Patterns of use of long‐acting bronchodilators in patients with COPD: A nationwide follow‐up study of new users in New Zealand

Background and objective

While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long‐acting beta₂‐agonist (LABA) and long‐acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow‐up study to describe treatment patterns in new users of long‐acting bronchodilators.

Methods

National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan–Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non‐use during follow‐up.

Results

The study cohort included 83 435 patients with 290 400 person‐years of follow‐up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over‐ and under‐treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non‐use were common.

Conclusion

In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

     

去甲肾上腺素对肝星状细胞增殖和凋亡的影响

目的探讨交感神经递质去甲肾上腺素（NE）对HSC细胞株（CSFC）增殖和凋亡的影响。方法体外培养CFSC,分为以下6组：（1）空白对照组,为单纯CFSC培养;（2）交感兴奋（NE）组;（3）交感抑制（酚妥拉明＋普萘洛尔）组;（4）α肾上腺素受体（AR）阻滞（酚妥拉明）组;（5）β1AR阻滞（CGP20712A）组;（6）β2AR阻滞（ICI118551）组。MTT法测定细胞增殖;TUNEL法观察CFSC凋亡状况;流式细胞仪检测细胞凋亡率;倒置相差显微镜观察细胞形态学变化。结果MTT法显示,NE对CFSC具有明显的促增殖作用,加入α-AR、β1AR、β2AR阻滞剂后细胞增殖均受到明显抑制。NE作用于CFSC 24h,TUNEL法显示CFSC的凋亡率显著低于对照组（6.60%±3.05%与12.60%±4.76%,P〈0.05）;加入AR阻滞剂后CFSC凋亡率升高,其中α-AR和β2AR阻滞剂作用最显著。同时,流式细胞仪显示加入NE后CFSC凋亡率也显著降低（2.29%±0.22%与3.06%±0.57%,P〈0.05）;与TUNEL结果一致。NE对细胞形态没有明显影响。结论交感神经递质NE对体外活化的CFSC具有促增殖作用,并且可以抑制CFSC的凋亡,可能主要通过α受体和β2体起作用。     

β1受体阻滞剂对早期脓毒性休克病人心肌损伤及预后的影响

目的 观察β₁受体阻滞剂对早期脓毒性休克病人心肌损伤及预后的影响,评价治疗的安全性及探讨其影响病人预后的可能机制。方法 采用回顾性对照研究方法,选择2013年1月至2015年12月芜湖市第二人民医院重症医学科(ICU)54例确诊为脓毒性休克且临床资料完整的病人。根据是否使用β₁受体阻滞剂美托洛尔分为治疗组28例和对照组26例,记录两组病人治疗后72 h循环指标、血清降钙素原(PCT)、肌钙蛋白I(CTnI)、血乳酸(Lac)水平的变化及机械通气时间、住ICU时间和28 d病死率等。所有病人再根据28 d的生存结局分为存活组和死亡组,logistic回归分析影响病人预后的危险因素。结果72 h后治疗组心室率(HR)(90.6±8.9)次/分低于对照组(118.4±23.1)次/分(t=5.916,P＜0.001),两组病人心指数(CI)、平均动脉压(MAP)、血管活性药物的用量、72 h液体平衡量以及血清降钙素原(PCT)、血乳酸(Lac)水平、机械通气时间和病死率均差异无统计学意义(均P＞0.05),治疗组住ICU时间、肌钙蛋白I(CTnI)水平低于对照组(均P＜0.05);死亡组急性生理和慢性健康评分(APACHEⅡ评分)、CTnI、Lac水平高于存活组(P＜0.05),死亡组β₁受体阻滞剂使用率(31.6%)低于存活组(62.9%)(P＜0.05);logistic回归分析显示,CTnI＞1.21 μg/L、APACHEⅡ评分＞19.5分是早期脓毒性休克病人预后的危险因素,β₁受体阻滞剂是影响病人预后的保护性因素(P＜0.05)。结论 β₁受体阻滞剂可降低脓毒性休克早期病人的心率和心肌氧耗,减轻心肌损伤,且对血流动力学影响小,可以缩短住ICU时间,可能是此类病人预后的潜在保护因素。     

Staying awake – a genetic region that hinders α2 adrenergic receptor agonist‐induced sleep

How external stimuli prevent the onset of sleep has been little studied. This is usually considered to be a non‐specific type of phenomenon. However, the hypnotic drug dexmedetomidine, an agonist at α₂ adrenergic receptors, has unusual properties that make it useful for investigating this question. Dexmedetomidine is considered to produce an ‘arousable’ sleep‐like state, so that patients or animals given dexmedetomidine become alert following modest stimulation. We hypothesized that it might be more difficult to make mice unconscious with dexmedetomidine if there was a sufficient external stimulus. Employing a motorized rotating cylinder, which provided a continuous and controlled arousal stimulus, we quantitatively measured the ability of such a stimulus to prevent dexmedetomidine loss of righting reflex in two inbred strains of mice (C57BL/6 and 129X1). We found that whereas the C57BL/6 strain required a strong stimulus to prevent dexmedetomidine‐induced hypnosis, the 129X1 strain stayed awake even with minimal stimuli. Remarkably, this could be calibrated as a simple threshold trait, i.e. a binary ‘yes–no’ response, which after crossing the two mouse strains behaved as a dominant‐like trait. We carried out a genome‐wide linkage analysis on the F₂ progeny to determine if the ability of a stimulus to prevent dexmedetomidine hypnosis could be mapped to one or more chromosomal regions. We identified a locus on chromosome 4 with an associated Logarithm of Odds score exceeding the pre‐established threshold level. These results show that complex traits, such as the ability of a stimulus to reverse drug‐induced hypnosis, may have precise genetic determinants.     

p‐Synephrine,ephedrine, p‐octopamine and m‐synephrine: Comparative mechanistic,physiological and pharmacological properties

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p‐synephrine and p‐octopamine relative to ephedrine and m‐synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p‐synephrine and p‐octopamine as related to ephedrine and m‐synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p‐Synephrine and p‐octopamine exhibit little binding to α‐1, α‐2, β‐1 and β‐2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m‐synephrine. As a consequence, the effects of ephedrine and m‐synephrine cannot be directly extrapolated to p‐synephrine and p‐octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.     

β受体阻滞剂治疗婴儿血管瘤中国专家共识

【摘要】 β受体阻滞剂是目前治疗婴儿血管瘤的一线药物,主要包括口服普萘洛尔和外用噻吗洛尔/卡替洛尔滴眼液。β受体阻滞剂药物选择及给药方式主要根据患儿年龄、瘤体部位、分型、分类及大小等因素综合决定。本共识对口服普萘洛尔的适应证及禁忌证、治疗起始时间及剂量、疗程与停药指征、用药期间注意事项和不良反应的监测及处理和特殊人群治疗剂量、疗程以及外用β受体阻滞剂适应证、应用具体方法等进行总结,希望为皮肤科及相关专业医生规范应用β受体阻滞剂治疗婴儿血管瘤提供参考依据。     

湖南中部地区高血压人群CYP2D6和β1肾上腺素能受体基因多态性调查

【目的】探讨湖南中部娄底和湘潭地区高血压人群CYP2D6和β1肾上腺素能受体（β1-AR）基因多态性分布。【方法】湖南中部地区高血压患者403名,采用聚合酶链反应（PCR）和聚合酶链反应-限制性片断长度多态性方法（PCR-RFLP）进行CYP2D6和β1-AR基因分型。【结果】403例高血压患者中CYP2D6检测出CYP2D6的＊1、＊2、＊5、＊10四种等位基因,频率由高到低依次为＊10（67.5%）、＊1（17.5%）、＊2（9.2%）、＊5（5.8%）,突变基因型频率最高为CYP2D6＊10＊10（47.4%）。β1-AR 49位Ser和Gly等位基因频率分别为83.9%和16.1%;Ser/Ser、Ser/Gly和Gly/Gly基因型分布频率分别为68.7%、30.3%和1.0%。β1-AR 389位Arg和Gly等位基因频率分别为76.1%和23.9%,Arg/Arg、Gly/Arg和Gly/Gly基因型分布频率为55.3%、41.4%和3.2%。各基因型及等位基因频率在不同性别中分布无差异（均P〉0.05）。【结论】湖南中部地区高血压人群CYP2D6和β1-AR基因多态性分布符合Hardy-Weinberg遗传平衡,其中CYP2D6＊10和β1-AR 389位基因突变率最高,可能成为影响β受体阻滞剂降压疗效的显著因素之一。     

激动β_3肾上腺素受体对载脂蛋白E基因敲除小鼠肺脏血管紧张素受体表达的影响

目的探讨激动β3肾上腺素受体(β3-AR)对载脂蛋白E基因敲除(apoE-/-)老年高脂小鼠肺脏血管紧张素受体(ATR)表达的影响。方法野生型C57BL/6J小鼠10只作为对照组,apoE-/-老年高脂小鼠40只随机分为高脂模型组、β3-AR激动剂小剂量组(小剂量组)、β3-AR激动剂大剂量组(大剂量组)和β3-AR拮抗剂组(拮抗剂组),每组10只。给予高脂饮食饲养至36周龄后分别给予药物干预12周。采用全自动生化分析仪检测TC和VLDL/LDL-C水平,实时定量PCR或Western blot测定肺组织β3-AR、AT1R和AT2R的mRNA及蛋白表达水平。结果与高脂模型组比较,小剂量组、大剂量组TC和VLDL/LDL-C水平明显降低[(18.27±1.30)mmol/L,(17.06±1.50)mmol/L vs(22.20±1.29)mmol/L和(14.31±0.31)mmol/L,(12.78±0.55)mmol/L vs(19.41±0.40)mmol/L,P<0.01]。与对照组比较,高脂模型组和拮抗剂组AT1R mRNA和AT1R蛋白水平明显升高,AT2R mRNA、β3-AR蛋白水平明显降低(P<0.05)。与高脂模型组比较,小剂量组和大剂量组AT1R表达下调,AT2R和β3-AR表达上调(P<0.05,P<0.01)。结论β3-AR激动剂在改善apoE-/-老年高脂小鼠血脂代谢紊乱的同时,影响了肺组织β3-AR和ATR各亚型表达,这种受体间交互作用可能与维持高脂血症条件下肺脏的正常功能有关。