Prenatal glucocorticoids exposure and adverse cardiovascular effects in offspring.

Glucocorticoids (GCs) are steroid hormones fundamental to the body's normal physiological functions and are pivotal in fetal growth and development. During gestation, the mother's cortisol concentration (active GCs) escalates to accommodate the requirements of fetal organ development and maturation. A natural placental GCs barrier, primarily facilitated by 11ß hydroxysteroid dehydrogenase 2, exists between the mother and fetus. This enzyme transforms biologically active cortisol into biologically inactive corticosterone, thereby mitigating fetal GCs exposure. However, during pregnancy, the mother may be vulnerable to adverse factor exposures such as stress, hypoxia, caffeine, and synthetic GCs use. In these instances, maternal serum GCs levels may surge beyond the protective capacity of the placental GCs barrier. Moreover, these adverse factors could directly compromise the placental GCs barrier, resulting in excessive fetal exposure to GCs. It is well-documented that prenatal GCs exposure can detrimentally impact the offspring's cardiovascular system, particularly in relation to blood pressure, vascular function, and heart function. In this review, we succinctly delineate the alterations in GCs levels during pregnancy and the potential mechanisms driving these changes, and also analyze the possible causes of prenatal GCs exposure. Furthermore, we summarize the current advancements in understanding the adverse effects and mechanisms of prenatal GCs exposure on the offspring's cardiovascular system.

Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury.

Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid-induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.

Prediction of post-ESD esophageal stricture by a nomogram and risk factor analysis of ineffective oral steroids prophylaxis.

BACKGROUND AND AIMS: Several risk models for esophageal stricture after endoscopic submucosal dissection have been developed. However, some of them did not include the use of steroids in the risk analysis. Glucocorticoid sensitivity mediated by glucocorticoid receptor expression has not been discussed in this condition. METHODS: Clinical and endoscopic characteristics were included in the logistic regression model to establish a nomogram for stenosis prediction. The score for each risk factor was estimated. Risk factors of ineffective oral steroid prophylaxis were analyzed and glucocorticoid receptor expressions were detected by immunohistochemistry. RESULTS: Three hundred fourteen patients of endoscopic submucosal dissection for esophageal superficial neoplasms were included to develop the nomogram. The circumferential range(≤ 3/4, 3/4-1 or the whole circumference), longitudinal diameter reached 4 cm (yes or not) and lesion location (the cervical and upper thoracic part, the middle thoracic part or the lower thoracic part) consisted of the nomogram. Patients have a high risk of esophageal stricture if they have a total point greater than 36. In the simplified risk score model, the corresponding cutoff score was 1. 92 patients with oral steroid prophylaxis were separately analyzed and the circumferential mucosal defect involving 7/8 or more was an independent risk factor of ineffective prevention (OR 12.2, 95%CI 5.27-28.11). The expression of glucocorticoid receptor ß was higher in the stricture group (p = 0.042 for AOD; p = 0.016 for the scoring system). CONCLUSIONS: We established a nomogram for esophageal stricture prediction. Depending on the characteristics of lesions, it is possible to estimate the risk of stricture under routine post-ESD treatments (no steroids or oral steroids). Alternative treatments should be considered if the risk is extremely high, especially for patients with mucosal defects involving 7/8 or more of circumference in which oral steroid treatment tends to be ineffective. The higher glucocorticoid receptor ß may indicate potential glucocorticoid resistance.

Comparative performance analysis of large language models: ChatGPT-3.5, ChatGPT-4 and Google Gemini in glucocorticoid-induced osteoporosis.

BACKGROUNDS: The use of large language models (LLMs) in medicine can help physicians improve the quality and effectiveness of health care by increasing the efficiency of medical information management, patient care, medical research, and clinical decision-making. METHODS: We collected 34 frequently asked questions about glucocorticoid-induced osteoporosis (GIOP), covering topics related to the disease's clinical manifestations, pathogenesis, diagnosis, treatment, prevention, and risk factors. We also generated 25 questions based on the 2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis (2022 ACR-GIOP Guideline). Each question was posed to the LLM (ChatGPT-3.5, ChatGPT-4, and Google Gemini), and three senior orthopedic surgeons independently rated the responses generated by the LLMs. Three senior orthopedic surgeons independently rated the answers based on responses ranging between 1 and 4 points. A total score (TS) > 9 indicated 'good' responses, 6 ≤ TS ≤ 9 indicated 'moderate' responses, and TS < 6 indicated 'poor' responses. RESULTS: In response to the general questions related to GIOP and the 2022 ACR-GIOP Guidelines, Google Gemini provided more concise answers than the other LLMs. In terms of pathogenesis, ChatGPT-4 had significantly higher total scores (TSs) than ChatGPT-3.5. The TSs for answering questions related to the 2022 ACR-GIOP Guideline by ChatGPT-4 were significantly higher than those for Google Gemini. ChatGPT-3.5 and ChatGPT-4 had significantly higher self-corrected TSs than pre-corrected TSs, while Google Gemini self-corrected for responses that were not significantly different than before. CONCLUSIONS: Our study showed that Google Gemini provides more concise and intuitive responses than ChatGPT-3.5 and ChatGPT-4. ChatGPT-4 performed significantly better than ChatGPT3.5 and Google Gemini in terms of answering general questions about GIOP and the 2022 ACR-GIOP Guidelines. ChatGPT3.5 and ChatGPT-4 self-corrected better than Google Gemini.

[Joint pain - a rheumatic disease?] / Gelenkschmerzen ­ eine rheumatische Erkrankung?

Pain in the musculoskeletal system and therefore joint pain is one of the most common reasons for consulting a general practitioner (GP). Inflammatory rheumatic diseases are among the important differential diagnoses. However, the prevalence of rheumatological diseases is significantly lower than that of degenerative causes of pain. Incorrect referrals can be avoided if the causes of pain are better differentiated in GP practices. This article presents the first differential diagnostic steps that make it easier for the GP to make further treatment decisions. Physical examination, laboratory diagnostics and imaging are discussed, and the concept of "clinically suspect arthralgia" as well as the possible effects of treatment trials with glucocorticoids are presented.

The causality between use of glucocorticoids and risk of pancreatitis: a Mendelian randomization study.

Background and aim: To date, the association between glucocorticoid use and the risk of pancreatitis remains controversial. The aim of this study was the investigation of this possible relationship. Methods: We carried out a two-sample Mendelian randomization (MR) analysis using GWAS data from European ancestry, East Asian descendants and the FinnGen Biobank Consortium to evaluate this potential causal relationship. Genetic variants associated with glucocorticoid use were selected based on genome-wide significance (p < 5×10-8). Results: Our MR analysis of European ancestry data revealed no significant causal relationship between glucocorticoid use and AP (IVW: OR=1.084, 95% CI= 0.945-1.242, P=0.249; MR-Egger: OR=1.049, 95% CI= 0.686-1.603, P=0.828; weighted median: OR=1.026, 95% CI= 0.863-1.219, P=0.775) or CP (IVW: OR=1.027, 95% CI= 0.850-1.240, P=0.785; MR-Egger: OR= 1.625, 95% CI= 0.913-2.890, P= 0.111; weighted median: OR= 1.176, 95% CI= 0.909-1.523, P= 0.218). Sensitivity analyses, including MR-Egger and MR-PRESSO, indicated no evidence of pleiotropy or heterogeneity, confirming the robustness of our findings. Multivariable MR analysis adjusted for alcohol consumption, BMI, cholelithiasis and C-reactive protein levels supported these findings. Replicated analysis was performed on datasets from the FinnGen Biobank Consortium and East Asian descendants, and similar results were obtained. Conclusions: This MR analysis suggests that there is no causal association between glucocorticoid use and the risk of pancreatitis.

SOST/Sclerostin impairs the osteogenesis and angiogesis in glucocorticoid-associated osteonecrosis of femoral head.

BACKGROUND: Glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH) is a progressive bone disorder which frequently results in femoral head collapse and hip joint dysfunction. Sclerostin (SOST) is principally secreted by osteocytes in bone and plays an important role in bone homeostasis and homeostasis of skeletal integrity. Our previous study reported that short-term use of glucocorticoid increased serum sclerostin levels. Here this study is aimed to identify whether sclerostin played an essential role in the occurrence and development of GA-ONFH. METHODS: Glucocorticoid-induced osteonecrosis of femoral head (ARCO stage II) samples were collected and sclerostin staining was conducted. Osteocyte cell line Ocy454, MC3T3-E1 and endothelial cells was used. MC3T3-E1 or endothelial cells were co-cultured with Ocy454 or SOST-silencing Ocy454 in presence of dexamethasone to mimic the crosstalk of various cells in the bone niche. GA-ONFH rat model and SOST knockout model was built to better understand the phenomenon in vivo. RESULTS: Sclerostin was highly concentrated in osteonecrosis patient sample in the necrotic area. Co-culture with osteocytes aggravated the inhibition of dexamethasone on MC3T3-E1 and endothelial cells. Sclerostin derived from osteocytes impaired osteogenesis and angiogenesis via inhibiting the Wnt pathway. In GA-ONFH rat model, SOST knockout ameliorated the incidence of osteonecrosis and improved bone metabolism compared with the wild type group through histological, immunohistochemical and bone metabolic analyses. CONCLUSION: Sclerostin contribute to pathologic process of GA-ONFH by impairing osteogenesis and angiogenesis.

Real-world treatment patterns in patients with systemic lupus erythematosus: associations with comorbidities and damage.

OBJECTIVE: To assess treatment patterns and the association between long-term glucocorticoid (GC) and hydroxychloroquine (HCQ) use and damage accrual in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective study including patients with SLE using the computerised database of a large health maintenance organisation. Patients were matched with subjects from the general population. Multivariable logistic regression models were used to assess the association between GC cumulative daily doses, HCQ and comorbidities: Osteoporosis, cardiovascular disease (CVD), hypertension and diabetes mellitus. Models were adjusted for age, sex, socioeconomic status, smoking, disease duration and HCQ use. RESULTS: A total of 1073 patients with SLE were included, 87.79% were women. The age at first diagnosis was 37.23±14.36 and the SLE disease duration was 12.89±6.23 years. Initiation of HCQ within 12 months of SLE diagnosis increased from 51.02% in 2000 to 83.67% in 2010 and 93.02% in 2018. The annual usage of GC gradually decreased from 45.34% in 2000 to 30.76% in 2020. CVD and osteoporosis were more prevalent in SLE than in the general population. Multivariable logistic regression models revealed increased odds for comorbidities in patients receiving a mean daily dose of prednisone of more than 5 mg/day compared with those receiving 5 mg/day or less. CONCLUSIONS: CVD and osteoporosis were more prevalent in SLE than in the general population. The dose and frequency of GC treatment in patients with SLE have decreased over the years. Prednisone usage in doses exceeding 5 mg/day is associated with significantly increased odds of osteoporosis and CVD.

Topical Steroids Sold as Fade Creams in Beauty Supply Stores: A Danger for Cosmetic Consumers.

Topical corticosteroids are used extensively in dermatology. Class 1 high potency topical steroids (HPTS) can result in unwanted side effects such as skin hypopigmentation, atrophy, and acneiform eruptions. HPTS are only legally available by prescription to ensure appropriate use in the United States (US). The authors have noticed a recent increase in patients presenting with steroid acne after buying HPTS products in beauty supply stores. These products are marketed as fade creams to treat hyperpigmentation and uneven skin tone. We assessed skincare products containing HPTS (clobetasol or betamethasone) in 33 beauty supply stores in Miami, FL; Washington, DC; and Baltimore, MD. Out of 33 beauty supply stores, 14 (42.42%) contained HPTS skincare products, and they were all located in Miami. Out of 15 stores visited in Miami, 14 (93.33%) contained skincare products with clobetasol, and 5 (33.33%) contained skincare products with both clobetasol and betamethasone. Of the stores selling HPTS skincare products, the number of different brands available ranged from 1 to 7, with an average of 4.21 different brands per store. Our study reveals that HPTS are readily available in over-the-counter skincare products in many beauty supply stores. HPTS skincare products were only available in one of three cities suggesting there may be a regional supplier distributing these products. It may also indicate that there is less oversight of retail stores in Miami with HPTS products. More studies are needed to quantify the availability of these products in different locations throughout the US. Further Studies can help identify this problem and raise awareness among consumers of the dangers of HPTS skincare products in beauty supply stores. J Drugs Dermatol. 2024;23(9):709-712. doi:10.36849/JDD.7608.

Teriparatida para o tratamento de osteoporose secundária a glicocorticoides, pacientes do sexo masculino e pacientes que apresentaram infarto do miocárdio ou acidente vascular cerebral no ano anterior / Teriparatide for the treatment of osteoporosis secondary to glucocorticoids in male patients and patients who have had myocardial infarction or stroke in the previous year

INTRODUÇÃO: A osteoporose é uma enfermidade que aumenta a fragilidade óssea e suscetibilidade à fratura. No mundo, afeta aproximadamente 200 milhões de pessoas. Sua prevalência no Brasil varia de 6% a 33%. O tratamento indicado inclui estratégias não medicamentosas e medicamentosas, entre as quais encontram-se o carbonato de cálcio e a vitamina D como parte de todos os esquemas terapêuticos; os agentes anti reabsortivos (bifosfonatos - alendronato, risedronato, pamidronato e ácido zoledrônico); o modulador seletivo dos receptores de estrogênio (raloxifeno); os estrógenos conjugados; calcitonina e o agente anabólico (teriparatida). Estas são opções disponíveis no Protocolo Clínico de Diretrizes Terapêuticas (PCDT) de Osteoporose do Sistema Único de Saúde (SUS). Em caso de falha terapêutica, que pode acompanhar 25% dos pacientes, as diretrizes clínicas nacionais e internacionais de sociedades médicas recomendam o uso de denosumabe, teriparatida ou romosozumabe, dependendo da população. O objetivo do presente relatório é analisar as evidências econômicas do uso da teriparatida para o tratamento da falha terapêutica em: (a) homens; (b) pacientes com osteoporose severa por uso de glicocorticoides (GC); (c) pacientes com acidente vascular cerebral (AVC); e d) pacientes com infarto agudo do miocárdio (IAM) no ano anterior. PERGUNTA: A teriparatida é custo-efetiva no tratamento de: (a) homens com osteoporose, (b) pacientes com osteoporose severa por uso de GC, (c) pacientes com AVC ou IAM no ano anterior, como alternativa aos bifosfonatos? AVALIAÇÃO ECONÔMICA: A avaliação de custo-efetividade não demonstrou a superioridade da teriparatida quando comparada ao alendronato e ao risedronato no tratamento de homens ou pacientes utilizando ou com AVC ou IAM. Para pacientes com uso de glicocorticoides, a razão de custo-efetividade incremental se situou em torno do limiar de R$ 40.000,00/QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário, dependendo do market share, foi de 117 milhões para a população masculina, 17 milhões para pacientes usando glicocorticoides, 9,3 milhões com AVC e 10,3 milhões com IAM. O uso integral da teriparatida elevaria esse gasto para 187 milhões, 71 milhões, 37 milhões e 41 milhões, respectivamente. Deve-se observar que nesses valores pode haver dupla contagem, uma vez que as estimativas feitas para os homens não excluíram as comorbidades. EXPERIÊNCIAS INTERNACIONAIS/RECOMENDAÇÕES DE OUTRAS AGÊNCIAS DE ATS: Quanto ao uso da teriparatida em homens, o National Health System (NHS) a recomenda como alternativa de tratamento para a osteoporose secundária e prevenção de fraturas por fragilidade osteoporótica em homens intolerantes ao alendronato e risedronato ou com "resposta insatisfatória. É financiada pelo NHS England Specialized Commissioning. Na Nova Zelândia, a Pharmaceutical Management Agency (PHARMAC) sugere o financiamento da teriparatida como tratamento de última linha para a osteoporose, restringindo-a aos pacientes com evidência de fraturas contínuas e/ou T-escore <-3, após tentarem todos os tratamentos financiados para a osteoporose. Este uso está condicionado a uma redução significativa dos preços. A Austrália, por meio do The Pharmaceutical Benefits Scheme (PBS), incorporou a teriparatida para o tratamento de osteoporose grave em pacientes com risco alto de fratura com critérios muito bem estabelecidos. Deve ser a única terapia subsidiada pela PBS para esta condição, não excedendo um máximo de 18 meses. O informe de posicionamento terapêutico da teriparatida junto a Agência Espanhola de Medicamentos e Produtos Sanitários (AEMPS) indica seu uso para o tratamento de osteoporose em homens com aumento do risco de fratura. A Canadian Agency for Drugs and Technologies in Health (CADTH) não recomenda seu uso. A Pharmaceuticals and Medical Devices Agency (PMDA) do Japão não se posiciona quanto ao uso deste medicamento em homens com alto risco de fratura. O informe de posicionamento terapêutico para a teriparatida junto à AEMPS e à PMDA indicam seu uso para o tratamento de osteoporose associada à terapia sistêmica com GC, em homens e mulheres com incremento de risco de fratura. Não se encontrou posicionamento relacionado o seu uso em pacientes em uso de GC no sítio do NICE. O CADTH recomendou, em julho de 2009, a não incorporação do Forteo® para pessoas em uso de GC. Não se encontrou informe de posicionamento terapêutico para a teriparatida no tratamento de indivíduos com AVC ou IAM prévios, na PMDA, NICE, NHS, AEMPS ou PMDA. CONSIDERAÇÕES FINAIS: Na maioria dos cenários analisados, o uso dos bifosfonatos produz economia de recursos em relação à teriparatida no tratamento de homens ou com AVC ou IAM no ano anterior. A teriparatida não se mostrou custo-efetiva em nenhuma situação. A única alternativa em que ela mostrou possibilidades de ser custo efetiva foi em pacientes utilizando glicocorticóides. O impacto orçamentário de acordo com o market share variou de 9 milhões com AVC e 117 milhões para homens com ostorporose e falha terapêutica. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Embora a teriparatida só se mostre custo-efetiva para pacientes usando glicocorticóides e não haja economia de recursos, os membros do Comitê de Medicamentos, na 129ª reunião ordinária da Conitec, realizada no dia 8 de maio de 2024, deliberaram, por unanimidade, que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à restrição do uso da teriparatida para o tratamento no SUS da osteoporose em falha terapêutica para: (a) homens; (b) pacientes com osteoporose severa por uso de glicocorticoides (GC); (c) pacientes com acidente vascular cerebral (AVC) no ano anterior; e d) pacientes com infarto agudo do miocárdio (IAM) no ano anterior, haja vista que esses pacientes não são atendidos com as opções terapêuticas disponíveis no SUS. CONSULTA PÚBLICA: A Consulta Pública nº 040 foi realizada entre os dias 26/06/2024 e 15/07/2024. Foram recebidas 6 contribuições, todas de cunho técnico-científico. No total, 1 não concordou e não discordou da recomendação inicial da Conitec, 1 concordou e 4 discordaram. Embora as evidências clínicas não fossem objeto da análise do relatório da consulta pública, todos os participantes que discordaram da restrição do uso da teriparatida relataram a necessidade do uso do medicamento em pacientes com osteoporose grave. Nenhuma das contribuições sobre avaliação econômica apresentou argumentos, indicando apenas uma bibliografia genérica sobre a eficácia do teriparatida. A empresa argumentou que existe evidências da segurança, eficácia e efetividade nos ensaios clínicos e que houve uma autorização de aumento de 4,5% pela CMED que não foi repassado aos preços. Confirmou o preço da última proposta de R$ 12.282,06 para o fornecimento da teriparatida se as restrições fossem aprovadas As das contribuições recebidas na Consulta Pública não trouxeram novos fundamentos na parte econômica que justificassem a alteração da decisão preliminar. As evidências clínicas não estavam em avaliação e não foram objeto de análise. RECOMENDAÇÃO FINAL DA CONITEC: Através do registro de deliberação nº 918/2024, os membros do Comitê de Medicamentos, presentes na 132ª Reunião ordinária da Conitec, realizada no dia 07 de agosto de 2024, deliberaram por maioria pela recomendação FAVORÁVEL pela exclusão da teriparatida para o tratamento de osteoporose grave. O Comitê considerou que a terapia não era custo-efetiva nos cenários apresentados e uma alternativa mais econômica e conveniente estaria disponível em um horizonte tecnológico curto. DECISÃO: excluir, no âmbito do Sistema Único de Saúde - SUS, a teriparatida para o tratamento da osteoporose grave e falha terapêutica aos medicamentos disponíveis no SUS, publicada no Diário Oficial da União, número 183, Seção 1, página 147, em 20 de setembro de 2024.

Loss of BACH1 improves osteogenic differentiation in glucocorticoid-induced hBMSCs through restoring autophagy.

BACKGROUND: Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis. Recently, autophagy has been found to be related with the development of various diseases, including osteoporosis and osteoblast differentiation regulations. BTB and CNC homology 1 (BACH1) was a previously confirmed regulator for osteoblast differentiation, but whether it's could involve in glucocorticoid-induced human bone mesenchymal stem cells (hBMSCs) differentiation and autophagy regulation remain not been elucidated. METHODS: hBMSCs were identified by flow cytometry method, and its differentiation ability were measured by ARS staining, oil O red, and Alcian blue staining assays. Gene and proteins were quantified via qRT-PCR and western blot assays, respectively. Autophagy activity was determined using immunofluorescence. ChIP and dual luciferase assay validated the molecular interactions. RESULTS: The data revealed that isolated hBMSCs exhibited positive of CD29/CD44 and negative CD45/CD34. Moreover, BACH1 was abated gradually during osteoblast differentiation of hBMSCs, while dexamethasone (Dex) treatment led to BACH1 upregulation. Loss of BACH1 improved osteoblast differentiation and activated autophagy activity in Dex-challenged hBMSCs. Autophagy-related proteins (ATG3, ATG4, ATG5, ATG7, ATG12) were repressed after Dex treatment, while ATG3, ATG7 and BECN1 could be elevated by BACH1 knockdown, especially ATG7. Moreover, BACH1 could interact ATG7 promoter region to inhibit its transcription. Co-inhibition of ATG7 greatly overturned the protective roles of BACH1 loss on osteoblast differentiation and autophagy in Dex-induced hBMSCs. CONCLUSION: Taken together, our results demonstrated that silencing of BACH1 mitigated Dex-triggered osteogenic differentiation inhibition by transcriptionally activating ATG7-mediated autophagy, suggesting that BACH1 may be a therapeutic target for GIOP treatment.

Crebanine mitigates glucocorticoid-induced osteonecrosis of the femoral head by restoring bone remodelling homeostasis via attenuating oxidative stress.

The onset of osteonecrosis of the femoral head (ONFH) is intimately associated with the extensive administration of glucocorticoids (GCs). Long-term stimulation of GCs can induce oxidative stress in both osteoclasts (OCs) and osteoblasts (OBs), resulting in the disturbance of bone remodelling. An alkaloid named crebanine (CN) demonstrates pharmacological properties including anti-inflammation and reactive oxygen species (ROS) modulation. Our objective is to assess the therapeutic potential of CN in treating ONFH and elucidate the associated underlying mechanisms. The network pharmacology analysis uncovered that CN played a role in regulating ROS metabolism. In vitro, CN demonstrated its ability to reduce the dexamethasone (DEX)-stimulated generation of OCs and suppress their resorptive function by downregulating the level of osteoclast marker genes. Concurrently, CN also mitigated DEX-induced damage to OBs, facilitating the restoration of osteoblast marker gene expression, cellular differentiation and function. These effects were achieved by CN augmenting the antioxidant system to reduce intracellular ROS levels. Furthermore, in vitro results were corroborated by micro-CT and histological data, which also showed that CN attenuated MPS-induced ONFH in mice. This study highlights the therapeutic potential of CN in counteracting GCs-induced ONFH.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome, protein leaks from the blood into the urine through the glomeruli, resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the death rate to around 3%; however, corticosteroids have well-recognised potentially serious adverse events such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, cataracts, glaucoma and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, 2015 and 2020. OBJECTIVES: The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children: 1) children in their initial episode of SSNS and 2) children who experience a relapsing course of SSNS. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 9 July 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) performed in children (one to 18 years) during their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent. DATA COLLECTION AND ANALYSIS: Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: In this 2024 update, we included five new studies, resulting in 54 studies randomising 4670 children. Risk of bias methodology was often poorly performed, with only 31 studies and 28 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Ten studies were at low risk of performance bias (blinding of participants and personnel), and 12 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo-controlled RCTs. Twenty-seven studies (fewer than 50%) were at low risk for attrition bias, and 26 studies were at low risk for reporting bias (selective outcome reporting). In studies at low risk of selection bias evaluating children in their initial episode of SSNS, there is little or no difference in the number of children with frequent relapses when comparing two months of prednisone with three months or more (RR 0.96, 95% CI 0.83 to 1.10; 755 children, 5 studies; I2 = 0%; high certainty evidence) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 children, 3 studies; I2 = 35%; high certainty evidence). In analyses of studies at low risk of selection bias, there is little or no difference in the number of children with any relapse by 12 to 24 months when comparing two months of prednisone with three months or more (RR 0.93, 95% CI 0.81 to 1.06; 808 children; 6 studies; I2 = 47%) or when comparing three months with five to seven months of therapy (RR 0.88, 95% CI 0.70 to 1.11; 377 children, 3 studies; I2 = 53%). Little or no difference was noted in adverse events between the different treatment durations. Amongst children with relapsing SSNS, four small studies (177 children) utilising lower doses of prednisone compared with standard regimens found little or no differences between groups in the numbers with relapse (RR 1.01, 95% CI 0.85 to 1.20; I2 = 0%). A fifth study (117 children) reported little or no difference between two weeks and four weeks of alternate-day prednisone after remission with daily prednisone. A recent large, well-designed study with 271 children found that administering daily prednisone compared with alternate-day prednisone or no prednisone during viral infection did not reduce the risk of relapse. In contrast, four previous small studies in children with frequently relapsing disease had reported that daily prednisone during viral infections compared with alternate-day prednisone or no treatment reduced the risk of relapse. AUTHORS' CONCLUSIONS: There are four well-designed studies randomising 823 children, which have demonstrated that there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Small studies in children with relapsing disease have identified no differences in efficacy using lower induction doses or shorter durations of prednisone therapy. Large, well-designed studies are required to confirm these findings. While previous small studies had suggested that changing from alternate-day to daily prednisone therapy at the onset of infection reduced the likelihood of relapse, a much larger and well-designed study found no reduction in the number relapsing when administering daily prednisone at the onset of infection.

Corticosteroids for the treatment of Duchenne muscular dystrophy: a safety review.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration and weakness, caused by mutations in the dystrophin gene. DMD has effects in early age with significantly shortened lifespan and deteriorated quality of life in the second decade, creating an urgent need to develop better therapeutic options. Corticosteroid medication therapy is an integral tool for the management of DMD and several therapeutic options have been recently approved for use. AREAS COVERED: A comprehensive literature search was completed to examine efficacy and safety profiles of the three corticosteroid medications available for use in DMD patients. The review presents information about the three agents through clinical trials, significant preclinical trials, and comparative studies. EXPERT OPINION: Managing DMD takes a multidisciplinary approach, although long-term corticosteroid therapy remains a significant therapeutic tool. Based on the available published studies, unequivocal comparison between the benefits of the three medications cannot yet be made. When selecting a medication for a patient, the decision-making process will most likely rely on the minor differences in the adverse effect profiles. Whichever medication is utilized will surely be a part of a larger regimen that includes other novel therapeutic agents.