Ex vivo stimulation of cord blood mononuclear cells by dexamethasone and interleukin-7 results in the maturation of interferon-gamma-secreting effector memory T cells

The effects of dexamethasone phosphate and interleukin‐7 upon the proliferation of T‐cells and the production of interferon‐γ in the newborn's cord blood mononuclear cell cultures were studied. The capability of dexamethasone to enhance T‐cell proliferation induced by anti‐CD3 with interleukin‐7 in some newborn cord blood mononuclear cell cultures was identified. Dexamethasone suppressed production of interferon‐γ in 68‐h cell cultures stimulated with anti‐CD3 both in the presence of interleukin‐7 and without it. However, a 68‐h cultivation of newborn blood cells with dexamethasone, anti‐CD3 and interleukin‐7 resulted in the accumulation of T‐lymphocytes capable of producing interferon‐γ after restimulation. As a result of it the amount of interferon‐γ producing CD7⁺ T‐cells and the concentration of interferon‐γ in cultural supernatants were maximal in the cell cultures incubated with anti‐CD3, interleukin‐7 and dexamethasone during the first 68 h and subsequently restimulated with phorbol 12‐myristate 13‐acetate and ionomycin. The stimulation of neonatal or adult blood cells by dexamethasone, anti‐CD3 and interleukine‐7 also causes a decrease in the number of naïve T‐cells and central memory cells and an increase in the number of effector memory CD7⁺CD45RA⁺CD62L^– cells in cultures. It is possible that these effects are caused by the influence of dexamethasone on IL‐7 receptor expression: it is known that IL‐7 receptor alpha‐chain gene is a glucocorticoid‐inducible gene.     

Differential regulation of mast cell cytokines by both dexamethasone and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580

Activated mast cells generate multiple cytokines but it is not known if these can be differentially regulated by pharmacological agents. We report here that the glucocorticoid dexamethasone (DEX) preferentially inhibited Ag-induced expression of IL-4 and IL-6 mRNA relative to TNF-alpha mRNA in RBL-2H3 cells. Likewise, the drug more readily inhibited release of IL-4 than TNF-alpha protein. SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), enhanced Ag-induced TNF-alpha mRNA expression without affecting IL-4 or IL-6 mRNA. At the protein level, SB203580 exerted little effect on TNF-alpha release but inhibited IL-4 release; notably, the ratio of TNF-alpha : IL-4 increased markedly with the concentration of SB203580, confirming the differential regulation of these cytokines. PD98059, an inhibitor of MAPK kinase (MEK), a component of the p44/42 MAPK pathway, partially inhibited Ag-induced expression of mRNA for all three cytokines while cyclosporin A inhibited Ag-induced IL-4 and IL-6 mRNA more readily than TNF-alpha mRNA. Ag activation of the cells led to phosphorylation of p38 and p44/42 MAPK but this was not influenced by DEX. In conclusion, mast cell cytokines can be differentially regulated pre- and post-translationally by DEX and SB203580 but there does not appear to be a direct mechanistic link between the actions of these two drugs.     

Effect of antenatal dexamethasone therapy on maternal plasma human chorionic gonadotrophin, oestradiol and progesterone

The aim of this study was to determine whether the current regimen of dexamethasone administration to induce fetal lung maturation affected the circulating concentrations of placental hormone. A standard regimen of dexamethasone that comprised two doses of 12-mg intramuscular injections, 12 h apart was administered to 12 pregnant women to promote fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before starting the dexamethasone therapy, 24 h, and 48 h after completing therapy for the measurement of the plasma concentrations of human chorionic gonadotrophin (HCG), oestradiol and progesterone. There was a progressive fall in the plasma concentrations of HCG following dexamethasone therapy (P = 0.049 and P = 0.034, 24-h and 48-h post therapy respectively). There was an initial fall in the plasma concentrations of oestradiol after dexamethasone therapy (z = 3.059; P = 0.002, 24-h post therapy), which recovered by 48 h (P = 0.239). There was no difference between the plasma concentrations of progesterone at the three time points. The effect of dexamethasone on HCG concentrations suggests that it has a direct inhibitory effect on placental hormone synthesis or secretion. Further studies are needed to define the mechanism of action of dexamethasone on placental HCG production.     

地塞米松诱发大鼠卡氏肺孢子虫肺炎实验研究

目的 在地塞米松磷酸钠诱导下建立大鼠卡氏肺孢子虫肺炎的动物模型。方法 将40只雌性SD大鼠随机分为实验组和对照组,前者皮下注射地塞米松磷酸钠,1mg/次,2次/w;后者不做任何处理。观察两组大鼠的发病情况,并每隔3周两组各取5只动物进行病原学检查。结果 实验组大鼠第6周开始发病,肺印片、支气管肺泡灌洗液沉渣中查到卡氏肺孢子虫包囊及滋养体;对照组大鼠无异常表现,病原学检查阴性。结论 在地塞米松磷酸钠诱导下可成功建立大鼠卡氏肺孢子虫肺炎动物模型。     

不同抗炎药物对缺氧所致大鼠离体肺血管环张力变化的影响

为研究离体大鼠肺血管在缺氧时张力的变化,以及甾体、非甾体类抗炎药物对此变化影响的异同性,采用等长收缩技术,测定加入消炎痛或地塞米松前后张力改变的特点及两药作用的差异。结果发现Wistar大鼠与Sprague-Dawley大鼠肺血管环对缺氧的反应不同,后者仅出现收缩反应,而Wistar大鼠在收缩前出现一内皮依赖的舒张;COX非特异性抑制剂消炎痛对缺氧所致的舒张和收缩均有增强作用;COX-2特异性抑制剂地塞米松则在明显抑制舒张的同时轻度增强收缩反应。结果表明不同种属大鼠的肺血管缺氧反应可能存在差异;缩管性PGs和扩管性PGs分别调节急性肺血管缺氧的舒张和收缩反应,这一过程呈一定的内皮依赖性;非选择性和选择性的COX抑制剂对肺血管缺氧反应的作用不尽相同。     

Impact of Dexamethasone on Length of Stay and Early Pain Control in Direct Anterior Approach Total Hip Arthroplasty With Neuraxial Anesthesia

BackgroundDexamethasone has been shown to reduce postoperative pain and opioid consumption for total joint arthroplasty patients; however, its impact on patients who received neuraxial anesthesia (NA) is not well described. We examined the impact of perioperative dexamethasone on outcomes for patients undergoing direct anterior approach total hip arthroplasty (THA) under NA.MethodsA retrospective review was conducted for 376 THA patients from a single institution. Univariate analysis was used to compare postoperative outcomes for 164 THA patients receiving dexamethasone compared to 212 who did not receive dexamethasone.ResultsNo differences in age, gender, body mass index, or American Society of Anesthesiologists (ASA) Score were observed between the groups. Patients receiving perioperative dexamethasone reported statistically significantly lower postanesthesia care unit (PACU) pain numeric rating scale (Dexamethasone 1.6 vs No dexamethasone 2.3, P = .014) and received lower PACU morphine milligram equivalents (MME) (Dexamethasone 8.57 vs No dexamethasone 11.44, P < .001). Patients receiving dexamethasone had significantly shorter LOS (Dexamethasone 29.40 vs No dexamethasone 35.26 hrs., P < .001).ConclusionPerioperative dexamethasone is associated with decreased postoperative pain and narcotic consumption, and shorter length of stay for patients undergoing primary direct anterior approach THA with NA.     

Steroids to reduce the impact on delirium (STRIDE): a double-blind,randomised, placebo-controlled feasibility trial of pre-operative dexamethasone in people with hip fracture

Neuro-inflammation may be important in the pathogenesis of postoperative delirium following hip fracture surgery. Studies have suggested a potential role for steroids in reducing postoperative delirium; however, the potential efficacy and safety of pre-operative high-dose dexamethasone in this specific population is largely unknown. Conducting such a study could be challenging, considering the multidisciplinary team involvement and the emergency nature of the surgery. The aim of this study was to assess feasibility and effectiveness of dexamethasone given as early as possible following hospital admission for hip fracture, to inform whether a full-scale trial is warranted. This single-centre, randomised, double-blind, placebo-controlled study randomly allocated 79 participants undergoing hip fracture surgery to dexamethasone 20 mg or placebo pre-operatively. Eligibility and recruitment rates, timing of the intervention and adverse events were recorded. Incidence and severity of postoperative delirium were assessed using the 4AT delirium screening tool and the Memorial Delirium Assessment Scale. Postoperative pain, length of stay and mortality were also assessed. The eligibility rate for inclusion was 178/527 (34%), and 57/178 (32%) of eligible patients presented to hospital when no researcher was available (e.g. after-hours, weekends, public holidays). Recruitment was limited mainly by ethical limitations (not including patients with impaired cognition) and lack of weekend staffing. Median (IQR [range]) time from emergency department admission to drug administration was 13.3 (5.9–17.6 [1.8–139.6]) hours. There was a significant difference in delirium severity scores, favouring the dexamethasone group: median (IQR [range]) 5 (3–6 [3–7]) vs. 9 (6–13 [5–14]) in the placebo group, with the probability of superiority effect size being 0.89, p = 0.010. Delirium incidence did not differ between groups: 6/40 (15%) in the dexamethasone group vs. 9/39 (23%) in the placebo group, relative risk (95%CI) 0.65 (0.22–1.65), p = 0.360). A larger randomised controlled trial is feasible and ideally this should include people with existing cognitive impairment, seven days-a-week cover and a multicentre design.     

In Vitro Evaluation of Dexamethasone-β-D-Glucuronide for Colon-Specific Drug Delivery

Dexamethasone--D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozer et al., Pharm. Res. 8:445–454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone--D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl--D-glucoside and --D-glucuronide) and to evaluate the prodrug dexamethasone--D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (-D-glucosidase and -D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of -D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal -D-glucuronidase activity in the large intestine; however, -D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal -D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of -D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone--D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of -D-glucuronidase activity in the small intestine compared with that in the laboratory rat.     

黄芩甙、地塞米松对大鼠感染性脑水肿细胞因子的影响

目的 :探讨黄芩甙、地塞米松对大鼠感染性脑水肿白细胞介素 1(IL 1β)、肿瘤坏死因子α(TNF α)的影响。方法 :应用大鼠感染性脑水肿模型 ,采用干湿法、原子吸收分光光度法、ELISA测定各组脑组织水含量、钠离子含量及脑匀浆上清液中IL 1β,TNF α水平的变化 ;在光镜下观察各组脑组织的细胞形态学改变。结果 :在大鼠感染性脑水肿(感脑 )组脑水含量、钠离子、IL 1β、TNF α含量均比生理盐水 (对照 )组明显增高 (P <0 .0 1)。在黄芩甙和地塞米松两组则上述指标均下降 ,低于感脑组 (P <0 .0 5 ) ;而两组间各指标比较差异无显著性 (P >0 .0 5 ) ;脑组织水含量与IL 1β ,TNF α含量成正相关 (r分别为 0 9381,0 8349,P <0 .0 1)。对照组脑组织结构正常 ,感脑组织脑组织可见弥漫的灶性水肿区 ;黄芩甙和地塞米松组水肿明显减轻。结论 :黄芩甙、地塞米松对大鼠感染性脑水肿有保护作用 ,效果相近 ;作用机制与抑制IL 1β ,TNF α过度产生有关