Design,synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β2-adrenoceptor agonists

A series of novel β₂-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β₂-adrenoceptor agonistic effects and high β₂/β₁-selectivity with EC₅₀ values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.     

沙美特罗/氟替卡松吸入治疗对COPD患者临床疗效及 口咽部菌群和免疫功能的影响

目的研究沙美特罗/氟替卡松吸入治疗对慢性阻塞性肺病(COPD)患者临床疗效及口咽部菌群和免疫功能的影响。方法选取我院2015年1月至2017年12月确诊的COPD II-III级患者92例。按照随机数字表将研究对象随机分为研究组和对照组,每组46例。所有研究对象给予持续低通量吸氧、抗感染、祛痰止咳、解痉平喘等对症支持治疗,并服用盐酸氨溴索治疗。研究组在常规治疗基础上加用沙美特罗/氟替卡松干粉剂。观察患者临床疗效,记录患者肺功能指标并测定CD_4~+细胞、CD_8~+细胞、CD_4~+/CD_8~+、IgA、IgM和IgG水平。采集患者的咽拭子进行培养,计算菌落比例并鉴定种属。结果治疗后,研究组总有效率为93.48%,明显高于对照组的80.43%,差异有统计学意义(P0.05)。肺功能指标显示治疗后两组患者肺功能均有所上升,研究组肺功能指标水平上升幅度大于对照组(P0.05)。治疗后研究组患者CD_4~+细胞和CD_4~+/CD_8~+水平高于对照组,而CD_8~+细胞水平低于照组,差异均有统计学意义(P0.05)。两组患者治疗前后免疫球蛋白水平差异无统计学意义(P0.05)。治疗后研究组患者发现9种细菌,对照组发现6种,各菌株的构成比具有一定差异。结论沙美特罗/氟替卡松对COPD患者临床疗效显著,能有效提升肺功能,改善患者免疫功能,对口咽部菌群的影响较小,提示该吸入治疗方法值得临床应用推广。     

白三烯调节剂及沙美特罗治疗对支气管哮喘的疗效及对患者FeNO、血清IL-10、hs-CRP水平的影响

摘要 目的：探究白三烯调节剂及沙美特罗治疗支气管哮喘患者的临床效果及对患者呼气一氧化氮(fractional exhaled nitric oxide,FeNO)、血清白细胞介素-10(interleukine-10,IL-10)和超敏C反应蛋白(high-sensitive C-reactive protein,hs-CRP)水平的影响。方法：选择2019年3月至2020年3月于我院接受治疗的60例支气管哮喘患者,按照随机数字表法将其均分为研究组与对照组(每组各30例患者)。对照组患者接受沙美特罗治疗,研究组患者在对照组基础上加用白三烯调节剂治疗,对比两组患者治疗前后FeNO、血清IL-10、hs-CRP水平、第1秒用力呼气容积占预计值百分比(the percentage of forced expiratory volume in predicted value,FEV₁ %)、呼气峰流量(peak expiratory flow,PEF)和哮喘控制测试(asthma control test,ACT)的变化及治疗过程中不良反应的发生情况。结果：治疗后,研究组患者FeNO、血清hs-CRP水平均显著低于对照组,血清IL-10水平、FEV₁ %、PEF和ACT均明显高于对照组(P<0.05)。两组治疗过程中不良反应的发生率比较差异无统计学意义(P>0.05)。结论：白三烯调节剂联合沙美特罗对支气管炎哮喘具有较好的治疗效果,能够显著改善患者机体炎性状态,同时调节患者的肺功能,且治疗安全性较高。     

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     

Rapid chiral high-performance liquid chromatographic assay for salmeterol and α-hydroxysalmeterol: Application to in vitro metabolism studies

A rapid and sensitive chiral high-performance liquid chromatographic (HPLC) assay for the simultaneous determination of salmeterol and its principal human metabolite α-hydroxysalmeterol is described. The two pairs of enantiomers were resolved on a chiral-cellobiohydrolase column and detected by electrochemical detection at +700 mV. Standard curves were linear over the concentration range 0.1 to 4.0 μM for α-hydroxysalmeterol enantiomers and 2.5 to 40.0 μM for salmeterol enantiomers. Intra- and inter-day coefficients of variation were <10%. The method was applied to a study of human hepatic metabolism in vitro which showed that microsomal metabolism of salmeterol to α-hydroxysalmeterol is not stereoselective.     

噻托溴铵联合沙美特罗治疗慢性阻塞性肺疾病的临床效果

目的:探讨噻托溴铵联合沙美特罗治疗慢性阻塞性肺疾病的临床效果。方法:选取我院2008年8月~2016年8月期间收治的68例慢性阻塞性肺疾病患者,由电脑随机均分为两组,每组34例,其中对照组给予沙美特罗进行治疗,而观察组在此基础上施加噻托溴铵治疗。对比观察两组患者治疗前后肺功能指标的变化、运动能力、生活质量、预后及不良事件发生率。结果:治疗前,两组患者的肺功能各项指标、6分钟步行距离(6MWD)和圣乔治呼吸问卷(SGRQ)评分均无明显差异(P0.05)。治疗后均较治疗前有明显改善,且观察组同期改善程度均显著高于对照组(P0.05)。观察组在治疗后12个月内发生急性加重的例数明显少于对照组(P0.05),且不良事件发生率明显低于对照组(P0.05)。结论:联合使用噻托溴铵与沙美特罗治疗慢性阻塞性肺疾病,可更好地改善患者的肺功能、运动能力及生活质量,且急性加重率和不良事件发生率更低,值得进一步推广与应用。     

An <Emphasis Type="Italic">Insilico</Emphasis> approach to High Altitude Pulmonary Edema - Molecular modeling of human β<Subscript>2</Subscript> adrenergic receptor and its interaction with Salmeterol &; Nifedipine

Knowledge of the three-dimensional structures of protein targets from genomic data has the potential to accelerate researches pertaining to drug discovery. Human β₂ adrenergic receptor is a G-protein-coupled receptor with seven transmembrane helices, and is important in pharmaceutical targeting on pulmonary and cardiovascular diseases. The human β₂ adrenergic receptor has been found to play a very important role in the pathogenesis of high altitude pulmonary edema (HAPE). In the present study, a high quality of protein 3D structure has been predicted for the human β₂ adrenergic receptor sequence with primary accession number P07550. Homologous template protein sequence with known 3D structure was identified and the template-query protein sequence validation was done by multiple sequence alignment method. The homology model was performed through Modeller and depended on the quality of the sequence alignment by BLAST, template structure and the consolidated result performed by Gene silico meta-server. The statistical verification of the generated model was evaluated by PROCHECK which revealed that the structure modeled through Modeller to be of good quality with 84.1% of residues in the most favored region. Docking studies were carried out after modeling with two well known ligands namely Salmeterol and Nifedipine, and the fitness score revealed that Salmeterol has a higher fitness score than Nifedipine. Estimation of binding affinity by X-Score revealed that Salmeterol had −10.40 binding affinity while Nifedipine showed −9.62 binding affinity. From the present study, it can be concluded that the generated model of human β₂ adrenergic receptor can be used for further studies related to this receptor and Salmeterol was found to have a high binding affinity with human β₂ adrenergic receptor.     

Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial

Background

Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.

Methods

Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.

Results

In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.

Conclusion

The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00563381","term_id":"NCT00563381"}}NCT00563381; Study identifier: BI 205.389.     

Effect of salmeterol on polymorphonuclear leukocyte (PMNL) chemiluminescence In Vitro

Although beta-agonists remain an important aspect of the treatment of asthma, their role has recently been questioned. Salmeterol has recently been developed as a betaagonist with prolonged bronchodilator action. Using lucigenin-enhanced chemiluminescence, we have shown that salmeterol inhibits this aspect of phagocyte function in vitro in a concentration-dependent manner. However, salmeterol differs from classical beta₂-agonists in that at concentrations between 10^?5 and 10^?3 mol/L, its effects on phagocytes cannot be completely reversed by washing the cells or by propanolol. The effects on phagocytes may not therefore be explicable on the basis of betaadrenergic mechanisms alone.     

参苓白术散联合沙美特罗治疗COPD的临床疗效分析

目的：探讨参苓白术散结合沙美特罗治疗对慢性阻塞性肺疾病（COPD）的临床疗效。方法：采用前瞻性随机对照设计。将93例COPD患者随机均分为三组（称为A、B、C组）,A组给予中药参苓白术散口服和沙美特罗喷雾剂吸入治疗,B组给予中药参苓白术散颗粒剂口服治疗,C组给予沙美特罗喷雾剂吸入治疗,治疗疗程3个月,观察治疗前后三组患者的临床症状和体征、中医症状评分以及肺功能包括FEV1、FVC和PEF变化情况。结果：治疗3个月后,给予中药参苓白术散剂口服和沙美特罗喷雾剂吸入治疗的A组患者临床症状和体征、中医症状评分以及肺功能较治疗前明显改善,FEV1和FVC分别提高了0-3L和0-37L,PEF也增加了44L／min,并且这两种药物联合治疗疗效也明显优于B、c组（P〈0．05）。结论：参苓白术散结合沙关特罗治疗能明显改善COPD患者临床表现和肺功能。