噻托溴铵联合奥达特罗治疗慢性阻塞性肺疾病患者的疗效及对免疫功能的影响

目的:探讨噻托溴铵联合奥达特罗治疗慢性阻塞性肺疾病(COPD)患者的疗效及对免疫功能的影响。方法:选取我院于2018年10月到2019年10月期间接收的108例COPD患者,按照随机数字表法将患者分为噻托溴铵组(n=36,噻托溴铵治疗)、奥达特罗组(n=36,奥达特罗治疗)、联合组(n=36,噻托溴铵联合奥达特罗治疗),比较三组患者疗效、肺功能、免疫功能及不良反应。结果:联合组治疗3个月后的临床总有效率、肺活量(FVC)、第1秒用力呼气容积(FEV1)、FEV1/FVC、CD3+、CD4+、免疫球蛋白G(Ig G)、免疫球蛋白M(Ig M)均高于奥达特罗组、噻托溴铵组(P0.05)。奥达特罗组、噻托溴铵组治疗3个月后的的临床总有效率、FVC、FEV1、FEV1/FVC、CD3+、CD4+、Ig G、Ig M比较差异无统计学意义(P0.05)。三组治疗期间不良反应发生率整体比较差异无统计学意义(P0.05)。结论:噻托溴铵联合奥达特罗治疗COPD患者,疗效显著,可有效改善免疫功能及肺功能,且不增加不良反应发生率。     

Randomised,double-blind,placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat? in patients with moderate to severe persistent asthma

Background

A Phase II, multicentre, randomised, double-blind, placebo-controlled, crossover trial comparing the 24-h forced expiratory volume in 1 s (FEV₁) time profile after 3 weeks’ treatment with once-daily (QD) or twice-daily (BID) olodaterol (at the same total daily dose) versus placebo delivered via Respimat® in patients with moderate to severe asthma.

Methods

Patients were randomised to different sequences of olodaterol with 2-week washout, either as a total daily dose of 5 μg (5 μg QD [AM] or 2.5 μg BID) or placebo, or 10 μg (10 μg QD [AM] or 5 μg BID) or placebo. Primary end point was FEV₁ area under the curve from 0 to 24 h (AUC_0–24) response (defined as change from study baseline FEV₁) after 3 weeks. Key secondary end points were FEV₁ AUC_0–12 and AUC_12–24 responses.

Results

Two hundred and six patients received treatment. All olodaterol treatments demonstrated statistically significant improvements in FEV₁ AUC_0–24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 μg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 μg QD (95 % CI 0.111, 0.189), 0.228 L for 5 μg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 μg QD (95 % CI 0.170, 0.247). These results were supported by the key secondary end points. Olodaterol 5 μg QD provided numerically lower mean values for 24-h bronchodilation than olodaterol 2.5 μg BID (p = 0.0465), with no statistically significant difference between treatment with olodaterol 10 μg QD and 5 μg BID. No relevant differences in morning and evening peak expiratory flow or Asthma Control Questionnaire scores at 3 weeks were observed between different doses and regimens. Adverse events were generally mild to moderate and comparable between groups.

Conclusions

All doses and dose frequencies provided adequate 24-h bronchodilation superior to placebo. Based on the results of this study, it would be reasonable to include both posologies of 5 μg olodaterol daily (5 μg QD or 2.5 μg BID, both delivered in two puffs per dose from the Respimat® inhaler) in subsequent studies. Further studies are necessary to confirm the optimum dosing regimen in asthma. No safety concerns were identified.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01311661","term_id":"NCT01311661"}}NCT01311661

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0243-1) contains supplementary material, which is available to authorized users.     

Dose-finding evaluation of once-daily treatment with olodaterol,a novel long-acting β2-agonist,in patients with asthma: results of a parallel-group study and a crossover study

Background

Olodaterol is a novel, inhaled long-acting β₂-agonist (LABA) with >24-hour duration of action investigated in asthma and chronic obstructive pulmonary disease.

Methods

Two multicentre studies examined the efficacy and safety of 4 weeks’ once-daily (QD) olodaterol (2, 5, 10 and 20 μg, with background inhaled corticosteroids) in patients with asthma. One randomised, double-blind, parallel-group study (1222.6; 296 patients) administered treatment in the morning. Pulmonary function tests (PFTs) were performed pre-dose (trough) and ≤3 hours post-dose (weeks 1 and 2), and ≤6 hours post-dose after 4 weeks; primary end point was trough forced expiratory volume in 1 second (FEV₁) response (change from baseline mean FEV₁) after 4 weeks. A second randomised, double-blind, placebo- and active-controlled (formoterol 12 μg twice-daily) incomplete-block crossover study (1222.27; 198 patients) administered QD treatments in the evening. PFTs were performed over a 24-hour dosing interval after 4 weeks; primary end point was FEV₁ area under the curve from 0–24 hours (AUC_0–24) response (change from study baseline [mean FEV₁] after 4 weeks).

Results

Study 1222.6 showed a statistically significant increase in trough FEV₁ response with olodaterol 20 μg (0.147 L; 95 % confidence interval [CI]: 0.059, 0.234; p = 0.001) versus placebo, with more limited efficacy and no evidence of dose response compared to placebo across the other olodaterol doses (2, 5 and 10 μg). Study 1222.27 demonstrated increases in FEV₁ AUC_0–24 responses at 4 weeks with all active treatments (p < 0.0001); adjusted mean (95 % CI) differences from placebo were 0.140 (0.097, 0.182), 0.182 (0.140, 0.224), 0.205 (0.163, 0.248) and 0.229 (0.186, 0.272) L for olodaterol 2, 5, 10 and 20 μg, respectively, and 0.169 (0.126, 0.211) for formoterol, providing evidence of increased efficacy with higher olodaterol dose. Olodaterol was generally well tolerated, with a few events associated with known sympathomimetic effects, mainly with 20 μg.

Conclusions

The LABA olodaterol has >24-hour duration of action. In patients with asthma, evidence of bronchodilator efficacy was demonstrated with statistically and clinically significant improvements in the primary end point of trough FEV₁ response measured in clinics over placebo for the highest administered dose of 20 μg in Study 1222.6, and statistically and clinically significant improvements versus placebo in FEV₁ AUC_0–24 responses at 4 weeks for all doses tested in Study 1222.27, which also exhibited a dose response. Bronchodilator efficacy was seen over placebo for all olodaterol doses for morning and evening peak expiratory flow in both studies. All doses were well tolerated.

Trial registrations

{"type":"clinical-trial","attrs":{"text":"NCT00467740","term_id":"NCT00467740"}}NCT00467740 (1222.6) and {"type":"clinical-trial","attrs":{"text":"NCT01013753","term_id":"NCT01013753"}}NCT01013753 (1222.27).

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0249-8) contains supplementary material, which is available to authorized users.     

Design,synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β2-adrenoceptor agonists

A series of β₂-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β₂-adrenoceptor and β₁-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β₂-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β₂-adrenoceptor agonistic effect with an EC₅₀ value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β₂-AR agonists.