Optimizing inhaled corticosteroid therapy in children with chronic asthma

Asthma is the most common chronic illness among children, and inhaled corticosteroids (ICS) are the most effective long-term therapy available for suppressing airway inflammation in persistent asthma. While the primary aim of ICS therapy is good efficacy with minimal side effects, early diagnosis and treatment of asthma can also improve asthma control and normalize lung function, and may prevent irreversible airway injury. Poor patient compliance is a major barrier to treatment. Simplified dosing regimens (e.g., once-daily administration), good inhaler technique, and education of the patient/caregiver should improve patient compliance. Concerns over ICS therapy are often based on the potential for systemic effects associated with oral corticosteroids (e.g., effects on bone mineral density, or growth suppression in children). Since adverse events are associated with high doses of ICS, the dose in all patients should be titrated to the minimum effective dose required to maintain control. Optimal distribution of an ICS in the lungs rather than the systemic compartment is affected by several factors, including the drug's pharmacokinetic profile, inhaler type, inhaler technique, and drug particle size. For young patients unable to use a dry-powder inhaler or pressurized metered-dose inhaler, a nebulizer facilitates drug delivery through passive inhalation; ICS therapy in the form of budesonide inhalation suspension can be given to children with persistent asthma from 12 months of age. In conclusion, selecting a drug with good efficacy and minimal side effects, such as budesonide, together with an easy-to-use delivery system and ongoing patient/caregiver education, is important in optimizing ICS therapy for children with persistent asthma.     

吸入性肾上腺糖皮质激素对咳嗽变异性哮喘呼吸道高反应性的影响

咳嗽变异性哮喘(cough variant asthma,CVA)是引起慢性咳嗽的最常见病因,约占其32%。1972年Glauser首次描述CVA,其唯一症状是慢性咳嗽,病理生理机制与支气管哮喘(简称哮喘)相似,以呼吸道炎症和呼吸道高反应性     

Effects of inhaled corticosteroid on bone turnover in children with bronchial asthma

Long-term usage of systemic steroids is associated with multiple side effects. One of the major morbidities is due to its effect on bone metabolism leading to bone loss and resulting in skeletal fractures. This study was conducted to determine the effects of inhaled steroids on bone mineral density (BMD) and biochemical bone markers. Twenty-four children with frequent episodic or mild persistent asthma who satisfied the clinical criteria for starting on inhaled corticosteroids (ICS) were enrolled into the study. The BMD scan was done using dual energy X-ray absorptiometry, prior to starting ICS therapy and 6 months later. Biochemical markers of bone metabolism, (i) serum osteocalcin as a bone formation marker, and (ii) urinary deoxypyridinoline (Upd) as a bone resorption marker, were taken prior to ICS treatment and at 2 monthly intervals. The biochemical markers were all taken in the morning. Twenty-four, age- and sex-matched children with mild episodic asthma, not requiring ICS, were used as controls for the BMD measurements. The BMD scan was done upon enrollment into the study and 6 months later. Twenty-four children on ICS and 24 controls completed the study. The subjects were on a mean dose of beclomethasone dipropionate (BDP) 0.4 mg/day. One subject needed a short course of Prednisolone in the early treatment period. None of the controls needed oral steroid therapy. One child in the control group sustained a greenstick fracture after an accidental fall. The mean rate of change of BMD was 1.8% +/- 12.3 in the subjects on BDP. This was lower than the 6.1% +/- 10.6 among the control subjects. However, this difference did not reach statistical significance (P = 0.16). There was a significant increase in serum osteocalcin level after 6 months of BDP treatment from 66.83 +/- 22.71 ng/mL to 81.61 +/- 24.66 ng/mL (P < 0.005). There was a decline in Upd from 36.2 +/- 47.1 nmol/mmol creatinine to 21.4 +/- 6.92 nmol/mmol creatinine. However, this did not reach statistical significance. There was no difference in the statural gain between the subjects on ICS and their controls. This study showed that 6 months of ICS therapy (mean dose 0.4 mg/day) had no significant adverse effect on bone metabolism in asthmatic children.     

Lung function and immunopathological changes after inhaled corticosteroid therapy in asthma.

Six patients with asthma (American Thoracic Society (ATS) criteria), maintained on inhaled beta 2-agonists alone, were treated with inhaled corticosteroid (budesonide 400 micrograms b.d.) for a period of three months. Prior to steroid therapy, baseline spirometry, bronchodilator response and bronchial hyperresponsiveness were documented and endobronchial biopsies were obtained for immunopathological analysis. Frozen sections of the biopsies were investigated using immunoperoxidase methods, with a panel of monoclonal antibodies selected to reveal the presence and distribution of lymphocyte and macrophage subsets and HLA-DR expression. After three months the studies were repeated. Studies before steroid therapy revealed a T-cell-dominated inflammation in the bronchial wall of all subjects. Baseline airway obstruction, median (range) forced expiratory volume in one second (FEV1) 78.5 (61-109)% of predicted, with a significant bronchodilator response 20.8 (14-33)% and bronchial hyperresponsiveness to histamine geometric mean (SD) PC20FEV1 0.69 (2.5) mg was documented. Steroid therapy caused a significant reduction in bronchial hyperresponsiveness to histamine, with an increase in geometric mean PC20FEV1 to 2.22 (3.2) mg post steroid (p less than 0.03). Concurrent with a reduction in bronchodilator response and an increase in spirometric variables (improved forced midexpiratory flow (FEF25-75) p less than 0.03), there were marked reductions observed in the overall numbers of T-lymphocytes (CD 2, 5, 8), the numbers of CD45RO+ T-cells, and the numbers of macrophages (RFD1+) with the phenotype of antigen presenting cells. In all six subjects, reductions in the quantitative expression of HLA-DR molecules were also seen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-dose inhaled corticosteroid therapy and risk of emergency department visits for asthma

BACKGROUND: Patients who visit the emergency department (ED) because of asthma frequently have a relapse. While the use of inhaled corticosteroids has been demonstrated to improve asthma symptoms and lung function, it is not clear whether their use after discharge from the ED reduces asthma relapse rates. OBJECTIVE: To determine whether inhaled corticosteroid therapy reduces ED asthma relapse rates. METHODS: We analyzed ED visit and medication data on patients 5 to 60 years of age who were enrolled in a government-sponsored drug plan and who visited an ED because of asthma between April 1, 1997, and March 31, 1999, in Alberta, Canada (N = 1293). Using a Cox proportional hazards model, we determined the relative risk (RR) of relapse ED visits among users and nonusers of inhaled corticosteroids after discharge from the ED. We also compared the RR of relapse ED visits across different dose categories. RESULTS: Users of inhaled corticosteroids after ED discharge had 45% fewer relapse ED visits than did nonusers (adjusted RR, 0.55; 95% confidence interval [CI], 0.44-0.69). Low-, medium-, and high-dose therapies were associated with similar reductions in the risk of relapse ED visits: low-dose therapy (RR, 0.52; 95% CI, 0.39-0.68), medium-dose therapy (RR, 0.51; 95% CI, 0.34-0.76), and high-dose therapy (RR, 0.67; 95% CI, 0.47-0.94). CONCLUSIONS: Inhaled corticosteroid therapy after ED discharge is associated with a significant reduction in the risk of subsequent ED visits. Low-dose therapy appears to be as effective as high-dose therapy. However, further studies are needed to determine the optimal dosing regimen for inhaled corticosteroid therapy for asthma.     

檞皮素对大鼠酒精性脂肪肝核转录因子表达的影响

目的:探讨檞皮素对大鼠酒精性脂肪肝的防治作用及其可能机制。方法:wistaur(?)鼠48只,随机分为:正常对照、酒精性脂肪肝模型、檞皮素处理、纳洛酮处理4组,实验4 wk末,处死所有大鼠,检测血AST,ALT和TNF-α,并行肝脏病理组织学及核转录因子(NF-ΚB)表达的检测。结果:檞皮素和纳洛酮组血AST,ALT和TNF-α明显低于模型组(檞皮素组:150.7±23.6 U/L,57.4±8.4 U/L,0.83±0.27μg/L;纳洛酮组:148.3±21.4 U/L,55.2±7.3 U/L,0.85±0.34μg/L vs 205.0±31.5 U/L,70.5±9.2 U/L,4.08±1.23μg/L;P<0.05),而高于正常对照组(127.6±17.8 U/L,47.9±7.1 U/L,0.22±0.10μg/L;P<0.05).檞皮素和纳洛酮组肝脏脂肪变程度较模型组轻,且懈皮素组肝内NF-ΚB表达水平显著低于模型组(60.27个/HP vs 28.49个/HP,P<0.05)。结论:檞皮素可能通过抑制NF-ΚB及TNF-α的表达,发挥防治酒精性脂肪肝的作用.     

Comparison of inhaled corticosteroid combined with theophylline and double-dose inhaled corticosteroid in moderate to severe asthma

OBJECTIVE: Recent studies have found that theophylline exerts anti-inflammatory and immunomodulatory effects. This study was performed to compare the efficacy of inhaled corticosteroids (ICS) combined with slow-release theophylline (SRT) with that of double-dose ICS in asthma control, anti-inflammatory activity and safety. METHODOLOGY: In a randomized, open, parallel, control trial, 41 patients with asthma were randomly treated with either beclomethasone dipropionate 500 microg b.i.d. (BDP group) or a combination of BDP 250 microg b.i.d and SRT 0.2 g b.i.d. (SRT/BDP group) for 6 weeks. At the start and at the end of treatment, lung function testing and sputum induction were performed, and plasma cortisol levels were measured. Sputum was analyzed for cell differential counts and the interleukin (IL)-5 level. Patients kept a record of peak expiratory flow (PEF), symptom score, and beta2-agonist use. RESULTS: Significant increases in the morning and the evening PEF and FEV1 were observed (P < 0.05), together with an obvious reduction in symptom score and beta2-agonist use (P < 0.01). Significant decreases in the percentage eosinophils and IL-5 level in induced sputum also occurred (P < 0.05). However, there was no difference between the two groups for all these parameters. There was no significant change in the plasma cortisol level for either group. CONCLUSIONS: Both ICS combined with SRT and double-dose ICS had the same effect on asthma control, improving symptoms and ameliorating lung function. Both therapies had similar anti-airway inflammatory effects and therapeutic safety. Combining SRT with ICS may allow a reduction in ICS dose when treating asthma.     

Effects of ketamine on proinflammatory cytokines and nuclear factor kappaB in polymicrobial sepsis rats

INTRODUCTION Sepsis/Septic shock is a complex pathophysiologic process characterized by profound hypotension, progressive metabolic acidosis, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and even death. Altho…     

成人支气管哮喘患者吸入糖皮质激素治疗的依从状况及其影响因素

目的探讨成人支气管哮喘患者应用糖皮质激素治疗的治疗依从性,并分析与其相关的影响因素。方法选取2014年3月至2015年6月我院收治的成人支气管哮喘患者160例,应用哮喘用药依从性量表对患者吸入糖皮质激素治疗依从性进行测评,并应用Logistic回归分析对于吸入糖皮质激素治疗相关的影响因素进行分析。结果 160例患者中,吸入糖皮质激素治疗依从性好的患者有60例,依从率为37.5%,治疗依从性较差的患者有100例;经影响吸入皮质激素治疗依从性的单因素分析显示,患者病情严重程度及吸入技术掌握程度及哮喘知识掌握程度与患者吸入糖皮质激素治疗依从性存在相关性,差异有统计学意义(P0.05);经Logistic多因素分析显示,哮喘知识的掌握程度、疾病严重程度及吸入技术掌握程度是影响支气管哮喘患者吸入糖皮质激素治疗依从性的影响因素。结论成人支气管哮喘患者应用糖皮质激素吸入治疗的依从性不高,应加强患者吸入技术及哮喘知识的宣教,以提高治疗依从性。     

Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma

BACKGROUND: Neutrophils, in addition to eosinophils, are prominent in the airways of patients with severe asthma who are usually on long-term oral and inhaled corticosteroid treatment. We determined whether inhaled or oral corticosteroid therapy can induce airway neutrophilia. METHODS: We performed two separate placebo-controlled studies in which patients with mild asthma were treated with either prednisolone (30mg per day for 7 days; n = 9) or placebo tablets (n = 8), or with either inhaled budesonide (800 microg twice daily for 4 weeks; n = 6) or inhaled placebo (n = 6). Fiberoptic bronchoscopy was performed before treatment and at day 7 of oral treatment, and at day 28 of inhaled therapy. Bronchial sections were immunostained with an antibody to major basic protein for eosinophils, and with an antibody to neutrophil elastase for neutrophils. Induced sputum was obtained in the prednisolone study. RESULTS: Neutrophils in airway submucosa increased after prednisolone from median 76 to 140/mm2 (P = 0.05); this change was higher than that after placebo (P = 0.04). Eosinophils decreased from 24 to 9/mm2 (P = 0.03), but this was not significantly different from placebo. Eosinophils and neutrophils, and levels of IL-8 and myeloperoxidase in induced sputum did not change after prednisolone. There was no change in neutrophil counts after budesonide, but the reduction in eosinophils was greater than placebo (P = 0.05). Budesonide improved bronchial responsiveness, but prednisolone did not. CONCLUSION: Corticosteroid therapy by the oral but not inhaled route can induce neutrophil recruitment into the airways of patients with mild asthma. This could explain the increase in airway neutrophils observed in severe asthmatics treated with oral corticosteroids.     

Effects of ketamine on proinflammatory cytokines and nuclear factor kappaB in polyrnicrobial sepsis rats

AIM: To explore the effects of ketamine on hemodynamics, plasma proinflammatory cytokine (TNF-α and IL-6) levels and nuclear factor kappa B (NF-κB) activation during polymicrobial sepsis.METHODS: Male Sprague-Dawlay rats were subjected to cecal ligation and puncture (CLP) or sham operation.The rats were randomly assigned into four equal groups:sham CLP group, CLP group, ketamine (KT)I groupand KTⅡ group. Thirty minutes before CLP, ketamine (5my/kg per hour and 10 my/kg per hour, respectively) was infused continuously through the left femoral vein cannula in KT I group or KTⅡgroup. Sham CLP group and CLP group received 0.9% saline only (5 mL/kg per hour). The right femoral artery was cannulated to monitor mean arterial pressure (MAP) and heart rates (HR),and draw blood samples. The proinflammatory cytokine (TNF-α and IL-6) levels of plasma were measured using enzyme-linked immunosorbent assays (ELISA). The hepatic NF-κB activation was determined by Western blot and HPIAS 2000 image analysis system.Twenty hours after CLP, the rats were killed by right femoral artery phlebotomization.RESULTS: CLP produced progressive hypotension,and a first increase followed by a decrease in HR. The hypotension was prevented, and the HR was slightly steady in ketamine treated rats. TNF-α levels of plasma reached a peak value at 2 h after CLP. Ketamine (KT I group or KTⅡgroup) caused a significant decrease compared with CLP group at 2, 5 and 9 h time points after CLP (14.3 ± 1.9 vs 4.3 ± 0.9, 9.7 ± 1.4 vs 4.3 ±0.9; 9.3 ± 1.5 vs 4.3 ± 0.9, 8.7 ± 1.4 vs 4.3 ± 0.9; 6.0± 1.5 vs 5.0 ± 1.7, 5.3 ± 0.8 vs 5.0 ± 1.7; P ＜ 0.01,respectively). The IL-6 levels of plasma firstly ascended and then descended in CLP group, and reached a peak value at 9 h after CLP. Ketamine (KT I group or KTⅡ group) caused a significant decrease compared with CLP group at 5, 9 or 20 h after CLP (135.0 ± 52.6 vs 60.0± 16.3, 112.5 ± 52.6 vs 60.0 ± 16.3; 410.0 ± 68.7 vs62.5 ± 12.5, 250.0 ± 28.0 vs 62.5 ± 12.5; 320.0 ± 25.9vs 52.5 ± 10.1, 215.0 ± 44.6 vs 52.5 ± 10.1; P ＜ 0.05,respectively). The IL-6 levels of plasma in KTⅡgroup were lower than those of KT I group at 9 h after CLP (250.0 ± 28.0 vs 410.0 ± 68.7; P ＜ 0.05). In addition,CLP increased hepatic NF-κB expression compared with sham CLP. Ketamine suppressed NF-κB activation in a dose-dependent manner at 4 h after CLP (237.7 ± 3.5 vs 246.9 ± 3.1; P ＜ 0.05).CONCLUSION: Ketamine stabilizes the hemodynamics,attenuates the proinflammatory cytokine responses,and inhibits hepatic NF-κB activation. These findings suggest that ketamine has protective effects against polymicrobial sepsis in rats.     

吸入性糖皮质激素治疗哮喘的进展

哮喘是涉及包括大气道和内径〈2mm的小气道,整个肺的慢性炎症,病理改变为支气管黏膜炎症伴支气管黏膜水肿,以及长期病程引起的气道重塑,在临床上表现为可逆性气流受限和受刺激后产生气道高反应性（airway hyperresponsiveness,AHR）。为了控制炎症这个主要病因,吸人型糖皮质激素（inhaled corticosteroids,ICS）于1972年开始应用于临床。由于其具有较大的脂溶性,对受体亲和力强,肝脏首过代谢率高,     

吸烟对支气管哮喘患者吸入糖皮质激素治疗的影响

目的 探讨吸烟对支气管哮喘(简称哮喘)患者临床症状、肺功能及气道炎症的影响,以及对激素治疗的敏感性.方法 选取2009年1 2月至2011年1月门诊就诊的40例慢性持续期哮喘患者,根据是否吸烟分为吸烟组(15例)和非吸烟组(23例).所有患者给予糖皮质激素(布地奈德)吸入治疗,必要时可吸入β2受体激动剂.发放哮喘日记卡及峰流速仪.记录治疗前及治疗28 d后哮喘症状评分、哮喘控制测试(ACT)评分、肺功能、晨间及夜间最高呼气流速(PEF),诱导痰中嗜酸粒细胞及中性粒细胞百分比,并测定痰液中白介素8(IL-8)及嗜酸粒细胞趋化因子(eotaxin)水平.结果 两组患者治疗前除性别构成外,年龄、病程、ACT评分、肺功能指标差异均无统计学意义.两组患者治疗后ACT评分(F=39.991,P<0.05)、FEV1%pred(F＝56.075,P<0.05)、PEV1%pred(F＝53.535,P<0.05),嗜酸粒细胞百分比(F＝15.271,P<0.05)及eotaxin(F=24.172,P<0.05)水平均较治疗前有明显改善,哮喘症状评分显著降低(P<0.05).其中非吸烟组以上指标的改善程度均优于吸烟组(P<0.05).结论 吸烟降低了哮喘患者对ICS治疗的反应性.对吸烟的哮喘患者,治疗可能需要特殊调整.     

吸烟对支气管哮喘患者糖皮质激素治疗的影响

目的通过本实验进一步探讨吸烟对支气管哮喘(简称哮喘)患者气道炎症的影响,了解吸烟哮喘患者对激素治疗的敏感性。方法选取35例慢性持续期哮喘患者,根据是否吸烟,分为吸烟组14例和非吸烟组21例。所有患者给予吸入糖皮质激素(ICS)治疗,必要时可吸入β2受体激动剂,发放哮喘日记卡及峰流速仪。分别记录治疗前及治疗28d后哮喘症状评分、哮喘控制测试(ACTTM)评分;第一秒用力呼气容积占预计值百分比(FEV1占预计值%)、第一秒用力呼气容积占用力肺活量百分比(FEV1/FVC%)、最大呼气流速占预计值百分比(PEF占预计值%)、每日晨间及夜间PEF;诱导痰中嗜酸粒细胞及中性粒细胞百分比并测定痰液中白介素8(IL-8)及嗜酸粒细胞趋化因子(eotaxin)水平。结果两组患者ICS治疗后ACTTM评分有明显改善,组间ACTTM评分比较差异具有统计学意义(t=5.542,P<0.05)。治疗后两组哮喘患者肺功能均有改善,组间比较FEV1占预计值%(t=4.740,P<0.05)、PEF占预计值%(t=5.190,P<0.05)差异有统计学意义。两组患者ICS治疗后组内比较嗜酸粒细胞百分比、eotaxin水平差异均有统计学意义。中性粒细胞百分比治疗前、后差异无统计学意义。治疗后组间比较中性粒细胞(t=7.707,P<0.05)、IL-8水平(t=4.557,P<0.05)、嗜酸粒细胞百分比(t=4.740,P<0.05)及eotaxin水平(t=2.064,P<0.05)差异均有统计学意义。结论两组患者ICS治疗28d后,其临床症状、肺功能及痰中炎性介质均有改善,但吸烟组改善程度较非吸烟组差。吸烟组哮喘患者诱导痰中中性粒细胞及IL-8水平高于非吸烟组哮喘患者,而嗜酸粒细胞及eotaxin水平低于后者。     

吸烟对轻度支气管哮喘患者吸入激素疗效的影响

目的　观察吸烟对轻度支气管哮喘患者吸入激素疗效的影响。方法　对不吸烟 (1 8例 )及吸烟 (1 7例 )的支气管哮喘患者每日吸入二丙酸倍氯米松 5 0 0μg治疗 4周 ,治疗前后进行肺功能测定及气道反应性试验 ,用药过程中监测呼气峰流速 (peak expiratory flow,PEF)。结果　不吸烟组患者治疗后的清晨 PEF、睡前 PEF、FEV1 %及气道反应性均较治疗前改善 (P<0 .0 5 )。而吸烟组患者在治疗前后上述指标却变化不大 (P>0 .0 5 )。结论　吸烟能明显减弱支气管哮喘患者吸入激素的疗效 ,支气管哮喘患者应积极戒烟以取得较好的疗效     

吸烟对支气管哮喘患者吸入糖皮质激素治疗的影响

目的 探讨吸烟对支气管哮喘(简称哮喘)患者临床症状、肺功能及气道炎症的影响,以及对激素治疗的敏感性.方法 选取2009年12月至2011年1月门诊就诊的40例慢性持续期哮喘患者,根据是否吸烟分为吸烟组(15例)和非吸烟组(23例).所有患者给予糖皮质激素(布地奈德)吸入治疗,必要时可吸入β2受体激动剂.发放哮喘日记卡及峰流速仪.记录治疗前及治疗28 d后哮喘症状评分、哮喘控制测试(ACT)评分、肺功能、晨间及夜间最高呼气流速(PEF),诱导痰中嗜酸粒细胞及中性粒细胞百分比,并测定痰液中白介素8(IL 8)及嗜酸粒细胞趋化因子(eotaxin)水平.结果 两组患者治疗前除性别构成外,年龄、病程、ACT评分、肺功能指标差异均无统计学意义.两组患者治疗后ACT评分(F=39.991,P＜0.05)、FEV1％ pred(F=56.075,P＜0.05)、PEF％ pred(F=53.535,P＜0.05),嗜酸粒细胞百分比(F=15.271,P＜0.05)及eotaxm(F=24.172,P＜0.05)水平均较治疗前有明显改善,哮喘症状评分显著降低(P ＜0.05).其中非吸烟组以上指标的改善程度均优于吸烟组(P＜0.05).结论 吸烟降低了哮喘患者对ICS治疗的反应性.对吸烟的哮喘患者,治疗可能需要特殊调整.     

Advances in single-entity inhaled corticosteroid therapy.

The aim of inhaled corticosteroid (ICS) therapy is to achieve optimal drug targeting by producing pulmonary effects with a minimum of systemic side effects. To achieve a favorable safety and efficacy profile, an ICS should possess the necessary pharmacokinetic and pharmacodynamic characteristics. Ideally, an ICS would have high pulmonary deposition efficiency, high systemic clearance, negligible oral bioavailability, sustained pulmonary residence time, selective binding to the corticosteroid receptor, and high plasma protein binding. Recent developments in ICS therapy have used these concepts in producing more effective compounds resulting in drugs with a very high therapeutic index. Additional developments may consider exploring improvements in delivery devices and drug formulations to improve pulmonary residence time.