Effect of long-term treatment with salmeterol on asthma control: a double blind,randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

Protective effect of budesonide/formoterol compared with formoterol,salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised,double-blind,cross-over study

Background

The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.

Methods

The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV₁ 95% of predicted) who previously demonstrated a ≥30% fall in forced expiratory volume in 1 second (FEV₁) after inhaling adenosine 5''-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 μg), formoterol (4.5 μg), salbutamol (2 × 100 μg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day.

Results

In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV₁ within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV₁.

Conclusions

A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

Trial Registration

ClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT00272753","term_id":"NCT00272753"}}NCT00272753     

Long-term effects of biofeedback-induced facial relaxation on measures of asthma severity in children

We studied the effects of electromyographic biofeedback on measures of asthma severity in children. Fifteen children received biofeedback training to reduce facial tension, and 14 children, who served as controls, received biofeedback training to maintain facial tension at a stable level. Assignment to experimental condition was random. As a result of training, electromyographic levels decreased in children trained in facial relaxation and remained fairly constant in children trained in facial tension stability. Biofeedback training was augmented for children in both groups by having them practice their facial exercises at home. Each child's condition was followed for a five-month period subsequent to biofeedback training. Throughout the experiment, the following measures of asthma severity were monitored: lung function, self-rated asthma severity, medication usage, and frequency of asthma attacks. In addition, standardized measures of attitudes toward asthma, self-concept, and chronic anxiety were recorded at regular intervals. As compared to the facial stability subjects, the facial relaxation subjects exhibited higher pulmonary scores, more positive attitudes toward asthma, and lower chronic anxiety during the follow-up period. Subjects in the two groups, however, did not differ on self-rated asthma severity, medication usage, frequency of asthma attacks, or self-concept. Based on the improvements we observed in pulmonary, attitude, and anxiety measures, we concluded that biofeedback training for facial relaxation contributes to the self-control of asthma and would be a valuable addition to asthma self-management programs.     

Inhaled budesonide inhibits OVA-induced airway narrowing, inflammation, and cys-LT synthesis in BN rats.

The objective of the present investigation was to examine the effects of an inhaled glucocorticoid, budesonide, on antigen-induced production of cysteinyl leukotrienes (cys-LTs) and pulmonary inflammatory cell infiltration in the Brown Norway rat, an animal model of asthma. Two weeks after sensitization to ovalbumin, rats were treated with budesonide (2.5 mg/kg) 18 and 1 h before challenge with antigen. Budesonide abolished the late response to ovalbumin (P<0.02) and strongly inhibited the in vivo synthesis of N-acetyl-leukotriene E(4), an indicator of cys-LT synthesis, during this period (P<0.005). Both total bronchoalveolar lavage (BAL) cells (P<0.01) and BAL macrophages (P<0.005) were markedly reduced to approximately 25% of their control levels after treatment with budesonide. It can be concluded that inhibition of the antigen-induced late response in Brown Norway rats by budesonide is associated with reductions in both BAL macrophages and cys-LT synthesis. It is possible that the effect of budesonide on cys-LT synthesis is related to its effects on pulmonary macrophages.     

早期吸入不同浓度布地奈德对哮喘大鼠气道炎症和重构的干预

目的:研究早期吸入不同浓度布地奈德对哮喘大鼠气道炎症和气道重构的干预情况。方法:32只Wistar大鼠随机分为4组:A对照组8只,B卵蛋白(OVA)致哮喘组8只,C卵蛋白致哮喘后吸入低浓度布地奈德治疗组8只,D卵蛋白致哮喘后吸入高浓度布地奈德治疗组8只。分别测定各组大鼠血中肿瘤坏死因子-α(TNF-α)及肺泡灌洗液(BALF)中内皮素-1(ET-1)的水平,计数BALF中细胞总数及分类。各组大鼠行肺组织切片HE染色,再行胶原染色、免疫组化NGF、TGF-β1染色,借助计算机图象分析软件测量单位气道面积炎性细胞数目,基底膜周径(Pbm)、平滑肌面积(WAm)、气道内壁面积(WAi)、胶原面积(Wcol),NGF及TGF-β1阳性信号积分吸光度。结果:B组BALF中细胞总数、嗜酸细胞分类及TNF-α、ET-1水平与A组比较均明显增加,差异有统计学意义(P<0.01),C组及D组较B组均明显降低,差异有统计学意义(P<0.01)。B组NGF及TGF-β1的表达、气道壁炎性细胞计数、气道内壁面积、平滑肌面积、胶原面积与A组比较均明显增加,差异有统计学意义(P<0.01),C组及D组与B组比较均明显降低,差异有统计学意义(P<0.01),C组及D组与A组比较差异有统计学意义(P<0.05,P<0.01),C组与D组差异均有统计学意义(P<0.05,P<0.01)。结论:早期吸入不同浓度的布地奈德均可明显抑制气道炎症和气道重构,高浓度较低浓度对气道炎症和气道重构的影响更明显。     

Long-term effects of biofeedback-induced facial relaxation on measures of asthma severity in children

We studied the effects of electromyographic biofeedback on measures of asthma severity in children. Fifteen children received biofeedback training to reduce facial tension, and 14 children, who served as controls, received biofeedback training to maintain facial tension at a stable level. Assignment to experimental condition was random. As a result of training, electromyographic levels decreased in children trained in facial relaxation and remained fairly constant in children trained in facial tension stability. Biofeedback training was augmented for children in both groups by having them practice their facial exercises at home. Each child's condition was followed for a five-month period subsequent to biofeedback training. Throughout the experiment, the following measures of asthma severity were monitored: lung function, self-rated asthma severity, medication usage, and frequency of asthma attacks. In addition, standardized measures of attitudes toward asthma, self-concept, and chronic anxiety were recorded at regular intervals. As compared to the facial stability subjects, the facial relaxation subjects exhibited higher pulmonary scores, more positive attitudes toward asthma, and lower chronic anxiety during the followup period. Subjects in the two groups, however, did not differ on self-rated asthma severity, medication usage, frequency of asthma attacks, or self-concept. Based on the improvements we observed in pulmonary, attitude, and anxiety measures, we concluded that biofeedback training for facial relaxation contributes to the self-control of asthma and would be a valuable addition to asthma self-management programs.This research was supported by NIH grant No. HL27402. We are grateful to Anita D. Baker, Lisa Barclay, Deborah L. Harm, and Douglas J. Miller for serving as experimenters and to Constance K. Cottrell and Cindy Stout for compiling summaries of the data.     

布地奈德溶液治疗哮喘急性发作的疗效评价

目的：评价吸入布地奈德溶液治疗哮喘急性发作的有效性和安全性。方法：选择54例哮喘急性发作的中重度患者接受1周的吸入布地奈德溶液治疗,随访2周,比较用药前、用药后第24小时,48小时,停药2周时FEVI值,PEF值。FVC值及患者对疗效的自我评价。结果：治疗后各项指标均有明显改善。在肺功能改善方面优于症状改善。无明显不良反应。结论：吸入布地奈德溶液临床疗效显著,安全性好,是目前治疗哮喘急性发作的最佳的吸入激素制剂之一。     

Inhaled corticosteroid effects both eosinophilic and non-eosinophilic inflammation in asthmatic patients

AIM: To determine induced sputum cell counts and interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha) and leukotriene B4 (LTB4) levels as markers of neutrophilic inflammation in moderate persistent asthma, and to evaluate the response to inhaled steroid therapy. METHODS: Forty-five moderate asthmatic patients and 10 non-smoker controls were included in this study. All patients received inhaled corticosteroid (800 microg of budesonide) for 12 weeks. Before and after treatment pulmonary function tests were performed, and symptom scores were determined. Blood was drawn for analysis of serum inflammatory markers, and sputum was induced. RESULTS: Induced sputum cell counts and inflammatory markers were significantly higher in patients with asthma than in the control group. The induced sputum eosinophil counts of 12 patients (26%) were found to be less than 5%, the non-eosinophilic group, and sputum neutrophil counts, IL-8 and TNF-alpha levels were significantly higher than the eosinophilic group (neutrophil, 50+/-14% versus 19+/-10%, p<0.01). In both groups, there was a significant decrease in sputum total cell counts and serum and sputum IL-8, TNF-alpha and LTB4 levels after the treatment. There was no change in sputum neutrophil counts. Although the sputum eosinophil count decreased only in the eosinophilic subjects, there was no significant difference in inflammatory markers between the groups. The symptom scores were significantly improved after treatment, while the improvement did not reach statistical significance on pulmonary function test parameters. CONCLUSION: Notably, in chronic asthma there is a subgroup of patients whose predominant inflammatory cells are not eosinophils. Sputum neutrophil counts and neutrophilic inflammatory markers are significantly higher in these patients. In the non-eosinophilic group, inhaled steroid caused an important decrease in inflammatory markers; however, there was no change in the sputum eosinophil and neutrophil counts.     

The effects of stimulant therapy,EEG biofeedback,and parenting style on the primary symptoms of attention-deficit/hyperactivity disorder

One hundred children, ages 6–19, who were diagnosed with attention-deficit/hyperactivity disorder (ADHD), either inattentive or combined types, participated in a study examining the effects of Ritalin, EEG biofeedback, and parenting style on the primary symptoms of ADHD. All of the patients participated in a 1-year, multimodal, outpatient program that included Ritalin, parent counseling, and academic support at school (either a 504 Plan or an IEP). Fifty-one of the participants also received EEG biofeedback therapy. Posttreatment assessments were conducted both with and without stimulant therapy. Significant improvement was noted on the Test of Variables of Attention (TOVA; L. M. Greenberg, 1996) and the Attention Deficit Disorders Evaluation Scale (ADDES; S. B. McCarney, 1995) when participants were tested while using Ritalin. However, only those who had received EEG biofeedback sustained these gains when tested without Ritalin. The results of a Quantitative Electroencephalographic Scanning Process (QEEG-Scan; V. J. Monastra et al., 1999) revealed significant reduction in cortical slowing only in patients who had received EEG biofeedback. Behavioral measures indicated that parenting style exerted a significant moderating effect on the expression of behavioral symptoms at home but not at school.     

布地奈德通过干预线粒体钙单转运蛋白影响哮喘大鼠气道上皮细胞自噬和屏障功能的机制

摘要 目的：探究布地奈德通过干预线粒体钙单转运蛋白影响哮喘大鼠气道上皮细胞自噬和屏障功能的机制。方法：30只雄性SD大鼠作为研究对象,并根据实验目的分为3组：对照组（正常大鼠,生理盐水干预,n=10）,哮喘组（通过OVA诱导大鼠哮喘模型,n=10）,布地奈德组（气雾剂布地奈德用于治疗过敏性哮喘的大鼠,n=10）。通过钙测定试剂盒和蛋白印迹分析大鼠气道上皮细胞中Ca²⁺的吸收和MCU蛋白表达;TEER和TRITC 荧光分析检测大鼠气道上皮中的屏障功能;免疫组化分析分气道上皮细胞屏障功能相关因子ZO-1、E-cadherin的蛋白表达;ELISAF分析BALF上清液中炎性因子IL-4、IL-5和IL-13的水平;二氢乙锭衍生物和蛋白印迹分析BALF中ROS含量和caspase-3活性。结果：哮喘组较对照组Ca²⁺浓度降低,MCU蛋白表达升高（P<0.05）,布地奈德组较哮喘组Ca²⁺浓度升高,MCU蛋白表达降低（P<0.05）。哮喘组较对照组TEER降低,TRITC升高（P<0.05）,布地奈德组较哮喘组TEER升高,TRITC降低（P<0.05）。哮喘组较对照组ZO-1、E-cadherin的蛋白表达降低（P<0.05）,布地奈德组较哮喘组ZO-1、E-cadherin的蛋白表达升高（P<0.05）。哮喘组较对照组IL-4、IL-5和IL-13的水平升高（P<0.05）,布地奈德组较哮喘组IL-4、IL-5和IL-13的水平降低（P<0.05）。对照组组支气管和肺泡结构未见异常,与对照组相比哮喘组大鼠表现出肺泡间隔增厚,可见的肺毛细血管水肿,以及肺毛细血管和肺泡间隙中的大量炎性细胞浸润（P<0.05）,与哮喘组相比,布地奈德组显著减轻肺部病变的严重程度（P<0.05）。哮喘组较对照组LC3B II/I、ATG5、Beclin-1 和LC3II 的表达升高（P<0.05）,布地奈德组较哮喘组LC3B II/I、ATG5、Beclin-1 和LC3II 的表达降低（P<0.05）。哮喘组较对照组ROS含量和caspase-3活性升高（P<0.05）,布地奈德组较哮喘组ROS含量和caspase-3活性降低（P<0.05）。结论：布地奈德通过调节MCU表达介导气道上皮细胞的屏障完整性和自噬水平,缓解哮喘气道炎症,改善哮喘症状。     

Respiratory Sinus Arrhythmia Biofeedback Therapy for Asthma: A Report of 20 Unmedicated Pediatric Cases Using the Smetankin Method

This multiple case study describes pulmonary function changes in 20 asthmatic children from 30 consecutive cases undergoing biofeedback training for increasing the amplitude of respiratory sinus arrhythmia (RSA). The Smetankin protocol was used, which, in addition to RSA biofeedback, includes instructions in relaxed abdominal pursed-lips breathing. Ten individuals were excluded, including 6 who had been taking asthma medication, 2 who developed viral infections during the treatment period, and 2 who dropped out prior to completing treatment. Patients each received 13 to 15 sessions of training. Asthma tended to be mild, with mean spirometric values close to normal levels. Nevertheless, significant improvements were noted in 2 spirometry measures taken during forced expiratory maneuvers from maximum vital capacity: FEV₁ and FEF50. These preliminary uncontrolled data suggest that the Smetankin protocol warrants further evaluation as a nonpharmacological psychophysiological treatment for this condition, although these data could not definitively prove that the method is effective.     

Combined budesonide/formoterol therapy in conjunction with allergen avoidance ameliorates house dust mite-induced airway remodeling and dysfunction

Allergic asthma is characterized by airway inflammation in response to chronic allergen exposure, resulting in remodeling of the airway wall accompanied by dysfunctional airway physiology. However, a link between the immune-inflammatory response to allergen and changes to airway structure and physiology has not yet been fully elucidated. Moreover, the impact of inhaled corticosteroids and beta(2)-agonists, the primary pharmacotherapy for asthma, on this process has not been completely evaluated. In this study, we employed a murine model of chronic exposure to a common environmental aeroallergen, house dust mite, to recapitulate the phenotype of clinical asthma. By examining the therapeutic effects of corticosteroid/beta(2)-agonist combination therapy with budesonide/formoterol (BUD/FORM) in this model of airway disease, we endeavored to determine the impact of BUD/FORM on lung inflammation, structure, and physiology. BUD/FORM was delivered either while allergen exposure was ongoing (concurrent therapy) or following the cessation of allergen exposure (postexposure therapy). Our results show that airway inflammation was substantially reduced in BUD/FORM-treated mice in the concurrent therapy group, whereas in the postexposure therapy group airway inflammation spontaneously resolved. In contrast, BUD/FORM was most effective in resolving several aspects of airway remodeling and bronchial hyperreactivity when delivered in conjunction with allergen withdrawal. This study demonstrates that although both BUD/FORM therapy and allergen avoidance independently reduce airway inflammation, only BUD/FORM therapy in conjunction with allergen avoidance can effectively reverse airway remodeling and bronchial hyperreactivity induced by chronic allergen exposure.     

Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma

Background

Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC₂₀).

Methods

10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC₂₀ were performed using mixed models and confirmed using family-based tests of association.

Results

Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC₂₀ (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC₂₀ at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC₂₀ by IPO13 variants among children treated with inhaled corticosteroids.

Conclusion

IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.     

Ozone-induced increase in exhaled 8-isoprostane in healthy subjects is resistant to inhaled budesonide

The aim of this study was to quantify lung oxidant stress after short-term ozone exposure as reflected by 8-isoprostane concentrations in exhaled breath condensate (EBC) and to investigate the effects of inhaled budesonide on this response. 8-Isoprostane is a prostaglandin-F(2 alpha) isomer that is formed in vivo by free radical-catalyzed peroxidation of arachidonic acid. EBC is a noninvasive method to collect airway secretions. We undertook a double-blind, randomized, placebo-controlled, crossover study with inhaled budesonide (800 microg) or placebo twice daily for 2 weeks prior to ozone exposure (400 parts per billion) for 2 h in nine healthy nonsmokers. Exhaled 8-isoprostane was measured by an enzyme immunoassay. 8-Isoprostane was increased 4 h after ozone exposure compared to pre-exposure values in both placebo (36.9 +/- 3.9 pg/ml, mean +/- SEM, vs. 16.9 +/- 0.7 pg/ml; p <.001) and budesonide groups (33.4 +/- 2.6 pg/ml vs. 15.8 +/- 0.3 pg/ml; p <.001). Pretreatment with budesonide did not affect the increases in 8-isoprostane (mean differences 3.4 pg/ml, 95% CI -8.9 to 15.7, p =.54). Short-term ozone exposure causes acute increase in lung oxidative stress as reflected by exhaled 8-isoprostane. This increase is resistant to pretreatment with a high dose of inhaled budesonide.     

Airway responses to methacholine in asymptomatic nonatopic cigarette smokers

We prospectively performed methacholine bronchoprovocation challenges on 46 young smokers to examine the effects of cigarette smoking on airway responsiveness. The subjects, ages 18-35 yr, had no past or present history or physical examination findings of asthma or other lung diseases, rhinitis, allergic diseases, or respiratory infections; were skin test negative to 29 common aeroallergens; and had base-line pulmonary function values greater than 80% predicted. Sixteen of 46 (35%) subjects had a 20% or greater drop in forced expiratory volume in 1 s at a provocative methacholine concentration less than or equal to 25 mg/ml. The degree of methacholine responsiveness was not dependent upon base-line pulmonary function values or the amount of cigarettes consumed, and there was no association between the amount of cigarettes consumed and base-line pulmonary function values. These data suggest that many young asymptomatic nonatopic smokers have increased airway responsiveness to inhaled methacholine without clinically significant hyperreactive airway disease.     

长期吸入布地奈德联合孟鲁司特钠治疗过敏性哮喘基因阳性患儿的临床观察

目的:观察长期吸入布地奈德联合孟鲁司特钠治疗过敏性哮喘基因阳性患儿的临床疗效。方法:将88例支气管哮喘患儿按简单随机法分为对照组(n=46)和研究组(n=42),两组均予以常规治疗,对照组在常规治疗基础上长期吸入布地奈德治疗,研究组在对照组基础上联合孟鲁斯特钠治疗,比较两组临床疗效、症状及体征消失时间,治疗前后嗜酸粒细胞阳离子蛋白(ECP)、嗜酸粒细胞(EOS)计数、免疫球蛋白(Ig E)、白介素-4(IL-4)和肺功能的变化及不良反应的发生情况。结果:治疗后,研究组总有效率显著高于对照组(97.62%vs. 84.78%,P0.05),气促、哮鸣音、肺部啰音、咳嗽消失时间均明显短于对照组(P0.05)。治疗前,两组ECP、EOS、Ig E、IL-4水平、峰值呼气流速(PEF)、第一秒用力呼气容积(FEV1)比较差异无统计学意义(P0.05);治疗后,两组ECP、EOS、Ig E及IL-4水平较治疗前下降(P0.05),研究组以上指标低于对照组(P0.05),两组治疗后PFE及FEV1较治疗前心脏上升,且研究组以上指标明显高于对照组(P0.05)。两组总不良反应发生率比较差异无统计学意义(P0.05)。结论:长期吸入布地奈德联合孟鲁斯特纳可提高过敏性哮喘基因阳性患儿的疗效,显著减轻患儿症状,控制气道炎症反应,改善肺功能。     

Budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses

Background

Combination therapy with budesonide and formoterol reduces exacerbations of asthma, which are closely associated with human rhinovirus (RV) infections in both children and adults. These data suggest that budesonide and formoterol inhibit virus-induced inflammatory responses of airway epithelial cells.

Methods

To test this hypothesis, bronchial epithelial (BE) cells were obtained from airway brushings of 8 subjects with moderate-to-severe allergic asthma and 9 with neither asthma nor respiratory allergies. Cultured BE cells were incubated for 24 hours with budesonide (1.77 μM), formoterol (0.1 μM), both, or neither, and then inoculated with RV-16 (5×10⁶ plaque forming units [PFU]/mL). After 24 hours, viral replication (RV RNA), cytokine secretion (CXCL8, CXCL10, TNFα, IFN-β, IL-28) and mRNA expression (CXCL8, CXCL10, TNF, IFNB1, IL28A&B) were analyzed.

Results

RV infection induced CXCL10 protein secretion and IFNB1 and IL28 mRNA expression. Drug treatments significantly inhibited secretion of CXCL10 in mock-infected, but not RV-infected, BE cells, and inhibited secretion of TNFα under both conditions. Neither budesonide nor formoterol, alone or in combination, significantly affected viral replication, nor did they inhibit RV-induced upregulation of IFNB1 and IL28 mRNA. Overall, RV replication was positively related to CXCL10 secretion and induction of IFNB1 and IL28 mRNA, but the positive relationship between RV RNA and CXCL10 secretion was stronger in normal subjects than in subjects with asthma.

Conclusions

Budesonide and formoterol can inhibit BE cell inflammatory responses in vitro without interfering with viral replication or production of interferons. These effects could potentially contribute to beneficial effects of budesonide/formoterol combination therapy in preventing RV-induced asthma exacerbations.     

Iatrogenic Cushing Syndrome in Patients Receiving Inhaled Budesonide and Itraconazole or Ritonavir: Two Cases and Literature Review

ObjectiveTo present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole.MethodsWe present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options.ResultsA 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 µg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 µg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 µg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation.ConclusionClinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir. (Endocr. Pract. 2013;19:e138-e141)     

Budesonide and formoterol reduce early innate anti-viral immune responses in vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10⁻⁶ M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.