Stimulation of central β2-adrenoceptors suppresses NFκB activity in rat brain: A role for IκB

In this study we examined the impact of systemic treatment with the long-acting brain penetrant β₂-adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain. Clenbuterol decreased NFκB activity (p65 DNA binding) in nuclear extracts prepared from rat cortex and hippocampus for up to 8 h following a single treatment. This was accompanied by increased expression of IκBα mRNA and protein. The temporal increase in IκB protein expression paralleled the suppression of NFκB activity, suggesting that IκBα mediates the suppression NFκB activity observed. These actions of clenbuterol were prevented by pre-treatment with the non-selective β-adrenoceptor antagonist propranolol, the β₂-adrenoceptor antagonist ICI-118,551, but not the β₁-adrenoceptor antagonist metoprolol, suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the β₂-adrenoceptor. In addition, the actions of clenbuterol were mimicked by systemic administration of another highly selective long-acting β₂-adrenoceptor agonist formoterol. As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus. In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide (LPS). In tandem, clenbuterol blocked expression of the NFκB-inducible genes TNF-α and ICAM-1 following LPS administration. Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that β₂-adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation-related neurodegeneration.     

Step-down from high dose fixed combination therapy in asthma patients: a randomized controlled trial

Background

Asthma guidelines suggest that therapy can be reduced once asthma is controlled. Despite these recommendations, asthmatic patients are seldom stepped down in clinical practice, and questions remain about when and how to reduce asthma therapy. The purpose of the present study was to evaluate lung function and asthma control in patients who were stepped down from the highest recommended dose of inhaled corticosteroid/long acting β₂ agonist combination therapy.

Methods

This was a prospective, randomised, controlled, two-arm parallel group study. Asthmatic patients who were fully controlled with a high daily dose (1000/100 μg) of fluticasone/salmeterol were randomly assigned to 6 months of open-label treatment with either 500/100 μg fluticasone/salmeterol Diskus daily or 400/24 μg extrafine beclomethasone/formoterol pMDI daily. The primary outcome was the change in morning peak expiratory flow (PEF) values between baseline and the end of treatment. The secondary outcomes included asthma control and exacerbation frequency.

Results

Four hundred twenty-two patients were included in the analysis. The PEF values remained above 95% of the predicted values throughout the study. The end-study morning PEF rates showed equivalence between the groups (difference between means, 2.49 L/min; 95% CI, -13.43 to 18.42). No changes from baseline were detected in PEF and forced expiratory volume in 1 second measured at the clinics, in the symptom scores or in the use of rescue medication. Asthma control was maintained in 95.2% of the patients at 6 months. No significant differences between the groups were detected in any other parameter, including exacerbation frequency and adverse events.

Conclusions

Stepping down patients whose asthma is controlled with the highest recommended dose of fluticasone/salmeterol to either 500/100 μg fluticasone/salmeterol daily or 400/24 μg extra-fine beclomethasone/formoterol daily provides comparable maintenance of lung function and asthma control.

Trial registration

clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00497237","term_id":"NCT00497237"}}NCT00497237     

布地奈德福莫特罗治疗支气管哮喘患者的临床疗效及对患者血清炎性因子水平的影响

目的:探讨布地奈德福莫特罗吸入治疗对慢性支气管哮喘患者的临床疗效及其对患者血清炎性因子水平、肺功能和生活质量的影响。方法:选择2014年2月至2016年2月于我院呼吸内科就诊并确诊为慢性支气管哮喘患者123例,根据随机数字表法分为观察组65例和对照组58例。比较两组患者治疗前后血清白介素17(IL-17)、白介素33(IL-33)、基质金属蛋白酶9(MMP-9)、肺功能、生活质量评分的变化、临床疗效有效率及不良反应的发生情况。结果:观察组的总有效率为92.3%(60/65),显著高于对照组(81.03%,P0.05)。治疗后,两组患者的血清IL-17、IL-33水平与治疗前相比均显著降低(P0.05),且观察组显著低于对照组(P0.05);两组血清MMP-9水平与治疗前相比差异均无统计学意义(P0.05);观察组患者的第一秒用力呼吸容积(FEV1)、峰值呼气流速(PEF)与第一秒用力呼气容积与用力肺活量比值(FEV1/FVC)水平均明显增加,且观察组上述指标明显高于对照组(P0.05);圣.乔治呼吸问卷(SGRQ)评分结果显示观察组患者的生活质量显著高于对照组患者。结论:布地奈德福莫特罗吸入治疗对慢性支气管哮喘临床效果显著,可显著控制炎症反应,改善肺功能,显著提升患者生活质量。     

Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week,randomized, placebo-controlled AUGMENT COPD study

Background

Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β₂-agonist, in patients with moderate to severe COPD are presented.

Methods

In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair^®/Pressair^®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV₁ (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV₁ (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed.

Results

At study end, improvements from baseline in 1-hour postdose FEV₁ were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV₁ were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV₁ over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.

Conclusions

Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01437397","term_id":"NCT01437397"}}NCT01437397.*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair^® and Genuair^® within all other licensed territories.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users.     

Inhibition of phosphodiesterase 4 modulates cytokine induction from toll like receptor activated,but not rhinovirus infected,primary human airway smooth muscle

Background

Virus-induced exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a significant health burden and occur even in those receiving the best current therapies. Rhinovirus (RV) infections are responsible for half of all COPD exacerbations. The mechanism by which exacerbations occur remains undefined, however it is likely to be due to virus-induced inflammation. Given that phophodiesterase 4 (PDE₄) inhibitors have an anti-inflammatory effect in patients with COPD they present a potential therapy prior to, and during, these exacerbations.

Methods

In the present study we investigated whether the PDE₄ inhibitor piclamilast (10^-6 M) could alter RV or viral mimetic (5 μg/mL of imiquimod or poly I:C) induced inflammation and RV replication in primary human airway smooth muscle cells (ASMC) and bronchial epithelial cells (HBEC). The mediators IL-6, IL-8, prostaglandin E₂ and cAMP production were assayed by ELISA and RV replication was assayed by viral titration.

Results

We found that in ASMCs the TLR3 agonist poly I:C induced IL-8 release was reduced while induced IL-6 release by the TLR7/8 agonist imiquimod was further increased by the presence of piclamilast. However, in RV infected ASMCs, virus replication and induced mediator release were unaltered by piclamilast, as was also found in HBECs. The novel findings of this study reveal that although PDE inhibitors may not influence RV-induced cytokine production in ASMCs and replication in either ASMCs or HBECs, they have the capacity to be anti-inflammatory during TLR activation by modulating the induction of these chemotactic cytokines.

Conclusion

By extrapolating our in vitro findings to exacerbations of COPD in vivo this suggests that PDE₄ inhibitors may have beneficial anti-inflammatory properties when patients are infected with bacteria or viruses other than RV.     

布地奈德联合福莫特罗治疗慢性阻塞性肺疾病合并感染患者的疗效观察

目的:探讨布地奈德联合福莫特罗治疗慢性阻塞性肺疾病(COPD)合并感染患者的临床疗效。方法:选择2012年10月~2014年10月我院收治的COPD合并感染患者共84例,按照随机数字表法将患者随机分为试验组和对照组。两组患者均给予常规综合治疗,在此基础上对照组给予布地奈德,试验组在对照组治疗基础上联合福莫特罗,观察患者治疗前后血气功能、肺功能指标和临床疗效。结果:治疗后试验组Pa CO2显著低于对照组(P0.05),Pa O2和Sa O2显著高于对照组(P0.05)。治疗后试验组FEV1、FVC和FEV1/FVC均显著高于对照组(P0.05)。实验组治疗后的总有效率为95.24%,显著高于对照组的78.57%(P0.05)。结论:采用布地奈德和福莫特罗联合应用治疗COPD合并感染患者有协同效果,能够有效改善患者的血气指标、肺功能和临床效果,值得推广应用。     

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.     

地奈德福莫特罗联合异丙托溴胺治疗慢性阻塞性肺疾病急性加重期的疗效及对FeNO、cTnI的影响

摘要 目的：探讨布地奈德福莫特罗联合异丙托溴胺治疗 慢性阻塞性肺疾病急性加重期的疗效及对呼出气一氧化氮（FeNO）、心肌肌钙蛋白（cTnI）的影响 。方法：选择2020年7月-2021年5月在我院接受治疗的80例慢性阻塞性肺疾病急性加重期患者,采用随机数表法分为试验组（n=41）和对照组（n=39）。对照组给予异丙托溴胺治疗,试验组在对照组的基础上联合布地奈德福莫特罗治疗。比较两组临床疗效、FeNO、cTnI、白细胞介素6（IL-6）、超敏C反应蛋白（CRP）、临床症状改善情况及不良反应发生情况。结果：治疗后,两组总有效率比较差异显著（P<0.05）;治疗前,试验组和对照组FeNO、cTnI比较无显著差异;治疗后,试验组和对照组FeNO、cTnI均随着时间的推移而降低,且试验组均低于对照组,差异显著（P<0.05）;治疗前,试验组和对照组血清IL-6及CRP比较无显著差异;治疗后,试验组和对照组血清IL-6及CRP均随着时间的推移而降低,且试验组均低于对照组,差异显著（P<0.05）;试验组憋喘、咳嗽、哮鸣音及湿啰音消失需要的时间均显著低于对照组,差异显著（P<0.05）;两组不良反应总发生率为9.76%、17.95%,无显著差异（P>0.05）。结论：在慢性阻塞性肺疾病急性加重期中应用布地奈德福莫特罗联合异丙托溴胺治疗疗效显著,可有效改善患者FeNO、cTnI水平,且不会增加并发症。