Normalization of enhanced hepatic gluconeogenesis by the antiglucocorticoid RU 38486 in acutely uraemic rats

Hepatic amino acid uptake, urea and glucose production are increased in acute uraemia. It has been shown that this metabolic pattern is mediated by glucocorticoids. Accordingly, the administration of the antiglucocorticoid RU 38486 to acutely uraemic rats resulted in a reduction of serum urea-N and glucose levels. To clarify whether this effect is due to a reduction in hepatic gluconeogenesis we examined the effect of the antiglucocorticoid RU 38486 on urea and glucose formation in isolated hepatocytes from sham-operated (SHAM) and bilaterally nephrectomized (BNX) rats receiving RU 38486 or the vehicle only. Hepatic glucose production in BNX rats was considerably increased from Na-pyruvate (+79%), alanine (+174%), glutamine (+158%), and serine (+87%) compared with SHAM animals. Concomitantly, hepatic urea formation was also enhanced from amino acid substrates in acutely uraemic rats. When uraemic animals were treated with RU 38486, glucose production from amino acids and Na-pyruvate was reduced to the range of SHAM animals or even lower. This effect could not be demonstrated in SHAM-operated controls. A comparable decrement in hepatic urea production was observed in BNX rats treated with the antiglucocorticoid. Thus, glucocorticoids appear to play a key role in the abnormal hepatic urea and glucose production of acutely uraemic rats.     

Oral beclomethasone dipropionate in patients with mild to moderate ulcerative colitis: A dose-finding study

Systemic glucocorticosteroids have demonstrated efficacy in ulcerative colitis (UC) but cause undesired systemic side effects. Beclomethasone dipropionate (BDP) has potent topical activity and is extensively metabolized. This randomized doubleblind study investigated an oral gastroresistant controlled-release preparation of BDP in 57 patients with mild to moderately severe extensive or left-sided UC. Patients were assigned to receive BDP 5 or 10 mg/d; a third group took a clinically inactive dose (1.6 g/d) of 5-aminosalicylic acid (5-ASA). Both BDP doses displayed excellent efficacy confirmed by results of endoscopy, biopsy, and clinical evaluation. Significant improvement from baseline occurred in most signs and symptoms of UC, particularly stool frequency, rectal bleeding, and mucus in the stool (P<.01). Tolerability was good in both BDP groups. Morning plasma cortisol levels decreased significantly from baseline with BDP 10 mg, but no significant changes in vital signs were observed at the end of treatment. Despite a small sample size and the open comparison with 5-ASA, this multicenter study showed the therapeutic equivalence of BDP 5 and 10 mg/d in alleviating clinical symptoms and improving endoscopic and biopsy scores in patients with mild to moderate UC. BDP 5 mg/d displayed better general tolerability and less reduction of plasma cortisol levels, however, and may be preferable to the higher dose in this indication.     

Randomized, Controlled Trial of Inhaled Budesonide as an Adjunct to Oral Prednisone in Acute Asthma

Objective: To compare the clinical effect of nebulized budesonide with placebo in acute pediatric asthma.
Methods: A randomized, controlled, double-blind trial with parallel design was used in the ED of a tertiary care children's hospital. Children aged 6 months to 18 years with a moderate to severe exacerbation of asthma [Pulmonary Index Score (PIS) ≥5 or ≤11 after a salbutamol nebulization of 0.15 mg/kg] were eligible. All patients received prednisone 1 mg/kg orally and nebulized salbutamol (0.15 mg/kg) every 30 minutes for 3 doses and then every hour for 4 hours. The intervention was 2 mg (4 mL) of nebulized budesonide or 4 mL of nebulized normal saline.
Results: Baseline characteristics were comparable in the budesonide group ( n = 24) and in the placebo group ( n - 20). There were no significant differences in the primary outcome measure (PIS) between the 2 groups. However, the PIS at 1 hour had a tendency to be lower in the budesonide group (median = 5) as compared with the placebo group (median = 6; p = 0.07). Survival analysis of release/discharge from the ED/hospital showed a more rapid rate in the budesonide group as compared with the placebo group (p = 0.02). No adverse effects were seen.
Conclusion: Although these preliminary results suggest that nebulized budesonide may be an effective adjunct to oral prednisone in the management of moderate to severe asthma exacerbations, a larger trial will be required before the widespread use of inhaled budesonide in acute asthma can be advocated.     

Upstream Effect for Atrial Fibrillation: Still a Dilemma?

Atrial fibrillation is the most common arrhythmia in clinical practice. Ion channel blocking agents are often characterized by limited long-term efficacy and several side effects. In addition, ablative invasive procedures are neither easily accessible nor always efficacious. The "upstream therapy," which includes angiotensin-converting enzyme inhibitors, aldosterone receptor antagonists, statins, glucocorticoids, and ω-3 poly-unsaturated fatty acids, targets arrhythmia substrate, influencing atrial structural and electrical remodeling that play an essential role in atrial fibrillation induction and maintenance. The mechanisms involved and the most important clinical evidence regarding the upstream therapy influence on atrial fibrillation are presented in this review. Some open questions are also proposed.     

糖皮质激素对重症肌无力患者外周血调节性T细胞中Foxp3及其胞内CTLA-4表达的影响

目的 研究糖皮质激素治疗重症肌无力( MG)患者外周血CD4 +CD25 +调节性 T 细胞( Treg )中 Foxp3 和胞内CTLA-4的表达水平的变化. 方法 收集MG患者34例,分为非治疗组8例和糖皮质激素治疗组26 例. 另将20 例健康者设为对照组. 采用流式细胞仪检测分析患者和健康者外周血CD4 +CD25 +Treg细胞Foxp3和胞内CTLA-4的变化.结果 ① MG非治疗组患者外周血 CD4 +CD25 +Treg细胞Foxp3和胞内CTLA-4水平较对照组显著下降( P<0. 05 );②糖皮质激素治疗能显著提升CD4 +CD25 +Treg细胞Foxp3和胞内CTLA-4表达比例( P <0. 05 ) ,但仍低于对照组( P <0. 05);③ CD4 +CD25 +Treg细胞Foxp3和胞内CTLA-4表达呈正相关性(r=0. 870,P<0. 001). 结论 MG患者外周血CD4 +CD25 +Treg Foxp3和胞内CTLA-4呈低表达,糖皮质激素治疗能显著提升Foxp3和胞内CTLA-4表达水平,但尚未达正常者免疫状态.     

2014年天津市红桥医院糖皮质激素类药物的使用情况分析

目的分析天津市红桥医院糖皮质激素类药物的使用情况,为临床管理和合理用药提供参考。方法对2014年天津市红桥医院糖皮质激素类药物的应用科室、使用量、给药途径、用药频度(DDDs)及药物利用指数(DUI)进行统计分析。结果 2014年糖皮质激素类药物使用率最高的科室为普通内科,使用率为43.55%;使用量最大的为注射用氢化可的松琥珀酸钠;给药途径主要为静脉、肌注,使用率为88.23%;全身性糖皮质激素的DUI值均小于1。结论天津市红桥医院糖皮质激素类药物的临床应用基本合理,但仍存在一些不合理情况,还需进一步加强管理。     

Hypothalamic‐Pituitary‐Adrenal Axis Functioning in Huntington's Disease and its Association with Depressive Symptoms and Suicidality

Hyperactivity of the hypothalamic‐pituitary‐adrenal (HPA) axis has been reported in Huntington's disease (HD). In non‐HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre‐motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow‐up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre‐motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUC_i) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre‐motor, early and advanced disease stages, β values differed between these groups. Remarkably, a higher AUC_i was significantly associated with depressive symptoms in pre‐motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUC_i in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre‐motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress‐induced HPA axis hyperactivity and deserves further longitudinal study.     

A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update

Abstract. Eastell R, Reid DM, Compston J, Cooper C, Fogelman I, Francis RM, Hosking DJ, Purdie DW, Ralston SH, Reeve J, Russell RGG, Stevenson JC, Torgerson DJ (University of Sheffield Medical School, Sheffield; University of Aberdeen, Aberdeen; University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge; Southampton General Hospital, Southampton; Guy's Hospital, London; Freeman Hospital, Newcastle upon Tyne; Nottingham City Hospital, Nottingham; Hull Royal Infirmary, Hull; Wynn Institute for Metabolic Research, London; and the University of York, York, UK). A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update (Review). J Intern Med 1998; 244: 271–292.
In the UK, over 250 000 patients take continuous oral glucocorticoids (GCs), yet no more than 14% receive any therapy to prevent bone loss, a major complication of GC treatment. Bone loss is rapid, particularly in the first year, and fracture risk may double. This review, based wherever possible on clinical evidence, aims to provide easy-to-use guidance with wide applicability. A treatment algorithm is presented for adults receiving GC doses of 7.5 mg day⁻¹ or more for 6 months or more. General measures, e.g. alternative GCs and routes of administration, and therapeutic interventions, e.g. cyclical etidronate and hormone replacement, are recommended.     

PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.