMPORTANCEFollowing acute infection, bovine alphaherpesvirus 1 (BoHV-1) establishes lifelong latency in sensory neurons in trigeminal ganglia (TG) and pharyngeal tonsil. The synthetic corticosteroid dexamethasone consistently induces BoHV-1 reactivation from latency. The number of TG neurons and cells in pharyngeal tonsil expressing the cellular transcription factor specificity protein 1 (Sp1) protein increases during early stages of dexamethasone-induced reactivation from latency. Silencing Sp1 expression impairs BoHV-1 replication in permissive cells. Interestingly, mithramycin A, a neuroprotective antibiotic that preferentially binds GC-rich DNA, impairs Sp1 functions and reduces BoHV-1 replication suggesting that it is a potential antiviral drug. The glucocorticoid receptor (GR) and Sp1 cooperatively transactivate the BoHV-1 immediate early transcript unit 1 (IEtu1) promoter, which drives expression of infected cell protein 0 (bICP0) and bICP4. Mithramycin A also reduced Sp1- and GR-mediated transactivation of the IEtu1 promoter. These studies revealed that GR and Sp1 trigger viral gene expression and replication following stressful stimuli.

Effect of Dexamethasone on Adhesion of Human Neutrophils and Concomitant Secretion.

Neutrophils play a dual role in protecting the body. They are able to penetrate infected tissues and destroy pathogens there by releasing aggressive bactericidal substances. While into the surrounding tissues, the aggressive products secreted by neutrophils initiate development of inflammatory processes. Invasion of neutrophils into tissues is observed during the development of pneumonia in the patients with lung diseases of various etiologies, including acute respiratory distress syndrome caused by coronavirus disease. Synthetic corticosteroid hormone dexamethasone has a therapeutic effect in treatment of lung diseases, including reducing mortality in the patients with severe COVID-19. The acute (short-term) effect of dexamethasone on neutrophil adhesion to fibrinogen and concomitant secretion was studied. Dexamethasone did not affect either attachment of neutrophils to the substrate or their morphology. Production of reactive oxygen species (ROS) and nitric oxide (NO) by neutrophils during adhesion also did not change in the presence of dexamethasone. Dexamethasone stimulated release of metalloproteinases in addition to the proteins secreted by neutrophils during adhesion under control conditions, and selectively stimulated release of free amino acid hydroxylysine, a product of lysyl hydroxylase. Metalloproteinases play a key role and closely interact with lysyl hydroxylase in the processes of modification of the extracellular matrix. Therapeutic effect of dexamethasone could be associated with its ability to reorganize extracellular matrix in the tissues by changing composition of the neutrophil secretions, which could result in the improved gas exchange in the patients with severe lung diseases.

Multi-Gram Scale Synthesis and Characterization of Mometasone Furoate EP Impurity C

Mometasone furoate is a synthetic corticosteroid used in the treatment of skin inflammatory conditions, hay fever and asthma. The industrial manufacturing routes to mometasone furoate are generally accompanied by the formation of numerous process impurities that need to be detected and quantified, as requested by regulatory authorities. The ready availability of such impurities in the required quantity and purity is therefore essential for toxicological studies, analytical method development and process validation. Herein, we report the multi-gram scale preparation of 21′-chloro-(16′α-methyl-3′,11′,20′-trioxo-pregna-1′,4′-dien-17′-yl)-furan-2-carboxylate (mometasone furoate EP impurity C), one of the known impurities of mometasone furoate. This study also includes the systematic investigation of the final acylation step, as well as the characterization of the difuroate enol ether intermediate and its conversion to the target impurity C.

Impaired glucocorticoid receptor function attenuates herpes simplex virus 1 production during explant-induced reactivation from latency in female mice.

A correlation exists between stress and increased episodes of human alpha-herpes virus 1 reactivation from latency. Stress increases corticosteroid levels; consequently, the glucocorticoid receptor (GR) is activated. Recent studies concluded that a GR agonist, but not an antagonist, accelerates productive infection and reactivation from latency. Furthermore, GR and certain stress-induced transcription factors cooperatively transactivate promoters that drive the expression of infected cell protein 0 (ICP0), ICP4, and VP16. This study revealed female mice expressing a GR containing a serine to alanine mutation at position 229 (GRS229A) shed significantly lower levels of infectious virus during explant-induced reactivation compared to male GRS229A or wild-type parental C57BL/6 mice. Furthermore, female GRS229A mice contained fewer VP16 + TG neurons compared to male GRS229A mice or wild-type mice during the early stages of explant-induced reactivation from latency. Collectively, these studies revealed that GR transcriptional activity has female-specific effects, whereas male mice can compensate for the loss of GR transcriptional activation.

SAT016 Small Compounds Modulate Glucocorticoid Receptor Function By Binding To A Novel Allosteric Pocket

Abstract Disclosure: A. Jimenez-Panizo: None. The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. This receptor exerts its functions by binding to corticosteroids through its ligand-binding domain (LBD), which harbors a hydrophobic pocket where ligands are encapsulated. Synthetic glucocorticoids, as Dexamethasone, are widely used in the clinic for the treatment of chronic inflammatory diseases. Unfortunately, their prolonged use is associated with critical side effects and most of the mechanisms underlying these collateral issues are still unknown. In this work, we present a deep biochemical and biophysical analysis showing how small molecules are able to bind a new allosteric pocket in solution and how these compounds can modulate GR transcriptional activity in cells. These findings can be essential to further understand GR signaling and how to better design synthetic corticosteroids to avoid side effects. Presentation: Saturday, June 17, 2023

FRI365 A Patient With A Bronchial Carcinoid Presents With Cushingoid Symptoms Due To A Potentially Dangerous Supplement

Abstract Disclosure: T. Morales: None. S. Samarasinghe: None. Introduction: Well-differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background. Clinical Case: A 59-year-old woman with an 11-year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Hormonal activation of her known bronchial carcinoid was considered. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n&amp;lt;15 mg/dL), elevated chromogranin A (201 ng/mL, n&amp;lt;103 ng/mL), normal histamine (&amp;lt;1.5 ng/mL, n &amp;lt;1.7 ng/mL), low-normal 7 AM serum cortisol (5.1 ug/dL, n 3.6-19.3 ug/dL), normal 7 AM ACTH (17 pg/mL, n&amp;lt;46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0-50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4-16.8 mcg/dL). Echocardiography showed no evidence of carcinoid heart disease. A Dotatate PET-CT scan to assess for neuroendocrine tumor progression showed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Ectopic Cushing syndrome was excluded given the low cortisol levels, and exogenous steroids were suspected, however the patient denied the use of oral, inhaled, or injected steroids. A cosyntropin stimulation test yielded a pre-stimulation cortisol of 6.2 ug/dL with an adequate post-stimulation cortisol of 23.5 ug/dL (n &amp;lt;46 pg/mL). At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King glucosamine supplements not listed on the product label, but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and death associated with such products. The patient’s symptoms gradually improved after discontinuation of the supplement. Conclusion: Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing. Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing.